Study to Evaluate Ospemifene in Patients With Moderate to Severe Vaginal Dryness Due to Menopause

• Sponsor: Shionogi (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02638337
• Collaborator: (none)
• Enrollment: 631
• Arms: 2
• Actual Duration (Months): 17.3

Study Details

Study Description

Brief Summary

The objective of this study is to evaluate the efficacy and safety of ospemifene 60 mg once daily (QD) compared with placebo in treatment of vulvo-vaginal atrophy (VVA) due to menopause in women with moderate to severe vaginal dryness as the most bothersome symptom (MBS) of VVA.

Condition or Disease	Intervention/Treatment	Phase
Vaginal Dryness	Drug: Ospemifene; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 631 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Randomized, Double-blind, Placebo-controlled Multicenter Study to Evaluate the Efficacy and Safety of Ospemifene in Patients With Moderate to Severe Vaginal Dryness, a Symptom of Vulvo-vaginal Atrophy (VVA) Due to Menopause
• Actual Study Start Date: Jan 26, 2016
• Actual Primary Completion Date: Jun 23, 2017
• Actual Study Completion Date: Jul 5, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ospemifene Participants will take one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Drug: Ospemifene; 60 mg tablet; Other Names: Osphena®
Placebo Comparator: Placebo Participants will take one tablet of matching placebo, orally, once a day for 12 weeks.	Drug: Placebo; Tablet identical to the ospemifene tablet without drug

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in the Percentage of Parabasal Cells in the Maturation Index of the Vaginal Smear at Week 12 [Baseline and Week 12]

   Parabasal cells are immature squamous cells in the lining of the vagina. A predominance of parabasal cells indicates absence of estrogenic stimulation and vaginal atrophy. Vaginal smear samples were taken from the middle third of the lateral vaginal wall and were evaluated at a central laboratory by a qualified pathologist. A decrease in parabasal cells indicates improvement in vaginal atrophy. To calculate least squares (LS) means, a mixed-effects model for repeated measures (MMRM) model was used.

2. Change From Baseline in the Percentage of Superficial Cells in the Maturation Index of the Vaginal Smear at Week 12 [Baseline and Week 12]

   Superficial cells are mature squamous cells in the lining of the vagina that can decrease in number after menopause resulting in vulvovaginal atrophy. Vaginal smear samples were taken from the middle third of the lateral vaginal wall and were evaluated at a central laboratory by a qualified pathologist. An increase in the number of superficial cells indicates improvement in atrophy. To calculate least squares (LS) means, a mixed-effects model for repeated measures (MMRM) model was used.

3. Change From Baseline in the Vaginal pH at Week 12 [Baseline and Week 12]

   The pH scale ranges from 0 to 14. A pH of 7 is neutral, less than 7 is acidic, and greater than 7 is basic. A typical vaginal pH in women of reproductive age is between 3.5 and 4.5, increasing to > 4.5 after menopause. Vaginal pH was measured by the investigator using a pH indicator strip at the middle third of the vaginal wall. To calculate least squares (LS) means, a mixed-effects model for repeated measures (MMRM) model was used.

4. Change From Baseline in the Severity of Self-reported Most Bothersome Symptom (MBS) of Vaginal Dryness at Week 12 [Baseline and Week 12]

   The severity of the most bothersome symptom of vaginal dryness was assessed by the participant through the VVA questionnaire as none = 0, mild = 1, moderate = 2, and severe = 3.

5. Number of Participants With Adverse Events [From the first dose of study drug up to 14 days after the last dose; 14 weeks]

   Treatment-related adverse events (AEs) were defined as AEs that were considered by the investigator to be related to investigational medicinal product, for which causal relationship with the study drug could be reasonably explained. A serious adverse event (SAE) is defined as any AE occurring at any dose that resulted in any of the following outcomes: Death Life-threatening condition Hospitalization or prolongation of existing hospitalization for treatment Persistent or significant disability/incapacity Congenital anomaly/birth defect Other medically important conditions that, based on medical judgment, may jeopardize the participant's health and may require medical intervention to prevent one of the outcomes listed above.

Secondary Outcome Measures

1. Change From Baseline in the Percentage of Parabasal Cells in the Maturation Index of the Vaginal Smear at Weeks 4 and 8 [Baseline and Weeks 4 and 8]

   Parabasal cells are immature squamous cells in the lining of the vagina. A predominance of parabasal cells indicates absence of estrogenic stimulation and vaginal atrophy. Vaginal smear samples were taken from the middle third of the lateral vaginal wall and were evaluated at a central laboratory by a qualified pathologist. A decrease in parabasal cells indicates improvement in vaginal atrophy.

2. Change From Baseline in the Percentage of Superficial Cells in the Maturation Index of the Vaginal Smear at Weeks 4 and 8 [Baseline and Weeks 4 and 8]

   Superficial cells are mature squamous cells in the lining of the vagina that can decrease in number after menopause resulting in vulvovaginal atrophy. Vaginal smear samples were taken from the middle third of the lateral vaginal wall and were evaluated at a central laboratory by a qualified pathologist. An increase in the number of superficial cells indicates improvement in atrophy.

3. Change From Baseline in the Vaginal pH [Baseline and Weeks 4 and 8]

   The pH scale ranges from 0 to 14. A pH of 7 is neutral, less than 7 is acidic, and greater than 7 is basic. A typical vaginal pH in women of reproductive age is between 3.5 and 4.5, increasing to > 4.5 after menopause. Vaginal pH was measured by the investigator using a pH indicator strip at the middle third of the vaginal wall.

4. Change From Baseline in the Severity of Self-reported Most Bothersome Symptom (MBS) of Vaginal Dryness at Weeks 4 and 8 [Baseline and Weeks 4 and 8]

   The severity of the most bothersome symptom of vaginal dryness was assessed by the participant through the VVA questionnaire as none = 0, mild = 1, moderate = 2, and severe = 3.

5. Change From Baseline in Vaginal and/or Vulvar Irritation or Itching [Baseline and Weeks 4, 8, and 12]

   The severity of vaginal and/or vulvar irritation or itching was assessed by the participant through the VVA questionnaire as none = 0, mild = 1, moderate = 2, and severe = 3.

6. Change From Baseline in Difficult or Painful Urination [Baseline and Weeks 4, 8, and 12]

   The severity of difficult or painful urination was assessed by the participant through the VVA questionnaire as none = 0, mild = 1, moderate = 2, and severe = 3.

7. Change From Baseline in Vaginal Pain Associated With Sexual Activity [Baseline and Weeks 4, 8, and 12]

   The severity of vaginal pain associated with sexual activity was assessed by the participant through the VVA questionnaire as none = 0, mild = 1, moderate = 2, and severe = 3.

8. Change From Baseline in Vaginal Bleeding Associated With Sexual Activity [Baseline and Weeks 4, 8, and 12]

   The severity of vaginal bleeding associated with sexual activity was assessed by the participant through the VVA questionnaire as none = 0, mild = 1, moderate = 2, and severe = 3.

9. Change From Baseline in Maturation Value [Baseline and Weeks 4, 8, and 12]

   The maturation value is an indicator of the level of maturation attained by the vaginal epithelium. Vaginal smear samples were taken from the middle third of the lateral vaginal wall and were evaluated at the central laboratory by a qualified pathologist. Parabasal cells (P), intermediary cells (I), and superficial cells (S) were counted and results were expressed as the maturation value (MV), whereby superficial cells were assigned a point value of 1.0, intermediate cells were assigned a point value of 0.5, and parabasal cells were assigned a point value of 0. The maturation value (MV) was defined as: (percentage of superficial cells * 1) + (percentage of intermediate cells * 0.5) + (percentage of parabasal calls * 0). Lower MV indicates lower estrogen effect.

10. Percentage of Participants Who Were Responders at Week 4, Week 8, and Week 12 [Baseline and Weeks 4, 8, and 12]

    A participant was defined as a responder if all the following conditions were met:: Increase from baseline in maturation value of at least 10 Decrease from baseline in vaginal pH of at least 0.5 Improvement from baseline (decrease in severity) of at least 1 point in the most bothersome symptom of vaginal dryness

11. Change From Baseline in Vaginal Health Index [Baseline and Weeks 4, 8, and 12]

    The investigator performed an evaluation of the vagina, assessing overall elasticity, fluid secretion, pH, condition of epithelial mucosa, and moisture. The severity of each characteristic was assessed using a 5-grade scale from 1 (worst) to 5 (best). The total score was calculated as the sum of the 5 individual scores and ranges from 5 to 25, where higher scores indicate better vaginal health

12. Change From Baseline in Vulvar Health Index [Baseline and Weeks 4, 8, and 12]

    The investigator performed a visual examination of the vulva, assessing the labia majora, labia minora, clitoris, introitus appearance and elasticity, color, discomfort and pain, and presence of other findings (eg, petechiae, excoriations, ulcers, etc). The severity of each characteristic was assessed on a 4-point scale as 0 = normal, 1 = mild, 2 = moderate, and 3 = severe. The total score was calculated by adding the 7 individual scores and ranges from 0 to 21, where lower scores indicate better vulvar health. A negative change from baseline indicates improvement.

13. Change From Baseline in Vulvovaginal Imaging Total Score at Week 12 [Baseline and Week 12]

    Vulvovaginal imaging was performed by trained site personnel following a standard procedure. Photographs were assessed by an Independent Panel Review (IPR) in a blinded fashion. Nine parameters (labia majora, labia minora, clitoris, urethra, introitus and elasticity, color, erythema, moisture, and other findings (petechiae, excoriation, ulceration, etc.)) were evaluated on a scale from 0 (normal/none) to 3 (severe). The total score was calculated from the sum of the 9 individual scores and ranged from 0 to 27 with lower values indicating better vulvovaginal health; a negative change from baseline indicates improvement.

14. Change From Baseline in Female Sexual Function Index Total Score [Baseline and Weeks 4, 8, and 12]

    The Female Sexual Function Index consists of 19 questions organized into 6 domains (desire, arousal, lubrication, orgasm, satisfaction, and pain) answered by the participant on a 5-point scale from 1 to 5. Where relevant, some questions also include an option of 0 if a question is not applicable due to no sexual activity. Each domain score was calculated by adding the scores of each item in the domain and multiplying by a domain factor. The total score was calculated by summing each domain score and ranges from 2 to 36, with higher values indicating better sexual function.

15. Change From Baseline in Female Sexual Function Index Domain Scores at Week 12 [Baseline and Week 12]

    The Female Sexual Function Index consists of 19 questions, organized into 6 domains (desire, arousal, lubrication, orgasm, satisfaction, and pain), answered by the participant on a scale from 1 to 5. Where relevant, some questions also include an option of 0 if not applicable due to no sexual activity. Each domain score was calculated by adding the scores of each item in the domain and multiplying by a domain factor. For all domains, higher values indicate better sexual function, according to the following: Desire (2 questions): domain score ranges from 1.2 to 6; Arousal (4 questions): domain score ranges from 0 to 6; Lubrication (4 questions): domain score ranges from 0 to 6; Orgasm (3 questions): domain score ranges from 0 to 6; Satisfaction (3 questions): domain score ranges from 0.8 to 6; Pain (3 questions): domain score ranges from 0 to 6.

16. Change From Baseline in Urinary Distress Inventory (UDI)-6 Total Score [Baseline and Weeks 4, 8, and 12]

    The presence or absence of urinary symptoms was assessed using the Urinary Distress Inventory (UDI)-6. The symptoms include frequent urination, urine leakage related to the feeling of urgency, urine leakage related to physical activity, coughing, or sneezing, small amounts of urine leakage, difficulty emptying bladder, and pain and discomfort in the lower abdominal or genital area. If a symptom was present, participants were asked to assess the degree to which they were bothered by it on the following 4-point scale: = present but doesn't bother her at all; = present and bothers her slightly; = present and bothers her moderately; = present and bothers her greatly. The total score was calculated by adding the 6 scores together (Absent = 0), and ranges from 0 to 24, with lower values indicating less urinary distress.

17. Change From Baseline in Bone Sialoprotein at Week 12 [Baseline and Week 12]

    Serum bone sialoprotein (BSP) was measured as a marker of bone resorption.

18. Change From Baseline in Type I Collagen C-Telopeptide (CTX) at Week 12 [Baseline and Week 12]

    Type I collagen C-telopeptide was measured as a marker of bone resorption.

19. Change From Baseline in Deoxypyridinoline at Week 12 [Baseline and Week 12]

    Deoxypyridinoline was measured as a marker of bone resorption.

20. Change From Baseline in Type I Collagen N-Telopeptide (NTX) at Week 12 [Baseline and Week 12]

    Type I collagen N-telopeptide was measured as a marker of bone resorption.

21. Change From Baseline in Tartrate-Resistant Acid Phosphatase 5b at Week 12 [Baseline and Week 12]

    Tartrate-resistant acid phosphatase 5b was measured as a marker of bone resorption.

22. Change From Baseline in Alkaline Phosphatase at Week 12 [Baseline and Week 12]

    Alkaline phosphatase was measured as a marker of bone formation.

23. Change From Baseline in Bone-specific Alkaline Phosphatase at Week 12 [Baseline and Week 12]

    Bone-specific alkaline phosphatase was measured as a marker of bone formation.

24. Change From Baseline in Osteocalcin at Week 12 [Baseline and Week 12]

    Osteocalcin was measured as a marker for bone formation.

25. Change From Baseline in Procollagen 1 N-Terminal Propeptide (P1NP) at Week 12 [Baseline and Week 12]

    Procollagen 1 N-terminal propeptide was measured as a marker of bone formation.

26. Mean Days of Lubricant Use Per Week [Week 1 to Week 12]

    The mean number of days/week that lubricant was used as documented by participants in an electronic daily diary.

27. Mean Days of Intercourse Per Week [Week 1 to Week 12]

    The mean number of days/week of intercourse as recorded by participants in an electronic daily diary.

28. Overall Satisfaction With Treatment at Week 12 [Week 12]

    Participants were asked to record their overall satisfaction with treatment in an electronic diary according to the following categories: Very satisfied, Moderately satisfied, About equally satisfied and dissatisfied, Moderately dissatisfied, and Very dissatisfied.

29. Change From Baseline in Estradiol at Week 12 [Baseline and Week 12]

30. Change From Baseline in Follicle-Stimulating Hormone at Week 12 [Baseline and Week 12]

31. Change From Baseline in Luteinizing Hormone at Week 12 [Baseline and Week 12]

32. Change From Baseline in Sex Hormone-Binding Globulin at Week 12 [Baseline and Week 12]

33. Change From Baseline in Testosterone at Week 12 [Baseline and Week 12]

34. Change From Baseline in Free Testosterone at Week 12 [Baseline and Week 12]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 80 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subject is postmenopausal.

• Subject has moderate to severe vaginal dryness as the self-reported MBS of VVA.

Exclusion Criteria:

• Subject has clinically significant abnormal findings in the physical examination.

• Subject has a body mass index (BMI) equal to or greater than 38 kg/m^2

• Subject has uncontrolled hypertension.

• Subject has clinically significant abnormal findings in the gynecological examination other than signs of vaginal atrophy.

• Subject has uterine/vaginal bleeding of unknown origin.

• Subject has a vaginal infection requiring medication (may be treated and be eligible for study).

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Shionogi

Investigators

• Study Director: Shionogi Clinical Trials Administrator Clinical Support Help Line, Shionogi

Study Documents (Full-Text)

• Study Protocol - Nov 2, 2016
• Statistical Analysis Plan - Aug 17, 2017

More Information

Publications

None provided.

• Responsible Party: Shionogi
• ClinicalTrials.gov Identifier: NCT02638337
• Other Study ID Numbers: 1517I0231
• First Posted: Dec 23, 2015
• Last Update Posted: Apr 2, 2019
• Last Verified: Mar 1, 2019

• Keywords provided by Shionogi: Vulvo-vaginal Atrophy; menopause

Study Results

Participant Flow

Recruitment Details	Participants were randomized at 68 sites in the United States.
Pre-assignment Detail	After a screening period of up to 4 weeks, participants who met all eligibility criteria were randomized in a 1:1 ratio to receive either ospemifene 60 mg once daily or matching placebo for 12 weeks. Randomization was stratified by severity of most bothersome symptom of vaginal dryness on Day 1 and by the presence or absence of the uterus.

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Period Title: Overall Study
STARTED	316	315
Received Treatment	313	315
COMPLETED	283	279
NOT COMPLETED	33	36

Baseline Characteristics

Arm/Group Title	Ospemifene	Placebo	Total
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.	Total of all reporting groups
Overall Participants	313	314	627
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.7 (6.6)	59.8 (7.2)	59.7 (6.9)
Age, Customized (Count of Participants)
>= 40 to < 45 years	3 1%	7 2.2%	10 1.6%
>= 45 to < 55 years	66 21.1%	58 18.5%	124 19.8%
>= 55 to < 65 years	171 54.6%	174 55.4%	345 55%
>= 65 years	73 23.3%	75 23.9%	148 23.6%
Sex: Female, Male (Count of Participants)
Female	313 100%	314 100%	627 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	84 26.8%	79 25.2%	163 26%
Not Hispanic or Latino	228 72.8%	234 74.5%	462 73.7%
Unknown or Not Reported	1 0.3%	1 0.3%	2 0.3%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	0 0%	7 2.2%	7 1.1%
Asian	1 0.3%	3 1%	4 0.6%
Black or African American	38 12.1%	32 10.2%	70 11.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
White	273 87.2%	266 84.7%	539 86%
Other	1 0.3%	6 1.9%	7 1.1%
Presence of Uterus (Count of Participants)
Yes	128 40.9%	132 42%	260 41.5%
No	185 59.1%	182 58%	367 58.5%
Current Hot Flashes (Count of Participants)
Yes	26 8.3%	28 8.9%	54 8.6%
No	287 91.7%	286 91.1%	573 91.4%
Previous Hormone Treatment as Prior Treatment (Count of Participants)
None	305 97.4%	307 97.8%	612 97.6%
Oral	5 1.6%	5 1.6%	10 1.6%
Transdermal	0 0%	0 0%	0 0%
Vaginal	4 1.3%	3 1%	7 1.1%
Other	0 0%	0 0%	0 0%
Duration of Vulvovaginal Atrophy (VVA) (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	8.36 (6.92)	8.98 (7.79)	8.67 (7.37)
Percentage of Parabasal Cells in the Vaginal Squamous Epithelium: (percentage of cells) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of cells]	25.8 (33.3)	28.3 (33.1)	27.0 (33.2)
Percentage of Superficial Cells in the Vaginal Squamous Epithelium (percentage of cells) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percentage of cells]	3.0 (7.6)	2.8 (6.9)	2.9 (7.2)
Vaginal pH (pH) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [pH]	6.11 (0.70)	6.14 (0.73)	6.12 (0.71)
Mean Severity of Most Bothersome Symptom of Vaginal Dryness (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	2.53 (0.50)	2.54 (0.50)	2.54 (0.5)
Severity of Most Bothersome Symptom of Vaginal Dryness (Count of Participants)
None	0 0%	0 0%	0 0%
Mild	0 0%	0 0%	0 0%
Moderate	148 47.3%	143 45.5%	291 46.4%
Severe	165 52.7%	171 54.5%	336 53.6%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the Percentage of Parabasal Cells in the Maturation Index of the Vaginal Smear at Week 12
Description	Parabasal cells are immature squamous cells in the lining of the vagina. A predominance of parabasal cells indicates absence of estrogenic stimulation and vaginal atrophy. Vaginal smear samples were taken from the middle third of the lateral vaginal wall and were evaluated at a central laboratory by a qualified pathologist. A decrease in parabasal cells indicates improvement in vaginal atrophy. To calculate least squares (LS) means, a mixed-effects model for repeated measures (MMRM) model was used.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available baseline data

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	306	308
Least Squares Mean (Standard Error) [percentage of cells]	-23.7 (1.4)	-1.9 (1.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	For the percentage of parabasal cells a mixed-effects model for repeated measures (MMRM) approach was used, with repeated measurements of the change from baseline as the response variable; treatment, week, treatment by week interaction, and study center as fixed effects; and baseline value modeled as a covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed-effects model repeated measures
	Comments	MMRM model with treatment, week, treatment by week interaction, and study center as fixed effects; and baseline value modeled as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-21.8
	Confidence Interval	(2-Sided) 95%; -25.7 to -18.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Change From Baseline in the Percentage of Superficial Cells in the Maturation Index of the Vaginal Smear at Week 12
Description	Superficial cells are mature squamous cells in the lining of the vagina that can decrease in number after menopause resulting in vulvovaginal atrophy. Vaginal smear samples were taken from the middle third of the lateral vaginal wall and were evaluated at a central laboratory by a qualified pathologist. An increase in the number of superficial cells indicates improvement in atrophy. To calculate least squares (LS) means, a mixed-effects model for repeated measures (MMRM) model was used.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available baseline data

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	306	308
Least Squares Mean (Standard Error) [percentage of cells]	7.8 (0.7)	0.6 (0.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed-effects model repeated measures
	Comments	MMRM model with treatment, week, treatment by week interaction, and study center as fixed effects; and baseline value modeled as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	7.2
	Confidence Interval	(2-Sided) 95%; 5.2 to 9.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Change From Baseline in the Vaginal pH at Week 12
Description	The pH scale ranges from 0 to 14. A pH of 7 is neutral, less than 7 is acidic, and greater than 7 is basic. A typical vaginal pH in women of reproductive age is between 3.5 and 4.5, increasing to > 4.5 after menopause. Vaginal pH was measured by the investigator using a pH indicator strip at the middle third of the vaginal wall. To calculate least squares (LS) means, a mixed-effects model for repeated measures (MMRM) model was used.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available baseline data

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	313	314
Least Squares Mean (Standard Error) [pH]	-1.01 (0.04)	-0.29 (0.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed-effects model repeated measures
	Comments	MMRM model with treatment, week, treatment by week interaction, and study center as fixed effects; and baseline value modeled as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.72
	Confidence Interval	(2-Sided) 95%; -0.84 to -0.59
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Change From Baseline in the Severity of Self-reported Most Bothersome Symptom (MBS) of Vaginal Dryness at Week 12
Description	The severity of the most bothersome symptom of vaginal dryness was assessed by the participant through the VVA questionnaire as none = 0, mild = 1, moderate = 2, and severe = 3.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available baseline data

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	313	314
Mean (Standard Deviation) [units on a scale]	-1.29 (1.01)	-0.91 (0.96)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	For the MBS of vaginal dryness a generalized estimating equations (GEE) model was used to fit a marginal proportional odds model to the longitudinal ordered categorical data, with repeated measurements of the change from baseline as the response variable; treatment, week, treatment by week interaction, and study center as fixed effects; and baseline severity of dryness modeled as a covariate.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Generalized estimating equations model
	Comments	GEE model with treatment, week, treatment by week interaction, and study center as fixed effects and baseline severity of dryness as a covariate.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.23
	Confidence Interval	(2-Sided) 95%; 1.62 to 3.06
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio is the exponential of the mean of cumulative log odds ratio.

5. Primary Outcome

Title	Number of Participants With Adverse Events
Description	Treatment-related adverse events (AEs) were defined as AEs that were considered by the investigator to be related to investigational medicinal product, for which causal relationship with the study drug could be reasonably explained. A serious adverse event (SAE) is defined as any AE occurring at any dose that resulted in any of the following outcomes: Death Life-threatening condition Hospitalization or prolongation of existing hospitalization for treatment Persistent or significant disability/incapacity Congenital anomaly/birth defect Other medically important conditions that, based on medical judgment, may jeopardize the participant's health and may require medical intervention to prevent one of the outcomes listed above.
Time Frame	From the first dose of study drug up to 14 days after the last dose; 14 weeks

Outcome Measure Data

Analysis Population Description

Participants who received at least 1 dose of study drug. Four participants randomized to placebo received ospemifene in error and are counted in the ospemifene group for safety assessments. One participant randomized to placebo who enrolled at 2 different sites at the same time was excluded.

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	317	310
Any adverse event	112 35.8%	103 32.8%
Treatment-related adverse events	28 8.9%	20 6.4%
Adverse events leading to withdrawal	6 1.9%	10 3.2%
Treatment-related AEs leading to withdrawal	5 1.6%	3 1%
Serious adverse events	5 1.6%	3 1%
Treatment-related serious adverse events	0 0%	0 0%
Adverse events with outcome of death	0 0%	0 0%

6. Secondary Outcome

Title	Change From Baseline in the Percentage of Parabasal Cells in the Maturation Index of the Vaginal Smear at Weeks 4 and 8
Description	Parabasal cells are immature squamous cells in the lining of the vagina. A predominance of parabasal cells indicates absence of estrogenic stimulation and vaginal atrophy. Vaginal smear samples were taken from the middle third of the lateral vaginal wall and were evaluated at a central laboratory by a qualified pathologist. A decrease in parabasal cells indicates improvement in vaginal atrophy.
Time Frame	Baseline and Weeks 4 and 8

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with baseline data

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	306	308
Week 4	-21.6 (1.3)	0.0 (1.3)
Week 8	-23.7 (1.3)	-1.9 (1.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed-effects model repeated measures
	Comments	MMRM model with treatment, week, treatment by week interaction, and study center as fixed effects; and baseline value modeled as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-21.6
	Confidence Interval	(2-Sided) 95%; -25.2 to -18.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed-effects model repeated measures
	Comments	MMRM model with treatment, week, treatment by week interaction, and study center as fixed effects; and baseline value modeled as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-21.8
	Confidence Interval	(2-Sided) 95%; -25.4 to -18.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in the Percentage of Superficial Cells in the Maturation Index of the Vaginal Smear at Weeks 4 and 8
Description	Superficial cells are mature squamous cells in the lining of the vagina that can decrease in number after menopause resulting in vulvovaginal atrophy. Vaginal smear samples were taken from the middle third of the lateral vaginal wall and were evaluated at a central laboratory by a qualified pathologist. An increase in the number of superficial cells indicates improvement in atrophy.
Time Frame	Baseline and Weeks 4 and 8

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available baseline data

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	306	308
Week 4	5.6 (0.6)	-0.2 (0.6)
Week 8	7.1 (0.7)	-0.2 (0.6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed-effects model repeated measures
	Comments	MMRM model with treatment, week, treatment by week interaction, and study center as fixed effects; and baseline value modeled as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	5.8
	Confidence Interval	(2-Sided) 95%; 4.2 to 7.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed-effects model repeated measures
	Comments	MMRM model with treatment, week, treatment by week interaction, and study center as fixed effects; and baseline value modeled as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	7.2
	Confidence Interval	(2-Sided) 95%; 5.5 to 9.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline in the Vaginal pH
Description	The pH scale ranges from 0 to 14. A pH of 7 is neutral, less than 7 is acidic, and greater than 7 is basic. A typical vaginal pH in women of reproductive age is between 3.5 and 4.5, increasing to > 4.5 after menopause. Vaginal pH was measured by the investigator using a pH indicator strip at the middle third of the vaginal wall.
Time Frame	Baseline and Weeks 4 and 8

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available baseline data

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	313	314
Week 4	-0.81 (0.04)	-0.24 (0.04)
Week 8	-0.95 (0.04)	-0.32 (0.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed-effects model repeated measures
	Comments	MMRM model with treatment, week, treatment by week interaction, and study center as fixed effects; and baseline value modeled as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.58
	Confidence Interval	(2-Sided) 95%; -0.69 to -0.46
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed-effects model repeated measures
	Comments	MMRM model with treatment, week, treatment by week interaction, and study center as fixed effects; and baseline value modeled as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.63
	Confidence Interval	(2-Sided) 95%; -0.75 to -0.51
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Change From Baseline in the Severity of Self-reported Most Bothersome Symptom (MBS) of Vaginal Dryness at Weeks 4 and 8
Description	The severity of the most bothersome symptom of vaginal dryness was assessed by the participant through the VVA questionnaire as none = 0, mild = 1, moderate = 2, and severe = 3.
Time Frame	Baseline and Weeks 4 and 8

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available data at baseline

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	313	314
Week 4	-0.83 (0.90)	-0.62 (0.89)
Week 8	-1.14 (0.97)	-0.84 (0.95)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0005
	Comments
	Method	Generalized estimating equations model
	Comments	GEE model with treatment, week, treatment by week interaction, and study center as fixed effects and baseline severity of dryness as a covariate.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.74
	Confidence Interval	(2-Sided) 95%; 1.27 to 2.36
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio is the exponential of the mean of cumulative log odds ratio.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Generalized estimating equations model
	Comments	GEE model with treatment, week, treatment by week interaction, and study center as fixed effects and baseline severity of dryness as a covariate.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	2.01
	Confidence Interval	(2-Sided) 95%; 1.47 to 2.74
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio is the exponential of the mean of cumulative log odds ratio.

10. Secondary Outcome

Title	Change From Baseline in Vaginal and/or Vulvar Irritation or Itching
Description	The severity of vaginal and/or vulvar irritation or itching was assessed by the participant through the VVA questionnaire as none = 0, mild = 1, moderate = 2, and severe = 3.
Time Frame	Baseline and Weeks 4, 8, and 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population; participants whose baseline values were moderate or severe were included

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	130	138
Week 4	-0.93 (1.00)	-0.99 (1.02)
Week 8	-1.17 (1.01)	-1.16 (1.04)
Week 12	-1.38 (1.00)	-1.40 (0.96)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6263
	Comments
	Method	Generalized estimating equations model
	Comments	GEE model with treatment, week, treatment by week interaction, and study center as fixed effects and baseline severity of dryness as a covariate.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.89
	Confidence Interval	(2-Sided) 95%; 0.55 to 1.43
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio is the exponential of the mean of cumulative log odds ratio.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7869
	Comments
	Method	Generalized estimating equations model
	Comments	GEE model with treatment, week, treatment by week interaction, and study center as fixed effects and baseline severity of dryness as a covariate.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.07
	Confidence Interval	(2-Sided) 95%; 0.66 to 1.75
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio is the exponential of the mean of cumulative log odds ratio.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8894
	Comments
	Method	Generalized estimating equations model
	Comments	GEE model with treatment, week, treatment by week interaction, and study center as fixed effects and baseline severity of dryness as a covariate.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95%; 0.65 to 1.64
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio is the exponential of the mean of cumulative log odds ratio.

11. Secondary Outcome

Title	Change From Baseline in Difficult or Painful Urination
Description	The severity of difficult or painful urination was assessed by the participant through the VVA questionnaire as none = 0, mild = 1, moderate = 2, and severe = 3.
Time Frame	Baseline and Weeks 4, 8, and 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population; participants whose baseline values were moderate or severe were included.

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	40	37
Week 4	-1.23 (1.01)	-1.21 (0.84)
Week 8	-1.42 (0.95)	-1.15 (0.97)
Week 12	-1.56 (0.93)	-1.38 (0.91)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8369
	Comments
	Method	Generalized estimating equations model
	Comments	GEE model with treatment, week, treatment by week interaction, and study center as fixed effects and baseline severity of dryness as a covariate.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.92
	Confidence Interval	(2-Sided) 95%; 0.40 to 2.10
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio is the exponential of the mean of cumulative log odds ratio.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3970
	Comments
	Method	Generalized estimating equations model
	Comments	GEE model with treatment, week, treatment by week interaction, and study center as fixed effects and baseline severity of dryness as a covariate.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.51
	Confidence Interval	(2-Sided) 95%; 0.58 to 3.95
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio is the exponential of the mean of cumulative log odds ratio.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5391
	Comments
	Method	Generalized estimating equations model
	Comments	GEE model with treatment, week, treatment by week interaction, and study center as fixed effects and baseline severity of dryness as a covariate.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.33
	Confidence Interval	(2-Sided) 95%; 0.54 to 3.26
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio is the exponential of the mean of cumulative log odds ratio.

12. Secondary Outcome

Title	Change From Baseline in Vaginal Pain Associated With Sexual Activity
Description	The severity of vaginal pain associated with sexual activity was assessed by the participant through the VVA questionnaire as none = 0, mild = 1, moderate = 2, and severe = 3.
Time Frame	Baseline and Weeks 4, 8, and 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population; participants whose baseline values were moderate or severe were included

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	201	203
Week 4	-1.24 (1.11)	-0.99 (1.11)
Week 8	-1.41 (1.08)	-1.26 (1.13)
Week 12	-1.55 (1.05)	-1.21 (1.07)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0095
	Comments
	Method	Generalized estimating equations model
	Comments	GEE model with treatment, week, treatment by week interaction, and study center as fixed effects and baseline severity of dryness as a covariate.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.65
	Confidence Interval	(2-Sided) 95%; 1.13 to 2.40
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio is the exponential of the mean of cumulative log odds ratio.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0542
	Comments
	Method	Generalized estimating equations model
	Comments	GEE model with treatment, week, treatment by week interaction, and study center as fixed effects and baseline severity of dryness as a covariate.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.45
	Confidence Interval	(2-Sided) 95%; 0.99 to 2.11
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio is the exponential of the mean of cumulative log odds ratio.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	Generalized estimating equations model
	Comments	GEE model with treatment, week, treatment by week interaction, and study center as fixed effects and baseline severity of dryness as a covariate.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.97
	Confidence Interval	(2-Sided) 95%; 1.35 to 2.88
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio is the exponential of the mean of cumulative log odds ratio.

13. Secondary Outcome

Title	Change From Baseline in Vaginal Bleeding Associated With Sexual Activity
Description	The severity of vaginal bleeding associated with sexual activity was assessed by the participant through the VVA questionnaire as none = 0, mild = 1, moderate = 2, and severe = 3.
Time Frame	Baseline and Weeks 4, 8, and 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population; participants whose baseline values were moderate or severe were included

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	51	37
Week 4	-1.17 (1.09)	-1.33 (1.14)
Week 8	-1.47 (0.92)	-1.58 (1.09)
Week 12	-1.55 (0.79)	-1.61 (1.06)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4336
	Comments
	Method	Generalized estimating equations model
	Comments	GEE model with treatment, week, treatment by week interaction, and study center as fixed effects and baseline severity of dryness as a covariate.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.71
	Confidence Interval	(2-Sided) 95%; 0.30 to 1.67
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio is the exponential of the mean of cumulative log odds ratio.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7672
	Comments
	Method	Generalized estimating equations model
	Comments	GEE model with treatment, week, treatment by week interaction, and study center as fixed effects and baseline severity of dryness as a covariate.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 95%; 0.37 to 2.08
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio is the exponential of the mean of cumulative log odds ratio.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7101
	Comments
	Method	Generalized estimating equations model
	Comments	GEE model with treatment, week, treatment by week interaction, and study center as fixed effects and baseline severity of dryness as a covariate.
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.86
	Confidence Interval	(2-Sided) 95%; 0.39 to 1.89
	Parameter Dispersion	Type: Value:
	Estimation Comments	Odds ratio is the exponential of the mean of cumulative log odds ratio.

14. Secondary Outcome

Title	Change From Baseline in Maturation Value
Description	The maturation value is an indicator of the level of maturation attained by the vaginal epithelium. Vaginal smear samples were taken from the middle third of the lateral vaginal wall and were evaluated at the central laboratory by a qualified pathologist. Parabasal cells (P), intermediary cells (I), and superficial cells (S) were counted and results were expressed as the maturation value (MV), whereby superficial cells were assigned a point value of 1.0, intermediate cells were assigned a point value of 0.5, and parabasal cells were assigned a point value of 0. The maturation value (MV) was defined as: (percentage of superficial cells * 1) + (percentage of intermediate cells * 0.5) + (percentage of parabasal calls * 0). Lower MV indicates lower estrogen effect.
Time Frame	Baseline and Weeks 4, 8, and 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available data at each time point

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	306	308
Week 4	13.33 (0.79)	-0.65 (0.75)
Week 8	15.34 (0.82)	0.61 (0.78)
Week 12	16.19 (0.87)	1.28 (0.83)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	13.98
	Confidence Interval	(2-Sided) 95%; 11.85 to 16.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	14.73
	Confidence Interval	(2-Sided) 95%; 12.50 to 16.96
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	14.91
	Confidence Interval	(2-Sided) 95%; 12.55 to 17.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Percentage of Participants Who Were Responders at Week 4, Week 8, and Week 12
Description	A participant was defined as a responder if all the following conditions were met:: Increase from baseline in maturation value of at least 10 Decrease from baseline in vaginal pH of at least 0.5 Improvement from baseline (decrease in severity) of at least 1 point in the most bothersome symptom of vaginal dryness
Time Frame	Baseline and Weeks 4, 8, and 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available data at each time point

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	313	314
Week 4	19.2 6.1%	2.6 0.8%
Week 8	27.9 8.9%	4.4 1.4%
Week 12	31.5 10.1%	6.0 1.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Fisher Exact
	Comments

16. Secondary Outcome

Title	Change From Baseline in Vaginal Health Index
Description	The investigator performed an evaluation of the vagina, assessing overall elasticity, fluid secretion, pH, condition of epithelial mucosa, and moisture. The severity of each characteristic was assessed using a 5-grade scale from 1 (worst) to 5 (best). The total score was calculated as the sum of the 5 individual scores and ranges from 5 to 25, where higher scores indicate better vaginal health
Time Frame	Baseline and Weeks 4, 8, and 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available data at each time point

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	312	312
Week 4	3.9 (0.2)	1.5 (0.2)
Week 8	5.0 (0.2)	2.1 (0.2)
Week 12	5.2 (0.2)	2.3 (0.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	2.5
	Confidence Interval	(2-Sided) 95%; 2.0 to 3.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	2.9
	Confidence Interval	(2-Sided) 95%; 2.4 to 3.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	2.8
	Confidence Interval	(2-Sided) 95%; 2.2 to 3.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Change From Baseline in Vulvar Health Index
Description	The investigator performed a visual examination of the vulva, assessing the labia majora, labia minora, clitoris, introitus appearance and elasticity, color, discomfort and pain, and presence of other findings (eg, petechiae, excoriations, ulcers, etc). The severity of each characteristic was assessed on a 4-point scale as 0 = normal, 1 = mild, 2 = moderate, and 3 = severe. The total score was calculated by adding the 7 individual scores and ranges from 0 to 21, where lower scores indicate better vulvar health. A negative change from baseline indicates improvement.
Time Frame	Baseline and Weeks 4, 8, and 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available data at each timepoint

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	308	308
Week 4	-2.2 (0.2)	-1.4 (0.2)
Week 8	-2.8 (0.2)	-1.7 (0.2)
week 12	-2.8 (0.2)	-1.6 (0.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.8
	Confidence Interval	(2-Sided) 95%; -1.3 to -0.4
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.1
	Confidence Interval	(2-Sided) 95%; -1.5 to -0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.2
	Confidence Interval	(2-Sided) 95%; -1.6 to -0.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

18. Secondary Outcome

Title	Change From Baseline in Vulvovaginal Imaging Total Score at Week 12
Description	Vulvovaginal imaging was performed by trained site personnel following a standard procedure. Photographs were assessed by an Independent Panel Review (IPR) in a blinded fashion. Nine parameters (labia majora, labia minora, clitoris, urethra, introitus and elasticity, color, erythema, moisture, and other findings (petechiae, excoriation, ulceration, etc.)) were evaluated on a scale from 0 (normal/none) to 3 (severe). The total score was calculated from the sum of the 9 individual scores and ranged from 0 to 27 with lower values indicating better vulvovaginal health; a negative change from baseline indicates improvement.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population; participants who agreed to participate in the optional vaginal imaging, and with available data at both time points were included.

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	135	141
Least Squares Mean (Standard Error) [units on a scale]	-1.1 (0.3)	-0.1 (0.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0118
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.0
	Confidence Interval	(2-Sided) 95%; -1.8 to -0.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

19. Secondary Outcome

Title	Change From Baseline in Female Sexual Function Index Total Score
Description	The Female Sexual Function Index consists of 19 questions organized into 6 domains (desire, arousal, lubrication, orgasm, satisfaction, and pain) answered by the participant on a 5-point scale from 1 to 5. Where relevant, some questions also include an option of 0 if a question is not applicable due to no sexual activity. Each domain score was calculated by adding the scores of each item in the domain and multiplying by a domain factor. The total score was calculated by summing each domain score and ranges from 2 to 36, with higher values indicating better sexual function.
Time Frame	Baseline and Weeks 4, 8, and 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available data at each time point

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	303	308
Week 4	4.13 (0.43)	4.11 (0.43)
Week 8	4.70 (0.49)	4.51 (0.49)
Week 12	5.71 (0.55)	4.13 (0.54)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9748
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.02
	Confidence Interval	(2-Sided) 95%; -1.17 to 1.20
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7865
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.19
	Confidence Interval	(2-Sided) 95%; -1.18 to 1.56
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0392
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	1.59
	Confidence Interval	(2-Sided) 95%; 0.08 to 3.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

20. Secondary Outcome

Title	Change From Baseline in Female Sexual Function Index Domain Scores at Week 12
Description	The Female Sexual Function Index consists of 19 questions, organized into 6 domains (desire, arousal, lubrication, orgasm, satisfaction, and pain), answered by the participant on a scale from 1 to 5. Where relevant, some questions also include an option of 0 if not applicable due to no sexual activity. Each domain score was calculated by adding the scores of each item in the domain and multiplying by a domain factor. For all domains, higher values indicate better sexual function, according to the following: Desire (2 questions): domain score ranges from 1.2 to 6; Arousal (4 questions): domain score ranges from 0 to 6; Lubrication (4 questions): domain score ranges from 0 to 6; Orgasm (3 questions): domain score ranges from 0 to 6; Satisfaction (3 questions): domain score ranges from 0.8 to 6; Pain (3 questions): domain score ranges from 0 to 6.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available baseline and Week 12 data

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	303	308
Desire	0.56 (0.07)	0.39 (0.06)
Arousal	0.64 (0.11)	0.44 (0.11)
Lubrication	1.29 (0.12)	0.89 (0.12)
Orgasm	0.78 (0.12)	0.63 (0.11)
Satisfaction	0.78 (0.09)	0.62 (0.09)
Pain	1.47 (0.12)	1.01 (0.12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Desire
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0752
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 95%; -0.02 to 0.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Arousal
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1867
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.20
	Confidence Interval	(2-Sided) 95%; -0.10 to 0.49
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Lubrication
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0161
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.40
	Confidence Interval	(2-Sided) 95%; 0.07 to 0.73
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Orgasm
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3400
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 95%; -0.16 to 0.48
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Satisfaction
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2195
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.16
	Confidence Interval	(2-Sided) 95%; -0.10 to 0.41
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Pain
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0103
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.45
	Confidence Interval	(2-Sided) 95%; 0.11 to 0.80
	Parameter Dispersion	Type: Value:
	Estimation Comments

21. Secondary Outcome

Title	Change From Baseline in Urinary Distress Inventory (UDI)-6 Total Score
Description	The presence or absence of urinary symptoms was assessed using the Urinary Distress Inventory (UDI)-6. The symptoms include frequent urination, urine leakage related to the feeling of urgency, urine leakage related to physical activity, coughing, or sneezing, small amounts of urine leakage, difficulty emptying bladder, and pain and discomfort in the lower abdominal or genital area. If a symptom was present, participants were asked to assess the degree to which they were bothered by it on the following 4-point scale: = present but doesn't bother her at all; = present and bothers her slightly; = present and bothers her moderately; = present and bothers her greatly. The total score was calculated by adding the 6 scores together (Absent = 0), and ranges from 0 to 24, with lower values indicating less urinary distress.
Time Frame	Baseline and Weeks 4, 8, and 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available data at each time point

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	311	314
Week 4	-0.8 (0.2)	-0.9 (0.2)
Week 8	-1.0 (0.2)	-1.4 (0.2)
Week 12	-1.3 (0.2)	-1.6 (0.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 4
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7230
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.1
	Confidence Interval	(2-Sided) 95%; -0.4 to 0.6
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 8
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1104
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.4
	Confidence Interval	(2-Sided) 95%; -0.1 to 0.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2448
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.3
	Confidence Interval	(2-Sided) 95%; -0.2 to 0.9
	Parameter Dispersion	Type: Value:
	Estimation Comments

22. Secondary Outcome

Title	Change From Baseline in Bone Sialoprotein at Week 12
Description	Serum bone sialoprotein (BSP) was measured as a marker of bone resorption.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available data

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	264	271
Least Squares Mean (Standard Error) [pg/mL]	-24964.3 (3922.5)	-20576.1 (3871.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4263
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-4388.3
	Confidence Interval	(2-Sided) 95%; -15214.8 to 6438.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

23. Secondary Outcome

Title	Change From Baseline in Type I Collagen C-Telopeptide (CTX) at Week 12
Description	Type I collagen C-telopeptide was measured as a marker of bone resorption.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available data

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	261	260
Least Squares Mean (Standard Error) [ng/mL]	-0.044 (0.008)	0.006 (0.008)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.049
	Confidence Interval	(2-Sided) 95%; -0.071 to -0.027
	Parameter Dispersion	Type: Value:
	Estimation Comments

24. Secondary Outcome

Title	Change From Baseline in Deoxypyridinoline at Week 12
Description	Deoxypyridinoline was measured as a marker of bone resorption.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available data

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	261	260
Least Squares Mean (Standard Error) [µmol/mol creatinine]	0.08 (0.16)	0.22 (0.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5159
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.14
	Confidence Interval	(2-Sided) 95%; -0.58 to 0.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

25. Secondary Outcome

Title	Change From Baseline in Type I Collagen N-Telopeptide (NTX) at Week 12
Description	Type I collagen N-telopeptide was measured as a marker of bone resorption.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available data

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	265	270
Least Squares Mean (Standard Error) [nmol bone collagen equivalents (BCE)/L]	-0.10 (0.23)	0.65 (0.23)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0227
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.75
	Confidence Interval	(2-Sided) 95%; -1.39 to -0.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

26. Secondary Outcome

Title	Change From Baseline in Tartrate-Resistant Acid Phosphatase 5b at Week 12
Description	Tartrate-resistant acid phosphatase 5b was measured as a marker of bone resorption.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available data

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	265	270
Least Squares Mean (Standard Error) [units/L]	-0.28 (0.04)	-0.06 (0.04)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0003
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.22
	Confidence Interval	(2-Sided) 95%; -0.34 to -0.10
	Parameter Dispersion	Type: Value:
	Estimation Comments

27. Secondary Outcome

Title	Change From Baseline in Alkaline Phosphatase at Week 12
Description	Alkaline phosphatase was measured as a marker of bone formation.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available data

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	258	261
Least Squares Mean (Standard Error) [units/L]	-4.6 (0.7)	1.6 (0.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-6.2
	Confidence Interval	(2-Sided) 95%; -8.1 to -4.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

28. Secondary Outcome

Title	Change From Baseline in Bone-specific Alkaline Phosphatase at Week 12
Description	Bone-specific alkaline phosphatase was measured as a marker of bone formation.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available data

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	265	270
Least Squares Mean (Standard Error) [units/L]	-0.50 (0.36)	0.84 (0.36)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0084
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-1.35
	Confidence Interval	(2-Sided) 95%; -2.35 to -0.35
	Parameter Dispersion	Type: Value:
	Estimation Comments

29. Secondary Outcome

Title	Change From Baseline in Osteocalcin at Week 12
Description	Osteocalcin was measured as a marker for bone formation.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available data

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	265	270
Least Squares Mean (Standard Error) [ng/mL]	-1.43 (0.31)	0.62 (0.31)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-2.06
	Confidence Interval	(2-Sided) 95%; -2.92 to -1.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

30. Secondary Outcome

Title	Change From Baseline in Procollagen 1 N-Terminal Propeptide (P1NP) at Week 12
Description	Procollagen 1 N-terminal propeptide was measured as a marker of bone formation.
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available data

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	261	260
Least Squares Mean (Standard Error) [ng/mL]	-3.22 (0.85)	2.04 (0.86)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	The ANCOVA model included treatment group as a fixed effect and baseline value as a covariate.
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-5.26
	Confidence Interval	(2-Sided) 95%; -7.64 to -2.89
	Parameter Dispersion	Type: Value:
	Estimation Comments

31. Secondary Outcome

Title	Mean Days of Lubricant Use Per Week
Description	The mean number of days/week that lubricant was used as documented by participants in an electronic daily diary.
Time Frame	Week 1 to Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available data

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	302	304
Mean (Standard Deviation) [days/week]	0.8 (1.3)	0.8 (1.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9575
	Comments
	Method	Welch's t-test
	Comments

32. Secondary Outcome

Title	Mean Days of Intercourse Per Week
Description	The mean number of days/week of intercourse as recorded by participants in an electronic daily diary.
Time Frame	Week 1 to Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available data

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	302	304
Mean (Standard Deviation) [days/week]	0.9 (1.0)	0.9 (1.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8772
	Comments
	Method	Welch's t-test
	Comments

33. Secondary Outcome

Title	Overall Satisfaction With Treatment at Week 12
Description	Participants were asked to record their overall satisfaction with treatment in an electronic diary according to the following categories: Very satisfied, Moderately satisfied, About equally satisfied and dissatisfied, Moderately dissatisfied, and Very dissatisfied.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available data

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	221	198
Very satisfied	83 26.5%	54 17.2%
Moderately satisfied	71 22.7%	52 16.6%
About equally satisfied and dissatisfied	43 13.7%	49 15.6%
Moderately dissatisfied	13 4.2%	26 8.3%
Very dissatisfied	11 3.5%	17 5.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Ospemifene, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0007
	Comments
	Method	Wilcoxon rank-sum test
	Comments

34. Secondary Outcome

Title	Change From Baseline in Estradiol at Week 12
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available data

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	266	269
Mean (Standard Deviation) [pg/mL]	-2.5 (19.6)	0.5 (10.3)

35. Secondary Outcome

Title	Change From Baseline in Follicle-Stimulating Hormone at Week 12
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available data

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	268	270
Mean (Standard Deviation) [IU/L]	-5.18 (12.64)	-1.96 (11.79)

36. Secondary Outcome

Title	Change From Baseline in Luteinizing Hormone at Week 12
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available data

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	266	270
Mean (Standard Deviation) [IU/L]	-1.58 (8.54)	-0.38 (7.59)

37. Secondary Outcome

Title	Change From Baseline in Sex Hormone-Binding Globulin at Week 12
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available data

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	262	267
Mean (Standard Deviation) [nmol/L]	30.44 (31.89)	1.73 (17.61)

38. Secondary Outcome

Title	Change From Baseline in Testosterone at Week 12
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available data

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	262	267
Mean (Standard Deviation) [ng/dL]	1.1 (9.1)	1.2 (20.2)

39. Secondary Outcome

Title	Change From Baseline in Free Testosterone at Week 12
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Intent-to-treat population with available data

Arm/Group Title	Ospemifene	Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.	Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
Measure Participants	262	267
Mean (Standard Deviation) [nmol/L]	0.0000 (0.0035)	0.0007 (0.0115)

Adverse Events

Time Frame	From the first dose of study drug up to 14 days after the last dose; 14 weeks
Adverse Event Reporting Description	Participants who received at least 1 dose of study drug. Four participants randomized to placebo received ospemifene in error and are counted in the ospemifene group for safety assessments. One participant randomized to placebo who enrolled at 2 different sites at the same time was excluded.
Arm/Group Title	Ospemifene		Placebo
Arm/Group Description	Participants received one tablet of ospemifene 60 mg orally, once a day for 12 weeks.		Participants received one tablet of matching placebo, orally, once a day for 12 weeks.
All Cause Mortality
	Ospemifene		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/317 (0%)		0/310 (0%)
Serious Adverse Events
	Ospemifene		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/317 (1.6%)		3/310 (1%)
Cardiac disorders
Acute myocardial infarction	1/317 (0.3%)		0/310 (0%)
Gastrointestinal disorders
Enterocolitis	0/317 (0%)		1/310 (0.3%)
Infections and infestations
Bronchitis	1/317 (0.3%)		0/310 (0%)
Injury, poisoning and procedural complications
Comminuted fracture	0/317 (0%)		1/310 (0.3%)
Upper limb fracture	1/317 (0.3%)		0/310 (0%)
Nervous system disorders
Transient global amnesia	0/317 (0%)		1/310 (0.3%)
Psychiatric disorders
Depression	1/317 (0.3%)		0/310 (0%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/317 (0.3%)		0/310 (0%)
Hypoxia	1/317 (0.3%)		0/310 (0%)
Other (Not Including Serious) Adverse Events
	Ospemifene		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	37/317 (11.7%)		42/310 (13.5%)
Infections and infestations
Nasopharyngitis	4/317 (1.3%)		8/310 (2.6%)
Upper respiratory tract infection	7/317 (2.2%)		11/310 (3.5%)
Urinary tract infection	7/317 (2.2%)		10/310 (3.2%)
Nervous system disorders
Headache	5/317 (1.6%)		7/310 (2.3%)
Vascular disorders
Hot flush	20/317 (6.3%)		8/310 (2.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The sponsor can embargo results from a PI's center until the combined results from the completed study have been published in full or the sponsor confirms there will be no multicenter study publication. Results communications must be provided to the sponsor for review at least 60 days before submission for publication. By written request, the sponsor can extend the embargo up to an additional 60 days. The sponsor cannot require changes to scientific content and cannot further extend the embargo.