REPLENISH: A Safety and Efficacy Study of the Combination Estradiol and Progesterone to Treat Vasomotor Symptoms

• Sponsor: TherapeuticsMD (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01942668
• Collaborator: (none)
• Enrollment: 1,845
• Locations: 119
• Arms: 5
• Actual Duration (Months): 38.8
• Patients Per Site: 15.5
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This study will be a prospective, randomized, double-blind, placebo-controlled, parallel group, multicenter trial of postmenopausal subjects with an intact uterus.

Condition or Disease	Intervention/Treatment	Phase
Menopause	Drug: Estradiol; Drug: Progesterone; Drug: Placebo	Phase 3

Detailed Description

Postmenopausal subjects with an intact uterus who meet the study entry criteria will be randomized to one of five treatment arms (four active and one placebo) and followed for 12 months. During the Screening period all subjects will be provided with a diary to self-assess the frequency and severity of their vasomotor symptoms. Subjects experiencing a minimum daily frequency of ≥7 (or ≥50 per week) moderate to severe hot flushes will participate in a VMS Substudy during the first 12 weeks of treatment. The Substudy subjects will be stratified by treatment arm within the sites, and only Substudy subjects have the possibility of being randomized to placebo. Subjects who qualify for the study except for experiencing a minimum daily frequency of ≥7 (or ≥50 per week) moderate to severe hot flushes will be stratified within sites to one of the four active treatment arms and followed for 12 months, but will not participate in the VMS Substudy. (However, VMS information will be collected from all subjects during the first 12 weeks of treatment.) All Study Subjects: Postmenopausal women with an intact uterus who seek relief from hot flushes and meet all other inclusion/exclusion criteria are eligible for 12 months of study treatment.

VMS Substudy Subjects: A subset of All Study Subjects who have ≥7 per day or ≥50 per week moderate to severe hot flushes (as determined during Screening) are eligible for the 12-week VMS Substudy and for a total of 12 months of study treatment.

Clinical evaluations will be performed at the following time points:

• Screening Period (Week: - 8.5) (up to -60 Days)

• Visit 1 Randomization (Week 0) (Day 1)

• Visit 2 Interim (Week 4)

• Visit 3 Interim (Week 8)

• Visit 4 Interim (Week 12)

• Visit 5 Interim (Month 6)

• Visit 6 Interim (Month 9)

• Visit 7 End of Treatment (Month 12)

Study Design

• Study Type: Interventional
• Actual Enrollment: 1845 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Study Safety and Efficacy Study of the Combination Estradiol and Progesterone to Treat Vasomotor Symptoms in Postmenopausal Women With an Intact Uterus
• Actual Study Start Date: Aug 5, 2013
• Actual Primary Completion Date: Oct 28, 2016
• Actual Study Completion Date: Oct 28, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment 1 Combined Estradiol 1 mg / Progesterone 100 mg softgel capsule formulation and placebo taken orally once a day for twelve months.	Drug: Estradiol; Other Names: 17B-estradiol Estrace ; Drug: Progesterone; Other Names: Prometrium ; Drug: Placebo
Experimental: Treatment 2 Combined Estradiol 0.5 mg / Progesterone 100 mg softgel capsule formulation and placebo taken orally once a day for twelve months.	Drug: Estradiol; Other Names: 17B-estradiol Estrace ; Drug: Progesterone; Other Names: Prometrium ; Drug: Placebo
Experimental: Treatment 3 Combined Estradiol 0.5 mg / Progesterone 50 mg softgel capsule formulation and placebo, taken orally once a day for twelve months.	Drug: Estradiol; Other Names: 17B-estradiol Estrace ; Drug: Progesterone; Other Names: Prometrium ; Drug: Placebo
Experimental: Treatment 4 Combined Estradiol 0.25 mg / Progesterone 50 mg softgel capsule formulation and placebo, taken orally once a day for twelve months.	Drug: Estradiol; Other Names: 17B-estradiol Estrace ; Drug: Progesterone; Other Names: Prometrium ; Drug: Placebo
Placebo Comparator: Placebo Two Placebo softgel capsules taken orally once a day for twelve months.	Drug: Placebo

Outcome Measures

Primary Outcome Measures

1. Co-Primary Efficacy Endpoint: Frequency of Moderate to Severe Vasomotor Symptoms (MITT-VMS) [Baseline and Week 4]

   Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 4. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.

2. Co-Primary Efficacy Endpoint: Frequency of Moderate to Severe Vasomotor Symptoms (MITT-VMS) [Baseline and Week 12]

   Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 12. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.

3. Co-Primary Efficacy Endpoint: Severity of Moderate to Severe Vasomotor Symptoms (MITT-VMS) [Baseline and Week 4]

   Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 4. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).

4. Co-Primary Efficacy Endpoint: Severity of Moderate to Severe Vasomotor Symptoms (MITT-VMS) [Baseline and Week 12]

   Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 12. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).

5. Primary Safety Endpoint: Endometrial Protection - Hyperplasia [Baseline and Month 12]

   Endometrial biopsies centrally evaluated by 2 primary pathologists using criteria from Blaustein's Pathology text. Pathologists classified bx into 1 of following 3 categories: Cat.1: Non-endometrial malignancy/non-hyperplasia; Cat.2: Endometrial hyperplasia; Cat.3: Endometrial malignancy. Consensus reached when 2 primary pathologist agreed on any of above categories; if primary pathologists disagreed on presence of hyperplasia, result of 3rd pathologist was utilized and final decision regarding presence of hyperplasia was based on diagnosis of majority. If all 3 reads disparate, final diagnosis based on most severe dx. Incidence rate calculated as: I=A/B where I=incidence rate at M12 evaluation, A=all new subjects with biopsies positive for endometrial hyperplasia during study but post-Baseline, B=all subjects w/biopsies following M11 meeting criteria specified plus all subjects w/biopsies positive for endometrial hyperplasia by any pathologists before M11.

Secondary Outcome Measures

1. Endometrial Protection - Hyperplasia [Baseline and Month 12]

   Endometrial biopsies centrally evaluated by 3 primary pathologists using criteria described in Blaustein's Pathology text. Pathologists classified biopsy into 1 of following 3 categories: Cat.1: Non-endometrial malignancy/non-hyperplasia; Cat.2: Endometrial hyperplasia; Cat.3: Endometrial malignancy. Consensus was reached when the 2 of 3 pathologist readers agreed on any of the above categories; if all three reads were disparate, the final diagnosis was based on the most severe diagnosis. Incidence rate calculated as: I=A/B where I=incidence rate at M12 evaluation, A=all new subjects with biopsies positive for endometrial hyperplasia during study but post-Baseline, B=all subjects with biopsies following M11 meeting the criteria specified plus all subjects with biopsies positive for endometrial hyperplasia by any of the pathologists before M11.

2. Frequency of Moderate to Severe Vasomotor Symptoms - Week 1 (MITT-VMS) [Baseline and Week 1]

   Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 1. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.

3. Frequency of Moderate to Severe Vasomotor Symptoms - Week 2 (MITT-VMS) [Baseline and Week 2]

   Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 2. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.

4. Frequency of Moderate to Severe Vasomotor Symptoms - Week 3 (MITT-VMS) [Baseline and Week 3]

   Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 3. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.

5. Frequency of Moderate to Severe Vasomotor Symptoms - Week 4 (MITT-VMS) [Baseline and Week 4]

   Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 4. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.

6. Frequency of Moderate to Severe Vasomotor Symptoms - Week 5 (MITT-VMS) [Baseline and Week 5]

   Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 5. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.

7. Frequency of Moderate to Severe Vasomotor Symptoms - Week 6 (MITT-VMS) [Baseline and Week 6]

   Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 6. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.

8. Frequency of Moderate to Severe Vasomotor Symptoms - Week 7 (MITT-VMS) [Baseline and Week 7]

   Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 7. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.

9. Frequency of Moderate to Severe Vasomotor Symptoms - Week 8 (MITT-VMS) [Baseline and Week 8]

   Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 8. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.

10. Frequency of Moderate to Severe Vasomotor Symptoms - Week 9 (MITT-VMS) [Baseline and Week 9]

    Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 9. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.

11. Frequency of Moderate to Severe Vasomotor Symptoms - Week 10 (MITT-VMS) [Baseline and Week 10]

    Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 10. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.

12. Frequency of Moderate to Severe Vasomotor Symptoms - Week 11 (MITT-VMS) [Baseline and Week 11]

    Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 11. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.

13. Frequency of Moderate to Severe Vasomotor Symptoms - Week 12 (MITT-VMS) [Baseline and Week 12]

    Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 12. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.

14. Severity of Moderate to Severe Vasomotor Symptoms - Week 1 (MITT-VMS) [Baseline and Week 1]

    Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 1. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).

15. Severity of Moderate to Severe Vasomotor Symptoms - Week 2 (MITT-VMS) [Baseline and Week 2]

    Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 2. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).

16. Severity of Moderate to Severe Vasomotor Symptoms - Week 3 (MITT-VMS) [Baseline and Week 3]

    Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 3. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).

17. Severity of Moderate to Severe Vasomotor Symptoms - Week 4 (MITT-VMS) [Baseline and Week 4]

    Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 4. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).

18. Severity of Moderate to Severe Vasomotor Symptoms - Week 5 (MITT-VMS) [Baseline and Week 5]

    Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 5. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).

19. Severity of Moderate to Severe Vasomotor Symptoms - Week 6 (MITT-VMS) [Baseline and Week 6]

    Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 6. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).

20. Severity of Moderate to Severe Vasomotor Symptoms - Week 7 (MITT-VMS) [Baseline and Week 7]

    Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 7. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).

21. Severity of Moderate to Severe Vasomotor Symptoms - Week 8 (MITT-VMS) [Baseline and Week 8]

    Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 8. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).

22. Severity of Moderate to Severe Vasomotor Symptoms - Week 9 (MITT-VMS) [Baseline and Week 9]

    Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 9. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).

23. Severity of Moderate to Severe Vasomotor Symptoms - Week 10 (MITT-VMS) [Baseline and Week 10]

    Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 10. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).

24. Severity of Moderate to Severe Vasomotor Symptoms - Week 11 (MITT-VMS) [Baseline and Week 11]

    Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 11. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).

25. Severity of Moderate to Severe Vasomotor Symptoms - Week 12 (MITT-VMS) [Baseline and Week 12]

    Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 12. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).

26. Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 1 (MITT-VMS) [Baseline and Week 1]

    Mean change in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 1. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of mild, moderate and severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of mild, moderate and severe hot flushes for the subject week.

27. Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 2 (MITT-VMS) [Baseline and Week 2]

    Mean change in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 2. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of mild, moderate and severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of mild, moderate and severe hot flushes for the subject week.

28. Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 3 (MITT-VMS) [Baseline and Week 3]

    Mean change in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 3. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of mild, moderate and severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of mild, moderate and severe hot flushes for the subject week.

29. Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 4 (MITT-VMS) [Baseline and Week 4]

    Mean change in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 4. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of mild, moderate and severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of mild, moderate and severe hot flushes for the subject week.

30. Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 5 (MITT-VMS) [Baseline and Week 5]

    Mean change in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 5. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of mild, moderate and severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of mild, moderate and severe hot flushes for the subject week.

31. Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 6 (MITT-VMS) [Baseline and Week 6]

    Mean change in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 6. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of mild, moderate and severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of mild, moderate and severe hot flushes for the subject week.

32. Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 7 (MITT-VMS) [Baseline and Week 7]

    Mean change in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 7. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of mild, moderate and severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of mild, moderate and severe hot flushes for the subject week.

33. Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 8 (MITT-VMS) [Baseline and Week 8]

    Mean change in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 8. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of mild, moderate and severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of mild, moderate and severe hot flushes for the subject week.

34. Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 9 (MITT-VMS) [Baseline and Week 9]

    Mean change in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 9. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of mild, moderate and severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of mild, moderate and severe hot flushes for the subject week.

35. Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 10 (MITT-VMS) [Baseline and Week 10]

    Mean change in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 10. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of mild, moderate and severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of mild, moderate and severe hot flushes for the subject week.

36. Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 11 (MITT-VMS) [Baseline and Week 11]

    Mean change in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 11. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of mild, moderate and severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of mild, moderate and severe hot flushes for the subject week.

37. Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 12 (MITT-VMS) [Baseline and Week 12]

    Mean change in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 12. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of mild, moderate and severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of mild, moderate and severe hot flushes for the subject week.

38. Severity of Mild, Moderate and Severe Vasomotor Symptoms - Week 1 (MITT-VMS) [Baseline and Week 1]

    Mean change in severity of mild, moderate and severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 1. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score =(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).

39. Severity of Mild, Moderate and Severe Vasomotor Symptoms - Week 2 (MITT-VMS) [Baseline and Week 2]

    Mean change in severity of mild, moderate and severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 2. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score =(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).

40. Severity of Mild, Moderate and Severe Vasomotor Symptoms - Week 3 (MITT-VMS) [Baseline and Week 3]

    Mean change in severity of mild, moderate and severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 3. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score =(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).

41. Severity of Mild, Moderate and Severe Vasomotor Symptoms - Week 4 (MITT-VMS) [Baseline and Week 4]

    Mean change in severity of mild, moderate and severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 4. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score =(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).

42. Severity of Mild, Moderate and Severe Vasomotor Symptoms - Week 5 (MITT-VMS) [Baseline and Week 5]

    Mean change in severity of mild, moderate and severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 5. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score =(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).

43. Severity of Mild, Moderate and Severe Vasomotor Symptoms - Week 6 (MITT-VMS) [Baseline and Week 6]

    Mean change in severity of mild, moderate and severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 6. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score =(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).

44. Severity of Mild, Moderate and Severe Vasomotor Symptoms - Week 7 (MITT-VMS) [Baseline and Week 7]

    Mean change in severity of mild, moderate and severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 7. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score =(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).

45. Severity of Mild, Moderate and Severe Vasomotor Symptoms - Week 8 (MITT-VMS) [Baseline and Week 8]

    Mean change in severity of mild, moderate and severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 8. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score =(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).

46. Severity of Mild, Moderate and Severe Vasomotor Symptoms - Week 9 (MITT-VMS) [Baseline and Week 9]

    Mean change in severity of mild, moderate and severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 9. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score =(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).

47. Severity of Mild, Moderate and Severe Vasomotor Symptoms - Week 10 (MITT-VMS) [Baseline and Week 10]

    Mean change in severity of mild, moderate and severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 10. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score =(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).

48. Severity of Mild, Moderate and Severe Vasomotor Symptoms - Week 11 (MITT-VMS) [Baseline and Week 11]

    Mean change in severity of mild, moderate and severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 11. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score =(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).

49. Severity of Mild, Moderate and Severe Vasomotor Symptoms - Week 12 (MITT-VMS) [Baseline and Week 12]

    Mean change in severity of mild, moderate and severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 12. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score =(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).

50. Reduction of Frequency of Moderate to Severe Vasomotor Symptoms - Week 1 (MITT-VMS) [Baseline and Week 1]

    Number of Subjects with >=50%, and separately, >=75% reduction in frequency of moderate to severe VMS from Baseline to Week 1.

51. Reduction of Frequency of Moderate to Severe Vasomotor Symptoms - Week 2 (MITT-VMS) [Baseline and Week 2]

    Number of Subjects with >=50%, and separately, >=75% reduction in frequency of moderate to severe vasomotor symptoms from Baseline to Week 2.

52. Reduction of Frequency of Moderate to Severe Vasomotor Symptoms - Week 3 (MITT-VMS) [Baseline and Week 3]

    Number of Subjects with >=50%, and separately, >=75% reduction in frequency of moderate to severe vasomotor symptoms from Baseline to Week 3.

53. Reduction of Frequency of Moderate to Severe Vasomotor Symptoms - Week 4 (MITT-VMS) [Baseline and Week 4]

    Number of Subjects with >=50%, and separately, >=75% reduction in frequency of moderate to severe vasomotor symptoms from Baseline to Week 4.

54. Reduction of Frequency of Moderate to Severe Vasomotor Symptoms - Week 5 (MITT-VMS) [Baseline and Week 5]

    Number of Subjects with >=50%, and separately, >=75% reduction in frequency of moderate to severe vasomotor symptoms from Baseline to Week 5.

55. Reduction of Frequency of Moderate to Severe Vasomotor Symptoms - Week 6 (MITT-VMS) [Baseline and Week 6]

    Number of Subjects with >=50%, and separately, >=75% reduction in frequency of moderate to severe vasomotor symptoms from Baseline to Week 6.

56. Reduction of Frequency of Moderate to Severe Vasomotor Symptoms - Week 7 (MITT-VMS) [Baseline and Week 7]

    Number of Subjects with >=50%, and separately, >=75% reduction in frequency of moderate to severe vasomotor symptoms from Baseline to Week 7.

57. Reduction of Frequency of Moderate to Severe Vasomotor Symptoms - Week 8 (MITT-VMS) [Baseline and Week 8]

    Number of Subjects with >=50%, and separately, >=75% reduction in frequency of moderate to severe vasomotor symptoms from Baseline to Week 8.

58. Reduction of Frequency of Moderate to Severe Vasomotor Symptoms - Week 9 (MITT-VMS) [Baseline and Week 9]

    Number of Subjects with >=50%, and separately, >=75% reduction in frequency of moderate to severe vasomotor symptoms from Baseline to Week 9.

59. Reduction of Frequency of Moderate to Severe Vasomotor Symptoms - Week 10 (MITT-VMS) [Baseline and Week 10]

    Number of Subjects with >=50%, and separately, >=75% reduction in frequency of moderate to severe vasomotor symptoms from Baseline to Week 10.

60. Reduction of Frequency of Moderate to Severe Vasomotor Symptoms - Week 11 (MITT-VMS) [Baseline and Week 11]

    Number of Subjects with >=50%, and separately, >=75% reduction in frequency of moderate to severe vasomotor symptoms from Baseline to Week 11.

61. Reduction of Frequency of Moderate to Severe Vasomotor Symptoms - Week 12 (MITT-VMS) [Baseline and Week 12]

    Number of Subjects with >=50%, and separately, >=75% reduction in frequency of moderate to severe vasomotor symptoms from Baseline to Week 12.

62. Reduction of Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 1 - (MITT-VMS) [Baseline and Week 1]

    Number of Subjects with >=50%, and separately, >=75% reduction in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 1.

63. Reduction of Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 2 - (MITT-VMS) [Baseline and Week 2]

    Number of Subjects with >=50%, and separately, >=75% reduction in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 2.

64. Reduction of Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 3 - (MITT-VMS) [Baseline and Week 3]

    Number of Subjects with >=50%, and separately, >=75% reduction in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 3.

65. Reduction of Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 4 - (MITT-VMS) [Baseline and Week 4]

    Number of Subjects with >=50%, and separately, >=75% reduction in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 4.

66. Reduction of Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 5 - (MITT-VMS) [Baseline and Week 5]

    Number of Subjects with >=50%, and separately, >=75% reduction in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 5.

67. Reduction of Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 6 - (MITT-VMS) [Baseline and Week 6]

    Number of Subjects with >=50%, and separately, >=75% reduction in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 6.

68. Reduction of Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 7 - (MITT-VMS) [Baseline and Week 7]

    Number of Subjects with >=50%, and separately, >=75% reduction in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 7.

69. Reduction of Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 8 - (MITT-VMS) [Baseline and Week 8]

    Number of Subjects with >=50%, and separately, >=75% reduction in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 8.

70. Reduction of Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 9 - (MITT-VMS) [Baseline and Week 9]

    Number of Subjects with >=50%, and separately, >=75% reduction in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 9.

71. Reduction of Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 10 - (MITT-VMS) [Baseline and Week 10]

    Number of Subjects with >=50%, and separately, >=75% reduction in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 10.

72. Reduction of Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 11 - (MITT-VMS) [Baseline and Week 11]

    Number of Subjects with >=50%, and separately, >=75% reduction in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 11.

73. Reduction of Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 12 - (MITT-VMS) [Baseline and Week 12]

    Number of Subjects with >=50%, and separately, >=75% reduction in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 12.

74. Clinical Global Impression (CGI) - Week 4 (MITT-VMS) [Baseline and Week 4]

    The number and percentage of subjects for each possible response to the CGI at Week 4. The CGI score is a seven point scale where subjects were asked to rate the total improvement, whether or not in her judgment it was due entirely to drug treatment, compared to her condition at admission to the study. Scale: Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse. Results for the top two responses (Very Much Improved and Much Improved) and No Change or Worsening (Minimally worse, Much worse, Very much worse) were combined for each group and active treatment groups compare to placebo.

75. Mean Change in Frequency of Moderate to Severe VMS for the Respective CGI Category - Week 4 (MITT-VMS) [Baseline and Week 4]

    Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 4 for the respective CGI category. The CGI score is a seven point scale where subjects were asked to rate the total improvement, whether or not in her judgment it was due entirely to drug treatment, compared to her condition at admission to the study. Scale: Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse. Results for the top two responses (Very Much Improved and Much Improved) and No Change or Worsening (Minimally worse, Much worse, Very much worse) were combined for each group and active treatment groups compare to placebo.

76. Clinical Global Impression (CGI) - Week 8 (MITT-VMS) [Baseline and Week 8]

    The number and percentage of subjects for each possible response to the CGI at Week 8. The CGI score is a seven point scale where subjects were asked to rate the total improvement, whether or not in her judgment it was due entirely to drug treatment, compared to her condition at admission to the study. Scale: Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse. Results for the top two responses (Very Much Improved and Much Improved) and No Change or Worsening (Minimally worse, Much worse, Very much worse) were combined for each group and active treatment groups compare to placebo.

77. Mean Change in Frequency of Moderate to Severe VMS for the Respective CGI Category - Week 8 (MITT-VMS) [Baseline and Week 8]

    Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 8 for the respective CGI category. The CGI score is a seven point scale where subjects were asked to rate the total improvement, whether or not in her judgment it was due entirely to drug treatment, compared to her condition at admission to the study. Scale: Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse. Results for the top two responses (Very Much Improved and Much Improved) and No Change or Worsening (Minimally worse, Much worse, Very much worse) were combined for each group and active treatment groups compare to placebo.

78. Clinical Global Impression (CGI) - Week 12 (MITT-VMS) [Baseline and Week 12]

    The number and percentage of subjects for each possible response to the CGI at Week 12. The CGI score is a seven point scale where subjects were asked to rate the total improvement, whether or not in her judgment it was due entirely to drug treatment, compared to her condition at admission to the study. Scale: Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse. Results for the top two responses (Very Much Improved and Much Improved) and No Change or Worsening (Minimally worse, Much worse, Very much worse) were combined for each group and active treatment groups compare to placebo.

79. Mean Change in Frequency of Moderate to Severe VMS for the Respective CGI Category - Week 12 (MITT-VMS) [Baseline and Week 12]

    Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 12 for the respective CGI category. The CGI score is a seven point scale where subjects were asked to rate the total improvement, whether or not in her judgment it was due entirely to drug treatment, compared to her condition at admission to the study. Scale: Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse. Results for the top two responses (Very Much Improved and Much Improved) and No Change or Worsening (Minimally worse, Much worse, Very much worse) were combined for each group and active treatment groups compare to placebo.

80. Number of Subjects Without Bleeding for Consecutive Cycles [Cycle 1 to 13]

    No bleeding was defined as the absence of bleeding. Cumulative rates for no bleeding was defined as the percentage of women who reported consecutive cycles of no bleeding for a given cycle of time.

81. Number of Subjects Without Bleeding for Consecutive Cycles [Cycle 2 to 13]

    No bleeding was defined as the absence of bleeding. Cumulative rates for no bleeding was defined as the percentage of women who reported consecutive cycles of no bleeding for a given cycle of time.

82. Number of Subjects Without Bleeding for Consecutive Cycles [Cycle 3 to 13]

    No bleeding was defined as the absence of bleeding. Cumulative rates for no bleeding was defined as the percentage of women who reported consecutive cycles of no bleeding for a given cycle of time.

83. Number of Subjects Without Bleeding for Consecutive Cycles [Cycle 4 to 13]

    No bleeding was defined as the absence of bleeding. Cumulative rates for no bleeding was defined as the percentage of women who reported consecutive cycles of no bleeding for a given cycle of time.

84. Number of Subjects Without Bleeding for Consecutive Cycles [Cycle 5 to 13]

    No bleeding was defined as the absence of bleeding. Cumulative rates for no bleeding was defined as the percentage of women who reported consecutive cycles of no bleeding for a given cycle of time.

85. Number of Subjects Without Bleeding for Consecutive Cycles [Cycle 6 to 13]

    No bleeding was defined as the absence of bleeding. Cumulative rates for no bleeding was defined as the percentage of women who reported consecutive cycles of no bleeding for a given cycle of time.

86. Number of Subjects Without Bleeding for Consecutive Cycles [Cycle 7 to 13]

    No bleeding was defined as the absence of bleeding. Cumulative rates for no bleeding was defined as the percentage of women who reported consecutive cycles of no bleeding for a given cycle of time.

87. Number of Subjects Without Bleeding for Consecutive Cycles [Cycle 8 to 13]

    No bleeding was defined as the absence of bleeding. Cumulative rates for no bleeding was defined as the percentage of women who reported consecutive cycles of no bleeding for a given cycle of time.

88. Number of Subjects Without Bleeding for Consecutive Cycles [Cycle 9 to 13]

    No bleeding was defined as the absence of bleeding. Cumulative rates for no bleeding was defined as the percentage of women who reported consecutive cycles of no bleeding for a given cycle of time.

89. Number of Subjects Without Bleeding for Consecutive Cycles [Cycle 10 to 13]

    No bleeding was defined as the absence of bleeding. Cumulative rates for no bleeding was defined as the percentage of women who reported consecutive cycles of no bleeding for a given cycle of time.

90. Number of Subjects Without Bleeding for Consecutive Cycles [Cycle 11 to 13]

    No bleeding was defined as the absence of bleeding. Cumulative rates for no bleeding was defined as the percentage of women who reported consecutive cycles of no bleeding for a given cycle of time.

91. Number of Subjects Without Bleeding for Consecutive Cycles [Cycle 12 to 13]

    No bleeding was defined as the absence of bleeding. Cumulative rates for no bleeding was defined as the percentage of women who reported consecutive cycles of no bleeding for a given cycle of time.

92. Number of Subjects Without Bleeding for Consecutive Cycles [The 13th Cycle]

    No bleeding was defined as the absence of bleeding. Cumulative rates for no bleeding was defined as the percentage of women who reported consecutive cycles of no bleeding for a given cycle of time.

93. Number of Subjects With Cumulative Amenorrhea From Cycle 1 to 13 [Cycle 1 to 13]

    Cumulative amenorrhea is defined as the absence of bleeding or spotting for a cumulative period. Cumulative rates of amenorrhea were defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. Within each treatment arm, the percentage of subjects with cumulative amenorrhea from Cycle 1 to 13 was calculated and compared between active and placebo treatments.

94. Number of Subjects With Cumulative Amenorrhea From Cycle 2 to 13 [Cycle 2 to 13]

    Cumulative amenorrhea is defined as the absence of bleeding or spotting for a cumulative period. Cumulative rates of amenorrhea were defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. Within each treatment arm, the percentage of subjects with cumulative amenorrhea from Cycle 2 to 13 was calculated and compared between active and placebo treatments.

95. Number of Subjects With Cumulative Amenorrhea From Cycle 3 to 13 [Cycle 3 to 13]

    Cumulative amenorrhea is defined as the absence of bleeding or spotting for a cumulative period. Cumulative rates of amenorrhea were defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. Within each treatment arm, the percentage of subjects with cumulative amenorrhea from Cycle 3 to 13 was calculated and compared between active and placebo treatments.

96. Number of Subjects With Cumulative Amenorrhea From Cycle 4 to 13 [Cycle 4 to 13]

    Cumulative amenorrhea is defined as the absence of bleeding or spotting for a cumulative period. Cumulative rates of amenorrhea were defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. Within each treatment arm, the percentage of subjects with cumulative amenorrhea from Cycle 4 to 13 was calculated and compared between active and placebo treatments.

97. Number of Subjects With Cumulative Amenorrhea From Cycle 5 to 13 [Cycle 5 to 13]

    Cumulative amenorrhea is defined as the absence of bleeding or spotting for a cumulative period. Cumulative rates of amenorrhea were defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. Within each treatment arm, the percentage of subjects with cumulative amenorrhea from Cycle 5 to 13 was calculated and compared between active and placebo treatments.

98. Number of Subjects With Cumulative Amenorrhea From Cycle 6 to 13 [Cycle 6 to 13]

    Cumulative amenorrhea is defined as the absence of bleeding or spotting for a cumulative period. Cumulative rates of amenorrhea were defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. Within each treatment arm, the percentage of subjects with cumulative amenorrhea from Cycle 6 to 13 was calculated and compared between active and placebo treatments.

99. Number of Subjects With Cumulative Amenorrhea From Cycle 7 to 13 [Cycle 7 to 13]

    Cumulative amenorrhea is defined as the absence of bleeding or spotting for a cumulative period. Cumulative rates of amenorrhea were defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. Within each treatment arm, the percentage of subjects with cumulative amenorrhea from Cycle 7 to 13 was calculated and compared between active and placebo treatments.

100. Number of Subjects With Cumulative Amenorrhea From Cycle 8 to 13 [Cycle 8 to 13]

     Cumulative amenorrhea is defined as the absence of bleeding or spotting for a cumulative period. Cumulative rates of amenorrhea were defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. Within each treatment arm, the percentage of subjects with cumulative amenorrhea from Cycle 8 to 13 was calculated and compared between active and placebo treatments.

101. Number of Subjects With Cumulative Amenorrhea From Cycle 9 to 13 [Cycle 9 to 13]

     Cumulative amenorrhea is defined as the absence of bleeding or spotting for a cumulative period. Cumulative rates of amenorrhea were defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. Within each treatment arm, the percentage of subjects with cumulative amenorrhea from Cycle 9 to 13 was calculated and compared between active and placebo treatments.

102. Number of Subjects With Cumulative Amenorrhea From Cycle 10 to 13 [Cycle 10 to 13]

     Cumulative amenorrhea is defined as the absence of bleeding or spotting for a cumulative period. Cumulative rates of amenorrhea were defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. Within each treatment arm, the percentage of subjects with cumulative amenorrhea from Cycle 10 to 13 was calculated and compared between active and placebo treatments.

103. Number of Subjects With Cumulative Amenorrhea From Cycle 11 to 13 [Cycle 11 to 13]

     Cumulative amenorrhea is defined as the absence of bleeding or spotting for a cumulative period. Cumulative rates of amenorrhea were defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. Within each treatment arm, the percentage of subjects with cumulative amenorrhea from Cycle 11 to 13 was calculated and compared between active and placebo treatments.

104. Number of Subjects With Cumulative Amenorrhea From Cycle 12 to 13 [Cycle 12 to 13]

     Cumulative amenorrhea is defined as the absence of bleeding or spotting for a cumulative period. Cumulative rates of amenorrhea were defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. Within each treatment arm, the percentage of subjects with cumulative amenorrhea from Cycle 12 to 13 was calculated and compared between active and placebo treatments.

105. Number of Subjects With Cumulative Amenorrhea From the 13th Cycle [The 13th Cycle]

     Cumulative amenorrhea is defined as the absence of bleeding or spotting for a cumulative period. Cumulative rates of amenorrhea were defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. Within each treatment arm, the percentage of subjects with cumulative amenorrhea from the 13th Cycle was calculated and compared between active and placebo treatments.

106. Subject Incidence With Spotting - Trimester 1 (Safety Pop.) [Trimester 1]

     Summary of subject incidence with spotting per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.

107. Subject Incidence With Spotting - Trimester 2 (Safety Pop.) [Trimester 2]

     Summary of subject incidence with spotting per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.

108. Subject Incidence With Spotting - Trimester 3 (Safety Pop.) [Trimester 3]

     Summary of subject incidence with spotting per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.

109. Subject Incidence With Spotting - Trimester 4 (Safety Pop.) [Trimester 4]

     Summary of subject incidence with spotting per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.

110. Number of Days With Spotting - Trimester 1 (Safety Pop.) [Trimester 1]

     Summary of the number of days with spotting per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.

111. Number of Days With Spotting - Trimester 2 (Safety Pop.) [Trimester 2]

     Summary of the number of days with spotting per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.

112. Number of Days With Spotting - Trimester 3 (Safety Pop.) [Trimester 3]

     Summary of the number of days with spotting per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.

113. Number of Days With Spotting - Trimester 4 (Safety Pop.) [Trimester 4]

     Summary of the number of days with spotting per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.

114. Subject Incidence With Bleeding - Trimester 1 (Safety Pop.) [Trimester 1]

     Summary of subject incidence with bleeding per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.

115. Subject Incidence With Bleeding - Trimester 2 (Safety Pop.) [Trimester 2]

     Summary of subject incidence with bleeding per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.

116. Subject Incidence With Bleeding - Trimester 3 (Safety Pop.) [Trimester 3]

     Summary of subject incidence with bleeding per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.

117. Subject Incidence With Bleeding - Trimester 4 (Safety Pop.) [Trimester 4]

     Summary of subject incidence with bleeding per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.

118. Number of Days With Bleeding - Trimester 1 (Safety Pop.) [Trimester 1]

     Summary of the number of days with bleeding per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.

119. Number of Days With Bleeding - Trimester 2 (Safety Pop.) [Trimester 2]

     Summary of the number of days with bleeding per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.

120. Number of Days With Bleeding - Trimester 3 (Safety Pop.) [Trimester 3]

     Summary of the number of days with bleeding per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.

121. Number of Days With Bleeding - Trimester 4 (Safety Pop.) [Trimester 4]

     Summary of the number of days with bleeding per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.

122. Menopause-specific Quality of Life Questionnaire (MENQOL) - Vasomotor Domain Score - Week 12 (MITT-VMS) [Baseline and Week 12]

     Changes in Vasomotor Domain Score from Baseline to Week 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Vasomotor domain score is mean of = Q1,Q2, Q3, with 1 being "not at all bothered" and 8 being "extremely bothered".

123. Menopause-specific Quality of Life Questionnaire (MENQOL) - Vasomotor Domain Score - Month 6 (MITT-VMS) [Baseline and Month 6]

     Changes in Vasomotor Domain Score from Baseline to Month 6. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Vasomotor domain score is mean of = Q1,Q2, Q3, with 1 being "not at all bothered" and 8 being "extremely bothered".

124. Menopause-specific Quality of Life Questionnaire (MENQOL) - Vasomotor Domain Score - Month 12 (MITT-VMS) [Baseline and Month 12]

     Changes in Vasomotor Domain Score from Baseline to Month 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Vasomotor domain score is mean of = Q1,Q2, Q3, with 1 being "not at all bothered" and 8 being "extremely bothered".

125. Menopause-specific Quality of Life Questionnaire (MENQOL) - Psychosocial Domain Score - Week 12 (MITT-VMS) [Baseline and Week 12]

     Changes in Psychosocial Domain Score from Baseline to Week 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Psychosocial domain score is mean of = Q4 to Q10, with 1 being "not at all bothered" and 8 being "extremely bothered".

126. Menopause-specific Quality of Life Questionnaire (MENQOL) - Psychosocial Domain Score - Month 6 (MITT-VMS) [Baseline and Month 6]

     Changes in Psychosocial Domain Score from Baseline to Month 6. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Psychosocial domain score is mean of = Q4 to Q10, with 1 being "not at all bothered" and 8 being "extremely bothered".

127. Menopause-specific Quality of Life Questionnaire (MENQOL) - Psychosocial Domain Score - Month 12 (MITT-VMS) [Baseline and Month 12]

     Changes in Psychosocial Domain Score from Baseline to Month 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Psychosocial domain score is mean of = Q4 to Q10, with 1 being "not at all bothered" and 8 being "extremely bothered".

128. Menopause-specific Quality of Life Questionnaire (MENQOL) - Physical Domain Score - Week 12 (MITT-VMS) [Baseline and Week 12]

     Changes in Physical Domain Score from Baseline to Week 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Physical domain score is mean of = Q11 to Q26, with 1 being "not at all bothered" and 8 being "extremely bothered".

129. Menopause-specific Quality of Life Questionnaire (MENQOL) - Physical Domain Score - Month 6 (MITT-VMS) [Baseline and Month 6]

     Changes in Physical Domain Score from Baseline to Month 6. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Physical domain score is mean of = Q11 to Q26, with 1 being "not at all bothered" and 8 being "extremely bothered".

130. Menopause-specific Quality of Life Questionnaire (MENQOL) - Physical Domain Score - Month 12 (MITT-VMS) [Baseline and Month 12]

     Changes in Physical Domain Score from Baseline to Month 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Physical domain score is mean of = Q11 to Q26, with 1 being "not at all bothered" and 8 being "extremely bothered".

131. Menopause-specific Quality of Life Questionnaire (MENQOL) - Sexual Domain Score - Week 12 (MITT-VMS) [Baseline and Week 12]

     Changes in Sexual Domain Score from Baseline to Week 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Sexual domain score is mean of = Q27 to Q29, with 1 being "not at all bothered" and 8 being "extremely bothered".

132. Menopause-specific Quality of Life Questionnaire (MENQOL) - Sexual Domain Score - Month 6 (MITT-VMS) [Baseline and Month 6]

     Changes in Sexual Domain Score from Baseline to Month 6. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Sexual domain score is mean of = Q27 to Q29, with 1 being "not at all bothered" and 8 being "extremely bothered".

133. Menopause-specific Quality of Life Questionnaire (MENQOL) - Sexual Domain Score - Month 12 (MITT-VMS) [Baseline and Month 12]

     Changes in Sexual Domain Score from Baseline to Month 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Sexual domain score is mean of = Q27 to Q29, with 1 being "not at all bothered" and 8 being "extremely bothered".

134. Menopause-specific Quality of Life Questionnaire (MENQOL) - Overall Scores - Week 12 (MITT-VMS) [Baseline and Week 12]

     Changes in Overall Scores from Baseline to Week 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. The scale contains four domains: vasomotor, psychosocial, physical and sexual. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The Overall Score is the mean of the 4 domain scores with 1 being "not at all bothered" and 8 being "extremely bothered".

135. Menopause-specific Quality of Life Questionnaire (MENQOL) - Overall Scores - Month 6 (MITT-VMS) [Baseline and Month 6]

     Changes in Overall Scores from Baseline to Month 6. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. The scale contains four domains: vasomotor, psychosocial, physical and sexual. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The Overall Score is the mean of the 4 domain scores with 1 being "not at all bothered" and 8 being "extremely bothered".

136. Menopause-specific Quality of Life Questionnaire (MENQOL) - Overall Scores - Month 12 (MITT-VMS) [Baseline and Month 12]

     Changes in Overall Scores from Baseline to Month 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. The scale contains four domains: vasomotor, psychosocial, physical and sexual. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The Overall Score is the mean of the 4 domain scores with 1 being "not at all bothered" and 8 being "extremely bothered".

137. Medical Outcomes Sleep Study (MOS) Sleep Scale - Total Sleep Score - Week 12 (MITT-VMS) [Baseline and Week 12]

     Change from Baseline to Wk 12 in MOS Total Sleep Score as compared w/Placebo. MOS-Sleep Self Report Questionnaire is 12 items that measure 6 dimensions of sleep over past 4 wks. Q1 scored on scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 self-reported hrs of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Total score includes items Q1, 3, 4, 5, 6, 7, 8, 9, & 12. Scoring method: Answers to Q3, 5, 6, 7, 8, 9 are reversed & rescaled to realign to be same direction and range (0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Answers to Q1, 4, & 12 are rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25; MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Total score= average of item scores; ranges =0 to 100, where higher score means worse outcome. If any of individual questions used to obtain total score is missing, total score will be set to missing value.

138. Medical Outcomes Sleep Study (MOS) Sleep Scale - Total Sleep Score - Month 6 (MITT-VMS) [Baseline and Month 6]

     Change from Baseline to Month 6 in MOS Total Sleep Score as compared w/Placebo. MOS-Sleep Self Report Questionnaire is 12 items that measure 6 dimensions of sleep over past 4 wks. Q1 scored on scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 self-reported hrs of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Total score includes items Q1, 3, 4, 5, 6, 7, 8, 9, & 12. Scoring method: Answers to Q3, 5, 6, 7, 8, 9 are reversed & rescaled to realign to be same direction and range (0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Answers to Q1, 4, & 12 are rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25; MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Total score= average of item scores; ranges =0 to 100, where higher score means worse outcome. If any of individual questions used to obtain total score is missing, total score will be set to missing value.

139. Medical Outcomes Sleep Study (MOS) Sleep Scale - Total Sleep Score - Month 12 (MITT-VMS) [Baseline and Month 12]

     Change from Baseline to Month 12 in MOS Total Sleep Score as compared w/Placebo. MOS-Sleep Self Report Questionnaire is 12 items that measure 6 dimensions of sleep over past 4 wks. Q1 scored on scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 self-reported hrs of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Total score includes items Q1, 3, 4, 5, 6, 7, 8, 9, & 12. Scoring method: Answers to Q3, 5, 6, 7, 8, 9 are reversed & rescaled to realign to be same direction and range (0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Answers to Q1, 4, & 12 are rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25; MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Total score= average of item scores; ranges =0 to 100, where higher score means worse outcome. If any of individual questions used to obtain total score is missing, total score will be set to missing value.

140. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Disturbance - Week 12 (MITT-VMS) [Baseline and Week 12]

     Change from Baseline to Wk 12 in MOS Sleep Disturbance individual score as compared with Placebo. MOS-Sleep Self Report Questionnaire is 12 items that measure 6 dimensions of sleep over past 4 wks. Q1 scored on scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 self-reported hrs of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep disturbance includes items Q1, Q3, Q7, Q8. Scoring method: Answer to Q1 is rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25. Answers to Q3, 7, 8 are reversed & rescaled to realign to be same direction and range(0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Score is average of item scores; score range=0 to 100, where higher score means worse outcome.

141. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Disturbance - Month 6 - (MITT-VMS) [Baseline and Month 6]

     Change from Baseline to Month 6 in MOS Sleep Disturbance individual score as compared with Placebo. MOS-Sleep Self Report Questionnaire is 12 items that measure 6 dimensions of sleep over past 4 wks. Q1 scored on scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 self-reported hrs of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep disturbance includes items Q1, Q3, Q7, Q8. Scoring method: Answer to Q1 is rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25. Answers to Q3, 7, 8 are reversed & rescaled to realign to be same direction and range(0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Score is average of item scores; score range=0 to 100, where higher score means worse outcome.

142. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Disturbance - Month 12 - (MITT-VMS) [Baseline and Month 12]

     Change from Baseline to Month 12 in MOS Sleep Disturbance individual score as compared with Placebo. MOS-Sleep Self Report Questionnaire is 12 items that measure 6 dimensions of sleep over past 4 wks. Q1 scored on scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 self-reported hrs of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep disturbance includes items Q1, Q3, Q7, Q8. Scoring method: Answer to Q1 is rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25. Answers to Q3, 7, 8 are reversed & rescaled to realign to be same direction and range(0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Score is average of item scores; score range=0 to 100, where higher score means worse outcome.

143. Medical Outcomes Sleep Study (MOS) Individual Score for Snoring - Week 12 - (MITT-VMS) [Baseline and Week 12]

     Change from Baseline to Wk 12 in MOS Snoring individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Snoring item is Q10. Scoring method: Answer to Q10 is reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score range=0 to 100, where higher score means worse outcome.

144. Medical Outcomes Sleep Study (MOS) Individual Score for Snoring - Month 6 - (MITT-VMS) [Baseline and Month 6]

     Change from Baseline to Month 6 in MOS Snoring individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Snoring item is Q10. Scoring method: Answer to Q10 is reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score range=0 to 100, where higher score means worse outcome.

145. Medical Outcomes Sleep Study (MOS) Individual Score for Snoring - Month 12 - (MITT-VMS) [Baseline and Month 12]

     Change from Baseline to Month 12 in MOS Snoring individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Snoring item is Q10. Scoring method: Answer to Q10 is reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score range=0 to 100, where higher score means worse outcome.

146. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Short of Breath or Headache - Week 12 - (MITT-VMS) [Baseline and Week 12]

     Change from Baseline to Wk 12 in MOS Sleep Short of Breath or Headache(SOBHA) individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. SOBHA item is Q5. Scoring method: Answer to Q5 is reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score range=0 to 100, where higher score means worse outcome.

147. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Short of Breath or Headache - Month 6 - (MITT-VMS) [Baseline and Month 6]

     Change from Baseline to Month 6 in MOS Sleep Short of Breath or Headache(SOBHA) individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. SOBHA item is Q5. Scoring method: Answer to Q5 is reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score range=0 to 100, where higher score means worse outcome.

148. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Short of Breath or Headache - Month 12 - (MITT-VMS) [Baseline and Month 12]

     Change from Baseline to Month 12 in MOS Sleep Short of Breath or Headache(SOBHA) individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. SOBHA item is Q5. Scoring method: Answer to Q5 is reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score range=0 to 100, where higher score means worse outcome.

149. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Adequacy - Week 12 - (MITT-VMS) [Baseline and Week 12]

     Change from Baseline to Wk 12 in MOS Sleep Adequacy individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Sleep Adequacy includes items Q4, Q12. Scoring method: Answers for Q4 and Q12 are reversed and rescaled to 0-100 as follows: MOS_4_new = (6-MOS_4_old) x 20; MOS_12_new = (6-MOS_12_old) x 20. Score is the average of item scores; score range = 0 to 100, where higher score means better outcome.

150. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Adequacy - Month 6 - (MITT-VMS) [Baseline and Month 6]

     Change from Baseline to Month 6 in MOS Sleep Adequacy individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Sleep Adequacy includes items Q4, Q12. Scoring method: Answers for Q4 and Q12 are reversed and rescaled to 0-100 as follows: MOS_4_new = (6-MOS_4_old) x 20; MOS_12_new = (6-MOS_12_old) x 20. Score is the average of item scores; score range = 0 to 100, where higher score means better outcome.

151. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Adequacy - Month 12 - (MITT-VMS) [Baseline and Month 12]

     Change from Baseline to Month 12 in MOS Sleep Adequacy individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Sleep Adequacy includes items Q4, Q12. Scoring method: Answers for Q4 and Q12 are reversed and rescaled to 0-100 as follows: MOS_4_new = (6-MOS_4_old) x 20; MOS_12_new = (6-MOS_12_old) x 20. Score is the average of item scores; score range = 0 to 100, where higher score means better outcome.

152. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Somnolence - Week 12 - (MITT-VMS) [Baseline and Week 12]

     Change from Baseline to Wk 12 in MOS Sleep Somnolence individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Sleep Somnolence items include Q6, Q9, Q11. Scoring method: Answers to Q6, Q 9 and Q11 are reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.

153. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Somnolence - Month 6 - (MITT-VMS) [Baseline and Month 6]

     Change from Baseline to Month 6 in MOS Sleep Somnolence individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Sleep Somnolence items include Q6, Q9, Q11. Scoring method: Answers to Q6, Q 9 and Q11 are reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.

154. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Somnolence - Month 12 - (MITT-VMS) [Baseline and Month 12]

     Change from Baseline to Month 12 in MOS Sleep Somnolence individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Sleep Somnolence items include Q6, Q9, Q11. Scoring method: Answers to Q6, Q 9 and Q11 are reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.

155. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Problems Index I - Week 12 - (MITT-VMS) [Baseline and Week 12]

     Change from Baseline to Wk 12 in MOS Sleep Problems Index I individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep Problems Index I includes items Q4, Q5, Q7, Q8, Q9, Q12. Scoring method: Answers to Q, 5, 7, 8, 9 are reversed & rescaled to realign to be same direction and range (0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Answers to Q4, & 12 are rescaled to 0-100 as follows: MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.

156. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Problems Index I - Month 6 - (MITT-VMS) [Baseline and Month 6]

     Change from Baseline to Month 6 in MOS Sleep Problems Index I individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep Problems Index I includes items Q4, Q5, Q7, Q8, Q9, Q12. Scoring method: Answers to Q, 5, 7, 8, 9 are reversed & rescaled to realign to be same direction and range (0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Answers to Q4, & 12 are rescaled to 0-100 as follows: MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.

157. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Problems Index I - Month 12 - (MITT-VMS) [Baseline and Month 12]

     Change from Baseline to Month 12 in MOS Sleep Problems Index I individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep Problems Index I includes items Q4, Q5, Q7, Q8, Q9, Q12. Scoring method: Answers to Q, 5, 7, 8, 9 are reversed & rescaled to realign to be same direction and range (0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Answers to Q4, & 12 are rescaled to 0-100 as follows: MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.

158. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Problems Index II - Week 12 - (MITT-VMS) [Baseline and Week 12]

     Change from Baseline to Wk 12 in MOS Sleep Problems Index II individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self reported hours of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep Problems Index II items include Q1, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q12. Scoring method: Answers to Q3, 5, 6, 7, 8, & 9 are reversed & rescaled to realign to be same direction and range 0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20, for n=Q3, 5, 6, 7, 8, and 9. Answers to Q1, 4 & 12 are rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25; MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.

159. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Problems Index II - Month 6 - (MITT-VMS) [Baseline and Month 6]

     Change from Baseline to Month 6 in MOS Sleep Problems Index II individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self reported hours of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep Problems Index II items include Q1, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q12. Scoring method: Answers to Q3, 5, 6, 7, 8, & 9 are reversed & rescaled to realign to be same direction and range 0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20, for n=Q3, 5, 6, 7, 8, and 9. Answers to Q1, 4 & 12 are rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25; MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.

160. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Problems Index II - Month 12 - (MITT-VMS) [Baseline and Month 12]

     Change from Baseline to Month 12 in MOS Sleep Problems Index II individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self reported hours of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep Problems Index II items include Q1, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q12. Scoring method: Answers to Q3, 5, 6, 7, 8, & 9 are reversed & rescaled to realign to be same direction and range 0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20, for n=Q3, 5, 6, 7, 8, and 9. Answers to Q1, 4 & 12 are rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25; MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.

161. Medical Outcomes Sleep Study (MOS) Optimal Sleep - Week 12 - (MITT-VMS) [Baseline and Week 12]

     Change from Baseline (BL) to Week 12 in MOS Optimal Sleep Score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items measuring 6 dimensions of sleep over the past 4 wks. Optimal sleep is based on Q2 (self-reported average hrs sleep per night in past 4 wks). Scoring method: hrs of sleep coded 0 (non-optimal) or 1 (optimal) where 1-6 hrs & 9-23 hrs = 0, 7-8 hrs = 1. Change from BL: subject sleeps 7-8 hrs at BL & 1-6 or 9-23 hrs at follow-up, change = -1; subject sleeps 1-6 or 9-23 hrs at BL & 7-8 hrs at follow-up, change = +1; subject sleeps 1-6 or 9-23 hrs at BL & 1-6 or 9-23 hrs at follow-up, change = 0. Mean change from BL: changes are summed to give the Net Total (equivalent to the number subjects w/ improved sleep hrs minus the number subjects w/ worsened sleep hrs), which is divided by the number of subjects to give the mean proportion of net change, where >0 = overall improvement and <0 = overall worsening in the study arm.

162. Medical Outcomes Sleep Study (MOS) Optimal Sleep - Month 6 - (MITT-VMS) [Baseline and Month 6]

     Change from Baseline (BL) to Month 6 in MOS Optimal Sleep Score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items measuring 6 dimensions of sleep over the past 4 wks. Optimal sleep is based on Q2 (self-reported average hrs sleep per night in past 4 wks). Scoring method: hrs of sleep coded 0 (non-optimal) or 1 (optimal) where 1-6 hrs & 9-23 hrs = 0, 7-8 hrs = 1. Change from BL: subject sleeps 7-8 hrs at BL & 1-6 or 9-23 hrs at follow-up, change = -1; subject sleeps 1-6 or 9-23 hrs at BL & 7-8 hrs at follow-up, change = +1; subject sleeps 1-6 or 9-23 hrs at BL & 1-6 or 9-23 hrs at follow-up, change = 0. Mean change from BL: changes are summed to give the Net Total (equivalent to the number subjects w/ improved sleep hrs minus the number subjects w/ worsened sleep hrs), which is divided by the number of subjects to give the mean proportion of net change, where >0 = overall improvement and <0 = overall worsening in the study arm.

163. Medical Outcomes Sleep Study (MOS) Optimal Sleep - Month 12 - (MITT-VMS) [Baseline and Month 12]

     Change from Baseline (BL) to Month 12 in MOS Optimal Sleep Score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items measuring 6 dimensions of sleep over the past 4 wks. Optimal sleep is based on Q2 (self-reported average hrs sleep per night in past 4 wks). Scoring method: hrs of sleep coded 0 (non-optimal) or 1 (optimal) where 1-6 hrs & 9-23 hrs = 0, 7-8 hrs = 1. Change from BL: subject sleeps 7-8 hrs at BL & 1-6 or 9-23 hrs at follow-up, change = -1; subject sleeps 1-6 or 9-23 hrs at BL & 7-8 hrs at follow-up, change = +1; subject sleeps 1-6 or 9-23 hrs at BL & 1-6 or 9-23 hrs at follow-up, change = 0. Mean change from BL: changes are summed to give the Net Total (equivalent to the number subjects w/ improved sleep hrs minus the number subjects w/ worsened sleep hrs), which is divided by the number of subjects to give the mean proportion of net change, where >0 = overall improvement and <0 = overall worsening in the study arm.

164. Menopause-specific Quality of Life Questionnaire (MENQOL) - Vasomotor Domain Score - Week 12 (MITT) [Baseline and Week 12]

     Changes in Vasomotor Domain Score from Baseline to Week 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Vasomotor domain score is mean of = Q1,Q2, Q3, with 1 being "not at all bothered" and 8 being "extremely bothered".

165. Menopause-specific Quality of Life Questionnaire (MENQOL) - Vasomotor Domain Score - Month 6 (MITT) [Baseline and Month 6]

     Changes in Vasomotor Domain Score from Baseline to Month 6. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Vasomotor domain score is mean of = Q1,Q2, Q3, with 1 being "not at all bothered" and 8 being "extremely bothered".

166. Menopause-specific Quality of Life Questionnaire (MENQOL) - Vasomotor Domain Score - Month 12 (MITT) [Baseline and Month 12]

     Changes in Vasomotor Domain Score from Baseline to Month 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Vasomotor domain score is mean of = Q1,Q2, Q3, with 1 being "not at all bothered" and 8 being "extremely bothered".

167. Menopause-specific Quality of Life Questionnaire (MENQOL) - Psychosocial Domain Score - Week 12 (MITT) [Baseline and Week 12]

     Changes in Psychosocial Domain Score from Baseline to Week 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Psychosocial domain score is mean of = Q4 to Q10, with 1 being "not at all bothered" and 8 being "extremely bothered".

168. Menopause-specific Quality of Life Questionnaire (MENQOL) - Psychosocial Domain Score - Month 6 (MITT) [Baseline and Month 6]

     Changes in Psychosocial Domain Score from Baseline to Month 6. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Psychosocial domain score is mean of = Q4 to Q10, with 1 being "not at all bothered" and 8 being "extremely bothered".

169. Menopause-specific Quality of Life Questionnaire (MENQOL) - Psychosocial Domain Score - Month 12 (MITT) [Baseline and Month 12]

     Changes in Psychosocial Domain Score from Baseline to Month 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Psychosocial domain score is mean of = Q4 to Q10, with 1 being "not at all bothered" and 8 being "extremely bothered".

170. Menopause-specific Quality of Life Questionnaire (MENQOL) - Physical Domain Score - Week 12 (MITT) [Baseline and Week 12]

     Changes in Physical Domain Score from Baseline to Week 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Physical domain score is mean of = Q11 to Q26, with 1 being "not at all bothered" and 8 being "extremely bothered".

171. Menopause-specific Quality of Life Questionnaire (MENQOL) - Physical Domain Score - Month 6 (MITT) [Baseline and Month 6]

     Changes in Physical Domain Score from Baseline to Month 6. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Physical domain score is mean of = Q11 to Q26, with 1 being "not at all bothered" and 8 being "extremely bothered".

172. Menopause-specific Quality of Life Questionnaire (MENQOL) - Physical Domain Score - Month 12 (MITT) [Baseline and Month 12]

     Changes in Physical Domain Score from Baseline to Month 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Physical domain score is mean of = Q11 to Q26, with 1 being "not at all bothered" and 8 being "extremely bothered".

173. Menopause-specific Quality of Life Questionnaire (MENQOL) - Sexual Domain Score - Week 12 (MITT) [Baseline and Week 12]

     Changes in Sexual Domain Score from Baseline to Week 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Sexual domain score is mean of = Q27 to Q29, with 1 being "not at all bothered" and 8 being "extremely bothered".

174. Menopause-specific Quality of Life Questionnaire (MENQOL) - Sexual Domain Score - Month 6 (MITT) [Baseline and Month 6]

     Changes in Sexual Domain Score from Baseline to Month 6. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Sexual domain score is mean of = Q27 to Q29, with 1 being "not at all bothered" and 8 being "extremely bothered".

175. Menopause-specific Quality of Life Questionnaire (MENQOL) - Sexual Domain Score - Month 12 (MITT) [Baseline and Month 12]

     Changes in Sexual Domain Score from Baseline to Month 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Sexual domain score is mean of = Q27 to Q29, with 1 being "not at all bothered" and 8 being "extremely bothered".

176. Menopause-specific Quality of Life Questionnaire (MENQOL) - Overall Scores - Week 12 (MITT) [Baseline and Week 12]

     Change in Overall Scores from Baseline to Week 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. The scale contains four domains: vasomotor, psychosocial, physical and sexual. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The Overall Score is the mean of the 4 domain scores with 1 being "not at all bothered" and 8 being "extremely bothered".

177. Menopause-specific Quality of Life Questionnaire (MENQOL) - Overall Scores - Month 6 (MITT) [Baseline and Month 6]

     Change in Overall Scores from Baseline to Month 6. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. The scale contains four domains: vasomotor, psychosocial, physical and sexual. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The Overall Score is the mean of the 4 domain scores with 1 being "not at all bothered" and 8 being "extremely bothered".

178. Menopause-specific Quality of Life Questionnaire (MENQOL) - Overall Scores - Month 12 (MITT) [Baseline and Month 12]

     Change in Overall Scores from Baseline to Month 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. The scale contains four domains: vasomotor, psychosocial, physical and sexual. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The Overall Score is the mean of the 4 domain scores with 1 being "not at all bothered" and 8 being "extremely bothered".

179. Medical Outcomes Sleep Study (MOS) Sleep Scale - Total Sleep Score - Week 12 (MITT) [Baseline and Week 12]

     Change from Baseline to Wk 12 in MOS Total Sleep Score as compared w/Placebo. MOS-Sleep Self Report Questionnaire is 12 items that measure 6 dimensions of sleep over past 4 wks. Q1 scored on scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 self-reported hrs of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Total score includes items Q1, 3, 4, 5, 6, 7, 8, 9, & 12. Scoring method: Answers to Q3, 5, 6, 7, 8, 9 are reversed & rescaled to realign to be same direction and range (0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Answers to Q1, 4, & 12 are rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25; MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Total score= average of item scores; ranges =0 to 100, where higher score means worse outcome. If any of individual questions used to obtain total score is missing, total score will be set to missing value.

180. Medical Outcomes Sleep Study (MOS) Sleep Scale - Total Sleep Score - Month 6 (MITT) [Baseline and Month 6]

     Change from Baseline to Month 6 in MOS Total Sleep Score as compared w/Placebo. MOS-Sleep Self Report Questionnaire is 12 items that measure 6 dimensions of sleep over past 4 wks. Q1 scored on scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 self-reported hrs of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Total score includes items Q1, 3, 4, 5, 6, 7, 8, 9, & 12. Scoring method: Answers to Q3, 5, 6, 7, 8, 9 are reversed & rescaled to realign to be same direction and range (0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Answers to Q1, 4, & 12 are rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25; MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Total score= average of item scores; ranges =0 to 100, where higher score means worse outcome. If any of individual questions used to obtain total score is missing, total score will be set to missing value.

181. Medical Outcomes Sleep Study (MOS) Sleep Scale - Total Sleep Score - Month 12 (MITT) [Baseline and Month 12]

     Change from Baseline to Month 12 in MOS Total Sleep Score as compared w/Placebo. MOS-Sleep Self Report Questionnaire is 12 items that measure 6 dimensions of sleep over past 4 wks. Q1 scored on scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 self-reported hrs of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Total score includes items Q1, 3, 4, 5, 6, 7, 8, 9, & 12. Scoring method: Answers to Q3, 5, 6, 7, 8, 9 are reversed & rescaled to realign to be same direction and range (0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Answers to Q1, 4, & 12 are rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25; MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Total score= average of item scores; ranges =0 to 100, where higher score means worse outcome. If any of individual questions used to obtain total score is missing, total score will be set to missing value.

182. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Disturbance - Week 12 - (MITT) [Baseline and Week 12]

     Change from Baseline to Wk 12 in MOS Sleep Disturbance individual score as compared with Placebo. MOS-Sleep Self Report Questionnaire is 12 items that measure 6 dimensions of sleep over past 4 wks. Q1 scored on scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 self-reported hrs of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep disturbance includes items Q1, Q3, Q7, Q8. Scoring method: Answer to Q1 is rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25. Answers to Q3, 7, 8 are reversed & rescaled to realign to be same direction and range(0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Score is average of item scores; score range=0 to 100, where higher score means worse outcome.

183. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Disturbance - Month 6 - (MITT) [Baseline and Month 6]

     Change from Baseline to Month 6 in MOS Sleep Disturbance individual score as compared with Placebo. MOS-Sleep Self Report Questionnaire is 12 items that measure 6 dimensions of sleep over past 4 wks. Q1 scored on scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 self-reported hrs of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep disturbance includes items Q1, Q3, Q7, Q8. Scoring method: Answer to Q1 is rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25. Answers to Q3, 7, 8 are reversed & rescaled to realign to be same direction and range(0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Score is average of item scores; score range=0 to 100, where higher score means worse outcome.

184. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Disturbance - Month 12 - (MITT) [Baseline and Month 12]

     Change from Baseline to Month 12 in MOS Sleep Disturbance individual score as compared with Placebo. MOS-Sleep Self Report Questionnaire is 12 items that measure 6 dimensions of sleep over past 4 wks. Q1 scored on scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 self-reported hrs of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep disturbance includes items Q1, Q3, Q7, Q8. Scoring method: Answer to Q1 is rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25. Answers to Q3, 7, 8 are reversed & rescaled to realign to be same direction and range(0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Score is average of item scores; score range=0 to 100, where higher score means worse outcome.

185. Medical Outcomes Sleep Study (MOS) Individual Score for Snoring - Week 12 - (MITT) [Baseline and Week 12]

     Change from Baseline to Wk 12 in MOS Snoring individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Snoring item is Q10. Scoring method: Answer to Q10 is reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score range=0 to 100, where higher score means worse outcome.

186. Medical Outcomes Sleep Study (MOS) Individual Score for Snoring - Month 6 - (MITT) [Baseline and Month 6]

     Change from Baseline to Month 6 in MOS Snoring individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Snoring item is Q10. Scoring method: Answer to Q10 is reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score range=0 to 100, where higher score means worse outcome.

187. Medical Outcomes Sleep Study (MOS) Individual Score for Snoring - Month 12 - (MITT) [Baseline and Month 12]

     Change from Baseline to Month 12 in MOS Snoring individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Snoring item is Q10. Scoring method: Answer to Q10 is reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score range=0 to 100, where higher score means worse outcome.

188. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Short of Breath or Headache - Week 12 - (MITT) [Baseline and Week 12]

     Change from Baseline to Wk 12 in MOS Sleep Short of Breath or Headache(SOBHA) individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. SOBHA item is Q5. Scoring method: Answer to Q5 is reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score range=0 to 100, where higher score means worse outcome.

189. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Short of Breath or Headache - Month 6 - (MITT) [Baseline and Month 6]

     Change from Baseline to Month 6 in MOS Sleep Short of Breath or Headache(SOBHA) individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. SOBHA item is Q5. Scoring method: Answer to Q5 is reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score range=0 to 100, where higher score means worse outcome.

190. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Short of Breath or Headache - Month 12 - (MITT) [Baseline and Month 12]

     Change from Baseline to Month 12 in MOS Sleep Short of Breath or Headache(SOBHA) individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. SOBHA item is Q5. Scoring method: Answer to Q5 is reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score range=0 to 100, where higher score means worse outcome.

191. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Adequacy - Week 12 - (MITT) [Baseline and Week 12]

     Change from Baseline to Wk 12 in MOS Sleep Adequacy individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Sleep Adequacy includes items Q4, Q12. Scoring method: Answers for Q4 and Q12 are reversed and rescaled to 0-100 as follows: MOS_4_new = (6-MOS_4_old) x 20; MOS_12_new = (6-MOS_12_old) x 20. Score is the average of item scores; score range = 0 to 100, where higher score means better outcome.

192. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Adequacy - Month 6 - (MITT) [Baseline and Month 6]

     Change from Baseline to Month 6 in MOS Sleep Adequacy individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Sleep Adequacy includes items Q4, Q12. Scoring method: Answers for Q4 and Q12 are reversed and rescaled to 0-100 as follows: MOS_4_new = (6-MOS_4_old) x 20; MOS_12_new = (6-MOS_12_old) x 20. Score is the average of item scores; score range = 0 to 100, where higher score means better outcome.

193. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Adequacy - Month 12 - (MITT) [Baseline and Month 12]

     Change from Baseline to Month 12 in MOS Sleep Adequacy individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Sleep Adequacy includes items Q4, Q12. Scoring method: Answers for Q4 and Q12 are reversed and rescaled to 0-100 as follows: MOS_4_new = (6-MOS_4_old) x 20; MOS_12_new = (6-MOS_12_old) x 20. Score is the average of item scores; score range = 0 to 100, where higher score means better outcome.

194. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Somnolence - Week 12 - (MITT) [Baseline and Week 12]

     Change from Baseline to Wk 12 in MOS Sleep Somnolence individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Sleep Somnolence items include Q6, Q9, Q11. Scoring method: Answers to Q6, Q 9 and Q11 are reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.

195. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Somnolence - Month 6 - (MITT) [Baseline and Month 6]

     Change from Baseline to Month 6 in MOS Sleep Somnolence individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Sleep Somnolence items include Q6, Q9, Q11. Scoring method: Answers to Q6, Q 9 and Q11 are reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.

196. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Somnolence - Month 12 - (MITT) [Baseline and Month 12]

     Change from Baseline to Month 12 in MOS Sleep Somnolence individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Sleep Somnolence items include Q6, Q9, Q11. Scoring method: Answers to Q6, Q 9 and Q11 are reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.

197. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Problems Index I - Week 12 - (MITT) [Baseline and Week 12]

     Change from Baseline to Wk 12 in MOS Sleep Problems Index I individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep Problems Index I includes items Q4, Q5, Q7, Q8, Q9, Q12. Scoring method: Answers to Q, 5, 7, 8, 9 are reversed & rescaled to realign to be same direction and range (0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Answers to Q4, & 12 are rescaled to 0-100 as follows: MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.

198. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Problems Index I - Month 6 - (MITT) [Baseline and Month 6]

     Change from Baseline to Month 6 in MOS Sleep Problems Index I individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep Problems Index I includes items Q4, Q5, Q7, Q8, Q9, Q12. Scoring method: Answers to Q, 5, 7, 8, 9 are reversed & rescaled to realign to be same direction and range (0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Answers to Q4, & 12 are rescaled to 0-100 as follows: MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.

199. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Problems Index I - Month 12 - (MITT) [Baseline and Month 12]

     Change from Baseline to Month 12 in MOS Sleep Problems Index I individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep Problems Index I includes items Q4, Q5, Q7, Q8, Q9, Q12. Scoring method: Answers to Q, 5, 7, 8, 9 are reversed & rescaled to realign to be same direction and range (0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Answers to Q4, & 12 are rescaled to 0-100 as follows: MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.

200. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Problems Index II - Week 12 - (MITT) [Baseline and Week 12]

     Change from Baseline to Wk 12 in MOS Sleep Problems Index II individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self reported hours of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep Problems Index II items include Q1, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q12. Scoring method: Answers to Q3, 5, 6, 7, 8, & 9 are reversed & rescaled to realign to be same direction and range 0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20, for n=Q3, 5, 6, 7, 8, and 9. Answers to Q1, 4 & 12 are rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25; MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.

201. Medical Outcomes Sleep Study (MOS) Sleep Problems Index II - Month 6 - (MITT) [Baseline and Month 6]

     Change from Baseline to Month 6 in MOS Sleep Problems Index II individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self reported hours of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep Problems Index II items include Q1, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q12. Scoring method: Answers to Q3, 5, 6, 7, 8, & 9 are reversed & rescaled to realign to be same direction and range 0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20, for n=Q3, 5, 6, 7, 8, and 9. Answers to Q1, 4 & 12 are rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25; MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.

202. Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Problems Index II - Month 12 - (MITT) [Baseline and Month 12]

     Change from Baseline to Month 12 in MOS Sleep Problems Index II individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self reported hours of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep Problems Index II items include Q1, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q12. Scoring method: Answers to Q3, 5, 6, 7, 8, & 9 are reversed & rescaled to realign to be same direction and range 0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20, for n=Q3, 5, 6, 7, 8, and 9. Answers to Q1, 4 & 12 are rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25; MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.

203. Medical Outcomes Sleep Study (MOS) Optimal Sleep - Week 12 - (MITT) [Baseline and Week 12]

     Change from Baseline (BL) to Wk 12 in MOS Optimal Sleep Score as compared with Placebo.The MOS-Sleep Self Report Questionnaire is composed of 12 items measuring 6 dimensions of sleep over the past 4 wks. Optimal sleep is based on Q2 (self-reported average hrs sleep per night in past 4 wks). Scoring method: hrs of sleep coded 0 (non-optimal) or 1 (optimal) where 1-6 hrs & 9-23 hrs = 0, 7-8 hrs = 1. Change from BL: subject sleeps 7-8 hrs at BL & 1-6 or 9-23 hrs at follow-up, change = -1; subject sleeps 1-6 or 9-23 hrs at BL & 7-8 hrs at follow-up, change = +1; subject sleeps 1-6 or 9-23 hrs at BL & 1-6 or 9-23 hrs at follow-up, change = 0. Mean change from BL: changes are summed to give the Net Total (equivalent to the number subjects w/ improved sleep hrs minus the number subjects w/ worsened sleep hrs), which is divided by the number of subjects to give the mean proportion of net change, where >0 = overall improvement and <0 = overall worsening in the study arm.

204. Medical Outcomes Sleep Study (MOS) Optimal Sleep - Month 6 - (MITT) [Baseline and Month 6]

     Change from Baseline (BL) to Month 6 in MOS Optimal Sleep Score as compared with Placebo.The MOS-Sleep Self Report Questionnaire is composed of 12 items measuring 6 dimensions of sleep over the past 4 wks. Optimal sleep is based on Q2 (self-reported average hrs sleep per night in past 4 wks). Scoring method: hrs of sleep coded 0 (non-optimal) or 1 (optimal) where 1-6 hrs & 9-23 hrs = 0, 7-8 hrs = 1. Change from BL: subject sleeps 7-8 hrs at BL & 1-6 or 9-23 hrs at follow-up, change = -1; subject sleeps 1-6 or 9-23 hrs at BL & 7-8 hrs at follow-up, change = +1; subject sleeps 1-6 or 9-23 hrs at BL & 1-6 or 9-23 hrs at follow-up, change = 0. Mean change from BL: changes are summed to give the Net Total (equivalent to the number subjects w/ improved sleep hrs minus the number subjects w/ worsened sleep hrs), which is divided by the number of subjects to give the mean proportion of net change, where >0 = overall improvement and <0 = overall worsening in the study arm.

205. Medical Outcomes Sleep Study (MOS) Optimal Sleep - Month 12 - (MITT) [Baseline and Month 12]

     Change from Baseline (BL) to Month 12 in MOS Optimal Sleep Score as compared with Placebo.The MOS-Sleep Self Report Questionnaire is composed of 12 items measuring 6 dimensions of sleep over the past 4 wks. Optimal sleep is based on Q2 (self-reported average hrs sleep per night in past 4 wks). Scoring method: hrs of sleep coded 0 (non-optimal) or 1 (optimal) where 1-6 hrs & 9-23 hrs = 0, 7-8 hrs = 1. Change from BL: subject sleeps 7-8 hrs at BL & 1-6 or 9-23 hrs at follow-up, change = -1; subject sleeps 1-6 or 9-23 hrs at BL & 7-8 hrs at follow-up, change = +1; subject sleeps 1-6 or 9-23 hrs at BL & 1-6 or 9-23 hrs at follow-up, change = 0. Mean change from BL: changes are summed to give the Net Total (equivalent to the number subjects w/ improved sleep hrs minus the number subjects w/ worsened sleep hrs), which is divided by the number of subjects to give the mean proportion of net change, where >0 = overall improvement and <0 = overall worsening in the study arm.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 65 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Be a female between the ages of 40 and 65 years (at the time of randomization) who is willing to participate in the study, as documented by signing the informed consent form.

2. Be a postmenopausal woman with an intact uterus and a Screening serum estradiol level of ≤50 pg/mL. Postmenopausal is defined herein as:

3. ≥ 12 months of spontaneous amenorrhea, or

4. at least 6 months of spontaneous amenorrhea with a Screening serum FSH level of

40 mIU/ml, or

1. ≥ 6 weeks postsurgical bilateral oophorectomy.

2. Be seeking treatment or relief for vasomotor symptoms associated with menopause.

3. To participate in the VMS Substudy, a subject must also report ≥7 moderate to severe hot flushes per day, or ≥50 per week, at the baseline assessment during Screening (subjects whose hot flushes are less frequent may still participate as non-Substudy subjects.

Note: A minimum of 14 consecutive days of complete hot flush diary data are required during the baseline assessment at Screening, and these consecutive days must occur within the last 14 days prior to the Randomization visit (not counting the Randomization visit day itself). The most recent 7 consecutive days of data prior to randomization (Day -7 to Day -1) will be used to determine the baseline number of mild, moderate and severe hot flushes for each subject.

1. Have a Body Mass Index (BMI) less than or equal to 34 kg/mP2P. (BMI values should be rounded to the nearest integer [e.g., 34.4 rounds down to 34, while 26.5 rounds up to 27]).

2. Be willing to abstain from using products (other than study medication) that contain estrogen, progestin, or progesterone throughout study participation.

3. Be judged by the principal or sub-investigator physician as being in otherwise generally good health based on a medical evaluation performed during the Screening period prior to the initial dose of study medication. The medical evaluation findings must include:

4. a normal or non-clinically significant physical examination, including vital signs (sitting blood pressure, heart rate, respiratory rate and temperature). Sitting systolic blood pressure is ≤140 mmHg and diastolic blood pressure ≤90 mmHg at Screening. A subject may be taking up to two antihypertensive medications.

5. a normal or non-clinically significant pelvic examination.

6. a mammogram that shows no sign of significant disease (can be performed within previous 6 months prior to initial dose of study medication). Subjects must have a BI-RADS 1 or 2 to enroll in the study. An incomplete mammogram result, i.e. BI-RADS 0, is not acceptable. The site must obtain a copy of the official report for the subject's study file, and it must be verified that the mammogram itself is available if needed for additional assessment.

7. a normal or non-clinically significant clinical breast examination. An acceptable breast examination is defined as no masses or other findings identified that are suspicious of malignancy.

8. a normal Screening Papanicolaou ("Pap") smear. (Subjects with findings of atypical glandular cells [AGC], AGUS, ASCUS with high risk HPV type upon reflex testing, LSIL, ASC-H, HSIL, dysplastic cells, or malignant cells must be excluded from randomization.)

9. an acceptable result from an evaluable Screening endometrial biopsy. The endometrial biopsy reports by the two central pathologists at Screening must each specify one of the following: proliferative endometrium; weakly proliferative endometrium; disordered proliferative pattern; secretory endometrium; endometrial tissue other (including benign, inactive or atrophic fragments of endometrial epithelium, glands, stroma, etc); endometrial tissue insufficient for diagnosis; no endometrium identified; or no tissue identified. However, at least one pathologist must identify sufficient tissue to evaluate the biopsy. Additionally, the endometrial biopsy reports by the two central pathologists of Other Findings at Screening must each specify one of the following: endometrial polyp not present; benign endometrial polyp; or polyp other. (See Exclusion criterion #27)

10. a normal or non-clinically significant 12-lead ECG.

Exclusion Criteria:

• To participate in the study, a subject must NOT:

1. Be currently hospitalized.

2. Have a history of thrombosis of deep veins or arteries or a thromboembolic disorder.

3. Have a history of coronary artery or cerebrovascular disease (e.g., myocardial infarction, angina, stroke, TIA).

4. Have a history of a chronic liver or kidney dysfunction/disorder (e.g., Hepatitis C or chronic renal failure).

5. Have a history of a malabsorption disorder (e.g., gastric bypass, Crohn's disease).

6. Have a history of gallbladder dysfunction/disorders (e.g., cholangitis, cholecystitis), unless gallbladder has been removed.

7. Have a history of diabetes, thyroid disease or any other endocrinological disease. (Subjects with diet-controlled diabetes or controlled hypothyroid disease at Screening are not excluded.)

8. Have a history of estrogen-dependent neoplasia.

9. Have a history of atypical ductal hyperplasia of the breast.

10. Have a finding of clinically significant uterine fibroids at Screening.

11. Have had a uterine ablation.

12. Have a history of undiagnosed vaginal bleeding.

13. Have any history of endometrial hyperplasia, melanoma, or uterine/endometrial, breast or ovarian cancer.

14. Have any history of other malignancy within the last 5 years, with the exception of basal cell (excluded if within 1 year) or non-invasive squamous cell (excluded if within 1 year) carcinoma of the skin.

15. Have a history of any other cardiovascular, hepatic, renal, pulmonary, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, psychological (e.g., bipolar disorder, schizophrenia, major depressive disorder), or musculoskeletal disease or disorder that is clinically significant in the opinion of the Principal Investigator or Medical Sub-Investigator.

16. Have any of the following clinical laboratory values at Screening:

17. fasting triglyceride of ≥300 mg/dL and/or total cholesterol of ≥300mg/dL

18. positive laboratory finding for Factor V Leiden mutation

19. AST or ALT ≥1.5 times the upper limit of normal (ULN)

20. fasting glucose >125 mg/dL

21. Be known to be pregnant or have a positive urine pregnancy test. (Note: A pregnancy test is not required for subjects who have had bilateral tubal ligation, bilateral oophorectomy, or are 55 years old or greater and have experienced cessation of menses for at least 1 year.)

22. Have contraindication to estrogen and/or progestin therapy or allergy to the use of estradiol and/or progesterone or any components of the investigational drugs.

23. Use 15 or more cigarettes per day or currently use any electronic cigarettes.

24. Have a history of drug and/or alcohol abuse within one year of start of study.

25. Have used, within 28 days prior to the initial dose of study medication at Visit 1, any medication known to induce or inhibit CYP3A4 enzyme activity that may affect estrogen and/or progestin drug metabolism. (See 48TUSection 4.3U48T)

26. Have used, within 28 days prior to Screening, or plan to use during the study, any prescription or over-the-counter (OTC) medications (including herbal products, such as St. John's Wort) that would be expected to alter progesterone or estrogen activity or is being used to treat vasomotor symptoms. (See Section 4.3U48T)

27. Have used estrogen alone or estrogen/progestin, SERM (selective estrogen receptor modulator), testosterone, or estrogen/testosterone for any of the following time periods:

28. Vaginal nonsystemic hormonal products (rings, creams, gels) within 7 days prior to Screening, or vaginal systemic products (e.g., FemRing) within 28 days prior to Screening.

29. Transdermal estrogen alone or estrogen/progestin products within 8 weeks prior to Screening.

30. Oral estrogen and/or progestin and/or SERM therapy within 8 weeks prior to Screening.

31. Progestational implants, estrogen or estrogen/progestational injectable drug therapy within 3 months prior to Screening.

32. Estrogen pellet therapy or progestational injectable drug therapy within 6 months prior to Screening.

33. Percutaneous estrogen lotions/gels within 8 weeks prior to Screening.

34. Oral, topical, vaginal, patch, implantable or injectable androgen therapy within 8 weeks prior to Screening.

35. Have used an intrauterine device (IUD) within the 12 weeks prior to Screening.

36. For subjects in the VMS Substudy only: use of medication that may affect the outcome of the vasomotor symptom endpoints within 28 days prior to Screening (e.g. SSRIs [selective serotonin reuptake inhibitors], SNRIs [serotonin and norepinephrine reuptake inhibitors], aldomet, dopaminergic or antidopaminergic drugs, gabapentin, clonidine, or bellergal.)

37. Have any reason which, in the opinion of the Principal Investigator or Medical Sub-Investigator, would prevent the subject from safely participating in the study or complying with protocol requirements.

38. Have a Screening endometrial biopsy sample that is found by both primary pathologists to have endometrial tissue insufficient for diagnosis, no endometrium identified, or no tissue identified. (With the approval of the Medical Monitor, the Screening endometrial biopsy may be repeated once.)

39. Endometrial polyps with atypical nuclei reported by at least 1 central pathologist.

40. Have contraindication to any planned study assessments (e.g., endometrial biopsy).

41. Have participated in another clinical trial within 30 days prior to Screening, have received an investigational drug within the three months prior to the initial dose of study medication, or be likely to participate in a clinical trial or receive another investigational medication during the study.

42. Currently use marijuana.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Simon Williamson Clinic	Birmingham	Alabama	United States	35211
2	Medical Affiliated Research Center	Huntsville	Alabama	United States	35801
3	Coastal Clinical Research	Mobile	Alabama	United States	36608
4	Mobile Ob-Gyn, P.C.	Mobile	Alabama	United States	36608
5	Montgomery Women's Health	Montgomery	Alabama	United States	36117
6	Advanced Research Associates	Glendale	Arizona	United States	85308
7	Cactus Clinical Research	Mesa	Arizona	United States	85209
8	Precision Trials	Phoenix	Arizona	United States	85032
9	Radiant Research (Tucson)	Tucson	Arizona	United States	85712
10	Visions Clinical Research Tucson	Tucson	Arizona	United States	85712
11	Health Star Research, LLC	Hot Springs	Arkansas	United States	71913
12	Sutter East Bay Medical Foundation	Berkeley	California	United States	94705
13	Grossmont Center for Clinical Research	La Mesa	California	United States	91942
14	Futura Research	Norwalk	California	United States	90650
15	Medical Center for Clinical Research	San Diego	California	United States	92108
16	Women's Health Care Research Corp.	San Diego	California	United States	92111
17	Radiant Research, Inc.	Santa Rosa	California	United States	95405
18	Diablo Clinical Research	Walnut Creek	California	United States	94598
19	Downtown Women's Healthcare	Denver	Colorado	United States	80209
20	Horizon's Clinical Research Center	Denver	Colorado	United States	80220
21	Red Rocks OB/Gyn	Lakewood	Colorado	United States	80228
22	Clinical Research Consulting	Milford	Connecticut	United States	06460
23	Coastal Connecticut Research	New London	Connecticut	United States	06320
24	South Florida Medical Research	Aventura	Florida	United States	33180
25	Nature Coast Clinical Research	Crystal River	Florida	United States	34429
26	Clinical Physiology Associates	Fort Myers	Florida	United States	33916
27	Southeastern Integrated Medical, PL, d/b/a Florida Medical Research	Gainesville	Florida	United States	32607
28	UF College of Medicine-Jacksonville, Dept. of Obstetrics and Gynecology	Jacksonville	Florida	United States	32207
29	Suncoast Research	Margate	Florida	United States	33063
30	Accelovance	Melbourne	Florida	United States	32934
31	Suncoast Clinical Research, Inc	New Port Richey	Florida	United States	34652
32	Ideal Clinical Research	North Miami Beach	Florida	United States	33162
33	Segal Institute	North Miami	Florida	United States	33161
34	Compass Research	Orlando	Florida	United States	32806
35	Radiant Research (St. Petersburg)	Pinellas Park	Florida	United States	33781
36	All Women's Healthcare of West Broward Discovery Clinical Research	Plantation	Florida	United States	33324
37	Comprehensive Clinical Trials	West Palm Beach	Florida	United States	33409
38	Radiant Research (Atlanta)	Atlanta	Georgia	United States	30328
39	Women's Health Associates	Atlanta	Georgia	United States	30342
40	Soapstone Center for Clinical Research	Decatur	Georgia	United States	30034
41	Wake Research - Mount Vernon Clinical Research	Sandy Springs	Georgia	United States	30328
42	Fellows Research Alliance	Savannah	Georgia	United States	31406
43	Elite Clinical Trials	Blackfoot	Idaho	United States	83221
44	Advanced Clinical Research	Meridian	Idaho	United States	83642
45	Biofortis	Addison	Illinois	United States	60101
46	Women's Health Practice	Champaign	Illinois	United States	61820
47	Radiant Research (Chicago)	Chicago	Illinois	United States	60654
48	The South Bend Clinic Granger	Granger	Indiana	United States	46530
49	Davis Clinic	Indianapolis	Indiana	United States	46250
50	Cypress Medical Research Center, LLC	Wichita	Kansas	United States	67226
51	Central Kentucky Research Associates	Lexington	Kentucky	United States	40509
52	Bluegrass Clinical Research	Louisville	Kentucky	United States	40291
53	Horizon Research Group	Eunice	Louisiana	United States	70535
54	Maryland Center for Sexual Health	Lutherville	Maryland	United States	21093
55	Quest Research Institute	Bingham Farms	Michigan	United States	48025
56	Female Pelvic Medicine & Urogynecology	Grand Rapids	Michigan	United States	49503
57	Beyer Research	Kalamazoo	Michigan	United States	49009
58	Saginaw Valley Medical Research Group	Saginaw	Michigan	United States	48604
59	Radiant Research (St. Louis)	Saint Louis	Missouri	United States	63141
60	Billings Clinical Research	Billings	Montana	United States	59101
61	Montana Health	Billings	Montana	United States	59102
62	Women's Clinic of Lincoln	Lincoln	Nebraska	United States	68510
63	Affiliated Clinical Research INC	Las Vegas	Nevada	United States	89113
64	Affiliated Clinical Research	Las Vegas	Nevada	United States	89128
65	Lawrence OB-GYN Clinical Research	Lawrenceville	New Jersey	United States	08648
66	Albuquerque Clinical Trials, Inc.	Albuquerque	New Mexico	United States	87102
67	Bosque Women's Care	Albuquerque	New Mexico	United States	87109
68	Southwest Clinical Research	Albuquerque	New Mexico	United States	87109
69	Columbia University	New York	New York	United States	10032
70	Suffolk OB/GYN	Port Jefferson	New York	United States	11777
71	Upstate Clinical Research Associates	Williamsville	New York	United States	14221
72	Women's Wellness Clinic	Durham	North Carolina	United States	27713
73	Carolina Medical Trials	High Point	North Carolina	United States	27262
74	Centre OBGYN	Raleigh	North Carolina	United States	27607
75	Wake County Research	Raleigh	North Carolina	United States	27612
76	Lyndhurst Clinical Research	Salem	North Carolina	United States	27103
77	Carolina Medical Trials	Winston-Salem	North Carolina	United States	27103
78	Hawthorne Research	Winston-Salem	North Carolina	United States	27103
79	Triad Ob-Gyn	Winston-Salem	North Carolina	United States	27103
80	Lillestol Research	Fargo	North Dakota	United States	58103
81	Radiant Research (Akron)	Akron	Ohio	United States	44311
82	University of Cincinnati Physicians Company	Cincinnati	Ohio	United States	45267-0457
83	Rapid Medical Research	Cleveland	Ohio	United States	44122
84	Columbus Center for Women's Health Research	Columbus	Ohio	United States	43213
85	HWC Women's Research Center	Englewood	Ohio	United States	45322
86	Lynn Health Science Institute	Oklahoma City	Oklahoma	United States	73112
87	Sunstone Medical Research	Medford	Oregon	United States	97504
88	The Clinical Trial Center	Jenkintown	Pennsylvania	United States	19046
89	Clinical Research of Philadelphia	Philadelphia	Pennsylvania	United States	19114
90	Clinical Trials Research Services, LLC	Pittsburgh	Pennsylvania	United States	15206
91	Omega Medical Research	Warwick	Rhode Island	United States	02886
92	Fellows Research Group	Bluffton	South Carolina	United States	29910
93	Vista Clinical Research	Columbia	South Carolina	United States	29201
94	Upstate Pharmaceutical Research	Greenville	South Carolina	United States	29615
95	Coastal Carolina Research Center	Mount Pleasant	South Carolina	United States	29464
96	Chattanooga Medical Research	Chattanooga	Tennessee	United States	37404
97	Volunteer Research Group/NOCCR	Knoxville	Tennessee	United States	37920
98	DiscoveResearch, Inc.	Bryan	Texas	United States	77802
99	Advanced Research Associates	Corpus Christi	Texas	United States	78414
100	Research Across America	Dallas	Texas	United States	75234
101	Brownstone Clinical Trials	Fort Worth	Texas	United States	76104
102	Advances in Health	Houston	Texas	United States	77030
103	The Women's Hospital of Texas	Houston	Texas	United States	77054
104	TMC Life Research	Houston	Texas	United States	77054
105	Protenium Clinical Research	Hurst	Texas	United States	76054
106	MacArthur OB/GYN	Irving	Texas	United States	75062
107	Clinical Trials of Texas	San Antonio	Texas	United States	78229
108	Stone Oak, LLC dba Discovery Clinical Trials	San Antonio	Texas	United States	78258
109	NECRSA	Schertz	Texas	United States	78154
110	PRO/ Salt Lake Women's Center	Draper	Utah	United States	84020
111	Wasatch Clinical Research, LLC	Salt Lake City	Utah	United States	84107
112	Jean Brown Research	Salt Lake City	Utah	United States	84124
113	UVA/Midlife Health at North Ridge	Charlottesville	Virginia	United States	22908
114	Clinical Research Center Eastern Virginia Medical School	Norfolk	Virginia	United States	23507
115	Virginia Women's Center	Richmond	Virginia	United States	23233
116	National Clinical Research-Richmond, Inc	Richmond	Virginia	United States	23294
117	Tidewater Clinical Research	Virginia Beach	Virginia	United States	23456
118	Seattle Women's Health Research, Gynecology	Seattle	Washington	United States	98105
119	North Spokane Women's Health	Spokane	Washington	United States	99027

Sponsors and Collaborators

• TherapeuticsMD

Investigators

• Study Director: Sebastian Mirkin, MD, TherapeuticsMD

Study Documents (Full-Text)

None provided.

More Information

Publications

• Gerlinger C, Gude K, Hiemeyer F, Schmelter T, Schäfers M. An empirically validated responder definition for the reduction of moderate to severe hot flushes in postmenopausal women. Menopause. 2012 Jul;19(7):799-803. doi: 10.1097/gme.0b013e31823de8ba.
• Hays RD and Stewart AL. Sleep measures. In AL Stewart & JE Ware (eds), Measuring functioning and well-being: The Medical Outcomes Study approach (pp 235-259). Durham, NC: Duke University Press, 1992.
• Hilditch JR, Lewis J, Peter A, van Maris B, Ross A, Franssen E, Guyatt GH, Norton PG, Dunn E. A menopause-specific quality of life questionnaire: development and psychometric properties. Maturitas. 1996 Jul;24(3):161-75. Erratum in: Maturitas 1996 Nov;25(3):231.
• Kurman RJ, Ellenson L H, and Ronnett B.M., ed. Blaustein's Pathology of the Female Genital Tract. 6th ed. New York, NY: Springer; 2011:305-452.
• Revicki D, Hays RD, Cella D, Sloan J. Recommended methods for determining responsiveness and minimally important differences for patient-reported outcomes. J Clin Epidemiol. 2008 Feb;61(2):102-9. doi: 10.1016/j.jclinepi.2007.03.012. Epub 2007 Aug 3. Review.
• Spritzer, K. L. & Hays, R. D. (2003, November). MOS Sleep Scale: A Manual for Use and Scoring, Version 1.0. Los Angeles, CA.

• Responsible Party: TherapeuticsMD
• ClinicalTrials.gov Identifier: NCT01942668
• Other Study ID Numbers: TXC12-05; REPLENISH Trial
• First Posted: Sep 16, 2013
• Last Update Posted: May 6, 2019
• Last Verified: Apr 1, 2019

• Keywords provided by TherapeuticsMD: Vasomotor symptoms; Hot flashes; Endometrial protection
• Additional relevant MeSH terms: Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Estradiol; Polyestradiol phosphate; Progesterone

Study Results

Participant Flow

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Period Title: Overall Study
STARTED	418	426	422	427	152
COMPLETED	284	305	312	281	93
NOT COMPLETED	134	121	110	146	59

Baseline Characteristics

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo	Total
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.	Total of all reporting groups
Overall Participants	415	424	421	424	151	1835
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	415 100%	424 100%	421 100%	424 100%	151 100%	1835 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.7 (4.37)	54.5 (4.52)	54.9 (4.27)	54.4 (4.04)	54.5 (4.32)	54.6 (4.31)
Sex: Female, Male (Count of Participants)
Female	415 100%	424 100%	421 100%	424 100%	151 100%	1835 100%
Male	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	415 100%	424 100%	421 100%	424 100%	151 100%	1835 100%

Outcome Measures

1. Primary Outcome

Title	Co-Primary Efficacy Endpoint: Frequency of Moderate to Severe Vasomotor Symptoms (MITT-VMS)
Description	Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 4. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	134	144	142	152	126
Mean (Standard Deviation) [weekly hot flushes]	-40.6 (30.59)	-35.1 (29.14)	-33.6 (30.64)	-38.9 (31.04)	-26.4 (27.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 4
	Method	Mixed Models Analysis
	Comments	Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-12.81
	Confidence Interval	(2-Sided) 95%; -19.29 to -6.32
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.30
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 4
	Method	Mixed Models Analysis
	Comments	Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-8.07
	Confidence Interval	(2-Sided) 95%; -14.46 to -1.68
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.25
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.141
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 4
	Method	Mixed Models Analysis
	Comments	Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.81
	Confidence Interval	(2-Sided) 95%; -11.21 to 1.59
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.26
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 4
	Method	Mixed Models Analysis
	Comments	Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-10.40
	Confidence Interval	(2-Sided) 95%; -16.73 to -4.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.22
	Estimation Comments	Adjusted for baseline using MMRM

2. Primary Outcome

Title	Co-Primary Efficacy Endpoint: Frequency of Moderate to Severe Vasomotor Symptoms (MITT-VMS)
Description	Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 12. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	124	129	124	135	115
Mean (Standard Deviation) [weekly hot flushes]	-55.1 (31.36)	-53.7 (31.93)	-50.2 (31.35)	-52.4 (33.90)	-40.2 (29.79)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments	Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-16.58
	Confidence Interval	(2-Sided) 95%; -23.33 to -9.82
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.44
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments	Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-15.07
	Confidence Interval	(2-Sided) 95%; -21.72 to -8.42
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.39
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments	Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-10.79
	Confidence Interval	(2-Sided) 95%; -17.48 to -4.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.41
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments	Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-11.71
	Confidence Interval	(2-Sided) 95%; -18.31 to -5.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.36
	Estimation Comments	Adjusted for baseline using MMRM

3. Primary Outcome

Title	Co-Primary Efficacy Endpoint: Severity of Moderate to Severe Vasomotor Symptoms (MITT-VMS)
Description	Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 4. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	134	144	142	152	126
Mean (Standard Deviation) [scores on a scale]	-0.48 (0.547)	-0.51 (0.563)	-0.40 (0.469)	-0.44 (0.514)	-0.34 (0.386)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.031
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 4
	Method	Mixed Models Analysis
	Comments	Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95%; -0.25 to -0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.061
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 4
	Method	Mixed Models Analysis
	Comments	Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -0.28 to -0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.060
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.401
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 4
	Method	Mixed Models Analysis
	Comments	Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.17 to 0.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.060
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.100
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 4
	Method	Mixed Models Analysis
	Comments	Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.21 to 0.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.059
	Estimation Comments	Adjusted for baseline using MMRM

4. Primary Outcome

Title	Co-Primary Efficacy Endpoint: Severity of Moderate to Severe Vasomotor Symptoms (MITT-VMS)
Description	Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 12. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	124	129	124	135	115
Mean (Standard Deviation) [scores on a scale]	-1.12 (0.963)	-0.90 (0.783)	-0.76 (0.744)	-0.71 (0.806)	-0.56 (0.603)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments	Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.57
	Confidence Interval	(2-Sided) 95%; -0.77 to -0.38
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.100
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments	Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.39
	Confidence Interval	(2-Sided) 95%; -0.59 to -0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.099
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.018
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments	Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.24
	Confidence Interval	(2-Sided) 95%; -0.43 to -0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.100
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.096
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments	Each co-primary endpt in each dose group tested at alpha=0.05;multiple dose groups vs. PBO comparisons are conducted using gatekeeping procedure
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.16
	Confidence Interval	(2-Sided) 95%; -0.36 to 0.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.098
	Estimation Comments	Adjusted for baseline using MMRM

5. Primary Outcome

Title	Primary Safety Endpoint: Endometrial Protection - Hyperplasia
Description	Endometrial biopsies centrally evaluated by 2 primary pathologists using criteria from Blaustein's Pathology text. Pathologists classified bx into 1 of following 3 categories: Cat.1: Non-endometrial malignancy/non-hyperplasia; Cat.2: Endometrial hyperplasia; Cat.3: Endometrial malignancy. Consensus reached when 2 primary pathologist agreed on any of above categories; if primary pathologists disagreed on presence of hyperplasia, result of 3rd pathologist was utilized and final decision regarding presence of hyperplasia was based on diagnosis of majority. If all 3 reads disparate, final diagnosis based on most severe dx. Incidence rate calculated as: I=A/B where I=incidence rate at M12 evaluation, A=all new subjects with biopsies positive for endometrial hyperplasia during study but post-Baseline, B=all subjects w/biopsies following M11 meeting criteria specified plus all subjects w/biopsies positive for endometrial hyperplasia by any pathologists before M11.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

Randomized subjects who had taken at least 1 capsule, had no major protocol violations, acceptable biopsy at baseline (evaluable tissue, no endometrial hyperplasia, polyp or cancer), had a biopsy at month 12 (on or after Study Day 326) or had a diagnosis of endometrial hyperplasia prior to month 12.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation taken orally once a day for twelve months.	Two Placebo capsules taken orally once a day for twelve months.
Measure Participants	280	303	306	274	92
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg
	Comments	Between group comparison is not intended. The purpose of the analysis is to calculate the incidence rate and the 95% CI of endometrial hyperplasia per FDA published guidance for Combined Estradiol 1 mg / Progesterone 100 mg.
	Type of Statistical Test	Other
	Comments	Per FDA guidance hyperplasia proportion must be <=1% with an upper bound of the one-sided 95% confidence interval <=4%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	incidence rate
	Estimated Value	0
	Confidence Interval	(1-Sided) 95%; to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments	This calculation is based on a binomial distribution.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg
	Comments	Between group comparison is not intended. The purpose of the analysis is to calculate the incidence rate and the 95% CI of endometrial hyperplasia per FDA published guidance for Combined Estradiol 0.5 mg / Progesterone 100 mg.
	Type of Statistical Test	Other
	Comments	Per FDA guidance hyperplasia proportion must be <=1% with an upper bound of the one-sided 95% confidence interval <=4%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	incidence rate
	Estimated Value	0
	Confidence Interval	(1-Sided) 95%; to 0.98
	Parameter Dispersion	Type: Value:
	Estimation Comments	This calculation is based on a binomial distribution.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg
	Comments	Between group comparison is not intended. The purpose of the analysis is to calculate the incidence rate and the 95% CI of endometrial hyperplasia per FDA published guidance for Combined Estradiol 0.5 mg / Progesterone 50 mg.
	Type of Statistical Test	Other
	Comments	Per FDA guidance hyperplasia proportion must be <=1% with an upper bound of the one-sided 95% confidence interval <=4%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	incidence rate
	Estimated Value	0
	Confidence Interval	(1-Sided) 95%; to 0.97
	Parameter Dispersion	Type: Value:
	Estimation Comments	This calculation is based on a binomial distribution.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg
	Comments	Between group comparison is not intended. The purpose of the analysis is to calculate the incidence rate and the 95% CI of endometrial hyperplasia per FDA published guidance for Combined Estradiol 0.25 mg / Progesterone 50 mg.
	Type of Statistical Test	Other
	Comments	Per FDA guidance hyperplasia proportion must be <=1% with an upper bound of the one-sided 95% confidence interval <=4%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	incidence rate
	Estimated Value	0
	Confidence Interval	(1-Sided) 95%; to 1.09
	Parameter Dispersion	Type: Value:
	Estimation Comments	This calculation is based on a binomial distribution.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	Between group comparison is not intended. The purpose of the analysis is to calculate the incidence rate and the 95% CI of endometrial hyperplasia per FDA published guidance for Placebo.
	Type of Statistical Test	Other
	Comments	Per FDA guidance hyperplasia proportion must be <=1% with an upper bound of the one-sided 95% confidence interval <=4%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	incidence rate
	Estimated Value	0
	Confidence Interval	(1-Sided) 95%; to 3.20
	Parameter Dispersion	Type: Value:
	Estimation Comments	This calculation is based on a binomial distribution.

6. Secondary Outcome

Title	Endometrial Protection - Hyperplasia
Description	Endometrial biopsies centrally evaluated by 3 primary pathologists using criteria described in Blaustein's Pathology text. Pathologists classified biopsy into 1 of following 3 categories: Cat.1: Non-endometrial malignancy/non-hyperplasia; Cat.2: Endometrial hyperplasia; Cat.3: Endometrial malignancy. Consensus was reached when the 2 of 3 pathologist readers agreed on any of the above categories; if all three reads were disparate, the final diagnosis was based on the most severe diagnosis. Incidence rate calculated as: I=A/B where I=incidence rate at M12 evaluation, A=all new subjects with biopsies positive for endometrial hyperplasia during study but post-Baseline, B=all subjects with biopsies following M11 meeting the criteria specified plus all subjects with biopsies positive for endometrial hyperplasia by any of the pathologists before M11.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

Randomized subjects who had taken at least 1 capsule, had no major protocol violations, acceptable biopsy at baseline (evaluable tissue, no endometrial hyperplasia, polyp or cancer), had a biopsy at month 12 (on or after Study Day 326) or had a diagnosis of endometrial hyperplasia prior to month 12.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	280	303	306	274	92
Count of Participants [Participants]	0 0%	0 0%	0 0%	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg
	Comments	Between group comparison is not intended. The purpose of the analysis is to calculate the incidence rate and the 95% CI of endometrial hyperplasia per FDA published guidance for Combined Estradiol 1 mg / Progesterone 100 mg.
	Type of Statistical Test	Other
	Comments	Per FDA guidance hyperplasia proportion must be <=1% with an upper bound of the one-sided 95% confidence interval <=4%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	incidence rate
	Estimated Value	0
	Confidence Interval	(1-Sided) 95%; to 1.06
	Parameter Dispersion	Type: Value:
	Estimation Comments	This calculation is based on a binomial distribution.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg
	Comments	Between group comparison is not intended. The purpose of the analysis is to calculate the incidence rate and the 95% CI of endometrial hyperplasia per FDA published guidance for Combined Estradiol 0.5 mg / Progesterone 100 mg.
	Type of Statistical Test	Other
	Comments	Per FDA guidance hyperplasia proportion must be <=1% with an upper bound of the one-sided 95% confidence interval <=4%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	incidence rate
	Estimated Value	0
	Confidence Interval	(1-Sided) 95%; to 0.98
	Parameter Dispersion	Type: Value:
	Estimation Comments	This calculation is based on a binomial distribution.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg
	Comments	Between group comparison is not intended. The purpose of the analysis is to calculate the incidence rate and the 95% CI of endometrial hyperplasia per FDA published guidance for Combined Estradiol 0.5 mg / Progesterone 50 mg.
	Type of Statistical Test	Other
	Comments	Per FDA guidance hyperplasia proportion must be <=1% with an upper bound of the one-sided 95% confidence interval <=4%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	incidence rate
	Estimated Value	0
	Confidence Interval	(1-Sided) 95%; to 0.97
	Parameter Dispersion	Type: Value:
	Estimation Comments	This calculation is based on a binomial distribution.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg
	Comments	Between group comparison is not intended. The purpose of the analysis is to calculate the incidence rate and the 95% CI of endometrial hyperplasia per FDA published guidance for Combined Estradiol 0.25 mg / Progesterone 50 mg.
	Type of Statistical Test	Other
	Comments	Per FDA guidance hyperplasia proportion must be <=1% with an upper bound of the one-sided 95% confidence interval <=4%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	incidence rate
	Estimated Value	0
	Confidence Interval	(1-Sided) 95%; to 1.09
	Parameter Dispersion	Type: Value:
	Estimation Comments	This calculation is based on a binomial distribution.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Placebo
	Comments	Between group comparison is not intended. The purpose of the analysis is to calculate the incidence rate and the 95% CI of endometrial hyperplasia per FDA published guidance for Placebo.
	Type of Statistical Test	Other
	Comments	Per FDA guidance hyperplasia proportion must be <=1% with an upper bound of the one-sided 95% confidence interval <=4%.
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	incidence rate
	Estimated Value	0
	Confidence Interval	(1-Sided) 95%; to 3.20
	Parameter Dispersion	Type: Value:
	Estimation Comments	This calculation is based on a binomial distribution.

7. Secondary Outcome

Title	Frequency of Moderate to Severe Vasomotor Symptoms - Week 1 (MITT-VMS)
Description	Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 1. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame	Baseline and Week 1

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	138	149	145	154	134
Mean (Standard Deviation) [weekly hot flushes]	-12.2 (20.10)	-11.5 (20.19)	-11.0 (20.94)	-16.3 (22.28)	-13.0 (21.25)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.588
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 1
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.36
	Confidence Interval	(2-Sided) 95%; -3.57 to 6.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.51
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.601
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 1
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.29
	Confidence Interval	(2-Sided) 95%; -3.56 to 6.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.47
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.202
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 1
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.17
	Confidence Interval	(2-Sided) 95%; -1.71 to 8.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.49
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.431
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 1
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.93
	Confidence Interval	(2-Sided) 95%; -6.76 to 2.89
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.46
	Estimation Comments	Adjusted for baseline using MMRM

8. Secondary Outcome

Title	Frequency of Moderate to Severe Vasomotor Symptoms - Week 2 (MITT-VMS)
Description	Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 2. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame	Baseline and Week 2

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	134	146	145	153	133
Mean (Standard Deviation) [weekly hot flushes]	-26.6 (27.67)	-21.2 (24.79)	-19.0 (28.32)	-25.4 (26.63)	-21.3 (24.75)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.154
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 2
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.35
	Confidence Interval	(2-Sided) 95%; -10.34 to 1.64
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.05
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.956
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 2
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -6.06 to 5.73
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.00
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.240
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 2
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.54
	Confidence Interval	(2-Sided) 95%; -2.37 to 9.46
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.01
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.353
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 2
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.77
	Confidence Interval	(2-Sided) 95%; -8.62 to 3.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.98
	Estimation Comments	Adjusted for baseline using MMRM

9. Secondary Outcome

Title	Frequency of Moderate to Severe Vasomotor Symptoms - Week 3 (MITT-VMS)
Description	Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 3. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame	Baseline and Week 3

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	136	144	144	153	131
Mean (Standard Deviation) [weekly hot flushes]	-34.3 (29.22)	-29.0 (26.73)	-28.1 (28.18)	-33.6 (27.76)	-25.1 (27.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 3
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-8.56
	Confidence Interval	(2-Sided) 95%; -14.75 to -2.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.16
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.227
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 3
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.76
	Confidence Interval	(2-Sided) 95%; -9.86 to 2.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.11
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.597
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 3
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.65
	Confidence Interval	(2-Sided) 95%; -7.77 to 4.47
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.12
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.019
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 3
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.24
	Confidence Interval	(2-Sided) 95%; -13.28 to -1.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.08
	Estimation Comments	Adjusted for baseline using MMRM

10. Secondary Outcome

Title	Frequency of Moderate to Severe Vasomotor Symptoms - Week 4 (MITT-VMS)
Description	Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 4. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	134	144	142	152	126
Mean (Standard Deviation) [weekly hot flushes]	-40.6 (30.59)	-35.1 (29.14)	-33.6 (30.64)	-38.9 (31.04)	-26.4 (27.05)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 4
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-12.81
	Confidence Interval	(2-Sided) 95%; -19.29 to -6.32
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.30
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 4
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-8.07
	Confidence Interval	(2-Sided) 95%; -14.46 to -1.68
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.25
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.141
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 4
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.81
	Confidence Interval	(2-Sided) 95%; -11.21 to 1.59
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.26
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 4
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-10.40
	Confidence Interval	(2-Sided) 95%; -16.73 to -4.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.22
	Estimation Comments	Adjusted for baseline using MMRM

11. Secondary Outcome

Title	Frequency of Moderate to Severe Vasomotor Symptoms - Week 5 (MITT-VMS)
Description	Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 5. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame	Baseline and Week 5

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	131	143	139	147	124
Mean (Standard Deviation) [weekly hot flushes]	-45.9 (32.31)	-39.5 (28.53)	-37.1 (30.64)	-43.5 (33.31)	-31.6 (28.96)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 5
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-15.59
	Confidence Interval	(2-Sided) 95%; -22.16 to -9.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.35
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 5
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-9.88
	Confidence Interval	(2-Sided) 95%; -16.34 to -3.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.29
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.075
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 5
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.90
	Confidence Interval	(2-Sided) 95%; -12.40 to 0.59
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.31
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 5
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-12.05
	Confidence Interval	(2-Sided) 95%; -18.47 to -5.64
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.27
	Estimation Comments	Adjusted for baseline using MMRM

12. Secondary Outcome

Title	Frequency of Moderate to Severe Vasomotor Symptoms - Week 6 (MITT-VMS)
Description	Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 6. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame	Baseline and Week 6

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	132	143	139	146	123
Mean (Standard Deviation) [weekly hot flushes]	-49.4 (32.76)	-41.7 (29.97)	-40.1 (33.62)	-45.5 (33.14)	-32.7 (28.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-17.87
	Confidence Interval	(2-Sided) 95%; -24.57 to -11.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.44
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-11.35
	Confidence Interval	(2-Sided) 95%; -18.00 to -4.70
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.39
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.022
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.82
	Confidence Interval	(2-Sided) 95%; -14.50 to -1.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.40
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-12.51
	Confidence Interval	(2-Sided) 95%; -19.11 to -5.91
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.36
	Estimation Comments	Adjusted for baseline using MMRM

13. Secondary Outcome

Title	Frequency of Moderate to Severe Vasomotor Symptoms - Week 7 (MITT-VMS)
Description	Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 7. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame	Baseline and Week 7

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	130	142	139	147	120
Mean (Standard Deviation) [weekly hot flushes]	-51.5 (31.51)	-45.0 (30.73)	-43.8 (33.20)	-47.7 (32.18)	-33.4 (29.37)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 7
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-17.75
	Confidence Interval	(2-Sided) 95%; -24.45 to -11.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.41
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 7
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-13.29
	Confidence Interval	(2-Sided) 95%; -19.88 to -6.70
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.36
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 7
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-10.22
	Confidence Interval	(2-Sided) 95%; -16.83 to -3.60
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.37
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 7
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-13.61
	Confidence Interval	(2-Sided) 95%; -20.15 to -7.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.33
	Estimation Comments	Adjusted for baseline using MMRM

14. Secondary Outcome

Title	Frequency of Moderate to Severe Vasomotor Symptoms - Week 8 (MITT-VMS)
Description	Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 8. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	129	140	137	147	120
Mean (Standard Deviation) [weekly hot flushes]	-52.3 (31.63)	-46.8 (30.64)	-45.4 (32.55)	-48.4 (32.82)	-36.0 (30.66)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 8
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-16.63
	Confidence Interval	(2-Sided) 95%; -23.35 to -9.91
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.42
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 8
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-12.97
	Confidence Interval	(2-Sided) 95%; -19.58 to -6.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.37
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 8
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-9.63
	Confidence Interval	(2-Sided) 95%; -16.27 to -2.99
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.38
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 8
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-11.97
	Confidence Interval	(2-Sided) 95%; -18.53 to -5.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.34
	Estimation Comments	Adjusted for baseline using MMRM

15. Secondary Outcome

Title	Frequency of Moderate to Severe Vasomotor Symptoms - Week 9 (MITT-VMS)
Description	Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 9. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame	Baseline and Week 9

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	124	137	132	141	119
Mean (Standard Deviation) [weekly hot flushes]	-52.6 (32.57)	-50.5 (31.01)	-47.4 (30.13)	-50.1 (33.92)	-36.4 (29.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 9
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-17.12
	Confidence Interval	(2-Sided) 95%; -23.79 to -10.44
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.40
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 9
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-15.58
	Confidence Interval	(2-Sided) 95%; -22.15 to -9.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.34
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 9
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-11.05
	Confidence Interval	(2-Sided) 95%; -17.65 to -4.44
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.36
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 9
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-13.02
	Confidence Interval	(2-Sided) 95%; -19.54 to -6.50
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.32
	Estimation Comments	Adjusted for baseline using MMRM

16. Secondary Outcome

Title	Frequency of Moderate to Severe Vasomotor Symptoms - Week 10 (MITT-VMS)
Description	Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 10. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame	Baseline and Week 10

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	126	133	129	140	118
Mean (Standard Deviation) [weekly hot flushes]	-53.2 (32.58)	-51.9 (32.79)	-49.0 (30.24)	-50.6 (33.36)	-37.1 (29.74)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 10
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-16.80
	Confidence Interval	(2-Sided) 95%; -23.58 to -10.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.45
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 10
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-15.66
	Confidence Interval	(2-Sided) 95%; -22.32 to -8.99
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.40
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 10
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-11.20
	Confidence Interval	(2-Sided) 95%; -17.90 to -4.49
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.41
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 10
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-12.16
	Confidence Interval	(2-Sided) 95%; -18.78 to -5.55
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.37
	Estimation Comments	Adjusted for baseline using MMRM

17. Secondary Outcome

Title	Frequency of Moderate to Severe Vasomotor Symptoms - Week 11 (MITT-VMS)
Description	Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 11. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame	Baseline and Week 11

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	126	134	129	137	118
Mean (Standard Deviation) [weekly hot flushes]	-53.7 (32.21)	-52.0 (31.24)	-49.4 (30.71)	-50.9 (34.33)	-36.7 (30.32)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 11
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-18.11
	Confidence Interval	(2-Sided) 95%; -24.92 to -11.29
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.47
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 11
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-16.45
	Confidence Interval	(2-Sided) 95%; -23.17 to -9.74
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.42
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 11
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-12.41
	Confidence Interval	(2-Sided) 95%; -19.15 to -5.66
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.44
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 11
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-13.60
	Confidence Interval	(2-Sided) 95%; -20.26 to -6.93
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.39
	Estimation Comments	Adjusted for baseline using MMRM

18. Secondary Outcome

Title	Frequency of Moderate to Severe Vasomotor Symptoms - Week 12 (MITT-VMS)
Description	Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 12. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of moderate to severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of moderate to severe hot flushes for the subject week.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	124	129	124	135	115
Mean (Standard Deviation) [weekly hot flushes]	-55.1 (31.36)	-53.7 (31.93)	-50.2 (31.35)	-52.4 (33.90)	-40.2 (29.79)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-16.58
	Confidence Interval	(2-Sided) 95%; -23.33 to -9.82
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.44
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-15.07
	Confidence Interval	(2-Sided) 95%; -21.72 to -8.42
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.39
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-10.79
	Confidence Interval	(2-Sided) 95%; -17.48 to -4.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.41
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-11.71
	Confidence Interval	(2-Sided) 95%; -18.31 to -5.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.36
	Estimation Comments	Adjusted for baseline using MMRM

19. Secondary Outcome

Title	Severity of Moderate to Severe Vasomotor Symptoms - Week 1 (MITT-VMS)
Description	Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 1. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame	Baseline and Week 1

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	138	149	145	154	134
Mean (Standard Deviation) [scores on a scale]	-0.24 (0.305)	-0.25 (0.270)	-0.23 (0.264)	-0.25 (0.327)	-0.25 (0.257)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.801
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 1
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.06 to 0.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.034
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.991
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 1
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 95%; -0.07 to 0.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.034
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.642
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 1
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.05 to 0.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.034
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.928
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 1
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.00
	Confidence Interval	(2-Sided) 95%; -0.07 to 0.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.034
	Estimation Comments	Adjusted for baseline using MMRM

20. Secondary Outcome

Title	Severity of Moderate to Severe Vasomotor Symptoms - Week 2 (MITT-VMS)
Description	Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 2. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame	Baseline and Week 2

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	134	146	145	153	133
Mean (Standard Deviation) [scores on a scale]	-0.34 (0.411)	-0.34 (0.390)	-0.27 (0.354)	-0.29 (0.314)	-0.28 (0.310)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.231
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 2
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.14 to 0.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.043
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.173
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 2
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.06
	Confidence Interval	(2-Sided) 95%; -0.14 to 0.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.042
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.717
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 2
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.07 to 0.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.042
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.849
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 2
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.09 to 0.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.042
	Estimation Comments	Adjusted for baseline using MMRM

21. Secondary Outcome

Title	Severity of Moderate to Severe Vasomotor Symptoms - Week 3 (MITT-VMS)
Description	Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 3. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame	Baseline and Week 3

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	136	144	144	153	131
Mean (Standard Deviation) [scores on a scale]	-0.43 (0.514)	-0.44 (0.437)	-0.32 (0.410)	-0.37 (0.424)	-0.32 (0.372)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.039
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 3
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.11
	Confidence Interval	(2-Sided) 95%; -0.21 to -0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.052
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.030
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 3
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.11
	Confidence Interval	(2-Sided) 95%; -0.21 to -0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.052
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.946
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 3
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.00
	Confidence Interval	(2-Sided) 95%; -0.10 to 0.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.052
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.309
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 3
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.15 to 0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.051
	Estimation Comments	Adjusted for baseline using MMRM

22. Secondary Outcome

Title	Severity of Moderate to Severe Vasomotor Symptoms - Week 4 (MITT-VMS)
Description	Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 4. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	134	144	142	152	126
Mean (Standard Deviation) [scores on a scale]	-0.48 (0.547)	-0.51 (0.563)	-0.40 (0.469)	-0.44 (0.514)	-0.34 (0.386)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.031
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 4
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95%; -0.25 to -0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.061
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 4
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -0.28 to -0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.060
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.401
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 4
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.17 to 0.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.060
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.100
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 4
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.21 to 0.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.059
	Estimation Comments	Adjusted for baseline using MMRM

23. Secondary Outcome

Title	Severity of Moderate to Severe Vasomotor Symptoms - Week 5 (MITT-VMS)
Description	Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 5. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame	Baseline and Week 5

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	131	143	139	147	124
Mean (Standard Deviation) [scores on a scale]	-0.64 (0.702)	-0.56 (0.558)	-0.44 (0.463)	-0.53 (0.610)	-0.42 (0.551)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 5
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.23
	Confidence Interval	(2-Sided) 95%; -0.37 to -0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.071
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.034
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 5
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 95%; -0.28 to -0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.070
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.790
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 5
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -0.16 to 0.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.070
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.086
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 5
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95%; -0.25 to 0.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.069
	Estimation Comments	Adjusted for baseline using MMRM

24. Secondary Outcome

Title	Severity of Moderate to Severe Vasomotor Symptoms - Week 6 (MITT-VMS)
Description	Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 6. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame	Baseline and Week 6

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	132	143	139	146	123
Mean (Standard Deviation) [scores on a scale]	-0.80 (0.840)	-0.61 (0.640)	-0.54 (0.578)	-0.63 (0.763)	-0.45 (0.573)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.36
	Confidence Interval	(2-Sided) 95%; -0.53 to -0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.084
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.030
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.18
	Confidence Interval	(2-Sided) 95%; -0.34 to -0.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.083
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.247
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.26 to 0.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.083
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.022
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.19
	Confidence Interval	(2-Sided) 95%; -0.35 to -0.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.082
	Estimation Comments	Adjusted for baseline using MMRM

25. Secondary Outcome

Title	Severity of Moderate to Severe Vasomotor Symptoms - Week 7 (MITT-VMS)
Description	Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 7. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame	Baseline and Week 7

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	130	142	139	147	120
Mean (Standard Deviation) [scores on a scale]	-0.81 (0.793)	-0.69 (0.694)	-0.63 (0.637)	-0.64 (0.764)	-0.44 (0.483)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 7
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.37
	Confidence Interval	(2-Sided) 95%; -0.54 to -0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.085
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 7
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.25
	Confidence Interval	(2-Sided) 95%; -0.42 to -0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.083
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.031
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 7
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.18
	Confidence Interval	(2-Sided) 95%; -0.34 to -0.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.084
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.016
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 7
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.20
	Confidence Interval	(2-Sided) 95%; -0.36 to -0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.083
	Estimation Comments	Adjusted for baseline using MMRM

26. Secondary Outcome

Title	Severity of Moderate to Severe Vasomotor Symptoms - Week 8 (MITT-VMS)
Description	Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 8. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	129	140	137	147	120
Mean (Standard Deviation) [scores on a scale]	-0.88 (0.854)	-0.70 (0.642)	-0.65 (0.685)	-0.64 (0.745)	-0.51 (0.563)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 8
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.38
	Confidence Interval	(2-Sided) 95%; -0.55 to -0.21
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.087
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 8
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.23
	Confidence Interval	(2-Sided) 95%; -0.40 to -0.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.086
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.087
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 8
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 95%; -0.32 to 0.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.086
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.092
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 8
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95%; -0.31 to 0.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.085
	Estimation Comments	Adjusted for baseline using MMRM

27. Secondary Outcome

Title	Severity of Moderate to Severe Vasomotor Symptoms - Week 9 (MITT-VMS)
Description	Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 9. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame	Baseline and Week 9

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	124	137	132	141	119
Mean (Standard Deviation) [scores on a scale]	-0.96 (0.892)	-0.74 (0.699)	-0.73 (0.720)	-0.71 (0.772)	-0.48 (0.536)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 9
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.48
	Confidence Interval	(2-Sided) 95%; -0.66 to -0.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.092
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 9
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.29
	Confidence Interval	(2-Sided) 95%; -0.47 to -0.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.090
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 9
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.24
	Confidence Interval	(2-Sided) 95%; -0.42 to -0.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.091
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 9
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.24
	Confidence Interval	(2-Sided) 95%; -0.42 to -0.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.090
	Estimation Comments	Adjusted for baseline using MMRM

28. Secondary Outcome

Title	Severity of Moderate to Severe Vasomotor Symptoms - Week 10 (MITT-VMS)
Description	Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 10. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame	Baseline and Week 10

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	126	133	129	140	118
Mean (Standard Deviation) [scores on a scale]	-1.05 (0.953)	-0.77 (0.727)	-0.78 (0.769)	-0.62 (0.739)	-0.53 (0.575)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 10
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.52
	Confidence Interval	(2-Sided) 95%; -0.71 to -0.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.096
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 10
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.28
	Confidence Interval	(2-Sided) 95%; -0.46 to -0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.094
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.016
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 10
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.23
	Confidence Interval	(2-Sided) 95%; -0.41 to -0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.095
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.310
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 10
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.28 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.094
	Estimation Comments	Adjusted for baseline using MMRM

29. Secondary Outcome

Title	Severity of Moderate to Severe Vasomotor Symptoms - Week 11 (MITT-VMS)
Description	Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 11. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame	Baseline and Week 11

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	126	134	129	137	118
Mean (Standard Deviation) [scores on a scale]	-1.04 (0.931)	-0.86 (0.777)	-0.78 (0.782)	-0.68 (0.767)	-0.54 (0.566)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 11
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.53
	Confidence Interval	(2-Sided) 95%; -0.72 to -0.34
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.098
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 11
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.37
	Confidence Interval	(2-Sided) 95%; -0.56 to -0.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.096
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 11
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.25
	Confidence Interval	(2-Sided) 95%; -0.44 to -0.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.097
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.076
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 11
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -0.36 to 0.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.096
	Estimation Comments	Adjusted for baseline using MMRM

30. Secondary Outcome

Title	Severity of Moderate to Severe Vasomotor Symptoms - Week 12 (MITT-VMS)
Description	Mean change in severity of moderate to severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 12. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score = (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of moderate to severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	124	129	124	135	115
Mean (Standard Deviation) [scores on a scale]	-1.12 (0.963)	-0.90 (0.783)	-0.76 (0.744)	-0.71 (0.806)	-0.56 (0.603)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.57
	Confidence Interval	(2-Sided) 95%; -0.77 to -0.38
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.100
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.39
	Confidence Interval	(2-Sided) 95%; -0.59 to -0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.099
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.018
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.24
	Confidence Interval	(2-Sided) 95%; -0.43 to -0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.100
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.096
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.16
	Confidence Interval	(2-Sided) 95%; -0.36 to 0.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.098
	Estimation Comments	Adjusted for baseline using MMRM

31. Secondary Outcome

Title	Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 1 (MITT-VMS)
Description	Mean change in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 1. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of mild, moderate and severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of mild, moderate and severe hot flushes for the subject week.
Time Frame	Baseline and Week 1

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	138	149	145	154	134
Mean (Standard Deviation) [weekly hot flushes]	-12.9 (22.12)	-12.4 (23.94)	-12.5 (24.62)	-17.7 (27.78)	-12.2 (23.76)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.865
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 1
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.49
	Confidence Interval	(2-Sided) 95%; -5.16 to 6.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.88
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.847
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 1
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.55
	Confidence Interval	(2-Sided) 95%; -5.01 to 6.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.83
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.463
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 1
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.09
	Confidence Interval	(2-Sided) 95%; -3.50 to 7.68
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.85
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.207
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 1
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.55
	Confidence Interval	(2-Sided) 95%; -9.07 to 1.97
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.81
	Estimation Comments	Adjusted for baseline using MMRM

32. Secondary Outcome

Title	Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 2 (MITT-VMS)
Description	Mean change in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 2. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of mild, moderate and severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of mild, moderate and severe hot flushes for the subject week.
Time Frame	Baseline and Week 2

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	134	146	145	153	133
Mean (Standard Deviation) [weekly hot flushes]	-28.2 (29.45)	-22.4 (30.53)	-21.8 (31.66)	-27.8 (32.35)	-21.7 (27.45)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.140
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 2
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.07
	Confidence Interval	(2-Sided) 95%; -11.80 to 1.67
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.43
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.982
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 2
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -6.70 to 6.55
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.38
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.492
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 2
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.33
	Confidence Interval	(2-Sided) 95%; -4.32 to 8.98
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.39
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.216
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 2
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.14
	Confidence Interval	(2-Sided) 95%; -10.72 to 2.43
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.35
	Estimation Comments	Adjusted for baseline using MMRM

33. Secondary Outcome

Title	Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 3 (MITT-VMS)
Description	Mean change in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 3. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of mild, moderate and severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of mild, moderate and severe hot flushes for the subject week.
Time Frame	Baseline and Week 3

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	136	144	144	153	131
Mean (Standard Deviation) [weekly hot flushes]	-37.4 (32.33)	-30.7 (32.00)	-31.3 (30.79)	-35.6 (33.52)	-25.8 (30.41)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 3
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-10.38
	Confidence Interval	(2-Sided) 95%; -17.26 to -3.50
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.50
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.277
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 3
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.75
	Confidence Interval	(2-Sided) 95%; -10.53 to 3.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.45
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.394
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 3
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.95
	Confidence Interval	(2-Sided) 95%; -9.75 to 3.84
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.46
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.022
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 3
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.86
	Confidence Interval	(2-Sided) 95%; -14.58 to -1.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.42
	Estimation Comments	Adjusted for baseline using MMRM

34. Secondary Outcome

Title	Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 4 (MITT-VMS)
Description	Mean change in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 4. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of mild, moderate and severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of mild, moderate and severe hot flushes for the subject week.
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	134	144	142	152	126
Mean (Standard Deviation) [weekly hot flushes]	-44.4 (34.53)	-37.7 (35.38)	-35.4 (34.58)	-41.5 (37.40)	-26.8 (30.52)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 4
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-15.32
	Confidence Interval	(2-Sided) 95%; -22.75 to -7.89
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.78
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.017
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 4
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-8.92
	Confidence Interval	(2-Sided) 95%; -16.24 to -1.60
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.73
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.223
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 4
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.56
	Confidence Interval	(2-Sided) 95%; -11.90 to 2.78
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.74
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 4
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-11.32
	Confidence Interval	(2-Sided) 95%; -18.57 to -4.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.69
	Estimation Comments	Adjusted for baseline using MMRM

35. Secondary Outcome

Title	Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 5 (MITT-VMS)
Description	Mean change in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 5. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of mild, moderate and severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of mild, moderate and severe hot flushes for the subject week.
Time Frame	Baseline and Week 5

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	131	143	139	147	124
Mean (Standard Deviation) [weekly hot flushes]	-49.9 (33.86)	-42.3 (34.15)	-40.1 (32.52)	-46.8 (39.88)	-33.3 (33.49)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 5
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-17.47
	Confidence Interval	(2-Sided) 95%; -24.65 to -10.28
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.66
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 5
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-10.26
	Confidence Interval	(2-Sided) 95%; -17.33 to -3.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.60
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.087
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 5
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.21
	Confidence Interval	(2-Sided) 95%; -13.31 to 0.89
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.62
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 5
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-12.66
	Confidence Interval	(2-Sided) 95%; -19.68 to -5.65
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.57
	Estimation Comments	Adjusted for baseline using MMRM

36. Secondary Outcome

Title	Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 6 (MITT-VMS)
Description	Mean change in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 6. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of mild, moderate and severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of mild, moderate and severe hot flushes for the subject week.
Time Frame	Baseline and Week 6

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	132	143	139	146	123
Mean (Standard Deviation) [weekly hot flushes]	-53.9 (35.34)	-44.9 (36.12)	-43.0 (34.84)	-49.4 (40.28)	-34.1 (33.32)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-20.32
	Confidence Interval	(2-Sided) 95%; -27.77 to -12.87
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.80
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-12.61
	Confidence Interval	(2-Sided) 95%; -19.95 to -5.28
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.73
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.027
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-8.33
	Confidence Interval	(2-Sided) 95%; -15.70 to -0.96
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.75
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-13.85
	Confidence Interval	(2-Sided) 95%; -21.13 to -6.58
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.71
	Estimation Comments	Adjusted for baseline using MMRM

37. Secondary Outcome

Title	Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 7 (MITT-VMS)
Description	Mean change in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 7. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of mild, moderate and severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of mild, moderate and severe hot flushes for the subject week.
Time Frame	Baseline and Week 7

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	130	142	139	147	120
Mean (Standard Deviation) [weekly hot flushes]	-56.1 (34.55)	-48.8 (36.92)	-47.2 (34.39)	-51.5 (39.69)	-33.4 (33.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 7
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-21.45
	Confidence Interval	(2-Sided) 95%; -28.87 to -14.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.78
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 7
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-16.10
	Confidence Interval	(2-Sided) 95%; -23.39 to -8.80
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.71
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 7
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-12.01
	Confidence Interval	(2-Sided) 95%; -19.34 to -4.68
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.73
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 7
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-15.73
	Confidence Interval	(2-Sided) 95%; -22.97 to -8.49
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.69
	Estimation Comments	Adjusted for baseline using MMRM

38. Secondary Outcome

Title	Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 8 (MITT-VMS)
Description	Mean change in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 8. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of mild, moderate and severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of mild, moderate and severe hot flushes for the subject week.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	129	140	137	147	120
Mean (Standard Deviation) [weekly hot flushes]	-57.1 (35.91)	-50.6 (37.73)	-49.5 (34.34)	-52.4 (40.65)	-36.9 (35.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 8
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-20.52
	Confidence Interval	(2-Sided) 95%; -28.06 to -12.97
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.84
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 8
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-15.37
	Confidence Interval	(2-Sided) 95%; -22.80 to -7.95
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.78
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 8
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-11.49
	Confidence Interval	(2-Sided) 95%; -18.95 to -4.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.80
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 8
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-13.82
	Confidence Interval	(2-Sided) 95%; -21.19 to -6.46
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.75
	Estimation Comments	Adjusted for baseline using MMRM

39. Secondary Outcome

Title	Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 9 (MITT-VMS)
Description	Mean change in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 9. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of mild, moderate and severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of mild, moderate and severe hot flushes for the subject week.
Time Frame	Baseline and Week 9

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	124	137	132	141	119
Mean (Standard Deviation) [weekly hot flushes]	-57.6 (36.43)	-54.7 (38.76)	-52.8 (33.68)	-54.5 (41.89)	-38.3 (35.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 9
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-20.34
	Confidence Interval	(2-Sided) 95%; -27.93 to -12.74
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.87
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 9
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-17.92
	Confidence Interval	(2-Sided) 95%; -25.39 to -10.45
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.80
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 9
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-12.97
	Confidence Interval	(2-Sided) 95%; -20.49 to -5.46
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.82
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 9
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-14.28
	Confidence Interval	(2-Sided) 95%; -21.70 to -6.87
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.78
	Estimation Comments	Adjusted for baseline using MMRM

40. Secondary Outcome

Title	Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 10 (MITT-VMS)
Description	Mean change in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 10. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of mild, moderate and severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of mild, moderate and severe hot flushes for the subject week.
Time Frame	Baseline and Week 10

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	126	133	129	140	118
Mean (Standard Deviation) [weekly hot flushes]	-58.5 (36.86)	-56.1 (39.97)	-53.7 (34.39)	-55.7 (41.55)	-38.3 (35.52)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 10
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-21.01
	Confidence Interval	(2-Sided) 95%; -28.72 to -13.29
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.93
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 10
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-18.37
	Confidence Interval	(2-Sided) 95%; -25.96 to -10.78
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.87
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 10
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-13.03
	Confidence Interval	(2-Sided) 95%; -20.66 to -5.39
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.89
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 10
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-14.65
	Confidence Interval	(2-Sided) 95%; -22.19 to -7.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.84
	Estimation Comments	Adjusted for baseline using MMRM

41. Secondary Outcome

Title	Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 11 (MITT-VMS)
Description	Mean change in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 11. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of mild, moderate and severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of mild, moderate and severe hot flushes for the subject week.
Time Frame	Baseline and Week 11

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	126	134	129	137	118
Mean (Standard Deviation) [weekly hot flushes]	-58.8 (36.58)	-57.0 (38.81)	-54.2 (34.38)	-56.1 (42.45)	-38.4 (35.85)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 11
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-21.83
	Confidence Interval	(2-Sided) 95%; -29.57 to -14.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.94
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 11
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-19.40
	Confidence Interval	(2-Sided) 95%; -27.02 to -11.77
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.88
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 11
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-13.98
	Confidence Interval	(2-Sided) 95%; -21.65 to -6.32
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.90
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 11
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-15.66
	Confidence Interval	(2-Sided) 95%; -23.23 to -8.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.85
	Estimation Comments	Adjusted for baseline using MMRM

42. Secondary Outcome

Title	Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 12 (MITT-VMS)
Description	Mean change in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 12. The baseline was the most recent 7 consecutive days of data prior to randomization. The weekly frequency of mild, moderate and severe hot flushes was calculated from the daily diary record using a forward counting process of 7 day intervals beginning with the baseline date. Weekly frequency equals total number of mild, moderate and severe hot flushes for the subject week.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	124	129	124	135	115
Mean (Standard Deviation) [weekly hot flushes]	-60.3 (36.42)	-58.8 (39.59)	-54.8 (34.94)	-57.0 (41.71)	-41.7 (36.35)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-20.61
	Confidence Interval	(2-Sided) 95%; -28.32 to -12.89
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.93
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-18.24
	Confidence Interval	(2-Sided) 95%; -25.84 to -10.65
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.87
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-12.62
	Confidence Interval	(2-Sided) 95%; -20.26 to -4.98
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.89
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-13.97
	Confidence Interval	(2-Sided) 95%; -21.51 to -6.43
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.84
	Estimation Comments	Adjusted for baseline using MMRM

43. Secondary Outcome

Title	Severity of Mild, Moderate and Severe Vasomotor Symptoms - Week 1 (MITT-VMS)
Description	Mean change in severity of mild, moderate and severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 1. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score =(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame	Baseline and Week 1

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	138	149	145	154	134
Mean (Standard Deviation) [scores on a scale]	-0.06 (0.211)	-0.05 (0.206)	-0.02 (0.197)	-0.08 (0.305)	-0.07 (0.200)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.676
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 1
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.04 to 0.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.027
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.436
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 1
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.03 to 0.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.027
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.106
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 1
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -0.01 to 0.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.027
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.752
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 1
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.06 to 0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.027
	Estimation Comments	Adjusted for baseline using MMRM

44. Secondary Outcome

Title	Severity of Mild, Moderate and Severe Vasomotor Symptoms - Week 2 (MITT-VMS)
Description	Mean change in severity of mild, moderate and severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 2. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score =(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame	Baseline and Week 2

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	134	146	145	153	133
Mean (Standard Deviation) [scores on a scale]	-0.16 (0.349)	-0.14 (0.342)	-0.06 (0.309)	-0.12 (0.288)	-0.11 (0.275)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.193
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 2
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.12 to 0.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.038
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.319
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 2
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -0.11 to 0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.037
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.239
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 2
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -0.03 to 0.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.037
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.720
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 2
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.09 to 0.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.037
	Estimation Comments	Adjusted for baseline using MMRM

45. Secondary Outcome

Title	Severity of Mild, Moderate and Severe Vasomotor Symptoms - Week 3 (MITT-VMS)
Description	Mean change in severity of mild, moderate and severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 3. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score =(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame	Baseline and Week 3

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	136	144	144	153	131
Mean (Standard Deviation) [scores on a scale]	-0.25 (0.480)	-0.24 (0.402)	-0.11 (0.379)	-0.20 (0.412)	-0.15 (0.350)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.030
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 3
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.11
	Confidence Interval	(2-Sided) 95%; -0.20 to -0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.049
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.060
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 3
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -0.19 to 0.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.048
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.506
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 3
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 95%; -0.06 to 0.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.048
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.232
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 3
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.06
	Confidence Interval	(2-Sided) 95%; -0.15 to 0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.048
	Estimation Comments	Adjusted for baseline using MMRM

46. Secondary Outcome

Title	Severity of Mild, Moderate and Severe Vasomotor Symptoms - Week 4 (MITT-VMS)
Description	Mean change in severity of mild, moderate and severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 4. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score =(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	134	144	142	152	126
Mean (Standard Deviation) [scores on a scale]	-0.31 (0.527)	-0.31 (0.540)	-0.19 (0.434)	-0.27 (0.507)	-0.17 (0.368)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.027
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 4
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95%; -0.24 to -0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.058
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 4
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 95%; -0.26 to -0.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.057
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.710
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 4
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -0.13 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.057
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.072
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 4
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.21 to 0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.057
	Estimation Comments	Adjusted for baseline using MMRM

47. Secondary Outcome

Title	Severity of Mild, Moderate and Severe Vasomotor Symptoms - Week 5 (MITT-VMS)
Description	Mean change in severity of mild, moderate and severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 5. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score =(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame	Baseline and Week 5

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	131	143	139	147	124
Mean (Standard Deviation) [scores on a scale]	-0.46 (0.680)	-0.37 (0.546)	-0.23 (0.441)	-0.36 (0.619)	-0.24 (0.524)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 5
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.23
	Confidence Interval	(2-Sided) 95%; -0.36 to -0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.069
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.062
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 5
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95%; -0.26 to 0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.068
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.886
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 5
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.12 to 0.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.068
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.067
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 5
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95%; -0.26 to 0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.067
	Estimation Comments	Adjusted for baseline using MMRM

48. Secondary Outcome

Title	Severity of Mild, Moderate and Severe Vasomotor Symptoms - Week 6 (MITT-VMS)
Description	Mean change in severity of mild, moderate and severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 6. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score =(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame	Baseline and Week 6

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	132	143	139	146	123
Mean (Standard Deviation) [scores on a scale]	-0.62 (0.835)	-0.42 (0.627)	-0.33 (0.588)	-0.46 (0.775)	-0.27 (0.548)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.36
	Confidence Interval	(2-Sided) 95%; -0.53 to -0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.084
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.053
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.16
	Confidence Interval	(2-Sided) 95%; -0.32 to 0.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.082
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.413
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.07
	Confidence Interval	(2-Sided) 95%; -0.23 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.083
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.018
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.19
	Confidence Interval	(2-Sided) 95%; -0.35 to -0.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.082
	Estimation Comments	Adjusted for baseline using MMRM

49. Secondary Outcome

Title	Severity of Mild, Moderate and Severe Vasomotor Symptoms - Week 7 (MITT-VMS)
Description	Mean change in severity of mild, moderate and severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 7. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score =(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame	Baseline and Week 7

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	130	142	139	147	120
Mean (Standard Deviation) [scores on a scale]	-0.65 (0.798)	-0.50 (0.687)	-0.42 (0.660)	-0.47 (0.773)	-0.27 (0.469)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 7
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.37
	Confidence Interval	(2-Sided) 95%; -0.54 to -0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.085
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 7
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.23
	Confidence Interval	(2-Sided) 95%; -0.40 to -0.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.083
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.072
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 7
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 95%; -0.32 to 0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.084
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.014
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 7
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.20
	Confidence Interval	(2-Sided) 95%; -0.37 to -0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.083
	Estimation Comments	Adjusted for baseline using MMRM

50. Secondary Outcome

Title	Severity of Mild, Moderate and Severe Vasomotor Symptoms - Week 8 (MITT-VMS)
Description	Mean change in severity of mild, moderate and severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 8. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score =(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	129	140	137	147	120
Mean (Standard Deviation) [scores on a scale]	-0.70 (0.858)	-0.51 (0.633)	-0.44 (0.701)	-0.47 (0.750)	-0.33 (0.545)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 8
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.38
	Confidence Interval	(2-Sided) 95%; -0.55 to -0.21
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.087
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.016
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 8
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.21
	Confidence Interval	(2-Sided) 95%; -0.37 to -0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.085
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.169
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 8
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95%; -0.29 to 0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.086
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.081
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 8
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 95%; -0.31 to 0.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.085
	Estimation Comments	Adjusted for baseline using MMRM

51. Secondary Outcome

Title	Severity of Mild, Moderate and Severe Vasomotor Symptoms - Week 9 (MITT-VMS)
Description	Mean change in severity of mild, moderate and severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 9. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score =(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame	Baseline and Week 9

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	124	137	132	141	119
Mean (Standard Deviation) [scores on a scale]	-0.78 (0.909)	-0.55 (0.708)	-0.51 (0.735)	-0.54 (0.780)	-0.31 (0.515)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 9
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.48
	Confidence Interval	(2-Sided) 95%; -0.66 to -0.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.092
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 9
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.27
	Confidence Interval	(2-Sided) 95%; -0.45 to -0.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.091
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.022
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 9
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.21
	Confidence Interval	(2-Sided) 95%; -0.39 to -0.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.091
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 9
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.25
	Confidence Interval	(2-Sided) 95%; -0.43 to -0.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.090
	Estimation Comments	Adjusted for baseline using MMRM

52. Secondary Outcome

Title	Severity of Mild, Moderate and Severe Vasomotor Symptoms - Week 10 (MITT-VMS)
Description	Mean change in severity of mild, moderate and severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 10. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score =(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame	Baseline and Week 10

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	126	133	129	140	118
Mean (Standard Deviation) [scores on a scale]	-0.87 (0.970)	-0.58 (0.731)	-0.57 (0.785)	-0.45 (0.754)	-0.35 (0.557)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 10
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.52
	Confidence Interval	(2-Sided) 95%; -0.71 to -0.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.096
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 10
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.26
	Confidence Interval	(2-Sided) 95%; -0.44 to -0.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.095
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.038
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 10
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.20
	Confidence Interval	(2-Sided) 95%; -0.39 to -0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.095
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.283
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 10
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.29 to 0.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.094
	Estimation Comments	Adjusted for baseline using MMRM

53. Secondary Outcome

Title	Severity of Mild, Moderate and Severe Vasomotor Symptoms - Week 11 (MITT-VMS)
Description	Mean change in severity of mild, moderate and severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 11. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score =(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame	Baseline and Week 11

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	126	134	129	137	118
Mean (Standard Deviation) [scores on a scale]	-0.86 (0.950)	-0.67 (0.788)	-0.56 (0.800)	-0.50 (0.776)	-0.36 (0.543)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 11
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.53
	Confidence Interval	(2-Sided) 95%; -0.72 to -0.34
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.099
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 11
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.35
	Confidence Interval	(2-Sided) 95%; -0.54 to -0.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.097
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.027
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 11
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.22
	Confidence Interval	(2-Sided) 95%; -0.41 to -0.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.098
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.071
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 11
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -0.36 to 0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.096
	Estimation Comments	Adjusted for baseline using MMRM

54. Secondary Outcome

Title	Severity of Mild, Moderate and Severe Vasomotor Symptoms - Week 12 (MITT-VMS)
Description	Mean change in severity of mild, moderate and severe vasomotor symptoms at Baseline to mild, moderate to severe vasomotor symptoms at Week 12. The baseline was the most recent 7 consecutive days of data prior to randomization. The severity score was derived as follows: mild = 1, moderate = 2, severe = 3. Baseline Weekly Severity Score =(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days). On Treatment Weekly Severity Score = [(number of mild hot flushes for 7 days) x 1 + (number of moderate hot flushes for 7 days) x 2 + (number of severe hot flushes for 7 days) x 3] / (total number of mild, moderate and severe hot flushes over 7 days).
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	124	129	124	135	115
Mean (Standard Deviation) [scores on a scale]	-0.94 (0.986)	-0.71 (0.784)	-0.54 (0.761)	-0.54 (0.824)	-0.39 (0.585)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.57
	Confidence Interval	(2-Sided) 95%; -0.77 to -0.37
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.101
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.37
	Confidence Interval	(2-Sided) 95%; -0.57 to -0.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.100
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.039
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.21
	Confidence Interval	(2-Sided) 95%; -0.40 to -0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.100
	Estimation Comments	Adjusted for baseline using MMRM

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.088
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -0.36 to 0.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.099
	Estimation Comments	Adjusted for baseline using MMRM

55. Secondary Outcome

Title	Reduction of Frequency of Moderate to Severe Vasomotor Symptoms - Week 1 (MITT-VMS)
Description	Number of Subjects with >=50%, and separately, >=75% reduction in frequency of moderate to severe VMS from Baseline to Week 1.
Time Frame	Baseline and Week 1

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	137	149	145	154	134
>=50% Reduction	15 3.6%	17 4%	15 3.6%	25 5.9%	16 10.6%
>=75% Reduction	3 0.7%	4 0.9%	4 1%	5 1.2%	1 0.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.850
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 1
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.622
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 1
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 1
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.374
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 1
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.706
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 1
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.372
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 1
	Method	Fisher Exact
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.316
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 1
	Method	Fisher Exact
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.221
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 1
	Method	Fisher Exact
	Comments

56. Secondary Outcome

Title	Reduction of Frequency of Moderate to Severe Vasomotor Symptoms - Week 2 (MITT-VMS)
Description	Number of Subjects with >=50%, and separately, >=75% reduction in frequency of moderate to severe vasomotor symptoms from Baseline to Week 2.
Time Frame	Baseline and Week 2

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	133	146	145	153	133
>=50% Reduction	44 10.6%	35 8.3%	34 8.1%	49 11.6%	35 23.2%
>=75% Reduction	21 5.1%	12 2.8%	15 3.6%	20 4.7%	6 4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.283
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 2
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 2
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.680
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 2
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.232
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 2
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.677
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 2
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.073
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 2
	Method	Fisher Exact
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.301
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 2
	Method	Fisher Exact
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 2
	Method	Fisher Exact
	Comments

57. Secondary Outcome

Title	Reduction of Frequency of Moderate to Severe Vasomotor Symptoms - Week 3 (MITT-VMS)
Description	Number of Subjects with >=50%, and separately, >=75% reduction in frequency of moderate to severe vasomotor symptoms from Baseline to Week 3.
Time Frame	Baseline and Week 3

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	135	144	144	153	131
>=50% Reduction	68 16.4%	59 13.9%	54 12.8%	71 16.7%	42 27.8%
>=75% Reduction	38 9.2%	24 5.7%	21 5%	29 6.8%	15 9.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 3
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 3
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.135
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 3
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.231
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 3
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.377
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 3
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.478
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 3
	Method	Fisher Exact
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.015
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 3
	Method	Fisher Exact
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.100
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 3
	Method	Fisher Exact
	Comments

58. Secondary Outcome

Title	Reduction of Frequency of Moderate to Severe Vasomotor Symptoms - Week 4 (MITT-VMS)
Description	Number of Subjects with >=50%, and separately, >=75% reduction in frequency of moderate to severe vasomotor symptoms from Baseline to Week 4.
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	133	144	142	152	126
>=50% Reduction	82 19.8%	70 16.5%	74 17.6%	81 19.1%	41 27.2%
>=75% Reduction	55 13.3%	34 8%	32 7.6%	45 10.6%	15 9.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 4
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 4
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 4
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.017
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 4
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 4
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.025
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 4
	Method	Fisher Exact
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 4
	Method	Fisher Exact
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 4
	Method	Fisher Exact
	Comments

59. Secondary Outcome

Title	Reduction of Frequency of Moderate to Severe Vasomotor Symptoms - Week 5 (MITT-VMS)
Description	Number of Subjects with >=50%, and separately, >=75% reduction in frequency of moderate to severe vasomotor symptoms from Baseline to Week 5.
Time Frame	Baseline and Week 5

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	130	143	139	147	124
>=50% Reduction	93 22.4%	80 18.9%	74 17.6%	90 21.2%	55 36.4%
>=75% Reduction	55 13.3%	47 11.1%	38 9%	54 12.7%	27 17.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 5
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 5
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.066
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 5
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.055
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 5
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.174
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 5
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.319
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 5
	Method	Fisher Exact
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 5
	Method	Fisher Exact
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 5
	Method	Fisher Exact
	Comments

60. Secondary Outcome

Title	Reduction of Frequency of Moderate to Severe Vasomotor Symptoms - Week 6 (MITT-VMS)
Description	Number of Subjects with >=50%, and separately, >=75% reduction in frequency of moderate to severe vasomotor symptoms from Baseline to Week 6.
Time Frame	Baseline and Week 6

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	131	143	139	146	123
>=50% Reduction	98 23.6%	85 20%	82 19.5%	95 22.4%	55 36.4%
>=75% Reduction	68 16.4%	51 12%	47 11.2%	56 13.2%	30 19.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 6
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 6
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.019
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 6
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.061
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 6
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.026
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 6
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.104
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 6
	Method	Fisher Exact
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 6
	Method	Fisher Exact
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.018
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 6
	Method	Fisher Exact
	Comments

61. Secondary Outcome

Title	Reduction of Frequency of Moderate to Severe Vasomotor Symptoms - Week 7 (MITT-VMS)
Description	Number of Subjects with >=50%, and separately, >=75% reduction in frequency of moderate to severe vasomotor symptoms from Baseline to Week 7.
Time Frame	Baseline and Week 7

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	129	142	139	147	120
>=50% Reduction	96 23.1%	93 21.9%	88 20.9%	101 23.8%	58 38.4%
>=75% Reduction	71 17.1%	63 14.9%	56 13.3%	58 13.7%	32 21.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 7
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 7
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 7
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 7
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.017
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 7
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.025
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 7
	Method	Fisher Exact
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 7
	Method	Fisher Exact
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.037
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 7
	Method	Fisher Exact
	Comments

62. Secondary Outcome

Title	Reduction of Frequency of Moderate to Severe Vasomotor Symptoms - Week 8 (MITT-VMS)
Description	Number of Subjects with >=50%, and separately, >=75% reduction in frequency of moderate to severe vasomotor symptoms from Baseline to Week 8.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	129	140	137	147	120
>=50% Reduction	102 24.6%	98 23.1%	90 21.4%	100 23.6%	60 39.7%
>=75% Reduction	78 18.8%	64 15.1%	59 14%	62 14.6%	37 24.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 8
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 8
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 8
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.016
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 8
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.012
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 8
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.053
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 8
	Method	Fisher Exact
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 8
	Method	Fisher Exact
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.074
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 8
	Method	Fisher Exact
	Comments

63. Secondary Outcome

Title	Reduction of Frequency of Moderate to Severe Vasomotor Symptoms - Week 9 (MITT-VMS)
Description	Number of Subjects with >=50%, and separately, >=75% reduction in frequency of moderate to severe vasomotor symptoms from Baseline to Week 9.
Time Frame	Baseline and Week 9

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	124	137	132	141	119
>=50% Reduction	98 23.6%	107 25.2%	92 21.9%	101 23.8%	63 41.7%
>=75% Reduction	72 17.3%	73 17.2%	63 15%	63 14.9%	35 23.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 9
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 9
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 9
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 9
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 9
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 9
	Method	Fisher Exact
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 9
	Method	Fisher Exact
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.015
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 9
	Method	Fisher Exact
	Comments

64. Secondary Outcome

Title	Reduction of Frequency of Moderate to Severe Vasomotor Symptoms - Week 10 (MITT-VMS)
Description	Number of Subjects with >=50%, and separately, >=75% reduction in frequency of moderate to severe vasomotor symptoms from Baseline to Week 10.
Time Frame	Baseline and Week 10

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	126	133	129	140	118
>=50% Reduction	95 22.9%	102 24.1%	100 23.8%	101 23.8%	68 45%
>=75% Reduction	78 18.8%	69 16.3%	62 14.7%	64 15.1%	37 24.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 10
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 10
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 10
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 10
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 10
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 10
	Method	Fisher Exact
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.018
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 10
	Method	Fisher Exact
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.021
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 10
	Method	Fisher Exact
	Comments

65. Secondary Outcome

Title	Reduction of Frequency of Moderate to Severe Vasomotor Symptoms - Week 11 (MITT-VMS)
Description	Number of Subjects with >=50%, and separately, >=75% reduction in frequency of moderate to severe vasomotor symptoms from Baseline to Week 11.
Time Frame	Baseline and Week 11

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	126	134	129	137	118
>=50% Reduction	95 22.9%	105 24.8%	97 23%	104 24.5%	59 39.1%
>=75% Reduction	79 19%	74 17.5%	65 15.4%	68 16%	34 22.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 11
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 11
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 11
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 11
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 11
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 11
	Method	Fisher Exact
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 11
	Method	Fisher Exact
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 11
	Method	Fisher Exact
	Comments

66. Secondary Outcome

Title	Reduction of Frequency of Moderate to Severe Vasomotor Symptoms - Week 12 (MITT-VMS)
Description	Number of Subjects with >=50%, and separately, >=75% reduction in frequency of moderate to severe vasomotor symptoms from Baseline to Week 12.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	124	129	124	135	115
>=50% Reduction	98 23.6%	104 24.5%	94 22.3%	99 23.3%	67 44.4%
>=75% Reduction	84 20.2%	75 17.7%	66 15.7%	68 16%	37 24.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Fisher Exact
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.015
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Fisher Exact
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Fisher Exact
	Comments

67. Secondary Outcome

Title	Reduction of Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 1 - (MITT-VMS)
Description	Number of Subjects with >=50%, and separately, >=75% reduction in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 1.
Time Frame	Baseline and Week 1

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	138	149	145	154	134
>=50% Reduction	14 3.4%	10 2.4%	12 2.9%	19 4.5%	10 6.6%
>=75% Reduction	2 0.5%	2 0.5%	1 0.2%	4 0.9%	1 0.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.523
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 1
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 1
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.821
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 1
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 1
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.828
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 1
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 1
	Method	Fisher Exact
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.239
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 1
	Method	Fisher Exact
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.377
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 1
	Method	Fisher Exact
	Comments

68. Secondary Outcome

Title	Reduction of Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 2 - (MITT-VMS)
Description	Number of Subjects with >=50%, and separately, >=75% reduction in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 2.
Time Frame	Baseline and Week 2

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	134	146	145	153	133
>=50% Reduction	36 8.7%	24 5.7%	30 7.1%	39 9.2%	21 13.9%
>=75% Reduction	15 3.6%	7 1.7%	9 2.1%	17 4%	4 2.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.036
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 2
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.015
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 2
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 2
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.546
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 2
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.352
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 2
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.261
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 2
	Method	Fisher Exact
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.058
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 2
	Method	Fisher Exact
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 2
	Method	Fisher Exact
	Comments

69. Secondary Outcome

Title	Reduction of Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 3 - (MITT-VMS)
Description	Number of Subjects with >=50%, and separately, >=75% reduction in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 3.
Time Frame	Baseline and Week 3

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	136	144	144	153	131
>=50% Reduction	63 15.2%	49 11.6%	50 11.9%	61 14.4%	33 21.9%
>=75% Reduction	33 8%	14 3.3%	15 3.6%	22 5.2%	6 4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 3
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 3
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.115
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 3
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.110
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 3
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.089
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 3
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.074
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 3
	Method	Fisher Exact
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 3
	Method	Fisher Exact
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 3
	Method	Fisher Exact
	Comments

70. Secondary Outcome

Title	Reduction of Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 4 - (MITT-VMS)
Description	Number of Subjects with >=50%, and separately, >=75% reduction in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 4.
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	134	144	142	152	126
>=50% Reduction	80 19.3%	62 14.6%	65 15.4%	73 17.2%	35 23.2%
>=75% Reduction	44 10.6%	28 6.6%	24 5.7%	33 7.8%	6 4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 4
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 4
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 4
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 4
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 4
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 4
	Method	Fisher Exact
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 4
	Method	Fisher Exact
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 4
	Method	Fisher Exact
	Comments

71. Secondary Outcome

Title	Reduction of Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 5 - (MITT-VMS)
Description	Number of Subjects with >=50%, and separately, >=75% reduction in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 5.
Time Frame	Baseline and Week 5

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	131	143	139	147	124
>=50% Reduction	86 20.7%	72 17%	69 16.4%	82 19.3%	47 31.1%
>=75% Reduction	48 11.6%	34 8%	27 6.4%	37 8.7%	13 8.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 5
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 5
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.048
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 5
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 5
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.063
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 5
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.058
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 5
	Method	Fisher Exact
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 5
	Method	Fisher Exact
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 5
	Method	Fisher Exact
	Comments

72. Secondary Outcome

Title	Reduction of Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 6 - (MITT-VMS)
Description	Number of Subjects with >=50%, and separately, >=75% reduction in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 6.
Time Frame	Baseline and Week 6

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	132	143	139	146	123
>=50% Reduction	92 22.2%	78 18.4%	76 18.1%	83 19.6%	52 34.4%
>=75% Reduction	61 14.7%	39 9.2%	39 9.3%	43 10.1%	16 10.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 6
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 6
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.050
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 6
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 6
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.048
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 6
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 6
	Method	Fisher Exact
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.020
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 6
	Method	Fisher Exact
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 6
	Method	Fisher Exact
	Comments

73. Secondary Outcome

Title	Reduction of Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 7 - (MITT-VMS)
Description	Number of Subjects with >=50%, and separately, >=75% reduction in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 7.
Time Frame	Baseline and Week 7

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	130	142	139	147	120
>=50% Reduction	93 22.4%	87 20.5%	81 19.2%	95 22.4%	49 32.5%
>=75% Reduction	63 15.2%	46 10.8%	44 10.5%	47 11.1%	16 10.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 7
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 7
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 7
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 7
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 7
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 7
	Method	Fisher Exact
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 7
	Method	Fisher Exact
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 7
	Method	Fisher Exact
	Comments

74. Secondary Outcome

Title	Reduction of Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 8 - (MITT-VMS)
Description	Number of Subjects with >=50%, and separately, >=75% reduction in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 8.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	129	140	137	147	120
>=50% Reduction	98 23.6%	85 20%	90 21.4%	93 21.9%	54 35.8%
>=75% Reduction	64 15.4%	53 12.5%	45 10.7%	51 12%	20 13.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 8
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 8
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 8
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 8
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 8
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 8
	Method	Fisher Exact
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 8
	Method	Fisher Exact
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 8
	Method	Fisher Exact
	Comments

75. Secondary Outcome

Title	Reduction of Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 9 - (MITT-VMS)
Description	Number of Subjects with >=50%, and separately, >=75% reduction in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 9.
Time Frame	Baseline and Week 9

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	124	137	132	141	119
>=50% Reduction	95 22.9%	95 22.4%	91 21.6%	94 22.2%	58 38.4%
>=75% Reduction	69 16.6%	63 14.9%	54 12.8%	56 13.2%	22 14.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 9
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 9
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 9
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 9
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 9
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 9
	Method	Fisher Exact
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 9
	Method	Fisher Exact
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 9
	Method	Fisher Exact
	Comments

76. Secondary Outcome

Title	Reduction of Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 10 - (MITT-VMS)
Description	Number of Subjects with >=50%, and separately, >=75% reduction in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 10.
Time Frame	Baseline and Week 10

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	126	133	129	140	118
>=50% Reduction	93 22.4%	94 22.2%	92 21.9%	93 21.9%	54 35.8%
>=75% Reduction	73 17.6%	60 14.2%	57 13.5%	57 13.4%	23 15.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 10
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 10
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 10
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 10
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 10
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 10
	Method	Fisher Exact
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 10
	Method	Fisher Exact
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 10
	Method	Fisher Exact
	Comments

77. Secondary Outcome

Title	Reduction of Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 11 - (MITT-VMS)
Description	Number of Subjects with >=50%, and separately, >=75% reduction in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 11.
Time Frame	Baseline and Week 11

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	126	134	129	137	118
>=50% Reduction	94 22.7%	97 22.9%	94 22.3%	95 22.4%	55 36.4%
>=75% Reduction	71 17.1%	64 15.1%	52 12.4%	62 14.6%	26 17.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 11
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 11
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 11
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 11
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 11
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 11
	Method	Fisher Exact
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 11
	Method	Fisher Exact
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 11
	Method	Fisher Exact
	Comments

78. Secondary Outcome

Title	Reduction of Frequency of Mild, Moderate and Severe Vasomotor Symptoms - Week 12 - (MITT-VMS)
Description	Number of Subjects with >=50%, and separately, >=75% reduction in frequency of mild, moderate and severe vasomotor symptoms from Baseline to Week 12.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	124	129	124	135	115
>=50% Reduction	97 23.4%	94 22.2%	90 21.4%	95 22.4%	55 36.4%
>=75% Reduction	73 17.6%	64 15.1%	50 11.9%	58 13.7%	32 21.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Fisher Exact
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Fisher Exact
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.056
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Fisher Exact
	Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=50% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Fisher Exact
	Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments	>=75% Reduction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.017
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Fisher Exact
	Comments

79. Secondary Outcome

Title	Clinical Global Impression (CGI) - Week 4 (MITT-VMS)
Description	The number and percentage of subjects for each possible response to the CGI at Week 4. The CGI score is a seven point scale where subjects were asked to rate the total improvement, whether or not in her judgment it was due entirely to drug treatment, compared to her condition at admission to the study. Scale: Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse. Results for the top two responses (Very Much Improved and Much Improved) and No Change or Worsening (Minimally worse, Much worse, Very much worse) were combined for each group and active treatment groups compare to placebo.
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	136	141	144	148	125
(Very) Much Improved	86 20.7%	71 16.7%	72 17.1%	75 17.7%	41 27.2%
Minimally Improved	37 8.9%	49 11.6%	49 11.6%	51 12%	49 32.5%
No Change or Worse	13 3.1%	21 5%	23 5.5%	22 5.2%	35 23.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-value is derived from comparing % Very Much Improved+Much Improved between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 4
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments	P-value is derived from comparing % Very Much Improved+Much Improved between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 4
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments	P-value is derived from comparing % Very Much Improved+Much Improved between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 4
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	P-value is derived from comparing % Very Much Improved+Much Improved between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 4
	Method	Fisher Exact
	Comments

80. Secondary Outcome

Title	Mean Change in Frequency of Moderate to Severe VMS for the Respective CGI Category - Week 4 (MITT-VMS)
Description	Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 4 for the respective CGI category. The CGI score is a seven point scale where subjects were asked to rate the total improvement, whether or not in her judgment it was due entirely to drug treatment, compared to her condition at admission to the study. Scale: Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse. Results for the top two responses (Very Much Improved and Much Improved) and No Change or Worsening (Minimally worse, Much worse, Very much worse) were combined for each group and active treatment groups compare to placebo.
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	136	141	144	148	125
(Very) Much Improved	-52.5 (27.28)	-48.6 (28.87)	-46.2 (31.23)	-55.7 (25.69)	-47.0 (24.17)
Minimally Improved	-24.1 (23.87)	-25.9 (21.43)	-29.2 (23.26)	-28.9 (26.08)	-26.8 (17.68)
No Change or Worse	-6.5 (23.08)	-6.6 (16.39)	-2.7 (16.22)	-5.3 (21.97)	-5.3 (13.68)

81. Secondary Outcome

Title	Clinical Global Impression (CGI) - Week 8 (MITT-VMS)
Description	The number and percentage of subjects for each possible response to the CGI at Week 8. The CGI score is a seven point scale where subjects were asked to rate the total improvement, whether or not in her judgment it was due entirely to drug treatment, compared to her condition at admission to the study. Scale: Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse. Results for the top two responses (Very Much Improved and Much Improved) and No Change or Worsening (Minimally worse, Much worse, Very much worse) were combined for each group and active treatment groups compare to placebo.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	130	139	134	141	117
(Very) Much Improved	101 24.3%	103 24.3%	98 23.3%	93 21.9%	62 41.1%
Minimally Improved	23 5.5%	24 5.7%	23 5.5%	35 8.3%	25 16.6%
No Change or Worse	6 1.4%	12 2.8%	13 3.1%	13 3.1%	30 19.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-value is derived from comparing % Very Much Improved+Much Improved between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 8
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-value is derived from comparing % Very Much Improved+Much Improved between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 8
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	P-value is derived from comparing % Very Much Improved+Much Improved between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 8
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	P-value is derived from comparing % Very Much Improved+Much Improved between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 8
	Method	Fisher Exact
	Comments

82. Secondary Outcome

Title	Mean Change in Frequency of Moderate to Severe VMS for the Respective CGI Category - Week 8 (MITT-VMS)
Description	Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 8 for the respective CGI category. The CGI score is a seven point scale where subjects were asked to rate the total improvement, whether or not in her judgment it was due entirely to drug treatment, compared to her condition at admission to the study. Scale: Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse. Results for the top two responses (Very Much Improved and Much Improved) and No Change or Worsening (Minimally worse, Much worse, Very much worse) were combined for each group and active treatment groups compare to placebo.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	130	139	134	141	117
(Very) Much Improved	-60.8 (28.49)	-55.1 (29.27)	-55.4 (29.06)	-57.8 (30.38)	-52.6 (24.62)
Minimally Improved	-28.7 (18.93)	-27.3 (25.22)	-27.2 (22.79)	-36.8 (24.81)	-27.0 (13.54)
No Change or Worse	-0.2 (28.80)	-15.2 (13.41)	-1.6 (19.93)	-7.4 (21.48)	-7.1 (21.46)

83. Secondary Outcome

Title	Clinical Global Impression (CGI) - Week 12 (MITT-VMS)
Description	The number and percentage of subjects for each possible response to the CGI at Week 12. The CGI score is a seven point scale where subjects were asked to rate the total improvement, whether or not in her judgment it was due entirely to drug treatment, compared to her condition at admission to the study. Scale: Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse. Results for the top two responses (Very Much Improved and Much Improved) and No Change or Worsening (Minimally worse, Much worse, Very much worse) were combined for each group and active treatment groups compare to placebo.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	123	133	131	139	116
(Very) Much Improved	101 24.3%	97 22.9%	102 24.2%	101 23.8%	62 41.1%
Minimally Improved	17 4.1%	29 6.8%	22 5.2%	24 5.7%	26 17.2%
No Change or Worse	5 1.2%	7 1.7%	7 1.7%	14 3.3%	28 18.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-value is derived from comparing % Very Much Improved+Much Improved between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-value is derived from comparing % Very Much Improved+Much Improved between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	P-value is derived from comparing % Very Much Improved+Much Improved between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	P-value is derived from comparing % Very Much Improved+Much Improved between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Fisher Exact
	Comments

84. Secondary Outcome

Title	Mean Change in Frequency of Moderate to Severe VMS for the Respective CGI Category - Week 12 (MITT-VMS)
Description	Mean change in frequency of moderate to severe vasomotor symptoms from Baseline to Week 12 for the respective CGI category. The CGI score is a seven point scale where subjects were asked to rate the total improvement, whether or not in her judgment it was due entirely to drug treatment, compared to her condition at admission to the study. Scale: Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse. Results for the top two responses (Very Much Improved and Much Improved) and No Change or Worsening (Minimally worse, Much worse, Very much worse) were combined for each group and active treatment groups compare to placebo.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	123	133	131	139	116
(Very) Much Improved	-58.8 (30.71)	-60.0 (28.37)	-58.2 (29.42)	-59.9 (28.01)	-56.2 (26.50)
Minimally Improved	-35.9 (24.78)	-34.9 (40.36)	-28.8 (21.99)	-40.6 (37.36)	-35.7 (19.55)
No Change or Worse	-30.7 (32.89)	-38.8 (18.99)	-8.6 (18.42)	-8.3 (31.84)	-9.2 (16.77)

85. Secondary Outcome

Title	Number of Subjects Without Bleeding for Consecutive Cycles
Description	No bleeding was defined as the absence of bleeding. Cumulative rates for no bleeding was defined as the percentage of women who reported consecutive cycles of no bleeding for a given cycle of time.
Time Frame	Cycle 1 to 13

Outcome Measure Data

Analysis Population Description

Subjects who received study drug for at least 1 complete 28-day cycle (at least 23 days in length); subjects who reported bleeding days during a partial cycle are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	278	299	304	268	90
Count of Participants [Participants]	204 49.2%	251 59.2%	263 62.5%	239 56.4%	82 54.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.000
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.122
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.280
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.692
	Comments
	Method	Fisher Exact
	Comments

86. Secondary Outcome

Title	Number of Subjects Without Bleeding for Consecutive Cycles
Description	No bleeding was defined as the absence of bleeding. Cumulative rates for no bleeding was defined as the percentage of women who reported consecutive cycles of no bleeding for a given cycle of time.
Time Frame	Cycle 2 to 13

Outcome Measure Data

Analysis Population Description

Subjects who received study drug for at least 1 complete 28-day cycle (at least 23 days in length); subjects who reported bleeding days during a partial cycle are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	278	299	304	268	90
Count of Participants [Participants]	209 50.4%	256 60.4%	265 62.9%	244 57.5%	84 55.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.000
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.069
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.131
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.661
	Comments
	Method	Fisher Exact
	Comments

87. Secondary Outcome

Title	Number of Subjects Without Bleeding for Consecutive Cycles
Description	No bleeding was defined as the absence of bleeding. Cumulative rates for no bleeding was defined as the percentage of women who reported consecutive cycles of no bleeding for a given cycle of time.
Time Frame	Cycle 3 to 13

Outcome Measure Data

Analysis Population Description

Subjects who received study drug for at least 1 complete 28-day cycle (at least 23 days in length); subjects who reported bleeding days during a partial cycle are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	278	299	304	268	90
Count of Participants [Participants]	214 51.6%	258 60.8%	267 63.4%	246 58%	85 56.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.000
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.040
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.082
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.495
	Comments
	Method	Fisher Exact
	Comments

88. Secondary Outcome

Title	Number of Subjects Without Bleeding for Consecutive Cycles
Description	No bleeding was defined as the absence of bleeding. Cumulative rates for no bleeding was defined as the percentage of women who reported consecutive cycles of no bleeding for a given cycle of time.
Time Frame	Cycle 4 to 13

Outcome Measure Data

Analysis Population Description

Subjects who received study drug for at least 1 complete 28-day cycle (at least 23 days in length); subjects who reported bleeding days during a partial cycle are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	278	299	304	268	90
Count of Participants [Participants]	217 52.3%	261 61.6%	273 64.8%	253 59.7%	86 57%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.000
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.032
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.137
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.792
	Comments
	Method	Fisher Exact
	Comments

89. Secondary Outcome

Title	Number of Subjects Without Bleeding for Consecutive Cycles
Description	No bleeding was defined as the absence of bleeding. Cumulative rates for no bleeding was defined as the percentage of women who reported consecutive cycles of no bleeding for a given cycle of time.
Time Frame	Cycle 5 to 13

Outcome Measure Data

Analysis Population Description

Subjects who received study drug for at least 1 complete 28-day cycle (at least 23 days in length); subjects who reported bleeding days during a partial cycle are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	278	299	304	268	90
Count of Participants [Participants]	224 54%	265 62.5%	278 66%	253 59.7%	86 57%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.000
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.067
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.260
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.792
	Comments
	Method	Fisher Exact
	Comments

90. Secondary Outcome

Title	Number of Subjects Without Bleeding for Consecutive Cycles
Description	No bleeding was defined as the absence of bleeding. Cumulative rates for no bleeding was defined as the percentage of women who reported consecutive cycles of no bleeding for a given cycle of time.
Time Frame	Cycle 6 to 13

Outcome Measure Data

Analysis Population Description

Subjects who received study drug for at least 1 complete 28-day cycle (at least 23 days in length); subjects who reported bleeding days during a partial cycle are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	278	299	304	268	90
Count of Participants [Participants]	227 54.7%	268 63.2%	280 66.5%	256 60.4%	86 57%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.095
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.352
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments

91. Secondary Outcome

Title	Number of Subjects Without Bleeding for Consecutive Cycles
Description	No bleeding was defined as the absence of bleeding. Cumulative rates for no bleeding was defined as the percentage of women who reported consecutive cycles of no bleeding for a given cycle of time.
Time Frame	Cycle 7 to 13

Outcome Measure Data

Analysis Population Description

Subjects who received study drug for at least 1 complete 28-day cycle (at least 23 days in length); subjects who reported bleeding days during a partial cycle are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	278	299	304	268	90
Count of Participants [Participants]	237 57.1%	271 63.9%	282 67%	256 60.4%	87 57.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.075
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.225
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.769
	Comments
	Method	Fisher Exact
	Comments

92. Secondary Outcome

Title	Number of Subjects Without Bleeding for Consecutive Cycles
Description	No bleeding was defined as the absence of bleeding. Cumulative rates for no bleeding was defined as the percentage of women who reported consecutive cycles of no bleeding for a given cycle of time.
Time Frame	Cycle 8 to 13

Outcome Measure Data

Analysis Population Description

Subjects who received study drug for at least 1 complete 28-day cycle (at least 23 days in length); subjects who reported bleeding days during a partial cycle are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	278	299	304	268	90
Count of Participants [Participants]	242 58.3%	276 65.1%	285 67.7%	258 60.8%	88 58.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.084
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.183
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.738
	Comments
	Method	Fisher Exact
	Comments

93. Secondary Outcome

Title	Number of Subjects Without Bleeding for Consecutive Cycles
Description	No bleeding was defined as the absence of bleeding. Cumulative rates for no bleeding was defined as the percentage of women who reported consecutive cycles of no bleeding for a given cycle of time.
Time Frame	Cycle 9 to 13

Outcome Measure Data

Analysis Population Description

Subjects who received study drug for at least 1 complete 28-day cycle (at least 23 days in length); subjects who reported bleeding days during a partial cycle are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	278	299	304	268	90
Count of Participants [Participants]	245 59%	279 65.8%	288 68.4%	259 61.1%	88 58.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.125
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.386
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.737
	Comments
	Method	Fisher Exact
	Comments

94. Secondary Outcome

Title	Number of Subjects Without Bleeding for Consecutive Cycles
Description	No bleeding was defined as the absence of bleeding. Cumulative rates for no bleeding was defined as the percentage of women who reported consecutive cycles of no bleeding for a given cycle of time.
Time Frame	Cycle 10 to 13

Outcome Measure Data

Analysis Population Description

Subjects who received study drug for at least 1 complete 28-day cycle (at least 23 days in length); subjects who reported bleeding days during a partial cycle are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	278	299	304	268	90
Count of Participants [Participants]	248 59.8%	281 66.3%	292 69.4%	261 61.6%	88 58.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.183
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.745
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments

95. Secondary Outcome

Title	Number of Subjects Without Bleeding for Consecutive Cycles
Description	No bleeding was defined as the absence of bleeding. Cumulative rates for no bleeding was defined as the percentage of women who reported consecutive cycles of no bleeding for a given cycle of time.
Time Frame	Cycle 11 to 13

Outcome Measure Data

Analysis Population Description

Subjects who received study drug for at least 1 complete 28-day cycle (at least 23 days in length); subjects who reported bleeding days during a partial cycle are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	276	297	302	266	90
Count of Participants [Participants]	251 60.5%	284 67%	294 69.8%	261 61.6%	88 58.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.035
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.536
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments

96. Secondary Outcome

Title	Number of Subjects Without Bleeding for Consecutive Cycles
Description	No bleeding was defined as the absence of bleeding. Cumulative rates for no bleeding was defined as the percentage of women who reported consecutive cycles of no bleeding for a given cycle of time.
Time Frame	Cycle 12 to 13

Outcome Measure Data

Analysis Population Description

Subjects who received study drug for at least 1 complete 28-day cycle (at least 23 days in length); subjects who reported bleeding days during a partial cycle are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	276	297	302	265	90
Count of Participants [Participants]	260 62.7%	284 67%	295 70.1%	260 61.3%	88 58.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.261
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.536
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments

97. Secondary Outcome

Title	Number of Subjects Without Bleeding for Consecutive Cycles
Description	No bleeding was defined as the absence of bleeding. Cumulative rates for no bleeding was defined as the percentage of women who reported consecutive cycles of no bleeding for a given cycle of time.
Time Frame	The 13th Cycle

Outcome Measure Data

Analysis Population Description

Subjects who received study drug for at least 1 complete 28-day cycle (at least 23 days in length); subjects who reported bleeding days during a partial cycle are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	276	294	302	264	90
Count of Participants [Participants]	268 64.6%	287 67.7%	296 70.3%	261 61.6%	89 58.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.463
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.687
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments

98. Secondary Outcome

Title	Number of Subjects With Cumulative Amenorrhea From Cycle 1 to 13
Description	Cumulative amenorrhea is defined as the absence of bleeding or spotting for a cumulative period. Cumulative rates of amenorrhea were defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. Within each treatment arm, the percentage of subjects with cumulative amenorrhea from Cycle 1 to 13 was calculated and compared between active and placebo treatments.
Time Frame	Cycle 1 to 13

Outcome Measure Data

Analysis Population Description

Subjects who received study drug for at least 1 complete 28-day cycle (at least 23 days in length); subjects who reported bleeding days during a partial cycle are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	278	299	304	268	90
Count of Participants [Participants]	156 37.6%	202 47.6%	207 49.2%	196 46.2%	71 47%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.048
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.049
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.328
	Comments
	Method	Fisher Exact
	Comments

99. Secondary Outcome

Title	Number of Subjects With Cumulative Amenorrhea From Cycle 2 to 13
Description	Cumulative amenorrhea is defined as the absence of bleeding or spotting for a cumulative period. Cumulative rates of amenorrhea were defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. Within each treatment arm, the percentage of subjects with cumulative amenorrhea from Cycle 2 to 13 was calculated and compared between active and placebo treatments.
Time Frame	Cycle 2 to 13

Outcome Measure Data

Analysis Population Description

Subjects who received study drug for at least 1 complete 28-day cycle (at least 23 days in length); subjects who reported bleeding days during a partial cycle are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	278	299	304	268	90
Count of Participants [Participants]	166 40%	220 51.9%	215 51.1%	212 50%	74 49%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.123
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.030
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.649
	Comments
	Method	Fisher Exact
	Comments

100. Secondary Outcome

Title	Number of Subjects With Cumulative Amenorrhea From Cycle 3 to 13
Description	Cumulative amenorrhea is defined as the absence of bleeding or spotting for a cumulative period. Cumulative rates of amenorrhea were defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. Within each treatment arm, the percentage of subjects with cumulative amenorrhea from Cycle 3 to 13 was calculated and compared between active and placebo treatments.
Time Frame	Cycle 3 to 13

Outcome Measure Data

Analysis Population Description

Subjects who received study drug for at least 1 complete 28-day cycle (at least 23 days in length); subjects who reported bleeding days during a partial cycle are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	278	299	304	268	90
Count of Participants [Participants]	174 41.9%	227 53.5%	225 53.4%	218 51.4%	77 51%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.059
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.023
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.426
	Comments
	Method	Fisher Exact
	Comments

101. Secondary Outcome

Title	Number of Subjects With Cumulative Amenorrhea From Cycle 4 to 13
Description	Cumulative amenorrhea is defined as the absence of bleeding or spotting for a cumulative period. Cumulative rates of amenorrhea were defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. Within each treatment arm, the percentage of subjects with cumulative amenorrhea from Cycle 4 to 13 was calculated and compared between active and placebo treatments.
Time Frame	Cycle 4 to 13

Outcome Measure Data

Analysis Population Description

Subjects who received study drug for at least 1 complete 28-day cycle (at least 23 days in length); subjects who reported bleeding days during a partial cycle are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	278	299	304	268	90
Count of Participants [Participants]	177 42.7%	236 55.7%	233 55.3%	229 54%	80 53%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.044
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.481
	Comments
	Method	Fisher Exact
	Comments

102. Secondary Outcome

Title	Number of Subjects With Cumulative Amenorrhea From Cycle 5 to 13
Description	Cumulative amenorrhea is defined as the absence of bleeding or spotting for a cumulative period. Cumulative rates of amenorrhea were defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. Within each treatment arm, the percentage of subjects with cumulative amenorrhea from Cycle 5 to 13 was calculated and compared between active and placebo treatments.
Time Frame	Cycle 5 to 13

Outcome Measure Data

Analysis Population Description

Subjects who received study drug for at least 1 complete 28-day cycle (at least 23 days in length); subjects who reported bleeding days during a partial cycle are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	278	299	304	268	90
Count of Participants [Participants]	183 44.1%	244 57.5%	240 57%	234 55.2%	80 53%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.110
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.045
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.853
	Comments
	Method	Fisher Exact
	Comments

103. Secondary Outcome

Title	Number of Subjects With Cumulative Amenorrhea From Cycle 6 to 13
Description	Cumulative amenorrhea is defined as the absence of bleeding or spotting for a cumulative period. Cumulative rates of amenorrhea were defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. Within each treatment arm, the percentage of subjects with cumulative amenorrhea from Cycle 6 to 13 was calculated and compared between active and placebo treatments.
Time Frame	Cycle 6 to 13

Outcome Measure Data

Analysis Population Description

Subjects who received study drug for at least 1 complete 28-day cycle (at least 23 days in length); subjects who reported bleeding days during a partial cycle are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	278	299	304	268	90
Count of Participants [Participants]	186 44.8%	250 59%	249 59.1%	236 55.7%	80 53%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.245
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.145
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments

104. Secondary Outcome

Title	Number of Subjects With Cumulative Amenorrhea From Cycle 7 to 13
Description	Cumulative amenorrhea is defined as the absence of bleeding or spotting for a cumulative period. Cumulative rates of amenorrhea were defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. Within each treatment arm, the percentage of subjects with cumulative amenorrhea from Cycle 7 to 13 was calculated and compared between active and placebo treatments.
Time Frame	Cycle 7 to 13

Outcome Measure Data

Analysis Population Description

Subjects who received study drug for at least 1 complete 28-day cycle (at least 23 days in length); subjects who reported bleeding days during a partial cycle are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	278	299	304	268	90
Count of Participants [Participants]	200 48.2%	253 59.7%	255 60.6%	238 56.1%	82 54.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.163
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.091
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.693
	Comments
	Method	Fisher Exact
	Comments

105. Secondary Outcome

Title	Number of Subjects With Cumulative Amenorrhea From Cycle 8 to 13
Description	Cumulative amenorrhea is defined as the absence of bleeding or spotting for a cumulative period. Cumulative rates of amenorrhea were defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. Within each treatment arm, the percentage of subjects with cumulative amenorrhea from Cycle 8 to 13 was calculated and compared between active and placebo treatments.
Time Frame	Cycle 8 to 13

Outcome Measure Data

Analysis Population Description

Subjects who received study drug for at least 1 complete 28-day cycle (at least 23 days in length); subjects who reported bleeding days during a partial cycle are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	278	299	304	268	90
Count of Participants [Participants]	209 50.4%	262 61.8%	262 62.2%	242 57.1%	84 55.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.178
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.097
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.522
	Comments
	Method	Fisher Exact
	Comments

106. Secondary Outcome

Title	Number of Subjects With Cumulative Amenorrhea From Cycle 9 to 13
Description	Cumulative amenorrhea is defined as the absence of bleeding or spotting for a cumulative period. Cumulative rates of amenorrhea were defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. Within each treatment arm, the percentage of subjects with cumulative amenorrhea from Cycle 9 to 13 was calculated and compared between active and placebo treatments.
Time Frame	Cycle 9 to 13

Outcome Measure Data

Analysis Population Description

Subjects who received study drug for at least 1 complete 28-day cycle (at least 23 days in length); subjects who reported bleeding days during a partial cycle are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	278	299	304	268	90
Count of Participants [Participants]	214 51.6%	267 63%	266 63.2%	246 58%	84 55.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.315
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.181
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.821
	Comments
	Method	Fisher Exact
	Comments

107. Secondary Outcome

Title	Number of Subjects With Cumulative Amenorrhea From Cycle 10 to 13
Description	Cumulative amenorrhea is defined as the absence of bleeding or spotting for a cumulative period. Cumulative rates of amenorrhea were defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. Within each treatment arm, the percentage of subjects with cumulative amenorrhea from Cycle 10 to 13 was calculated and compared between active and placebo treatments.
Time Frame	Cycle 10 to 13

Outcome Measure Data

Analysis Population Description

Subjects who received study drug for at least 1 complete 28-day cycle (at least 23 days in length); subjects who reported bleeding days during a partial cycle are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	278	299	304	268	90
Count of Participants [Participants]	222 53.5%	271 63.9%	273 64.8%	248 58.5%	85 56.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.387
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.215
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.639
	Comments
	Method	Fisher Exact
	Comments

108. Secondary Outcome

Title	Number of Subjects With Cumulative Amenorrhea From Cycle 11 to 13
Description	Cumulative amenorrhea is defined as the absence of bleeding or spotting for a cumulative period. Cumulative rates of amenorrhea were defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. Within each treatment arm, the percentage of subjects with cumulative amenorrhea from Cycle 11 to 13 was calculated and compared between active and placebo treatments.
Time Frame	Cycle 11 to 13

Outcome Measure Data

Analysis Population Description

Subjects who received study drug for at least 1 complete 28-day cycle (at least 23 days in length); subjects who reported bleeding days during a partial cycle are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	276	297	302	266	90
Count of Participants [Participants]	231 55.7%	275 64.9%	277 65.8%	249 58.7%	85 56.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.643
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.501
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments

109. Secondary Outcome

Title	Number of Subjects With Cumulative Amenorrhea From Cycle 12 to 13
Description	Cumulative amenorrhea is defined as the absence of bleeding or spotting for a cumulative period. Cumulative rates of amenorrhea were defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. Within each treatment arm, the percentage of subjects with cumulative amenorrhea from Cycle 12 to 13 was calculated and compared between active and placebo treatments.
Time Frame	Cycle 12 to 13

Outcome Measure Data

Analysis Population Description

Subjects who received study drug for at least 1 complete 28-day cycle (at least 23 days in length); subjects who reported bleeding days during a partial cycle are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	276	297	302	265	90
Count of Participants [Participants]	238 57.3%	278 65.6%	278 66%	252 59.4%	86 57%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.616
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.352
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments
	Method	Fisher Exact
	Comments

110. Secondary Outcome

Title	Number of Subjects With Cumulative Amenorrhea From the 13th Cycle
Description	Cumulative amenorrhea is defined as the absence of bleeding or spotting for a cumulative period. Cumulative rates of amenorrhea were defined as the percentage of women who reported consecutive cycles of amenorrhea for a given cycle of time. Within each treatment arm, the percentage of subjects with cumulative amenorrhea from the 13th Cycle was calculated and compared between active and placebo treatments.
Time Frame	The 13th Cycle

Outcome Measure Data

Analysis Population Description

Subjects who received study drug for at least 1 complete 28-day cycle (at least 23 days in length); subjects who reported bleeding days during a partial cycle are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	276	294	302	264	90
Count of Participants [Participants]	249 60%	282 66.5%	283 67.2%	254 59.9%	88 58.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.023
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.535
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.183
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.738
	Comments
	Method	Fisher Exact
	Comments

111. Secondary Outcome

Title	Subject Incidence With Spotting - Trimester 1 (Safety Pop.)
Description	Summary of subject incidence with spotting per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.
Time Frame	Trimester 1

Outcome Measure Data

Analysis Population Description

Subjects who had taken at least one dose (2 capsules) of IP and had at least one bleeding/spotting diary entry for Trimester 1. Subjects who reported bleeding/spotting diary only for partial trimester are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	312	329	334	307	103
Count of Participants [Participants]	90 21.7%	74 17.5%	68 16.2%	58 13.7%	10 6.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo during Trimester 1
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo during Trimester 1
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.012
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo during Trimester 1
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.032
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo during Trimester 1
	Method	Fisher Exact
	Comments

112. Secondary Outcome

Title	Subject Incidence With Spotting - Trimester 2 (Safety Pop.)
Description	Summary of subject incidence with spotting per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.
Time Frame	Trimester 2

Outcome Measure Data

Analysis Population Description

Subjects who had taken at least one dose (2 capsules) of IP and had at least one bleeding/spotting diary entry for Trimester 2. Subjects who reported bleeding/spotting diary only for partial trimester are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	309	323	325	302	98
Count of Participants [Participants]	76 18.3%	40 9.4%	48 11.4%	24 5.7%	4 2.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo during Trimester 2
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.022
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo during Trimester 2
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo during Trimester 2
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.256
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo during Trimester 2
	Method	Fisher Exact
	Comments

113. Secondary Outcome

Title	Subject Incidence With Spotting - Trimester 3 (Safety Pop.)
Description	Summary of subject incidence with spotting per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.
Time Frame	Trimester 3

Outcome Measure Data

Analysis Population Description

Subjects who had taken at least one dose (2 capsules) of IP and had at least one bleeding/spotting diary entry for Trimester 3. Subjects who reported bleeding/spotting diary only for partial trimester are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	298	311	320	288	97
Count of Participants [Participants]	54 13%	33 7.8%	29 6.9%	18 4.2%	2 1.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo during Trimester 3
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo during Trimester 3
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.025
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo during Trimester 3
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.182
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo during Trimester 3
	Method	Fisher Exact
	Comments

114. Secondary Outcome

Title	Subject Incidence With Spotting - Trimester 4 (Safety Pop.)
Description	Summary of subject incidence with spotting per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.
Time Frame	Trimester 4

Outcome Measure Data

Analysis Population Description

Subjects who had taken at least one dose (2 capsules) of IP and had at least one bleeding/spotting diary entry for Trimester 4. Subjects who reported bleeding/spotting diary only for partial trimester are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	282	304	308	276	93
Count of Participants [Participants]	47 11.3%	21 5%	27 6.4%	18 4.2%	4 2.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo during Trimester 4
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.469
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo during Trimester 4
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.188
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo during Trimester 4
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.613
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo during Trimester 4
	Method	Fisher Exact
	Comments

115. Secondary Outcome

Title	Number of Days With Spotting - Trimester 1 (Safety Pop.)
Description	Summary of the number of days with spotting per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.
Time Frame	Trimester 1

Outcome Measure Data

Analysis Population Description

Subjects who had taken at least one dose (2 capsules) of IP and had at least one bleeding/spotting diary entry for Trimester 1. Subjects who reported bleeding/spotting diary only for partial trimester are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	312	329	334	307	103
Mean (Standard Deviation) [Days]	3.0 (8.81)	1.7 (6.05)	1.3 (5.08)	0.8 (2.29)	0.6 (2.63)

116. Secondary Outcome

Title	Number of Days With Spotting - Trimester 2 (Safety Pop.)
Description	Summary of the number of days with spotting per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.
Time Frame	Trimester 2

Outcome Measure Data

Analysis Population Description

Subjects who had taken at least one dose (2 capsules) of IP and had at least one bleeding/spotting diary entry for Trimester 2. Subjects who reported bleeding/spotting diary only for partial trimester are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	309	323	325	302	98
Mean (Standard Deviation) [Days]	2.9 (8.63)	0.9 (3.85)	1.5 (9.16)	0.7 (4.30)	0.1 (0.74)

117. Secondary Outcome

Title	Number of Days With Spotting - Trimester 3 (Safety Pop.)
Description	Summary of the number of days with spotting per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.
Time Frame	Trimester 3

Outcome Measure Data

Analysis Population Description

Subjects who had taken at least one dose (2 capsules) of IP and had at least one bleeding/spotting diary entry for Trimester 3. Subjects who reported bleeding/spotting diary only for partial trimester are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	298	311	320	288	97
Mean (Standard Deviation) [Days]	2.5 (8.28)	0.7 (2.55)	0.9 (6.04)	0.3 (1.90)	0.0 (0.14)

118. Secondary Outcome

Title	Number of Days With Spotting - Trimester 4 (Safety Pop.)
Description	Summary of the number of days with spotting per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.
Time Frame	Trimester 4

Outcome Measure Data

Analysis Population Description

Subjects who had taken at least one dose (2 capsules) of IP and had at least one bleeding/spotting diary entry for Trimester 4. Subjects who reported bleeding/spotting diary only for partial trimester are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	282	304	308	276	93
Mean (Standard Deviation) [Days]	1.9 (7.59)	0.5 (3.36)	0.8 (5.75)	0.3 (1.17)	0.1 (0.67)

119. Secondary Outcome

Title	Subject Incidence With Bleeding - Trimester 1 (Safety Pop.)
Description	Summary of subject incidence with bleeding per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.
Time Frame	Trimester 1

Outcome Measure Data

Analysis Population Description

Subjects who had taken at least one dose (2 capsules) of IP and had at least one bleeding/spotting diary entry for Trimester 1. Subjects who reported bleeding/spotting diary only for partial trimester are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	312	329	334	307	103
Count of Participants [Participants]	48 11.6%	29 6.8%	25 5.9%	24 5.7%	4 2.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo during Trimester 1
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.135
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo during Trimester 1
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.260
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo during Trimester 1
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.257
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo during Trimester 1
	Method	Fisher Exact
	Comments

120. Secondary Outcome

Title	Subject Incidence With Bleeding - Trimester 2 (Safety Pop.)
Description	Summary of subject incidence with bleeding per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.
Time Frame	Trimester 2

Outcome Measure Data

Analysis Population Description

Subjects who had taken at least one dose (2 capsules) of IP and had at least one bleeding/spotting diary entry for Trimester 2. Subjects who reported bleeding/spotting diary only for partial trimester are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	309	323	325	302	98
Count of Participants [Participants]	45 10.8%	23 5.4%	19 4.5%	5 1.2%	2 1.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo during Trimester 2
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.085
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo during Trimester 2
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.184
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo during Trimester 2
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.681
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo during Trimester 2
	Method	Fisher Exact
	Comments

121. Secondary Outcome

Title	Subject Incidence With Bleeding - Trimester 3 (Safety Pop.)
Description	Summary of subject incidence with bleeding per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.
Time Frame	Trimester 3

Outcome Measure Data

Analysis Population Description

Subjects who had taken at least one dose (2 capsules) of IP and had at least one bleeding/spotting diary entry for Trimester 3. Subjects who reported bleeding/spotting diary only for partial trimester are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	298	311	320	288	97
Count of Participants [Participants]	25 6%	21 5%	16 3.8%	7 1.7%	1 0.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo during Trimester 3
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.036
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo during Trimester 3
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.138
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo during Trimester 3
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.685
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo during Trimester 3
	Method	Fisher Exact
	Comments

122. Secondary Outcome

Title	Subject Incidence With Bleeding - Trimester 4 (Safety Pop.)
Description	Summary of subject incidence with bleeding per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.
Time Frame	Trimester 4

Outcome Measure Data

Analysis Population Description

Subjects who had taken at least one dose (2 capsules) of IP and had at least one bleeding/spotting diary entry for Trimester 4. Subjects who reported bleeding/spotting diary only for partial trimester are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	282	304	308	276	93
Count of Participants [Participants]	27 6.5%	16 3.8%	9 2.1%	5 1.2%	2 1.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.023
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo during Trimester 4
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.265
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo during Trimester 4
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo during Trimester 4
	Method	Fisher Exact
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	1.000
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo during Trimester 4
	Method	Fisher Exact
	Comments

123. Secondary Outcome

Title	Number of Days With Bleeding - Trimester 1 (Safety Pop.)
Description	Summary of the number of days with bleeding per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.
Time Frame	Trimester 1

Outcome Measure Data

Analysis Population Description

Subjects who had taken at least one dose (2 capsules) of IP and had at least one bleeding/spotting diary entry for Trimester 1. Subjects who reported bleeding/spotting diary only for partial trimester are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	312	329	334	307	103
Mean (Standard Deviation) [Days]	1.2 (5.22)	0.5 (2.21)	0.5 (2.24)	0.4 (1.79)	0.2 (1.01)

124. Secondary Outcome

Title	Number of Days With Bleeding - Trimester 2 (Safety Pop.)
Description	Summary of the number of days with bleeding per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.
Time Frame	Trimester 2

Outcome Measure Data

Analysis Population Description

Subjects who had taken at least one dose (2 capsules) of IP and had at least one bleeding/spotting diary entry for Trimester 2. Subjects who reported bleeding/spotting diary only for partial trimester are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	309	323	325	302	98
Mean (Standard Deviation) [Days]	0.9 (3.22)	0.4 (1.85)	0.4 (2.02)	0.2 (1.77)	0.1 (0.42)

125. Secondary Outcome

Title	Number of Days With Bleeding - Trimester 3 (Safety Pop.)
Description	Summary of the number of days with bleeding per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.
Time Frame	Trimester 3

Outcome Measure Data

Analysis Population Description

Subjects who had taken at least one dose (2 capsules) of IP and had at least one bleeding/spotting diary entry for Trimester 3. Subjects who reported bleeding/spotting diary only for partial trimester are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	298	311	320	288	97
Mean (Standard Deviation) [Days]	0.5 (2.32)	0.5 (2.29)	0.2 (1.43)	0.1 (0.67)	0.0 (0.10)

126. Secondary Outcome

Title	Number of Days With Bleeding - Trimester 4 (Safety Pop.)
Description	Summary of the number of days with bleeding per trimester as recorded in a daily diary. A trimester is defined as every 90 days since Day 1.
Time Frame	Trimester 4

Outcome Measure Data

Analysis Population Description

Subjects who had taken at least one dose (2 capsules) of IP and had at least one bleeding/spotting diary entry for Trimester 4. Subjects who reported bleeding/spotting diary only for partial trimester are also included.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	282	304	308	276	93
Mean (Standard Deviation) [Days]	0.8 (3.48)	0.4 (2.06)	0.2 (1.20)	0.0 (0.26)	0.1 (0.43)

127. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Vasomotor Domain Score - Week 12 (MITT-VMS)
Description	Changes in Vasomotor Domain Score from Baseline to Week 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Vasomotor domain score is mean of = Q1,Q2, Q3, with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	124	135	132	142	116
Mean (Standard Deviation) [Score on a Scale]	-3.8 (1.98)	-3.3 (2.04)	-3.3 (1.97)	-3.2 (2.13)	-2.2 (1.83)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.65
	Confidence Interval	(2-Sided) 95%; -2.13 to -1.17
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.246
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.31
	Confidence Interval	(2-Sided) 95%; -1.79 to -0.84
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.242
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.17
	Confidence Interval	(2-Sided) 95%; -1.64 to -0.69
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.242
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.04
	Confidence Interval	(2-Sided) 95%; -1.51 to -0.58
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.238
	Estimation Comments

128. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Vasomotor Domain Score - Month 6 (MITT-VMS)
Description	Changes in Vasomotor Domain Score from Baseline to Month 6. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Vasomotor domain score is mean of = Q1,Q2, Q3, with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	116	130	118	126	104
Mean (Standard Deviation) [score on a scale]	-4.3 (1.94)	-4.1 (1.99)	-4.0 (2.12)	-3.5 (1.95)	-3.0 (2.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.40
	Confidence Interval	(2-Sided) 95%; -1.91 to -0.89
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.258
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.32
	Confidence Interval	(2-Sided) 95%; -1.81 to -0.82
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.253
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.12
	Confidence Interval	(2-Sided) 95%; -1.63 to -0.62
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.257
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.69
	Confidence Interval	(2-Sided) 95%; -1.19 to -0.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.254
	Estimation Comments

129. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Vasomotor Domain Score - Month 12 (MITT-VMS)
Description	Changes in Vasomotor Domain Score from Baseline to Month 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Vasomotor domain score is mean of = Q1,Q2, Q3, with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	97	118	104	104	93
Mean (Standard Deviation) [score on a scale]	-4.0 (2.15)	-4.1 (1.77)	-4.0 (2.11)	-3.4 (1.75)	-2.8 (2.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.20
	Confidence Interval	(2-Sided) 95%; -1.75 to -0.66
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.276
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.46
	Confidence Interval	(2-Sided) 95%; -1.98 to -0.94
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.265
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.23
	Confidence Interval	(2-Sided) 95%; -1.76 to -0.69
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.272
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.72
	Confidence Interval	(2-Sided) 95%; -1.26 to -0.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.272
	Estimation Comments

130. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Psychosocial Domain Score - Week 12 (MITT-VMS)
Description	Changes in Psychosocial Domain Score from Baseline to Week 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Psychosocial domain score is mean of = Q4 to Q10, with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	124	135	131	142	116
Mean (Standard Deviation) [score on a scale]	-1.1 (1.42)	-0.9 (1.56)	-1.2 (1.69)	-1.1 (1.36)	-1.0 (1.66)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.284
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -0.49 to 0.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.161
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.732
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.36 to 0.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.158
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.437
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95%; -0.44 to 0.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.159
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.439
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95%; -0.43 to 0.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.156
	Estimation Comments

131. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Psychosocial Domain Score - Month 6 (MITT-VMS)
Description	Changes in Psychosocial Domain Score from Baseline to Month 6. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Psychosocial domain score is mean of = Q4 to Q10, with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	116	130	118	126	104
Mean (Standard Deviation) [score on a scale]	-1.3 (1.64)	-1.1 (1.44)	-1.1 (1.76)	-1.0 (1.57)	-1.0 (1.61)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.040
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.35
	Confidence Interval	(2-Sided) 95%; -0.68 to -0.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.169
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.066
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.30
	Confidence Interval	(2-Sided) 95%; -0.63 to 0.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.165
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.469
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95%; -0.45 to 0.21
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.168
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.616
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -0.41 to 0.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.166
	Estimation Comments

132. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Psychosocial Domain Score - Month 12 (MITT-VMS)
Description	Changes in Psychosocial Domain Score from Baseline to Month 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Psychosocial domain score is mean of = Q4 to Q10, with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	97	118	104	104	93
Mean (Standard Deviation) [score on a scale]	-1.1 (1.51)	-1.3 (1.61)	-1.1 (1.84)	-1.0 (1.67)	-1.0 (1.61)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.250
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.21
	Confidence Interval	(2-Sided) 95%; -0.57 to 0.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.183
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.54
	Confidence Interval	(2-Sided) 95%; -0.88 to -0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.175
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.796
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.40 to 0.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.179
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.955
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.01
	Confidence Interval	(2-Sided) 95%; -0.36 to 0.34
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.179
	Estimation Comments

133. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Physical Domain Score - Week 12 (MITT-VMS)
Description	Changes in Physical Domain Score from Baseline to Week 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Physical domain score is mean of = Q11 to Q26, with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	124	135	131	142	116
Mean (Standard Deviation) [score on a scale]	-1.1 (1.30)	-1.0 (1.32)	-1.5 (1.50)	-1.0 (1.30)	-1.0 (1.38)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.474
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.38 to 0.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.143
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.378
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95%; -0.40 to 0.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.140
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.018
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.33
	Confidence Interval	(2-Sided) 95%; -0.61 to -0.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.141
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.730
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.32 to 0.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.138
	Estimation Comments

134. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Physical Domain Score - Month 6 (MITT-VMS)
Description	Changes in Physical Domain Score from Baseline to Month 6. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Physical domain score is mean of = Q11 to Q26, with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	116	130	118	126	104
Mean (Standard Deviation) [score on a scale]	-1.2 (1.32)	-1.1 (1.37)	-1.5 (1.61)	-1.0 (1.28)	-1.1 (1.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.197
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.20
	Confidence Interval	(2-Sided) 95%; -0.49 to 0.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.152
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.308
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.15
	Confidence Interval	(2-Sided) 95%; -0.44 to 0.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.148
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.117
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.24
	Confidence Interval	(2-Sided) 95%; -0.54 to 0.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.152
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.739
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.34 to 0.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.149
	Estimation Comments

135. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Physical Domain Score - Month 12 (MITT-VMS)
Description	Changes in Physical Domain Score from Baseline to Month 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Physical domain score is mean of = Q11 to Q26, with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	97	118	104	104	93
Mean (Standard Deviation) [score on a scale]	-1.0 (1.57)	-1.2 (1.29)	-1.4 (1.60)	-1.1 (1.44)	-0.9 (1.39)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.635
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.08
	Confidence Interval	(2-Sided) 95%; -0.42 to 0.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.171
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.43
	Confidence Interval	(2-Sided) 95%; -0.75 to -0.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.164
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.092
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.28
	Confidence Interval	(2-Sided) 95%; -0.62 to 0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.169
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.243
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.20
	Confidence Interval	(2-Sided) 95%; -0.53 to 0.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.168
	Estimation Comments

136. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Sexual Domain Score - Week 12 (MITT-VMS)
Description	Changes in Sexual Domain Score from Baseline to Week 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Sexual domain score is mean of = Q27 to Q29, with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	124	135	130	141	116
Mean (Standard Deviation) [score on a scale]	-1.5 (2.03)	-1.1 (1.98)	-1.7 (2.04)	-1.4 (2.16)	-1.3 (2.22)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.049
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.41
	Confidence Interval	(2-Sided) 95%; -0.83 to -0.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.210
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.773
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 95%; -0.34 to 0.46
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.206
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.081
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.36
	Confidence Interval	(2-Sided) 95%; -0.77 to 0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.208
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.625
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.50 to 0.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.204
	Estimation Comments

137. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Sexual Domain Score - Month 6 (MITT-VMS)
Description	Changes in Sexual Domain Score from Baseline to Month 6. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Sexual domain score is mean of = Q27 to Q29, with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	115	130	118	125	104
Mean (Standard Deviation) [score on a scale]	-1.3 (2.18)	-1.2 (2.03)	-1.6 (2.12)	-1.4 (2.13)	-1.3 (1.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.221
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.27
	Confidence Interval	(2-Sided) 95%; -0.70 to 0.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.221
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.992
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.00
	Confidence Interval	(2-Sided) 95%; -0.42 to 0.42
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.214
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.181
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.29
	Confidence Interval	(2-Sided) 95%; -0.72 to 0.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.219
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.846
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -0.47 to 0.38
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.216
	Estimation Comments

138. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Sexual Domain Score - Month 12 (MITT-VMS)
Description	Changes in Sexual Domain Score from Baseline to Month 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Sexual domain score is mean of = Q27 to Q29, with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	96	118	103	104	93
Mean (Standard Deviation) [score on a scale]	-1.0 (2.44)	-1.5 (2.20)	-1.5 (2.26)	-1.4 (2.19)	-1.1 (2.29)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.421
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.21
	Confidence Interval	(2-Sided) 95%; -0.71 to 0.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.257
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.044
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.49
	Confidence Interval	(2-Sided) 95%; -0.97 to -0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.244
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.093
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.42
	Confidence Interval	(2-Sided) 95%; -0.92 to 0.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.252
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.247
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.29
	Confidence Interval	(2-Sided) 95%; -0.79 to 0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.252
	Estimation Comments

139. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Overall Scores - Week 12 (MITT-VMS)
Description	Changes in Overall Scores from Baseline to Week 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. The scale contains four domains: vasomotor, psychosocial, physical and sexual. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The Overall Score is the mean of the 4 domain scores with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	124	135	132	142	116
Mean (Standard Deviation) [score on a scale]	-1.9 (1.20)	-1.6 (1.23)	-1.9 (1.41)	-1.7 (1.31)	-1.4 (1.36)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.58
	Confidence Interval	(2-Sided) 95%; -0.87 to -0.29
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.145
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.016
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.34
	Confidence Interval	(2-Sided) 95%; -0.62 to -0.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.143
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.48
	Confidence Interval	(2-Sided) 95%; -0.76 to -0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.143
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.023
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.32
	Confidence Interval	(2-Sided) 95%; -0.60 to -0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.141
	Estimation Comments

140. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Overall Scores - Month 6 (MITT-VMS)
Description	Changes in Overall Scores from Baseline to Month 6. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. The scale contains four domains: vasomotor, psychosocial, physical and sexual. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The Overall Score is the mean of the 4 domain scores with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	116	130	118	126	104
Mean (Standard Deviation) [score on a scale]	-2.0 (1.22)	-1.8 (1.22)	-2.1 (1.50)	-1.7 (1.24)	-1.6 (1.31)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.55
	Confidence Interval	(2-Sided) 95%; -0.84 to -0.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.150
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.42
	Confidence Interval	(2-Sided) 95%; -0.71 to -0.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.146
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.44
	Confidence Interval	(2-Sided) 95%; -0.73 to -0.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.149
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.179
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.20
	Confidence Interval	(2-Sided) 95%; -0.49 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.147
	Estimation Comments

141. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Overall Scores - Month 12 (MITT-VMS)
Description	Changes in Overall Scores from Baseline to Month 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. The scale contains four domains: vasomotor, psychosocial, physical and sexual. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The Overall Score is the mean of the 4 domain scores with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	97	118	104	104	93
Mean (Standard Deviation) [score on a scale]	-1.8 (1.45)	-2.0 (1.27)	-2.0 (1.50)	-1.7 (1.29)	-1.5 (1.50)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.012
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.43
	Confidence Interval	(2-Sided) 95%; -0.76 to -0.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.169
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.73
	Confidence Interval	(2-Sided) 95%; -1.05 to -0.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.162
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.49
	Confidence Interval	(2-Sided) 95%; -0.81 to -0.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.166
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.070
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.30
	Confidence Interval	(2-Sided) 95%; -0.63 to 0.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.166
	Estimation Comments

142. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Sleep Scale - Total Sleep Score - Week 12 (MITT-VMS)
Description	Change from Baseline to Wk 12 in MOS Total Sleep Score as compared w/Placebo. MOS-Sleep Self Report Questionnaire is 12 items that measure 6 dimensions of sleep over past 4 wks. Q1 scored on scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 self-reported hrs of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Total score includes items Q1, 3, 4, 5, 6, 7, 8, 9, & 12. Scoring method: Answers to Q3, 5, 6, 7, 8, 9 are reversed & rescaled to realign to be same direction and range (0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Answers to Q1, 4, & 12 are rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25; MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Total score= average of item scores; ranges =0 to 100, where higher score means worse outcome. If any of individual questions used to obtain total score is missing, total score will be set to missing value.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	122	134	131	136	111
Mean (Standard Deviation) [score on a scale]	-16.7 (16.99)	-13.1 (16.22)	-18.5 (19.41)	-14.6 (18.80)	-11.5 (19.67)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.033
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.39
	Confidence Interval	(2-Sided) 95%; -8.44 to -0.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.059
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.207
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.54
	Confidence Interval	(2-Sided) 95%; -6.50 to 1.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.015
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.024
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.60
	Confidence Interval	(2-Sided) 95%; -8.58 to -0.61
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.030
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.207
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.53
	Confidence Interval	(2-Sided) 95%; -6.47 to 1.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.007
	Estimation Comments

143. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Sleep Scale - Total Sleep Score - Month 6 (MITT-VMS)
Description	Change from Baseline to Month 6 in MOS Total Sleep Score as compared w/Placebo. MOS-Sleep Self Report Questionnaire is 12 items that measure 6 dimensions of sleep over past 4 wks. Q1 scored on scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 self-reported hrs of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Total score includes items Q1, 3, 4, 5, 6, 7, 8, 9, & 12. Scoring method: Answers to Q3, 5, 6, 7, 8, 9 are reversed & rescaled to realign to be same direction and range (0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Answers to Q1, 4, & 12 are rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25; MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Total score= average of item scores; ranges =0 to 100, where higher score means worse outcome. If any of individual questions used to obtain total score is missing, total score will be set to missing value.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	113	124	118	123	101
Mean (Standard Deviation) [score on a scale]	-17.8 (17.28)	-16.0 (16.60)	-19.8 (21.18)	-16.6 (19.01)	-11.7 (19.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.48
	Confidence Interval	(2-Sided) 95%; -9.68 to -1.28
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.138
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.012
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.25
	Confidence Interval	(2-Sided) 95%; -9.36 to -1.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.093
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.58
	Confidence Interval	(2-Sided) 95%; -9.75 to -1.41
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.122
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.018
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.99
	Confidence Interval	(2-Sided) 95%; -9.11 to -0.87
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.096
	Estimation Comments

144. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Sleep Scale - Total Sleep Score - Month 12 (MITT-VMS)
Description	Change from Baseline to Month 12 in MOS Total Sleep Score as compared w/Placebo. MOS-Sleep Self Report Questionnaire is 12 items that measure 6 dimensions of sleep over past 4 wks. Q1 scored on scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 self-reported hrs of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Total score includes items Q1, 3, 4, 5, 6, 7, 8, 9, & 12. Scoring method: Answers to Q3, 5, 6, 7, 8, 9 are reversed & rescaled to realign to be same direction and range (0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Answers to Q1, 4, & 12 are rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25; MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Total score= average of item scores; ranges =0 to 100, where higher score means worse outcome. If any of individual questions used to obtain total score is missing, total score will be set to missing value.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	96	117	102	100	92
Mean (Standard Deviation) [score on a scale]	-14.9 (21.09)	-15.8 (17.72)	-20.6 (21.58)	-17.6 (18.81)	-10.3 (21.78)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.058
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.61
	Confidence Interval	(2-Sided) 95%; -9.38 to 0.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.427
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.48
	Confidence Interval	(2-Sided) 95%; -12.04 to -2.92
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.322
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.96
	Confidence Interval	(2-Sided) 95%; -12.67 to -3.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.397
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.78
	Confidence Interval	(2-Sided) 95%; -11.50 to -2.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.404
	Estimation Comments

145. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Disturbance - Week 12 (MITT-VMS)
Description	Change from Baseline to Wk 12 in MOS Sleep Disturbance individual score as compared with Placebo. MOS-Sleep Self Report Questionnaire is 12 items that measure 6 dimensions of sleep over past 4 wks. Q1 scored on scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 self-reported hrs of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep disturbance includes items Q1, Q3, Q7, Q8. Scoring method: Answer to Q1 is rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25. Answers to Q3, 7, 8 are reversed & rescaled to realign to be same direction and range(0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Score is average of item scores; score range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	124	135	132	142	116
Mean (Standard Deviation) [score on a scale]	-22.3 (23.72)	-17.7 (24.75)	-23.6 (25.07)	-19.3 (26.31)	-15.1 (26.65)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.020
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.48
	Confidence Interval	(2-Sided) 95%; -11.92 to -1.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.770
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.216
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.36
	Confidence Interval	(2-Sided) 95%; -8.69 to 1.97
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.715
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.033
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.85
	Confidence Interval	(2-Sided) 95%; -11.22 to -0.48
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.734
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.265
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.99
	Confidence Interval	(2-Sided) 95%; -8.27 to 2.28
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.685
	Estimation Comments

146. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Disturbance - Month 6 - (MITT-VMS)
Description	Change from Baseline to Month 6 in MOS Sleep Disturbance individual score as compared with Placebo. MOS-Sleep Self Report Questionnaire is 12 items that measure 6 dimensions of sleep over past 4 wks. Q1 scored on scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 self-reported hrs of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep disturbance includes items Q1, Q3, Q7, Q8. Scoring method: Answer to Q1 is rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25. Answers to Q3, 7, 8 are reversed & rescaled to realign to be same direction and range(0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Score is average of item scores; score range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	116	130	118	126	104
Mean (Standard Deviation) [score on a scale]	-23.5 (25.99)	-21.3 (24.42)	-26.9 (26.91)	-22.4 (26.76)	-15.4 (27.57)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.54
	Confidence Interval	(2-Sided) 95%; -13.14 to -1.93
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.854
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.016
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.72
	Confidence Interval	(2-Sided) 95%; -12.18 to -1.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.781
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-8.69
	Confidence Interval	(2-Sided) 95%; -14.28 to -3.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.847
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.028
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.18
	Confidence Interval	(2-Sided) 95%; -11.68 to -0.68
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.800
	Estimation Comments

147. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Disturbance - Month 12 - (MITT-VMS)
Description	Change from Baseline to Month 12 in MOS Sleep Disturbance individual score as compared with Placebo. MOS-Sleep Self Report Questionnaire is 12 items that measure 6 dimensions of sleep over past 4 wks. Q1 scored on scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 self-reported hrs of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep disturbance includes items Q1, Q3, Q7, Q8. Scoring method: Answer to Q1 is rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25. Answers to Q3, 7, 8 are reversed & rescaled to realign to be same direction and range(0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Score is average of item scores; score range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	97	118	104	104	93
Mean (Standard Deviation) [score on a scale]	-20.0 (28.25)	-22.3 (24.84)	-26.1 (27.21)	-26.1 (25.32)	-14.1 (28.67)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.040
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.56
	Confidence Interval	(2-Sided) 95%; -12.80 to -0.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.180
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-10.02
	Confidence Interval	(2-Sided) 95%; -15.99 to -4.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.040
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-9.96
	Confidence Interval	(2-Sided) 95%; -16.11 to -3.81
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.129
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.029
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.85
	Confidence Interval	(2-Sided) 95%; -12.99 to -0.70
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.127
	Estimation Comments

148. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Snoring - Week 12 - (MITT-VMS)
Description	Change from Baseline to Wk 12 in MOS Snoring individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Snoring item is Q10. Scoring method: Answer to Q10 is reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	121	135	130	141	116
Mean (Standard Deviation) [score on a scale]	-0.5 (23.73)	-3.6 (25.84)	-7.1 (28.49)	-5.7 (24.65)	-5.7 (25.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.294
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.15
	Confidence Interval	(2-Sided) 95%; -2.75 to 9.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.003
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.327
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.86
	Confidence Interval	(2-Sided) 95%; -2.87 to 8.60
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.922
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.637
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.39
	Confidence Interval	(2-Sided) 95%; -7.18 to 4.39
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.947
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.952
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.17
	Confidence Interval	(2-Sided) 95%; -5.51 to 5.86
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.893
	Estimation Comments

149. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Snoring - Month 6 - (MITT-VMS)
Description	Change from Baseline to Month 6 in MOS Snoring individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Snoring item is Q10. Scoring method: Answer to Q10 is reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	112	130	118	125	104
Mean (Standard Deviation) [score on a scale]	0.7 (26.29)	-5.5 (26.24)	-8.8 (24.47)	-6.1 (30.29)	-3.5 (27.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.573
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.82
	Confidence Interval	(2-Sided) 95%; -4.51 to 8.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.219
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.769
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.91
	Confidence Interval	(2-Sided) 95%; -7.01 to 5.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.107
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.047
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.33
	Confidence Interval	(2-Sided) 95%; -12.56 to -0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.176
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.409
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.59
	Confidence Interval	(2-Sided) 95%; -8.74 to 3.56
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.133
	Estimation Comments

150. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Snoring - Month 12 - (MITT-VMS)
Description	Change from Baseline to Month 12 in MOS Snoring individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Snoring item is Q10. Scoring method: Answer to Q10 is reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	95	118	104	103	93
Mean (Standard Deviation) [score on a scale]	-1.1 (28.04)	-10.5 (29.43)	-6.2 (27.03)	-8.0 (26.77)	-4.5 (26.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.579
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.91
	Confidence Interval	(2-Sided) 95%; -4.85 to 8.67
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.443
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.223
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.99
	Confidence Interval	(2-Sided) 95%; -10.43 to 2.44
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.275
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.542
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.05
	Confidence Interval	(2-Sided) 95%; -8.67 to 4.56
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.367
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.476
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.41
	Confidence Interval	(2-Sided) 95%; -9.04 to 4.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.376
	Estimation Comments

151. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Short of Breath or Headache - Week 12 - (MITT-VMS)
Description	Change from Baseline to Wk 12 in MOS Sleep Short of Breath or Headache(SOBHA) individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. SOBHA item is Q5. Scoring method: Answer to Q5 is reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	124	135	132	142	116
Mean (Standard Deviation) [score on a scale]	-7.7 (26.83)	-4.3 (22.18)	-12.3 (29.62)	-7.9 (27.67)	-3.6 (25.52)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.631
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.25
	Confidence Interval	(2-Sided) 95%; -6.34 to 3.84
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.593
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.651
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.15
	Confidence Interval	(2-Sided) 95%; -3.84 to 6.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.540
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.813
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.61
	Confidence Interval	(2-Sided) 95%; -5.67 to 4.45
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.578
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.869
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.42
	Confidence Interval	(2-Sided) 95%; -5.35 to 4.52
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.515
	Estimation Comments

152. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Short of Breath or Headache - Month 6 - (MITT-VMS)
Description	Change from Baseline to Month 6 in MOS Sleep Short of Breath or Headache(SOBHA) individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. SOBHA item is Q5. Scoring method: Answer to Q5 is reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	116	129	118	126	104
Mean (Standard Deviation) [score on a scale]	-9.7 (27.72)	-5.0 (27.50)	-11.0 (33.55)	-7.3 (26.96)	-2.1 (23.47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.074
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.00
	Confidence Interval	(2-Sided) 95%; -10.48 to 0.48
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.790
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.748
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.87
	Confidence Interval	(2-Sided) 95%; -6.22 to 4.47
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.722
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.987
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 95%; -5.46 to 5.56
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.805
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.709
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.02
	Confidence Interval	(2-Sided) 95%; -6.41 to 4.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.741
	Estimation Comments

153. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Short of Breath or Headache - Month 12 - (MITT-VMS)
Description	Change from Baseline to Month 12 in MOS Sleep Short of Breath or Headache(SOBHA) individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. SOBHA item is Q5. Scoring method: Answer to Q5 is reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	97	118	103	104	93
Mean (Standard Deviation) [score on a scale]	-8.9 (30.41)	-7.1 (24.60)	-12.4 (34.65)	-10.8 (27.15)	-2.8 (27.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.379
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.61
	Confidence Interval	(2-Sided) 95%; -8.44 to 3.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.968
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.279
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.07
	Confidence Interval	(2-Sided) 95%; -8.64 to 2.49
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.832
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.894
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.39
	Confidence Interval	(2-Sided) 95%; -6.19 to 5.40
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.949
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.308
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.98
	Confidence Interval	(2-Sided) 95%; -8.72 to 2.76
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.923
	Estimation Comments

154. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Adequacy - Week 12 - (MITT-VMS)
Description	Change from Baseline to Wk 12 in MOS Sleep Adequacy individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Sleep Adequacy includes items Q4, Q12. Scoring method: Answers for Q4 and Q12 are reversed and rescaled to 0-100 as follows: MOS_4_new = (6-MOS_4_old) x 20; MOS_12_new = (6-MOS_12_old) x 20. Score is the average of item scores; score range = 0 to 100, where higher score means better outcome.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	124	135	132	142	116
Mean (Standard Deviation) [score on a scale]	12.8 (28.30)	11.0 (26.57)	17.3 (30.06)	10.7 (28.33)	11.3 (26.09)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.558
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.81
	Confidence Interval	(2-Sided) 95%; -4.24 to 7.86
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.081
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.233
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.61
	Confidence Interval	(2-Sided) 95%; -2.34 to 9.57
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.031
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.043
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	6.16
	Confidence Interval	(2-Sided) 95%; 0.20 to 12.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.036
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.488
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.07
	Confidence Interval	(2-Sided) 95%; -3.80 to 7.95
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.990
	Estimation Comments

155. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Adequacy - Month 6 - (MITT-VMS)
Description	Change from Baseline to Month 6 in MOS Sleep Adequacy individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Sleep Adequacy includes items Q4, Q12. Scoring method: Answers for Q4 and Q12 are reversed and rescaled to 0-100 as follows: MOS_4_new = (6-MOS_4_old) x 20; MOS_12_new = (6-MOS_12_old) x 20. Score is the average of item scores; score range = 0 to 100, where higher score means better outcome.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	116	130	118	126	104
Mean (Standard Deviation) [score on a scale]	13.2 (28.61)	15.2 (26.89)	14.7 (30.12)	15.2 (28.75)	9.5 (27.36)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.205
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.07
	Confidence Interval	(2-Sided) 95%; -2.23 to 10.37
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.206
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	9.58
	Confidence Interval	(2-Sided) 95%; 3.43 to 15.74
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.133
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.115
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.04
	Confidence Interval	(2-Sided) 95%; -1.23 to 11.32
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.193
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	8.94
	Confidence Interval	(2-Sided) 95%; 2.75 to 15.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.152
	Estimation Comments

156. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Adequacy - Month 12 - (MITT-VMS)
Description	Change from Baseline to Month 12 in MOS Sleep Adequacy individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Sleep Adequacy includes items Q4, Q12. Scoring method: Answers for Q4 and Q12 are reversed and rescaled to 0-100 as follows: MOS_4_new = (6-MOS_4_old) x 20; MOS_12_new = (6-MOS_12_old) x 20. Score is the average of item scores; score range = 0 to 100, where higher score means better outcome.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	97	118	104	104	93
Mean (Standard Deviation) [score on a scale]	10.4 (28.43)	10.5 (31.07)	17.6 (31.61)	13.7 (27.70)	10.0 (31.76)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.796
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; -6.34 to 8.27
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.719
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.150
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.14
	Confidence Interval	(2-Sided) 95%; -1.87 to 12.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.568
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.019
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	8.58
	Confidence Interval	(2-Sided) 95%; 1.39 to 15.77
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.657
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.041
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.51
	Confidence Interval	(2-Sided) 95%; 0.30 to 14.71
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 3.667
	Estimation Comments

157. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Somnolence - Week 12 - (MITT-VMS)
Description	Change from Baseline to Wk 12 in MOS Sleep Somnolence individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Sleep Somnolence items include Q6, Q9, Q11. Scoring method: Answers to Q6, Q 9 and Q11 are reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	124	135	132	142	116
Mean (Standard Deviation) [score on a scale]	-11.3 (20.70)	-9.2 (17.82)	-10.4 (22.61)	-10.8 (21.78)	-8.7 (20.62)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.221
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.69
	Confidence Interval	(2-Sided) 95%; -7.00 to 1.62
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.197
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.511
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.42
	Confidence Interval	(2-Sided) 95%; -5.65 to 2.81
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.154
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.761
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.66
	Confidence Interval	(2-Sided) 95%; -3.60 to 4.92
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.168
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.332
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.07
	Confidence Interval	(2-Sided) 95%; -6.25 to 2.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.128
	Estimation Comments

158. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Somnolence - Month 6 - (MITT-VMS)
Description	Change from Baseline to Month 6 in MOS Sleep Somnolence individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Sleep Somnolence items include Q6, Q9, Q11. Scoring method: Answers to Q6, Q 9 and Q11 are reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	116	130	118	126	104
Mean (Standard Deviation) [score on a scale]	-10.1 (21.60)	-10.8 (21.46)	-12.4 (22.98)	-10.5 (23.69)	-9.6 (21.64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.687
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.00
	Confidence Interval	(2-Sided) 95%; -5.86 to 3.86
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.474
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.373
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.15
	Confidence Interval	(2-Sided) 95%; -6.88 to 2.58
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.411
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.714
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.91
	Confidence Interval	(2-Sided) 95%; -5.75 to 3.94
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.466
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.711
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.90
	Confidence Interval	(2-Sided) 95%; -5.67 to 3.87
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.427
	Estimation Comments

159. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Somnolence - Month 12 - (MITT-VMS)
Description	Change from Baseline to Month 12 in MOS Sleep Somnolence individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Sleep Somnolence items include Q6, Q9, Q11. Scoring method: Answers to Q6, Q 9 and Q11 are reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	97	118	104	104	93
Mean (Standard Deviation) [score on a scale]	-8.0 (22.93)	-11.1 (21.51)	-13.1 (20.03)	-13.4 (23.82)	-6.7 (25.95)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.415
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.19
	Confidence Interval	(2-Sided) 95%; -7.46 to 3.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.682
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.019
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.01
	Confidence Interval	(2-Sided) 95%; -11.04 to -0.97
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.564
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.074
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.72
	Confidence Interval	(2-Sided) 95%; -9.90 to 0.46
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.639
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.030
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.75
	Confidence Interval	(2-Sided) 95%; -10.94 to -0.57
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.637
	Estimation Comments

160. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Problems Index I - Week 12 - (MITT-VMS)
Description	Change from Baseline to Wk 12 in MOS Sleep Problems Index I individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep Problems Index I includes items Q4, Q5, Q7, Q8, Q9, Q12. Scoring method: Answers to Q, 5, 7, 8, 9 are reversed & rescaled to realign to be same direction and range (0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Answers to Q4, & 12 are rescaled to 0-100 as follows: MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	124	135	132	142	116
Mean (Standard Deviation) [score on a scale]	-15.2 (17.45)	-11.3 (17.04)	-17.7 (19.47)	-13.5 (19.65)	-9.9 (20.50)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.059
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.99
	Confidence Interval	(2-Sided) 95%; -8.13 to 0.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.109
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.215
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.57
	Confidence Interval	(2-Sided) 95%; -6.63 to 1.49
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.067
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.015
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.10
	Confidence Interval	(2-Sided) 95%; -9.19 to -1.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.084
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.122
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.16
	Confidence Interval	(2-Sided) 95%; -7.17 to 0.85
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.042
	Estimation Comments

161. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Problems Index I - Month 6 - (MITT-VMS)
Description	Change from Baseline to Month 6 in MOS Sleep Problems Index I individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep Problems Index I includes items Q4, Q5, Q7, Q8, Q9, Q12. Scoring method: Answers to Q, 5, 7, 8, 9 are reversed & rescaled to realign to be same direction and range (0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Answers to Q4, & 12 are rescaled to 0-100 as follows: MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	116	130	118	126	104
Mean (Standard Deviation) [score on a scale]	-16.1 (16.64)	-14.3 (16.56)	-18.0 (20.71)	-15.7 (19.34)	-9.8 (20.37)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.013
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.32
	Confidence Interval	(2-Sided) 95%; -9.52 to -1.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.135
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.76
	Confidence Interval	(2-Sided) 95%; -9.85 to -1.68
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.080
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.59
	Confidence Interval	(2-Sided) 95%; -9.77 to -1.40
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.132
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.68
	Confidence Interval	(2-Sided) 95%; -9.79 to -1.57
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.093
	Estimation Comments

162. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Problems Index I - Month 12 - (MITT-VMS)
Description	Change from Baseline to Month 12 in MOS Sleep Problems Index I individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep Problems Index I includes items Q4, Q5, Q7, Q8, Q9, Q12. Scoring method: Answers to Q, 5, 7, 8, 9 are reversed & rescaled to realign to be same direction and range (0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Answers to Q4, & 12 are rescaled to 0-100 as follows: MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	97	118	104	104	93
Mean (Standard Deviation) [score on a scale]	-13.3 (20.52)	-13.5 (18.04)	-18.9 (21.49)	-16.1 (20.01)	-9.1 (22.62)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.171
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.39
	Confidence Interval	(2-Sided) 95%; -8.24 to 1.47
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.470
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.49
	Confidence Interval	(2-Sided) 95%; -11.14 to -1.85
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.364
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.39
	Confidence Interval	(2-Sided) 95%; -12.17 to -2.61
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.434
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.69
	Confidence Interval	(2-Sided) 95%; -11.46 to -1.92
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.429
	Estimation Comments

163. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Problems Index II - Week 12 - (MITT-VMS)
Description	Change from Baseline to Wk 12 in MOS Sleep Problems Index II individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self reported hours of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep Problems Index II items include Q1, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q12. Scoring method: Answers to Q3, 5, 6, 7, 8, & 9 are reversed & rescaled to realign to be same direction and range 0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20, for n=Q3, 5, 6, 7, 8, and 9. Answers to Q1, 4 & 12 are rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25; MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	124	135	132	142	116
Mean (Standard Deviation) [score on a scale]	-16.8 (17.14)	-13.1 (16.16)	-18.5 (19.34)	-14.4 (19.19)	-11.8 (19.56)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.039
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.21
	Confidence Interval	(2-Sided) 95%; -8.21 to -0.21
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.037
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.232
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.39
	Confidence Interval	(2-Sided) 95%; -6.31 to 1.53
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.997
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.030
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.37
	Confidence Interval	(2-Sided) 95%; -8.32 to -0.42
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.012
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.262
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.22
	Confidence Interval	(2-Sided) 95%; -6.09 to 1.66
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.973
	Estimation Comments

164. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Problems Index II - Month 6 - (MITT-VMS)
Description	Change from Baseline to Month 6 in MOS Sleep Problems Index II individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self reported hours of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep Problems Index II items include Q1, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q12. Scoring method: Answers to Q3, 5, 6, 7, 8, & 9 are reversed & rescaled to realign to be same direction and range 0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20, for n=Q3, 5, 6, 7, 8, and 9. Answers to Q1, 4 & 12 are rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25; MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	116	130	118	126	104
Mean (Standard Deviation) [score on a scale]	-17.5 (17.40)	-16.0 (16.69)	-19.8 (21.18)	-17.0 (19.02)	-11.6 (19.31)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.41
	Confidence Interval	(2-Sided) 95%; -9.57 to -1.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.119
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.54
	Confidence Interval	(2-Sided) 95%; -9.60 to -1.48
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.065
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.74
	Confidence Interval	(2-Sided) 95%; -9.90 to -1.59
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.115
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.32
	Confidence Interval	(2-Sided) 95%; -9.40 to -1.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.078
	Estimation Comments

165. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Problems Index II - Month 12 - (MITT-VMS)
Description	Change from Baseline to Month 12 in MOS Sleep Problems Index II individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self reported hours of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep Problems Index II items include Q1, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q12. Scoring method: Answers to Q3, 5, 6, 7, 8, & 9 are reversed & rescaled to realign to be same direction and range 0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20, for n=Q3, 5, 6, 7, 8, and 9. Answers to Q1, 4 & 12 are rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25; MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	97	118	104	104	93
Mean (Standard Deviation) [score on a scale]	-14.7 (21.13)	-15.7 (17.65)	-20.5 (21.49)	-17.4 (19.48)	-10.5 (21.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.083
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.21
	Confidence Interval	(2-Sided) 95%; -8.96 to 0.55
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.421
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.36
	Confidence Interval	(2-Sided) 95%; -11.91 to -2.81
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.317
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.92
	Confidence Interval	(2-Sided) 95%; -12.60 to -3.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.384
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.005
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.78
	Confidence Interval	(2-Sided) 95%; -11.46 to -2.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.381
	Estimation Comments

166. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Optimal Sleep - Week 12 - (MITT-VMS)
Description	Change from Baseline (BL) to Week 12 in MOS Optimal Sleep Score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items measuring 6 dimensions of sleep over the past 4 wks. Optimal sleep is based on Q2 (self-reported average hrs sleep per night in past 4 wks). Scoring method: hrs of sleep coded 0 (non-optimal) or 1 (optimal) where 1-6 hrs & 9-23 hrs = 0, 7-8 hrs = 1. Change from BL: subject sleeps 7-8 hrs at BL & 1-6 or 9-23 hrs at follow-up, change = -1; subject sleeps 1-6 or 9-23 hrs at BL & 7-8 hrs at follow-up, change = +1; subject sleeps 1-6 or 9-23 hrs at BL & 1-6 or 9-23 hrs at follow-up, change = 0. Mean change from BL: changes are summed to give the Net Total (equivalent to the number subjects w/ improved sleep hrs minus the number subjects w/ worsened sleep hrs), which is divided by the number of subjects to give the mean proportion of net change, where >0 = overall improvement and <0 = overall worsening in the study arm.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	123	134	132	142	115
Mean (Standard Deviation) [Proportion of Net Change]	0.2 (0.55)	0.2 (0.54)	0.2 (0.45)	0.2 (0.53)	0.2 (0.58)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.938
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.00
	Confidence Interval	(2-Sided) 95%; -0.12 to 0.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.060
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.779
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.10 to 0.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.059
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.646
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.03
	Confidence Interval	(2-Sided) 95%; -0.14 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.059
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.421
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.05
	Confidence Interval	(2-Sided) 95%; -0.07 to 0.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.058
	Estimation Comments

167. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Optimal Sleep - Month 6 - (MITT-VMS)
Description	Change from Baseline (BL) to Month 6 in MOS Optimal Sleep Score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items measuring 6 dimensions of sleep over the past 4 wks. Optimal sleep is based on Q2 (self-reported average hrs sleep per night in past 4 wks). Scoring method: hrs of sleep coded 0 (non-optimal) or 1 (optimal) where 1-6 hrs & 9-23 hrs = 0, 7-8 hrs = 1. Change from BL: subject sleeps 7-8 hrs at BL & 1-6 or 9-23 hrs at follow-up, change = -1; subject sleeps 1-6 or 9-23 hrs at BL & 7-8 hrs at follow-up, change = +1; subject sleeps 1-6 or 9-23 hrs at BL & 1-6 or 9-23 hrs at follow-up, change = 0. Mean change from BL: changes are summed to give the Net Total (equivalent to the number subjects w/ improved sleep hrs minus the number subjects w/ worsened sleep hrs), which is divided by the number of subjects to give the mean proportion of net change, where >0 = overall improvement and <0 = overall worsening in the study arm.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	115	129	118	125	104
Mean (Standard Deviation) [Proportion of Net Change]	0.3 (0.52)	0.2 (0.52)	0.2 (0.57)	0.1 (0.57)	0.2 (0.52)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.075
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; -0.01 to 0.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.063
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.074
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; -0.01 to 0.23
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.062
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.370
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 95%; -0.07 to 0.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.063
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.851
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.11 to 0.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.062
	Estimation Comments

168. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Optimal Sleep - Month 12 - (MITT-VMS)
Description	Change from Baseline (BL) to Month 12 in MOS Optimal Sleep Score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items measuring 6 dimensions of sleep over the past 4 wks. Optimal sleep is based on Q2 (self-reported average hrs sleep per night in past 4 wks). Scoring method: hrs of sleep coded 0 (non-optimal) or 1 (optimal) where 1-6 hrs & 9-23 hrs = 0, 7-8 hrs = 1. Change from BL: subject sleeps 7-8 hrs at BL & 1-6 or 9-23 hrs at follow-up, change = -1; subject sleeps 1-6 or 9-23 hrs at BL & 7-8 hrs at follow-up, change = +1; subject sleeps 1-6 or 9-23 hrs at BL & 1-6 or 9-23 hrs at follow-up, change = 0. Mean change from BL: changes are summed to give the Net Total (equivalent to the number subjects w/ improved sleep hrs minus the number subjects w/ worsened sleep hrs), which is divided by the number of subjects to give the mean proportion of net change, where >0 = overall improvement and <0 = overall worsening in the study arm.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

Randomized to the VMS Substudy, taken one dose of IP, and had at least 5 days of VMS diary data for baseline measurement of freq. & severity of moderate to severe hot flushes, and had at least 4 days of VMS diary data for 1 on-treatment week of reporting freq. & severity of hot flushes following initiation of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	96	117	104	104	93
Mean (Standard Deviation) [Proportion of Net Change]	0.2 (0.47)	0.3 (0.58)	0.1 (0.57)	0.1 (0.51)	0.2 (0.47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.452
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.05
	Confidence Interval	(2-Sided) 95%; -0.18 to 0.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.067
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.244
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.07
	Confidence Interval	(2-Sided) 95%; -0.05 to 0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.064
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.354
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.06
	Confidence Interval	(2-Sided) 95%; -0.19 to 0.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.065
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.527
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -0.17 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.065
	Estimation Comments

169. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Vasomotor Domain Score - Week 12 (MITT)
Description	Changes in Vasomotor Domain Score from Baseline to Week 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Vasomotor domain score is mean of = Q1,Q2, Q3, with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	354	364	375	376	117
Mean (Standard Deviation) [score on a scale]	-3.5 (2.02)	-3.1 (2.00)	-3.1 (2.01)	-2.9 (1.94)	-2.2 (1.84)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.92
	Confidence Interval	(2-Sided) 95%; -2.29 to -1.55
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.190
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.44
	Confidence Interval	(2-Sided) 95%; -1.81 to -1.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.189
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.44
	Confidence Interval	(2-Sided) 95%; -1.81 to -1.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.189
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.25
	Confidence Interval	(2-Sided) 95%; -1.62 to -0.88
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.188
	Estimation Comments

170. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Vasomotor Domain Score - Month 6 (MITT)
Description	Changes in Vasomotor Domain Score from Baseline to Month 6. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Vasomotor domain score is mean of = Q1,Q2, Q3, with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	316	333	342	324	104
Mean (Standard Deviation) [score on a scale]	-4.0 (1.95)	-3.7 (2.02)	-3.5 (2.15)	-3.3 (1.94)	-3.0 (2.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.73
	Confidence Interval	(2-Sided) 95%; -2.12 to -1.34
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.199
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.29
	Confidence Interval	(2-Sided) 95%; -1.68 to -0.91
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.197
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.20
	Confidence Interval	(2-Sided) 95%; -1.58 to -0.81
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.197
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.96
	Confidence Interval	(2-Sided) 95%; -1.34 to -0.57
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.198
	Estimation Comments

171. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Vasomotor Domain Score - Month 12 (MITT)
Description	Changes in Vasomotor Domain Score from Baseline to Month 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Vasomotor domain score is mean of = Q1,Q2, Q3, with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	283	304	312	280	93
Mean (Standard Deviation) [score on a scale]	-3.8 (2.05)	-3.7 (1.89)	-3.4 (2.06)	-3.3 (1.80)	-2.8 (2.26)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.65
	Confidence Interval	(2-Sided) 95%; -2.06 to -1.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.207
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.47
	Confidence Interval	(2-Sided) 95%; -1.87 to -1.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.204
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.30
	Confidence Interval	(2-Sided) 95%; -1.70 to -0.90
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.205
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.08
	Confidence Interval	(2-Sided) 95%; -1.48 to -0.67
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.207
	Estimation Comments

172. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Psychosocial Domain Score - Week 12 (MITT)
Description	Changes in Psychosocial Domain Score from Baseline to Week 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Psychosocial domain score is mean of = Q4 to Q10, with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	354	363	373	376	117
Mean (Standard Deviation) [score on a scale]	-1.1 (1.52)	-1.0 (1.66)	-1.1 (1.58)	-1.0 (1.49)	-1.0 (1.68)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.126
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.20
	Confidence Interval	(2-Sided) 95%; -0.46 to 0.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.131
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.200
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -0.42 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.130
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.222
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.16
	Confidence Interval	(2-Sided) 95%; -0.41 to 0.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.130
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.358
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95%; -0.37 to 0.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.130
	Estimation Comments

173. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Psychosocial Domain Score - Month 6 (MITT)
Description	Changes in Psychosocial Domain Score from Baseline to Month 6. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Psychosocial domain score is mean of = Q4 to Q10, with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	316	330	343	324	104
Mean (Standard Deviation) [score on a scale]	-1.3 (1.68)	-1.1 (1.65)	-1.1 (1.65)	-1.0 (1.55)	-1.0 (1.61)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.023
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.31
	Confidence Interval	(2-Sided) 95%; -0.59 to -0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.138
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.045
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.28
	Confidence Interval	(2-Sided) 95%; -0.55 to -0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.138
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.384
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95%; -0.39 to 0.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.137
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.424
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.11
	Confidence Interval	(2-Sided) 95%; -0.38 to 0.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.138
	Estimation Comments

174. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Psychosocial Domain Score - Month 12 (MITT)
Description	Changes in Psychosocial Domain Score from Baseline to Month 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Psychosocial domain score is mean of = Q4 to Q10, with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	282	303	312	280	93
Mean (Standard Deviation) [score on a scale]	-1.1 (1.65)	-1.1 (1.74)	-1.1 (1.66)	-1.0 (1.64)	-1.0 (1.61)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.153
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.22
	Confidence Interval	(2-Sided) 95%; -0.52 to 0.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.152
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.058
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.29
	Confidence Interval	(2-Sided) 95%; -0.58 to 0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.151
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.550
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.09
	Confidence Interval	(2-Sided) 95%; -0.39 to 0.21
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.151
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.854
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.03
	Confidence Interval	(2-Sided) 95%; -0.33 to 0.27
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.153
	Estimation Comments

175. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Physical Domain Score - Week 12 (MITT)
Description	Changes in Physical Domain Score from Baseline to Week 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Physical domain score is mean of = Q11 to Q26, with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	354	364	374	376	117
Mean (Standard Deviation) [score on a scale]	-1.1 (1.41)	-1.1 (1.44)	-1.3 (1.40)	-1.1 (1.39)	-1.0 (1.38)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.181
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.16
	Confidence Interval	(2-Sided) 95%; -0.38 to 0.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.116
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.108
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.19
	Confidence Interval	(2-Sided) 95%; -0.41 to 0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.116
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.014
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.28
	Confidence Interval	(2-Sided) 95%; -0.51 to -0.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.115
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.323
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.11
	Confidence Interval	(2-Sided) 95%; -0.34 to 0.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.115
	Estimation Comments

176. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Physical Domain Score - Month 6 (MITT)
Description	Changes in Physical Domain Score from Baseline to Month 6. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Physical domain score is mean of = Q11 to Q26, with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	316	332	343	324	104
Mean (Standard Deviation) [score on a scale]	-1.2 (1.42)	-1.1 (1.46)	-1.2 (1.46)	-1.0 (1.39)	-1.1 (1.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.056
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.24
	Confidence Interval	(2-Sided) 95%; -0.48 to 0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.124
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.279
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95%; -0.38 to 0.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.124
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.435
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.10
	Confidence Interval	(2-Sided) 95%; -0.34 to 0.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.123
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.607
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.06
	Confidence Interval	(2-Sided) 95%; -0.31 to 0.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.124
	Estimation Comments

177. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Physical Domain Score - Month 12 (MITT)
Description	Changes in Physical Domain Score from Baseline to Month 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Physical domain score is mean of = Q11 to Q26, with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	282	304	312	280	93
Mean (Standard Deviation) [score on a scale]	-1.1 (1.52)	-1.1 (1.48)	-1.2 (1.43)	-1.1 (1.50)	-0.9 (1.39)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.060
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.26
	Confidence Interval	(2-Sided) 95%; -0.53 to 0.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.138
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.026
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.30
	Confidence Interval	(2-Sided) 95%; -0.57 to -0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.137
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.097
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.23
	Confidence Interval	(2-Sided) 95%; -0.49 to 0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.136
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.230
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -0.44 to 0.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.138
	Estimation Comments

178. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Sexual Domain Score - Week 12 (MITT)
Description	Changes in Sexual Domain Score from Baseline to Week 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Sexual domain score is mean of = Q27 to Q29, with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	352	364	371	375	117
Mean (Standard Deviation) [score on a scale]	-1.4 (2.06)	-1.3 (2.21)	-1.5 (2.02)	-1.5 (2.15)	-1.3 (2.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.107
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.27
	Confidence Interval	(2-Sided) 95%; -0.61 to 0.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.170
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.302
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -0.51 to 0.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.169
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.106
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.27
	Confidence Interval	(2-Sided) 95%; -0.60 to 0.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.169
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.156
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.24
	Confidence Interval	(2-Sided) 95%; -0.57 to 0.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.169
	Estimation Comments

179. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Sexual Domain Score - Month 6 (MITT)
Description	Changes in Sexual Domain Score from Baseline to Month 6. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Sexual domain score is mean of = Q27 to Q29, with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	315	332	342	322	104
Mean (Standard Deviation) [score on a scale]	-1.4 (2.11)	-1.4 (2.12)	-1.4 (2.05)	-1.3 (2.10)	-1.3 (1.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.081
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.31
	Confidence Interval	(2-Sided) 95%; -0.65 to 0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.177
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.212
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.22
	Confidence Interval	(2-Sided) 95%; -0.56 to 0.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.175
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.345
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.17
	Confidence Interval	(2-Sided) 95%; -0.51 to 0.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.175
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.829
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.04
	Confidence Interval	(2-Sided) 95%; -0.38 to 0.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.176
	Estimation Comments

180. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Sexual Domain Score - Month 12 (MITT)
Description	Changes in Sexual Domain Score from Baseline to Month 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The scale contains four domains: vasomotor, psychosocial, physical and sexual. Each domain is scored separately. Sexual domain score is mean of = Q27 to Q29, with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	281	304	310	278	93
Mean (Standard Deviation) [score on a scale]	-1.3 (2.26)	-1.4 (2.32)	-1.3 (2.10)	-1.2 (2.25)	-1.1 (2.29)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.029
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.44
	Confidence Interval	(2-Sided) 95%; -0.84 to -0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.201
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.026
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.45
	Confidence Interval	(2-Sided) 95%; -0.84 to -0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.199
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.093
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.33
	Confidence Interval	(2-Sided) 95%; -0.72 to 0.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.199
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.223
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.25
	Confidence Interval	(2-Sided) 95%; -0.64 to 0.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.202
	Estimation Comments

181. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Overall Scores - Week 12 (MITT)
Description	Change in Overall Scores from Baseline to Week 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. The scale contains four domains: vasomotor, psychosocial, physical and sexual. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The Overall Score is the mean of the 4 domain scores with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	354	364	375	376	117
Mean (Standard Deviation) [score on a scale]	-1.8 (1.31)	-1.6 (1.38)	-1.7 (1.35)	-1.6 (1.35)	-1.4 (1.36)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.62
	Confidence Interval	(2-Sided) 95%; -0.85 to -0.40
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.49
	Confidence Interval	(2-Sided) 95%; -0.71 to -0.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.11
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.52
	Confidence Interval	(2-Sided) 95%; -0.75 to -0.30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.11
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.42
	Confidence Interval	(2-Sided) 95%; -0.64 to -0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.11
	Estimation Comments

182. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Overall Scores - Month 6 (MITT)
Description	Change in Overall Scores from Baseline to Month 6. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. The scale contains four domains: vasomotor, psychosocial, physical and sexual. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The Overall Score is the mean of the 4 domain scores with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	316	333	343	324	104
Mean (Standard Deviation) [score on a scale]	-2.0 (1.32)	-1.8 (1.38)	-1.8 (1.39)	-1.7 (1.29)	-1.6 (1.31)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.61
	Confidence Interval	(2-Sided) 95%; -0.85 to -0.38
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.45
	Confidence Interval	(2-Sided) 95%; -0.69 to -0.22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.36
	Confidence Interval	(2-Sided) 95%; -0.59 to -0.12
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.030
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.26
	Confidence Interval	(2-Sided) 95%; -0.50 to -0.03
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.12
	Estimation Comments

183. Secondary Outcome

Title	Menopause-specific Quality of Life Questionnaire (MENQOL) - Overall Scores - Month 12 (MITT)
Description	Change in Overall Scores from Baseline to Month 12. The MENQOL is self-administered questionnaire which assessed changes in quality of life over a one-month period. It is composed of 29 questions indicating if subject experienced the problem (Yes/No) and if Yes, rating scale ranged from 0=Not bothered at all to 6=Extremely bothered. The scale contains four domains: vasomotor, psychosocial, physical and sexual. For analysis, the original scores were converted to the analysis score ranging from 1-8 where No=1, 0=2, 1=3...and 6=8. The Overall Score is the mean of the 4 domain scores with 1 being "not at all bothered" and 8 being "extremely bothered".
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	283	304	312	280	93
Mean (Standard Deviation) [score on a scale]	-1.8 (1.43)	-1.8 (1.45)	-1.7 (1.38)	-1.6 (1.38)	-1.5 (1.50)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.62
	Confidence Interval	(2-Sided) 95%; -0.89 to -0.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.13
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.62
	Confidence Interval	(2-Sided) 95%; -0.88 to -0.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.13
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.47
	Confidence Interval	(2-Sided) 95%; -0.73 to -0.21
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.13
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.37
	Confidence Interval	(2-Sided) 95%; -0.63 to -0.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.13
	Estimation Comments

184. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Sleep Scale - Total Sleep Score - Week 12 (MITT)
Description	Change from Baseline to Wk 12 in MOS Total Sleep Score as compared w/Placebo. MOS-Sleep Self Report Questionnaire is 12 items that measure 6 dimensions of sleep over past 4 wks. Q1 scored on scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 self-reported hrs of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Total score includes items Q1, 3, 4, 5, 6, 7, 8, 9, & 12. Scoring method: Answers to Q3, 5, 6, 7, 8, 9 are reversed & rescaled to realign to be same direction and range (0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Answers to Q1, 4, & 12 are rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25; MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Total score= average of item scores; ranges =0 to 100, where higher score means worse outcome. If any of individual questions used to obtain total score is missing, total score will be set to missing value.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	350	358	370	365	112
Mean (Standard Deviation) [score on a scale]	-15.1 (17.64)	-13.0 (17.42)	-13.9 (17.40)	-13.3 (18.22)	-11.5 (19.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.88
	Confidence Interval	(2-Sided) 95%; -8.08 to -1.69
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.629
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.027
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.61
	Confidence Interval	(2-Sided) 95%; -6.80 to -0.42
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.626
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.034
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.44
	Confidence Interval	(2-Sided) 95%; -6.61 to -0.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.618
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.119
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.53
	Confidence Interval	(2-Sided) 95%; -5.71 to 0.65
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.621
	Estimation Comments

185. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Sleep Scale - Total Sleep Score - Month 6 (MITT)
Description	Change from Baseline to Month 6 in MOS Total Sleep Score as compared w/Placebo. MOS-Sleep Self Report Questionnaire is 12 items that measure 6 dimensions of sleep over past 4 wks. Q1 scored on scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 self-reported hrs of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Total score includes items Q1, 3, 4, 5, 6, 7, 8, 9, & 12. Scoring method: Answers to Q3, 5, 6, 7, 8, 9 are reversed & rescaled to realign to be same direction and range (0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Answers to Q1, 4, & 12 are rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25; MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Total score= average of item scores; ranges =0 to 100, where higher score means worse outcome. If any of individual questions used to obtain total score is missing, total score will be set to missing value.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	313	321	339	317	101
Mean (Standard Deviation) [score on a scale]	-15.6 (18.13)	-14.8 (16.10)	-14.7 (18.95)	-14.6 (18.93)	-11.7 (19.40)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.39
	Confidence Interval	(2-Sided) 95%; -8.73 to -2.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.700
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.39
	Confidence Interval	(2-Sided) 95%; -8.72 to -2.06
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.696
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.88
	Confidence Interval	(2-Sided) 95%; -8.19 to -1.58
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.685
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.42
	Confidence Interval	(2-Sided) 95%; -7.75 to -1.09
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.698
	Estimation Comments

186. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Sleep Scale - Total Sleep Score - Month 12 (MITT)
Description	Change from Baseline to Month 12 in MOS Total Sleep Score as compared w/Placebo. MOS-Sleep Self Report Questionnaire is 12 items that measure 6 dimensions of sleep over past 4 wks. Q1 scored on scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 self-reported hrs of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Total score includes items Q1, 3, 4, 5, 6, 7, 8, 9, & 12. Scoring method: Answers to Q3, 5, 6, 7, 8, 9 are reversed & rescaled to realign to be same direction and range (0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Answers to Q1, 4, & 12 are rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25; MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Total score= average of item scores; ranges =0 to 100, where higher score means worse outcome. If any of individual questions used to obtain total score is missing, total score will be set to missing value.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	281	300	308	270	92
Mean (Standard Deviation) [score on a scale]	-14.4 (18.36)	-14.5 (17.85)	-15.3 (18.78)	-15.3 (19.28)	-10.3 (21.78)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.54
	Confidence Interval	(2-Sided) 95%; -10.18 to -2.90
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.855
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.61
	Confidence Interval	(2-Sided) 95%; -11.23 to -4.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.843
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.44
	Confidence Interval	(2-Sided) 95%; -11.04 to -3.84
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.835
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.76
	Confidence Interval	(2-Sided) 95%; -10.41 to -3.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.863
	Estimation Comments

187. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Disturbance - Week 12 - (MITT)
Description	Change from Baseline to Wk 12 in MOS Sleep Disturbance individual score as compared with Placebo. MOS-Sleep Self Report Questionnaire is 12 items that measure 6 dimensions of sleep over past 4 wks. Q1 scored on scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 self-reported hrs of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep disturbance includes items Q1, Q3, Q7, Q8. Scoring method: Answer to Q1 is rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25. Answers to Q3, 7, 8 are reversed & rescaled to realign to be same direction and range(0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Score is average of item scores; score range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	354	365	374	376	117
Mean (Standard Deviation) [score on a scale]	-21.0 (23.74)	-18.1 (24.62)	-18.7 (23.11)	-17.3 (24.88)	-14.9 (26.57)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.34
	Confidence Interval	(2-Sided) 95%; -11.55 to -3.13
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.146
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.60
	Confidence Interval	(2-Sided) 95%; -9.80 to -1.40
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.139
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.016
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.13
	Confidence Interval	(2-Sided) 95%; -9.31 to -0.95
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.132
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.154
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.04
	Confidence Interval	(2-Sided) 95%; -7.22 to 1.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.130
	Estimation Comments

188. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Disturbance - Month 6 - (MITT)
Description	Change from Baseline to Month 6 in MOS Sleep Disturbance individual score as compared with Placebo. MOS-Sleep Self Report Questionnaire is 12 items that measure 6 dimensions of sleep over past 4 wks. Q1 scored on scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 self-reported hrs of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep disturbance includes items Q1, Q3, Q7, Q8. Scoring method: Answer to Q1 is rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25. Answers to Q3, 7, 8 are reversed & rescaled to realign to be same direction and range(0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Score is average of item scores; score range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	317	333	343	324	104
Mean (Standard Deviation) [score on a scale]	-22.3 (25.24)	-20.2 (22.46)	-20.1 (25.12)	-19.4 (24.85)	-15.4 (27.57)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-8.38
	Confidence Interval	(2-Sided) 95%; -12.72 to -4.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.213
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.52
	Confidence Interval	(2-Sided) 95%; -11.83 to -3.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.201
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.32
	Confidence Interval	(2-Sided) 95%; -11.63 to -3.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.193
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.011
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.60
	Confidence Interval	(2-Sided) 95%; -9.93 to -1.27
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.207
	Estimation Comments

189. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Disturbance - Month 12 - (MITT)
Description	Change from Baseline to Month 12 in MOS Sleep Disturbance individual score as compared with Placebo. MOS-Sleep Self Report Questionnaire is 12 items that measure 6 dimensions of sleep over past 4 wks. Q1 scored on scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 self-reported hrs of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep disturbance includes items Q1, Q3, Q7, Q8. Scoring method: Answer to Q1 is rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25. Answers to Q3, 7, 8 are reversed & rescaled to realign to be same direction and range(0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Score is average of item scores; score range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	283	305	312	280	93
Mean (Standard Deviation) [score on a scale]	-20.2 (25.27)	-19.9 (24.90)	-19.9 (25.01)	-19.7 (24.13)	-14.1 (28.67)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-8.97
	Confidence Interval	(2-Sided) 95%; -13.76 to -4.19
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.439
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-9.60
	Confidence Interval	(2-Sided) 95%; -14.34 to -4.85
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.420
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-9.30
	Confidence Interval	(2-Sided) 95%; -14.03 to -4.56
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.412
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.72
	Confidence Interval	(2-Sided) 95%; -12.51 to -2.93
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.442
	Estimation Comments

190. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Snoring - Week 12 - (MITT)
Description	Change from Baseline to Wk 12 in MOS Snoring individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Snoring item is Q10. Scoring method: Answer to Q10 is reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	351	364	371	375	117
Mean (Standard Deviation) [score on a scale]	-2.6 (25.30)	-4.7 (26.08)	-4.5 (28.93)	-3.4 (26.94)	-5.6 (25.03)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.434
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.02
	Confidence Interval	(2-Sided) 95%; -3.03 to 7.07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.576
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.442
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.97
	Confidence Interval	(2-Sided) 95%; -3.06 to 7.00
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.564
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.558
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.50
	Confidence Interval	(2-Sided) 95%; -3.52 to 6.51
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.558
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.534
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.59
	Confidence Interval	(2-Sided) 95%; -3.42 to 6.60
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.555
	Estimation Comments

191. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Snoring - Month 6 - (MITT)
Description	Change from Baseline to Month 6 in MOS Snoring individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Snoring item is Q10. Scoring method: Answer to Q10 is reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	312	332	340	323	104
Mean (Standard Deviation) [score on a scale]	-2.4 (28.00)	-6.0 (25.73)	-6.8 (27.32)	-3.7 (28.98)	-3.5 (27.08)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.927
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.25
	Confidence Interval	(2-Sided) 95%; -5.08 to 5.58
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.719
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.541
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.65
	Confidence Interval	(2-Sided) 95%; -6.95 to 3.64
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.699
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.171
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.68
	Confidence Interval	(2-Sided) 95%; -8.96 to 1.60
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.691
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.667
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.17
	Confidence Interval	(2-Sided) 95%; -6.48 to 4.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.708
	Estimation Comments

192. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Snoring - Month 12 - (MITT)
Description	Change from Baseline to Month 12 in MOS Snoring individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Snoring item is Q10. Scoring method: Answer to Q10 is reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	280	305	311	277	93
Mean (Standard Deviation) [score on a scale]	-3.4 (29.62)	-7.5 (27.71)	-5.0 (28.57)	-4.5 (24.79)	-4.5 (26.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.662
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	1.25
	Confidence Interval	(2-Sided) 95%; -4.36 to 6.87
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.863
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.635
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.35
	Confidence Interval	(2-Sided) 95%; -6.91 to 4.21
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.834
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.877
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.44
	Confidence Interval	(2-Sided) 95%; -5.98 to 5.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.827
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.893
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.39
	Confidence Interval	(2-Sided) 95%; -6.01 to 5.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.867
	Estimation Comments

193. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Short of Breath or Headache - Week 12 - (MITT)
Description	Change from Baseline to Wk 12 in MOS Sleep Short of Breath or Headache(SOBHA) individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. SOBHA item is Q5. Scoring method: Answer to Q5 is reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	354	364	374	376	117
Mean (Standard Deviation) [score on a scale]	-6.0 (24.56)	-6.0 (23.67)	-7.1 (27.97)	-6.3 (27.03)	-3.4 (25.50)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.830
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.44
	Confidence Interval	(2-Sided) 95%; -4.48 to 3.59
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.058
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.755
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.64
	Confidence Interval	(2-Sided) 95%; -4.66 to 3.38
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.050
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.802
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.51
	Confidence Interval	(2-Sided) 95%; -3.50 to 4.53
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.046
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.823
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.46
	Confidence Interval	(2-Sided) 95%; -4.46 to 3.55
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.043
	Estimation Comments

194. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Short of Breath or Headache - Month 6 - (MITT)
Description	Change from Baseline to Month 6 in MOS Sleep Short of Breath or Headache(SOBHA) individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. SOBHA item is Q5. Scoring method: Answer to Q5 is reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	317	332	343	324	104
Mean (Standard Deviation) [score on a scale]	-6.2 (28.14)	-5.9 (24.36)	-7.5 (27.19)	-5.7 (26.34)	-2.1 (23.47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.255
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.46
	Confidence Interval	(2-Sided) 95%; -6.71 to 1.78
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.166
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.293
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.27
	Confidence Interval	(2-Sided) 95%; -6.49 to 1.96
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.154
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.502
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.44
	Confidence Interval	(2-Sided) 95%; -5.66 to 2.77
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.148
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.495
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.47
	Confidence Interval	(2-Sided) 95%; -5.71 to 2.76
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.161
	Estimation Comments

195. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Short of Breath or Headache - Month 12 - (MITT)
Description	Change from Baseline to Month 12 in MOS Sleep Short of Breath or Headache(SOBHA) individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. SOBHA item is Q5. Scoring method: Answer to Q5 is reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	283	305	311	280	93
Mean (Standard Deviation) [score on a scale]	-6.6 (27.64)	-6.4 (23.58)	-7.9 (28.34)	-6.5 (28.07)	-2.8 (27.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.389
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.96
	Confidence Interval	(2-Sided) 95%; -6.42 to 2.50
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.274
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.281
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.43
	Confidence Interval	(2-Sided) 95%; -6.85 to 1.99
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.253
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.504
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.51
	Confidence Interval	(2-Sided) 95%; -5.92 to 2.91
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.250
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.460
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.68
	Confidence Interval	(2-Sided) 95%; -6.15 to 2.78
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.277
	Estimation Comments

196. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Adequacy - Week 12 - (MITT)
Description	Change from Baseline to Wk 12 in MOS Sleep Adequacy individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Sleep Adequacy includes items Q4, Q12. Scoring method: Answers for Q4 and Q12 are reversed and rescaled to 0-100 as follows: MOS_4_new = (6-MOS_4_old) x 20; MOS_12_new = (6-MOS_12_old) x 20. Score is the average of item scores; score range = 0 to 100, where higher score means better outcome.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	354	365	374	376	117
Mean (Standard Deviation) [score on a scale]	11.9 (29.12)	9.0 (27.40)	11.4 (27.54)	11.9 (27.30)	11.3 (25.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.084
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	4.35
	Confidence Interval	(2-Sided) 95%; -0.58 to 9.28
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.513
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.298
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	2.61
	Confidence Interval	(2-Sided) 95%; -2.30 to 7.53
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.506
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.136
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.72
	Confidence Interval	(2-Sided) 95%; -1.17 to 8.62
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.496
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.163
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.48
	Confidence Interval	(2-Sided) 95%; -1.41 to 8.37
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.492
	Estimation Comments

197. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Adequacy - Month 6 - (MITT)
Description	Change from Baseline to Month 6 in MOS Sleep Adequacy individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Sleep Adequacy includes items Q4, Q12. Scoring method: Answers for Q4 and Q12 are reversed and rescaled to 0-100 as follows: MOS_4_new = (6-MOS_4_old) x 20; MOS_12_new = (6-MOS_12_old) x 20. Score is the average of item scores; score range = 0 to 100, where higher score means better outcome.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	317	333	343	324	104
Mean (Standard Deviation) [score on a scale]	10.5 (26.86)	11.7 (28.11)	11.0 (28.85)	14.5 (27.92)	9.5 (27.36)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.054
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.11
	Confidence Interval	(2-Sided) 95%; -0.08 to 10.31
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.647
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.10
	Confidence Interval	(2-Sided) 95%; 1.93 to 12.26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.634
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.025
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.90
	Confidence Interval	(2-Sided) 95%; 0.75 to 11.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.623
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	8.38
	Confidence Interval	(2-Sided) 95%; 3.20 to 13.55
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.638
	Estimation Comments

198. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Adequacy - Month 12 - (MITT)
Description	Change from Baseline to Month 12 in MOS Sleep Adequacy individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Sleep Adequacy includes items Q4, Q12. Scoring method: Answers for Q4 and Q12 are reversed and rescaled to 0-100 as follows: MOS_4_new = (6-MOS_4_old) x 20; MOS_12_new = (6-MOS_12_old) x 20. Score is the average of item scores; score range = 0 to 100, where higher score means better outcome.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	283	305	312	280	93
Mean (Standard Deviation) [score on a scale]	9.8 (27.33)	12.0 (29.86)	12.6 (27.71)	14.1 (28.81)	10.0 (31.76)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.089
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.02
	Confidence Interval	(2-Sided) 95%; -0.76 to 10.80
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.945
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.010
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.56
	Confidence Interval	(2-Sided) 95%; 1.83 to 13.29
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.920
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.009
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.65
	Confidence Interval	(2-Sided) 95%; 1.94 to 13.36
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.911
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.007
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	7.89
	Confidence Interval	(2-Sided) 95%; 2.11 to 13.67
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.944
	Estimation Comments

199. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Somnolence - Week 12 - (MITT)
Description	Change from Baseline to Wk 12 in MOS Sleep Somnolence individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Sleep Somnolence items include Q6, Q9, Q11. Scoring method: Answers to Q6, Q 9 and Q11 are reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	354	365	374	376	117
Mean (Standard Deviation) [score on a scale]	-9.2 (20.49)	-8.1 (18.67)	-7.6 (19.57)	-8.9 (21.09)	-8.7 (20.54)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.349
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.64
	Confidence Interval	(2-Sided) 95%; -5.07 to 1.79
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.749
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.499
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.18
	Confidence Interval	(2-Sided) 95%; -4.60 to 2.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.743
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.936
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.14
	Confidence Interval	(2-Sided) 95%; -3.27 to 3.55
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.737
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.696
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.68
	Confidence Interval	(2-Sided) 95%; -4.08 to 2.72
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.736
	Estimation Comments

200. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Somnolence - Month 6 - (MITT)
Description	Change from Baseline to Month 6 in MOS Sleep Somnolence individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Sleep Somnolence items include Q6, Q9, Q11. Scoring method: Answers to Q6, Q 9 and Q11 are reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	317	333	343	324	104
Mean (Standard Deviation) [score on a scale]	-9.4 (22.40)	-8.4 (19.88)	-9.6 (20.04)	-8.7 (21.65)	-9.6 (21.64)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.572
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.09
	Confidence Interval	(2-Sided) 95%; -4.86 to 2.69
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.924
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.553
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.14
	Confidence Interval	(2-Sided) 95%; -4.89 to 2.62
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.914
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.456
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-1.42
	Confidence Interval	(2-Sided) 95%; -5.16 to 2.32
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.907
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.949
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95%; -3.89 to 3.64
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.919
	Estimation Comments

201. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Somnolence - Month 12 - (MITT)
Description	Change from Baseline to Month 12 in MOS Sleep Somnolence individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-Q12 are scored 1-6 ranging from 1=All of the time to 6=None of the time. Sleep Somnolence items include Q6, Q9, Q11. Scoring method: Answers to Q6, Q 9 and Q11 are reversed & rescaled to 0 to 100 such that 0="best possible" & 100="worst possible". MOS_n_new <- (6-MOS_n_old) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	283	305	312	280	93
Mean (Standard Deviation) [score on a scale]	-8.5 (22.79)	-9.2 (19.17)	-9.9 (19.33)	-9.4 (23.06)	-6.7 (25.95)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.097
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.36
	Confidence Interval	(2-Sided) 95%; -7.34 to 0.61
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.026
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.34
	Confidence Interval	(2-Sided) 95%; -9.28 to -1.40
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.010
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.014
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.94
	Confidence Interval	(2-Sided) 95%; -8.87 to -1.01
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.003
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.056
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.88
	Confidence Interval	(2-Sided) 95%; -7.86 to 0.10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.029
	Estimation Comments

202. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Problems Index I - Week 12 - (MITT)
Description	Change from Baseline to Wk 12 in MOS Sleep Problems Index I individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep Problems Index I includes items Q4, Q5, Q7, Q8, Q9, Q12. Scoring method: Answers to Q, 5, 7, 8, 9 are reversed & rescaled to realign to be same direction and range (0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Answers to Q4, & 12 are rescaled to 0-100 as follows: MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	354	365	374	376	117
Mean (Standard Deviation) [score on a scale]	-13.5 (17.90)	-11.4 (18.02)	-12.2 (18.29)	-12.8 (19.33)	-9.8 (20.47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.92
	Confidence Interval	(2-Sided) 95%; -8.18 to -1.65
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.665
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.023
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.79
	Confidence Interval	(2-Sided) 95%; -7.05 to -0.53
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.660
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.047
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.28
	Confidence Interval	(2-Sided) 95%; -6.52 to -0.04
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.653
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.039
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.41
	Confidence Interval	(2-Sided) 95%; -6.65 to -0.17
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.652
	Estimation Comments

203. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Problems Index I - Month 6 - (MITT)
Description	Change from Baseline to Month 6 in MOS Sleep Problems Index I individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep Problems Index I includes items Q4, Q5, Q7, Q8, Q9, Q12. Scoring method: Answers to Q, 5, 7, 8, 9 are reversed & rescaled to realign to be same direction and range (0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Answers to Q4, & 12 are rescaled to 0-100 as follows: MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	317	333	343	324	104
Mean (Standard Deviation) [score on a scale]	-14.0 (17.60)	-12.9 (16.76)	-13.2 (19.16)	-13.8 (19.77)	-9.8 (20.37)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.69
	Confidence Interval	(2-Sided) 95%; -9.05 to -2.33
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.713
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.58
	Confidence Interval	(2-Sided) 95%; -8.93 to -2.24
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.704
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.12
	Confidence Interval	(2-Sided) 95%; -8.45 to -1.79
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.697
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.003
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.11
	Confidence Interval	(2-Sided) 95%; -8.46 to -1.76
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.708
	Estimation Comments

204. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Problems Index I - Month 12 - (MITT)
Description	Change from Baseline to Month 12 in MOS Sleep Problems Index I individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self-reported hours of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep Problems Index I includes items Q4, Q5, Q7, Q8, Q9, Q12. Scoring method: Answers to Q, 5, 7, 8, 9 are reversed & rescaled to realign to be same direction and range (0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20. Answers to Q4, & 12 are rescaled to 0-100 as follows: MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	283	305	312	280	93
Mean (Standard Deviation) [score on a scale]	-12.8 (18.19)	-13.0 (18.36)	-13.7 (19.02)	-14.0 (20.14)	-9.1 (22.62)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.01
	Confidence Interval	(2-Sided) 95%; -9.71 to -2.32
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.885
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.22
	Confidence Interval	(2-Sided) 95%; -10.89 to -3.55
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.871
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.92
	Confidence Interval	(2-Sided) 95%; -10.58 to -3.27
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.863
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.42
	Confidence Interval	(2-Sided) 95%; -10.12 to -2.72
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.886
	Estimation Comments

205. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Problems Index II - Week 12 - (MITT)
Description	Change from Baseline to Wk 12 in MOS Sleep Problems Index II individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self reported hours of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep Problems Index II items include Q1, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q12. Scoring method: Answers to Q3, 5, 6, 7, 8, & 9 are reversed & rescaled to realign to be same direction and range 0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20, for n=Q3, 5, 6, 7, 8, and 9. Answers to Q1, 4 & 12 are rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25; MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	354	365	374	376	117
Mean (Standard Deviation) [score on a scale]	-15.1 (17.64)	-13.0 (17.38)	-13.9 (17.40)	-13.4 (18.47)	-11.8 (19.48)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.004
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.60
	Confidence Interval	(2-Sided) 95%; -7.75 to -1.44
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.609
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.030
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.49
	Confidence Interval	(2-Sided) 95%; -6.64 to -0.34
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.605
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.049
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-3.15
	Confidence Interval	(2-Sided) 95%; -6.29 to -0.02
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.598
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.121
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-2.48
	Confidence Interval	(2-Sided) 95%; -5.61 to 0.65
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.597
	Estimation Comments

206. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Sleep Problems Index II - Month 6 - (MITT)
Description	Change from Baseline to Month 6 in MOS Sleep Problems Index II individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self reported hours of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep Problems Index II items include Q1, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q12. Scoring method: Answers to Q3, 5, 6, 7, 8, & 9 are reversed & rescaled to realign to be same direction and range 0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20, for n=Q3, 5, 6, 7, 8, and 9. Answers to Q1, 4 & 12 are rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25; MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	317	333	343	324	104
Mean (Standard Deviation) [score on a scale]	-15.5 (18.15)	-14.6 (16.41)	-14.9 (18.95)	-14.8 (18.87)	-11.6 (19.31)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.44
	Confidence Interval	(2-Sided) 95%; -8.74 to -2.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.682
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.53
	Confidence Interval	(2-Sided) 95%; -8.81 to -2.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.674
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.002
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-5.12
	Confidence Interval	(2-Sided) 95%; -8.39 to -1.85
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.667
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.006
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.64
	Confidence Interval	(2-Sided) 95%; -7.93 to -1.35
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.677
	Estimation Comments

207. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Individual Score for Sleep Problems Index II - Month 12 - (MITT)
Description	Change from Baseline to Month 12 in MOS Sleep Problems Index II individual score as compared with Placebo. The MOS-Sleep Self Report Questionnaire is composed of 12 items that measure 6 dimensions of sleep over the past 4 weeks. Q1 is scored on a scale 1-5: 1=0-15 min, 2=16-30 min...5=>60 mins. Q2 is self reported hours of sleep per night. Q3-12 scored 1-6 where 1=All of the time to 6=None of the time. Sleep Problems Index II items include Q1, Q3, Q4, Q5, Q6, Q7, Q8, Q9, Q12. Scoring method: Answers to Q3, 5, 6, 7, 8, & 9 are reversed & rescaled to realign to be same direction and range 0 to 100 with 0="best possible" & 100="worst possible" as follows: MOS_n_new = (6-MOS_n_old) x 20, for n=Q3, 5, 6, 7, 8, and 9. Answers to Q1, 4 & 12 are rescaled to 0-100 as follows: MOS_1_new =(MOS_1_old - 1) x 25; MOS_4_new =(MOS_4_old - 1) x 20; MOS_12_new=(MOS_12_old - 1) x 20. Score is the average of item scores; score range range=0 to 100, where higher score means worse outcome.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	283	305	312	280	93
Mean (Standard Deviation) [score on a scale]	-14.3 (18.35)	-14.6 (17.95)	-15.4 (18.74)	-15.1 (19.43)	-10.5 (21.71)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.28
	Confidence Interval	(2-Sided) 95%; -9.91 to -2.65
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.849
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.58
	Confidence Interval	(2-Sided) 95%; -11.18 to -3.98
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.835
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-7.43
	Confidence Interval	(2-Sided) 95%; -11.02 to -3.84
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.828
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-6.54
	Confidence Interval	(2-Sided) 95%; -10.17 to -2.91
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.851
	Estimation Comments

208. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Optimal Sleep - Week 12 - (MITT)
Description	Change from Baseline (BL) to Wk 12 in MOS Optimal Sleep Score as compared with Placebo.The MOS-Sleep Self Report Questionnaire is composed of 12 items measuring 6 dimensions of sleep over the past 4 wks. Optimal sleep is based on Q2 (self-reported average hrs sleep per night in past 4 wks). Scoring method: hrs of sleep coded 0 (non-optimal) or 1 (optimal) where 1-6 hrs & 9-23 hrs = 0, 7-8 hrs = 1. Change from BL: subject sleeps 7-8 hrs at BL & 1-6 or 9-23 hrs at follow-up, change = -1; subject sleeps 1-6 or 9-23 hrs at BL & 7-8 hrs at follow-up, change = +1; subject sleeps 1-6 or 9-23 hrs at BL & 1-6 or 9-23 hrs at follow-up, change = 0. Mean change from BL: changes are summed to give the Net Total (equivalent to the number subjects w/ improved sleep hrs minus the number subjects w/ worsened sleep hrs), which is divided by the number of subjects to give the mean proportion of net change, where >0 = overall improvement and <0 = overall worsening in the study arm.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	353	364	372	376	116
Mean (Standard Deviation) [Proportion of Net Change]	0.2 (0.53)	0.1 (0.56)	0.2 (0.49)	0.1 (0.52)	0.2 (0.59)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.225
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.06
	Confidence Interval	(2-Sided) 95%; -0.04 to 0.16
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.049
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.741
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -0.08 to 0.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.049
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.414
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -0.06 to 0.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.049
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.690
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Week 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -0.11 to 0.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.049
	Estimation Comments

209. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Optimal Sleep - Month 6 - (MITT)
Description	Change from Baseline (BL) to Month 6 in MOS Optimal Sleep Score as compared with Placebo.The MOS-Sleep Self Report Questionnaire is composed of 12 items measuring 6 dimensions of sleep over the past 4 wks. Optimal sleep is based on Q2 (self-reported average hrs sleep per night in past 4 wks). Scoring method: hrs of sleep coded 0 (non-optimal) or 1 (optimal) where 1-6 hrs & 9-23 hrs = 0, 7-8 hrs = 1. Change from BL: subject sleeps 7-8 hrs at BL & 1-6 or 9-23 hrs at follow-up, change = -1; subject sleeps 1-6 or 9-23 hrs at BL & 7-8 hrs at follow-up, change = +1; subject sleeps 1-6 or 9-23 hrs at BL & 1-6 or 9-23 hrs at follow-up, change = 0. Mean change from BL: changes are summed to give the Net Total (equivalent to the number subjects w/ improved sleep hrs minus the number subjects w/ worsened sleep hrs), which is divided by the number of subjects to give the mean proportion of net change, where >0 = overall improvement and <0 = overall worsening in the study arm.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	316	331	339	323	104
Mean (Standard Deviation) [Proportion of Net Change]	0.2 (0.56)	0.2 (0.55)	0.2 (0.53)	0.1 (0.56)	0.2 (0.52)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.045
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.11
	Confidence Interval	(2-Sided) 95%; 0.00 to 0.21
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.052
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.069
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.09
	Confidence Interval	(2-Sided) 95%; -0.01 to 0.20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.052
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.126
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.08
	Confidence Interval	(2-Sided) 95%; -0.02 to 0.18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.052
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.907
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 6
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.01
	Confidence Interval	(2-Sided) 95%; -0.10 to 0.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.052
	Estimation Comments

210. Secondary Outcome

Title	Medical Outcomes Sleep Study (MOS) Optimal Sleep - Month 12 - (MITT)
Description	Change from Baseline (BL) to Month 12 in MOS Optimal Sleep Score as compared with Placebo.The MOS-Sleep Self Report Questionnaire is composed of 12 items measuring 6 dimensions of sleep over the past 4 wks. Optimal sleep is based on Q2 (self-reported average hrs sleep per night in past 4 wks). Scoring method: hrs of sleep coded 0 (non-optimal) or 1 (optimal) where 1-6 hrs & 9-23 hrs = 0, 7-8 hrs = 1. Change from BL: subject sleeps 7-8 hrs at BL & 1-6 or 9-23 hrs at follow-up, change = -1; subject sleeps 1-6 or 9-23 hrs at BL & 7-8 hrs at follow-up, change = +1; subject sleeps 1-6 or 9-23 hrs at BL & 1-6 or 9-23 hrs at follow-up, change = 0. Mean change from BL: changes are summed to give the Net Total (equivalent to the number subjects w/ improved sleep hrs minus the number subjects w/ worsened sleep hrs), which is divided by the number of subjects to give the mean proportion of net change, where >0 = overall improvement and <0 = overall worsening in the study arm.
Time Frame	Baseline and Month 12

Outcome Measure Data

Analysis Population Description

All randomized subjects who took at least one dose (2 capsules) of IP.

Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 100 mg	Combined Estradiol 0.5 mg / Progesterone 50 mg	Combined Estradiol 0.25 mg / Progesterone 50 mg	Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.	Two Placebo softgel capsules taken orally once a day for twelve months.
Measure Participants	282	303	311	280	93
Mean (Standard Deviation) [Proportion of Net Change]	0.1 (0.51)	0.2 (0.56)	0.1 (0.55)	0.1 (0.52)	0.2 (0.47)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 1 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.992
	Comments	p-value is derived from comparison between Combined Estradiol 1 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.00
	Confidence Interval	(2-Sided) 95%; -0.11 to 0.11
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.055
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 100 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.450
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 100 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.04
	Confidence Interval	(2-Sided) 95%; -0.07 to 0.15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.054
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.5 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.663
	Comments	p-value is derived from comparison between Combined Estradiol 0.5 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.02
	Confidence Interval	(2-Sided) 95%; -0.13 to 0.08
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.054
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Combined Estradiol 0.25 mg / Progesterone 50 mg, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.309
	Comments	p-value is derived from comparison between Combined Estradiol 0.25 mg / Progesterone 50 mg against Placebo at Month 12
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.06
	Confidence Interval	(2-Sided) 95%; -0.16 to 0.05
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.055
	Estimation Comments

Adverse Events

Time Frame	Adverse Event data were collected on or after the subject signed Informed Consent through fifteen days following the last dose of Investigational Product. Treatment Emergent Adverse Event data were collected on or after the first dose of IP through fifteen days following the last dose of IP.
Arm/Group Title	Combined Estradiol 1 mg / Progesterone 100 mg		Combined Estradiol 0.5 mg / Progesterone 100 mg		Combined Estradiol 0.5 mg / Progesterone 50 mg		Combined Estradiol 0.25 mg / Progesterone 50 mg		Placebo
Arm/Group Description	Combined Estradiol 1 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.		Combined Estradiol 0.5 mg / Progesterone 100 mg formulation and placebo softgel capsules taken orally once a day for twelve months.		Combined Estradiol 0.5 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.		Combined Estradiol 0.25 mg / Progesterone 50 mg formulation and placebo softgel capsules taken orally once a day for twelve months.		Two Placebo softgel capsules taken orally once a day for twelve months.
All Cause Mortality
	Combined Estradiol 1 mg / Progesterone 100 mg		Combined Estradiol 0.5 mg / Progesterone 100 mg		Combined Estradiol 0.5 mg / Progesterone 50 mg		Combined Estradiol 0.25 mg / Progesterone 50 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/415 (0%)		0/424 (0%)		1/421 (0.2%)		0/424 (0%)		0/151 (0%)
Serious Adverse Events
	Combined Estradiol 1 mg / Progesterone 100 mg		Combined Estradiol 0.5 mg / Progesterone 100 mg		Combined Estradiol 0.5 mg / Progesterone 50 mg		Combined Estradiol 0.25 mg / Progesterone 50 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/415 (2.2%)		15/424 (3.5%)		9/421 (2.1%)		11/424 (2.6%)		2/151 (1.3%)
Cardiac disorders
Cardiac Tamponade	0/415 (0%)		0/424 (0%)		1/421 (0.2%)		0/424 (0%)		0/151 (0%)
Coronary Artery Disease	1/415 (0.2%)		0/424 (0%)		0/421 (0%)		0/424 (0%)		0/151 (0%)
Stress Cardiomyopothy	0/415 (0%)		1/424 (0.2%)		0/421 (0%)		0/424 (0%)		0/151 (0%)
Gastrointestinal disorders
Colitis Ischaemic	1/415 (0.2%)		0/424 (0%)		0/421 (0%)		0/424 (0%)		0/151 (0%)
Colitis Ulcerative	0/415 (0%)		0/424 (0%)		1/421 (0.2%)		0/424 (0%)		0/151 (0%)
Gastroduodenal Haemorrhage	0/415 (0%)		0/424 (0%)		0/421 (0%)		1/424 (0.2%)		0/151 (0%)
Gastroduodenitis	0/415 (0%)		1/424 (0.2%)		0/421 (0%)		0/424 (0%)		0/151 (0%)
Pancreatitis	0/415 (0%)		0/424 (0%)		1/421 (0.2%)		0/424 (0%)		0/151 (0%)
Pancreatitis Acute	1/415 (0.2%)		0/424 (0%)		0/421 (0%)		0/424 (0%)		0/151 (0%)
Small Intestinal Obstruction	0/415 (0%)		0/424 (0%)		1/421 (0.2%)		0/424 (0%)		0/151 (0%)
General disorders
Non-Cardiac Chest Pain	0/415 (0%)		0/424 (0%)		0/421 (0%)		1/424 (0.2%)		0/151 (0%)
Hepatobiliary disorders
Hepatic Steatosis	0/415 (0%)		1/424 (0.2%)		0/421 (0%)		0/424 (0%)		0/151 (0%)
Immune system disorders
Angioedema	0/415 (0%)		0/424 (0%)		0/421 (0%)		1/424 (0.2%)		0/151 (0%)
Infections and infestations
Bronchitis	0/415 (0%)		1/424 (0.2%)		0/421 (0%)		0/424 (0%)		0/151 (0%)
Cholecystitis Infective	0/415 (0%)		0/424 (0%)		0/421 (0%)		0/424 (0%)		1/151 (0.7%)
Clostridium Difficile Colitis	0/415 (0%)		0/424 (0%)		1/421 (0.2%)		0/424 (0%)		0/151 (0%)
Diverticulitis	2/415 (0.5%)		0/424 (0%)		0/421 (0%)		0/424 (0%)		0/151 (0%)
Gastroenteritis Viral	1/415 (0.2%)		0/424 (0%)		0/421 (0%)		0/424 (0%)		0/151 (0%)
Infectious Mononucleosis	0/415 (0%)		0/424 (0%)		1/421 (0.2%)		0/424 (0%)		0/151 (0%)
Pneumonia	0/415 (0%)		2/424 (0.5%)		0/421 (0%)		0/424 (0%)		0/151 (0%)
Urosepsis	0/415 (0%)		1/424 (0.2%)		0/421 (0%)		0/424 (0%)		0/151 (0%)
Injury, poisoning and procedural complications
Ankle Fracture	0/415 (0%)		1/424 (0.2%)		0/421 (0%)		0/424 (0%)		0/151 (0%)
Foot Fracture	0/415 (0%)		1/424 (0.2%)		0/421 (0%)		0/424 (0%)		0/151 (0%)
Humerus Fracture	0/415 (0%)		0/424 (0%)		0/421 (0%)		1/424 (0.2%)		0/151 (0%)
Incisional Hernia	1/415 (0.2%)		0/424 (0%)		0/421 (0%)		0/424 (0%)		0/151 (0%)
Jaw Fracture	0/415 (0%)		0/424 (0%)		0/421 (0%)		1/424 (0.2%)		0/151 (0%)
Tibia Fracture	0/415 (0%)		0/424 (0%)		1/421 (0.2%)		0/424 (0%)		0/151 (0%)
Musculoskeletal and connective tissue disorders
Chondrocalcinosis Pyrophosphate	0/415 (0%)		0/424 (0%)		0/421 (0%)		1/424 (0.2%)		0/151 (0%)
Intervertebral Disc Protrusion	0/415 (0%)		1/424 (0.2%)		0/421 (0%)		0/424 (0%)		0/151 (0%)
Osteoarthritis	0/415 (0%)		1/424 (0.2%)		0/421 (0%)		0/424 (0%)		0/151 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast Cancer Female	2/415 (0.5%)		1/424 (0.2%)		0/421 (0%)		0/424 (0%)		0/151 (0%)
Invasive Ductal Breast Carcinoma	0/415 (0%)		1/424 (0.2%)		0/421 (0%)		1/424 (0.2%)		0/151 (0%)
Lung Cancer Metastatic	0/415 (0%)		1/424 (0.2%)		0/421 (0%)		0/424 (0%)		0/151 (0%)
Myelodysplastic Syndrome	0/415 (0%)		1/424 (0.2%)		0/421 (0%)		0/424 (0%)		0/151 (0%)
Non-Small Cell Lung Cancer Stage IV	0/415 (0%)		0/424 (0%)		1/421 (0.2%)		0/424 (0%)		0/151 (0%)
Nervous system disorders
Balance Disorder	0/415 (0%)		0/424 (0%)		0/421 (0%)		1/424 (0.2%)		0/151 (0%)
Cerebellar Infarction	0/415 (0%)		0/424 (0%)		1/421 (0.2%)		0/424 (0%)		0/151 (0%)
Cerebrovascular Accident	0/415 (0%)		0/424 (0%)		1/421 (0.2%)		0/424 (0%)		0/151 (0%)
Seizure	0/415 (0%)		1/424 (0.2%)		0/421 (0%)		0/424 (0%)		0/151 (0%)
Subarachnoid Haemorrhage	0/415 (0%)		0/424 (0%)		1/421 (0.2%)		0/424 (0%)		0/151 (0%)
Psychiatric disorders
Psychotic Disorder	1/415 (0.2%)		0/424 (0%)		0/421 (0%)		0/424 (0%)		0/151 (0%)
Reproductive system and breast disorders
Uterine Leiomyoma	0/415 (0%)		0/424 (0%)		1/421 (0.2%)		0/424 (0%)		0/151 (0%)
Uterine Prolapse	0/415 (0%)		0/424 (0%)		0/421 (0%)		0/424 (0%)		1/151 (0.7%)
Respiratory, thoracic and mediastinal disorders
Acute Respiratory Failure	0/415 (0%)		0/424 (0%)		0/421 (0%)		1/424 (0.2%)		0/151 (0%)
Chronic Obstructive Pulmonary Disease	0/415 (0%)		0/424 (0%)		0/421 (0%)		2/424 (0.5%)		0/151 (0%)
Pleural Effusion	0/415 (0%)		0/424 (0%)		1/421 (0.2%)		0/424 (0%)		0/151 (0%)
Pneumonia Aspiration	0/415 (0%)		0/424 (0%)		0/421 (0%)		1/424 (0.2%)		0/151 (0%)
Vascular disorders
Aortic Aneurysm	1/415 (0.2%)		0/424 (0%)		0/421 (0%)		0/424 (0%)		0/151 (0%)
Aortic Thrombosis	0/415 (0%)		0/424 (0%)		1/421 (0.2%)		0/424 (0%)		0/151 (0%)
Deep Vein Thrombosis	0/415 (0%)		0/424 (0%)		1/421 (0.2%)		0/424 (0%)		0/151 (0%)
Peripheral Arterial Occlusive Disease	0/415 (0%)		1/424 (0.2%)		0/421 (0%)		0/424 (0%)		0/151 (0%)
Other (Not Including Serious) Adverse Events
	Combined Estradiol 1 mg / Progesterone 100 mg		Combined Estradiol 0.5 mg / Progesterone 100 mg		Combined Estradiol 0.5 mg / Progesterone 50 mg		Combined Estradiol 0.25 mg / Progesterone 50 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	324/415 (78.1%)		277/424 (65.3%)		291/421 (69.1%)		232/424 (54.7%)		41/151 (27.2%)
Gastrointestinal disorders
Nausea	20/415 (4.8%)		25/424 (5.9%)		19/421 (4.5%)		16/424 (3.8%)		2/151 (1.3%)
Abdominal Pain	22/415 (5.3%)		10/424 (2.4%)		14/421 (3.3%)		15/424 (3.5%)		4/151 (2.6%)
Diarrhoea	13/415 (3.1%)		13/424 (3.1%)		11/421 (2.6%)		11/424 (2.6%)		2/151 (1.3%)
Abdominal Distension	15/415 (3.6%)		6/424 (1.4%)		11/421 (2.6%)		11/424 (2.6%)		1/151 (0.7%)
Infections and infestations
Nasopharyngitis	25/415 (6%)		41/424 (9.7%)		37/421 (8.8%)		24/424 (5.7%)		4/151 (2.6%)
Upper Respiratory Tract Infection	22/415 (5.3%)		26/424 (6.1%)		34/421 (8.1%)		15/424 (3.5%)		6/151 (4%)
Sinusitis	20/415 (4.8%)		15/424 (3.5%)		13/421 (3.1%)		13/424 (3.1%)		3/151 (2%)
Vulvovaginal Mycotic Infection	14/415 (3.4%)		15/424 (3.5%)		14/421 (3.3%)		5/424 (1.2%)		4/151 (2.6%)
Influenza	4/415 (1%)		6/424 (1.4%)		14/421 (3.3%)		12/424 (2.8%)		2/151 (1.3%)
Musculoskeletal and connective tissue disorders
Back Pain	22/415 (5.3%)		11/424 (2.6%)		15/421 (3.6%)		15/424 (3.5%)		1/151 (0.7%)
Nervous system disorders
Headache	31/415 (7.5%)		24/424 (5.7%)		45/421 (10.7%)		43/424 (10.1%)		4/151 (2.6%)
Dizziness	17/415 (4.1%)		15/424 (3.5%)		10/421 (2.4%)		8/424 (1.9%)		3/151 (2%)
Reproductive system and breast disorders
Breast Tenderness	45/415 (10.8%)		19/424 (4.5%)		25/421 (5.9%)		10/424 (2.4%)		1/151 (0.7%)
Pelvic Pain	17/415 (4.1%)		15/424 (3.5%)		10/421 (2.4%)		7/424 (1.7%)		0/151 (0%)
Vaginal Discharge	16/415 (3.9%)		13/424 (3.1%)		7/421 (1.7%)		7/424 (1.7%)		1/151 (0.7%)
Vaginal Haemorrhage	14/415 (3.4%)		10/424 (2.4%)		3/421 (0.7%)		8/424 (1.9%)		1/151 (0.7%)
Vascular disorders
Hypertension	7/415 (1.7%)		13/424 (3.1%)		9/421 (2.1%)		12/424 (2.8%)		2/151 (1.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.