Efficacy and Safety of S-equol on Vasomotor Symptoms in Menopausal Patients

• Sponsor: Ausio Pharmaceuticals, LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00962585
• Collaborator: (none)
• Enrollment: 169
• Locations: 9
• Arms: 4
• Duration (Months): 17
• Patients Per Site: 18.8
• Patients Per Site Per Month: 1.1

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the safety and effectiveness of S-equol in menopausal patients with hot flushes and night sweats.

Condition or Disease	Intervention/Treatment	Phase
Menopause	Drug: Placebo; Drug: S-equol	Phase 2

Detailed Description

The study is a randomized, double blind, multicenter, placebo controlled, parallel group, proof of concept study comparing the efficacy, safety, and acceptability of 3 doses of S-equol to placebo in menopausal patients with vasomotor symptoms. The study objective is an evaluation of the dose response of 3 dose levels of AUS-131 (S-equol) and placebo with respect to reducing the mean number of moderate to severe vasomotor symptoms after 4 weeks of treatment. The safety of S-equol will be evaluated during the study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 169 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Randomized, Double Blind, Multicenter, Placebo Controlled, Proof of Concept Trial to Assess the Efficacy and Safety of 4 Weeks Treatment With AUS-131 (S-equol) on Vasomotor Symptoms in Menopausal Patients
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: Nov 1, 2011
• Actual Study Completion Date: Nov 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo	Drug: Placebo
Experimental: S-equol 10 mg BID S-equol 20 mg total daily dose	Drug: S-equol; Eligible patients meeting all study entry criteria were randomly assigned to receive one of the following active treatments for 4 weeks: S-equol 10 mg BID (20 mg total daily dose) S-equol 50 mg BID (100 mg total daily dose) S-equol 150 mg BID (300 mg total daily dose); Other Names: AUS-131
Experimental: S-equol 50 mg BID S-equol 100 mg total daily dose	Drug: S-equol; Eligible patients meeting all study entry criteria were randomly assigned to receive one of the following active treatments for 4 weeks: S-equol 10 mg BID (20 mg total daily dose) S-equol 50 mg BID (100 mg total daily dose) S-equol 150 mg BID (300 mg total daily dose); Other Names: AUS-131
Experimental: S-equol 150 mg BID S-equol 300 mg total daily dose	Drug: S-equol; Eligible patients meeting all study entry criteria were randomly assigned to receive one of the following active treatments for 4 weeks: S-equol 10 mg BID (20 mg total daily dose) S-equol 50 mg BID (100 mg total daily dose) S-equol 150 mg BID (300 mg total daily dose); Other Names: AUS-131

Outcome Measures

Primary Outcome Measures

1. Mean Change in Frequency of Moderate to Severe Vasomotor Symptoms (MSVS) Baseline at Week 4 (2-week Period) [4 weeks from Baseline (2-week run-in period)]

   The primary efficacy endpoint for this study was the change from Baseline (Day 0) in the frequency of MSVS (difference between Baseline [2-week run-in period] and Week 4), where the baseline MSVS frequency was captured over 14 ± 2 day period. Moderate is defined as "sensation of heat with sweating, able to continue activity"; severe is defined as "sensation of heat with sweating, causing cessation of activity". Patients used the take-home daily diary to record MSVS information during the run-in period and treatment period and analyses were performed as specified. Treatment group differences are estimated using least squares (LS) means and 95% confidence intervals based on the mean square error from the ANCOVA. LSMeans refer to overall adjusted mean frequency of MSVS.

Secondary Outcome Measures

1. Mean Change in Frequency of MSVS From Baseline at Week 4 (1-week Period) [4 weeks from Baseline (period following first 7 days of 2-week run-in period)]

   Change from Baseline in the frequency of MSVS (difference between Baseline [period following first 7 days of 2-week run-in period] and period following first 7 days of 2-week Week 4 period), where the Baseline MSVS frequency was captured at visit 3 (Day 0), in the period following the first 7 days, as per CRF. Note: this endpoint is identical to the primary endpoint, however, instead of a 14 ± 2 day period, the period following the first 7 days was used, at Baseline and visit 3. Treatment group differences are estimated using least squares (LS) means and 95% confidence intervals based on the mean square error from the ANCOVA. LSMeans refer to overall adjusted mean frequency of MSVS.

2. Change From Baseline (Day 0) in the Frequency of MSVS at Week 1 and Week 2 [1 and 2 weeks from Baseline (Day 0)]

   The frequency of MSVS per week, at each of the protocol visits, was calculated as follows, for each patient: [# of Moderate+Severe hot flushes)/(Current protocol visit date-Previous protocol visit date (days)] * 7. The ANCOVA procedure tested the following hypotheses: H0: μ1 = μp versus HA: μ1 ≠ μp, where μ1 and μp denote the mean frequency of MSVS, adjusted for Baseline MSVS values, in the treatment and placebo groups, respectively. LSMeans refer to the overall adjusted mean frequecy of MSVS.

3. Change From Baseline (Day 0) in the Severity of VMS as Recorded in the Patient Diary at Week 1, Week 2, and Week 4 [1, 2, and 4 weeks from Baseline (Day 0)]

   The severity of vasomotor symptoms per week at each of the protocol visits was calculated for each patient as follows: [(Sum of scores of Mild, Moderate, Severe hot flushes)/(Current protocol visit date - Previous protocol visit date (days)] * 7, where severity of vasomotor symptoms were scored as: 1 = mild, 2 = moderate and 3 = severe. Higher values represented worse severity. LSMeans refer to the overall adjusted mean severity of VMS. Hot Flush Classification: Mild: sensation of heat without sweating; Moderate: sensation of heat with sweating, able to continue activity; Severe: sensation of heat with sweating, causing cessation of activity. Patients recorded the number of hot flushes (day and night) in their diaries related to the severity (mild/moderate/severe).

4. Change From Baseline (Day 0) in Vaginal pH at Week 2 and Week 4 [2 and 4 weeks from Baseline (Day 0)]

   The pH scale measures how acidic or basic a substance is. The pH scale ranges from 0 to 14. A pH of 7 is neutral. A pH less than 7 is acidic. A pH greater than 7 is basic. The pH scale is logarithmic and as a result, each whole pH value below 7 is ten times more acidic than the next higher value. Normal vaginal pH is 3.8 to 4.5, slightly acidic. The LSMeans refer to overall adjusted mean pH.

5. Change From Baseline in Vaginal Maturation Index at Week 2 and Week 4 [2 and 4 weeks from Baseline (Day 0)]

   The Vaginal Maturation Index was calculated by examining the maturation of the vaginal epithelium as adjudged by the cell types exfoliated. Parabasal cells are the least mature cells, intermediate cells display mild maturation, and superficial cells display the most maturity. The cell count is expressed as a percentage. The Vaginal Maturation Index was calculated as: 0.2*(parabasal cells, %)+0.6*(intermediate cells, %)+1.0*(superficial cells, %). This method is described in Menopause 2005;12(6):708-15. The index serves as an objective means of evaluating hormonal secretion or response; lower values indicate more immature cells on the surface (atrophy), while higher values indicate more mature epithelium. The LSMeans refer to overall adjusted mean percent of cells counted.

6. Change From Baseline in Estradiol Concentration at Weeks 2 and 4 [2 and 4 weeks from Baseline (Day 0)]

   The LSMeans refer to overall adjusted mean estradiol concentration.

7. Change From Baseline in Progesterone Concentration at Week 2 and Week 4 [2 and 4 weeks from Baseline (Day 0)]

   No repeated measures ANCOVA results are presented for change from Baseline in progesterone concentrations since the model did not converge.

8. Mean Change in the Menopause Rating Scale Total Score From Baseline at Week 4 [4 weeks from Baseline (Day 0)]

   MRS consists of 11 menopause symptoms. The scoring scheme is simple, i.e., the score increases point by point with increasing severity of subjectively perceived symptoms in each of the 11 items (severity 0 [no complaints] 4 scoring points [extremely severe symptoms]). The respondent provides her personal perception by checking one of 5 possible boxes of "severity" for each of the items. The composite score (total score) is the sum of the 11 item scores, which can range from 0 (no symptoms) to 44 (extremely severe symptoms). Low total scores represent less severe menopause symptoms while higher scores represent more severe symptoms.

9. Mean Precentage Change in the Menopause Rating Scale Total Score From Baseline at Week 4 [4 weeks from Baseline (Day 0)]

   Percentage change from Baseline at Week 4 = (Week 4 value - Day 0 value)/(Day 0 value) x 100. Note: MRS consists of 11 symptoms, where each symptom is assigned a score from 0 to 4 (0 = 'None' and 4 = 'Extremely severe').

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• 12 months of spontaneous amenorrhea, or 6 months of spontaneous amenorrhea with serum follicle stimulating hormone (FSH) concentrations > 40 mIU/mL, or 6 weeks postsurgical bilateral oophorectomy with or without hysterectomy, or hysterectomy with 2 (measured 14 days apart) serum FSH concentrations > 40 mIU/mL.

• Is likely to experience at least 50 moderate to severe vasomotor symptoms ([MSVS] hot flushes and nocturnal sweating) per week while not receiving estrogen replacement therapy based on history of menopause, in the judgment of the investigator.

• Documented experiencing at least 50 MSVS per week during the 14 day baseline period before the Randomization Visit (Visit 3), based on the patient diary entries (calculated mean MSVS/week for the 14 day baseline period).

• If ≥ 40 years of age, has a documented negative mammogram and a normal clinical breast examination with no findings indicative of breast malignancy.

• Has a body mass index (BMI) < 35.0 kg/m2.

Exclusion Criteria:

• Has a known history of allergic reaction or clinically significant intolerance to ingredients of the study drug.

• Received any of the following:oral or dermal estrogen/progestin or selective estrogen receptor modulator (SERM) containing drug product therapy within 8 weeks before Screening, injectable or implantable estrogen/progestin therapy within 3 months before Screening, hormone releasing intrauterine device

• Had unexplained or otherwise abnormal vaginal bleeding within 6 months before Screening.

• Has a history of, or currently has, any of the following conditions: thrombophlebitis, thromboembolic disease, estrogen dependent neoplasia, or carcinoma of the breast.

• Has a history of any untreated or uncontrolled endocrine disorders (e.g., hyperparathyroidism, uncontrolled hyperthyroidism).

• Has any clinically significant unstable cardiac, respiratory, neurological, immunological, hematological, hepatic, renal, endocrine, or gastric disease or any other condition that, in the opinion of the investigator, could compromise the patient's welfare, ability to communicate with the study staff, or otherwise contraindicate study participation.

• Has clinically significant depression or severe psychiatric disturbances.

• Has active liver disease with aspartate aminotransferase (AST) > 3 times the upper limit of normal (ULN), alanine aminotransferase (ALT) > 3 times ULN, unexplained alkaline phosphatase > 3 times ULN, total bilirubin > 2 times ULN, renal insufficiency with creatinine > 1.7 mg/dL, or clinically significant abnormal hemoglobin, white blood cell count, or platelet count.

• Has an endometrial thickness ≥ 4 mm.

• Has a history indicative of endometrial hyperplasia or cancer.

• Shows presence of any manifest premalignant or malignant disease except treated skin cancers (except melanoma).

• Has known or suspected history of alcoholism or drug abuse or misuse within the past 5 years.

• Has resting systolic blood pressure (BP) > 160 mmHg or < 90 mmHg, or diastolic BP > 90 mmHg or < 60 mmHg at Screening.

• Has a history of smoking more than 5 cigarettes daily within the year before Screening.

• Has tested positive on the urine drug screen. Patients who test positive at Screening and can produce documentation from their physician for the medication that caused the positive test may be considered for study enrollment at the discretion of the investigator.

• Has significant difficulties swallowing capsules or is unable to tolerate oral medication.

• Has participated in another clinical trial or received any investigational drug or device or investigational therapy within 30 days before Screening.

• Has a disorder that affects gastrointestinal absorption.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Bluegrass Clinical Research	Louisville	Kentucky	United States	40291
2	Greater Cincinnati OB/GYN, Inc.	Cincinnati,	Ohio	United States	45267-0457
3	Rapid Medical Research	Cleveland	Ohio	United States	44122
4	Radiant Research, Inc	Greenville	South Carolina	United States	29621
5	Advanced Clinical Research	West Jordon	Utah	United States	84088
6	Sydney Centre for Reproductive Health Research	Ashfield	New South Wales	Australia	2131
7	Royal Hospital for Women	Randwick	New South Wales	Australia	2031
8	Women's Health Center, Royal Adelaide Hospital	Adelaide	South Australia	Australia	5000
9	Emeritus Research	Malvern East	Victoria	Australia	3144

Sponsors and Collaborators

• Ausio Pharmaceuticals, LLC

Investigators

• Principal Investigator: Michael A Thomas, MD, University of Cincinnati

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ausio Pharmaceuticals, LLC
• ClinicalTrials.gov Identifier: NCT00962585
• Other Study ID Numbers: AUS-CT03
• First Posted: Aug 20, 2009
• Last Update Posted: Apr 8, 2014
• Last Verified: Mar 1, 2014

• Additional relevant MeSH terms: Equol

Study Results

Participant Flow

Recruitment Details	Patients for this trial were screened from 9 investigative sites in the United States and Australia. Participants were women of menopausal status and experiencing vasomotor symptoms and nocturnal sweating.
Pre-assignment Detail	After completing screening visit assessments, subjects were instructed to refrain from taking prohibited medications throughout the study. Patients who were taking prohibited medications at the time of the screening visit discontinued their use and completed a suitable washout period before progressing to the next visit.

Arm/Group Title	S-equol 10 mg BID	S-equol 50 mg BID	S-equol 150 mg BID	Placebo
Arm/Group Description	20 mg total daily dose of S-equol	100 mg total daily dose of S-equol	300 mg total daily dose of S-equol	Placebo treatment arm
Period Title: Overall Study
STARTED	43	42	42	42
COMPLETED	37	40	39	42
NOT COMPLETED	6	2	3	0

Baseline Characteristics

Arm/Group Title	S-equol 10 mg BID	S-equol 50 mg BID	S-equol 150 mg BID	Placebo	Total
Arm/Group Description	20 mg total daily dose of S-equol	100 mg total daily dose of S-equol	300 mg total daily dose of S-equol	Placebo treatment arm	Total of all reporting groups
Overall Participants	43	42	42	42	169
Age, Customized (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.8 (7.9)	53.1 (6.9)	54.9 (5.8)	56.2 (6.7)	54.5 (6.9)
Sex: Female, Male (Count of Participants)
Female	43 100%	42 100%	42 100%	42 100%	169 100%
Male	0 0%	0 0%	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (participants) [Number]
Asian	0 0%	0 0%	0 0%	1 2.4%	1 0.6%
Black or African American	4 9.3%	7 16.7%	10 23.8%	5 11.9%	26 15.4%
White	39 90.7%	35 83.3%	32 76.2%	34 81%	140 82.8%
Unknown or Not Reported	0 0%	0 0%	0 0%	2 4.8%	2 1.2%
Height (centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters]	165.3 (5.1)	164.1 (4.6)	165.4 (6.7)	163.3 (5.9)	164.5 (5.6)
Weight (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]	74.1 (11.6)	73.0 (10.7)	74.4 (10.1)	73.2 (12.8)	73.7 (11.3)
Body Mass Index (kilogram/meter^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilogram/meter^2]	27.1 (3.9)	27.1 (4.1)	27.2 (3.5)	27.4 (4.1)	27.2 (3.9)

Outcome Measures

1. Primary Outcome

Title	Mean Change in Frequency of Moderate to Severe Vasomotor Symptoms (MSVS) Baseline at Week 4 (2-week Period)
Description	The primary efficacy endpoint for this study was the change from Baseline (Day 0) in the frequency of MSVS (difference between Baseline [2-week run-in period] and Week 4), where the baseline MSVS frequency was captured over 14 ± 2 day period. Moderate is defined as "sensation of heat with sweating, able to continue activity"; severe is defined as "sensation of heat with sweating, causing cessation of activity". Patients used the take-home daily diary to record MSVS information during the run-in period and treatment period and analyses were performed as specified. Treatment group differences are estimated using least squares (LS) means and 95% confidence intervals based on the mean square error from the ANCOVA. LSMeans refer to overall adjusted mean frequency of MSVS.
Time Frame	4 weeks from Baseline (2-week run-in period)

Outcome Measure Data

Analysis Population Description

The analysis population consists of all randomized patients who received at least 1 dose of randomized study drug starting at visit 3, who had at least 1 post-dose efficacy assessment. Missing efficacy data were not imputed.

Arm/Group Title	S-equol 10 mg BID	S-equol 50 mg BID	S-equol 150 mg BID	Placebo
Arm/Group Description	20 mg total daily dose of S-equol	100 mg total daily dose of S-equol	300 mg total daily dose of S-equol	Placebo treatment arm
Measure Participants	42	42	41	42
Baseline (Day 0)	73.5	69.5	70.4	67.9
Week 4	41.7 (32.8)	46.1 (27.8)	39.3 (27.3)	39.3 (25.1)
Change from Baseline at Week 4	-30.1 (29.0)	-23.4 (30.2)	-31.1 (23.4)	-28.6 (22.1)
LSMean	40.78	46.63	40.59	39.65

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	S-equol 10 mg BID, S-equol 50 mg BID, S-equol 150 mg BID, Placebo
	Comments	# of MSVS per week at each protocol visits = (# of Moderate+Severe hot flushes)/(Current protocol visit date-Previous protocol visit date (days)) x 7. The ANCOVA procedure was used to test the following hypotheses: H0: μ1 = μp versus HA: μ1 ≠ μp where μ1 and μp denote the mean frequency of MSVS (at Week 4 in case of primary efficacy endpoint), adjusted for Baseline MSVS values, in the treatment and placebo groups, respectively.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5730
	Comments	P-value was not adjusted for multiple comparisons and the a priori threshold for statistical significance was P <0.05.
	Method	ANCOVA
	Comments	Model (Analysis of covariance): Week 4 = Baseline (MSVS) + Treatment + Site Difference Between Means: S-equol treatment group - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	S-equol 10 mg BID, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	1.13
	Confidence Interval	(2-Sided) 95%; -10.06 to 12.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	S-equol 50 mg BID, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	6.98
	Confidence Interval	(2-Sided) 95%; -3.87 to 17.84
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	S-equol 150 mg BID, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	0.94
	Confidence Interval	(2-Sided) 95%; -10.16 to 12.04
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Mean Change in Frequency of MSVS From Baseline at Week 4 (1-week Period)
Description	Change from Baseline in the frequency of MSVS (difference between Baseline [period following first 7 days of 2-week run-in period] and period following first 7 days of 2-week Week 4 period), where the Baseline MSVS frequency was captured at visit 3 (Day 0), in the period following the first 7 days, as per CRF. Note: this endpoint is identical to the primary endpoint, however, instead of a 14 ± 2 day period, the period following the first 7 days was used, at Baseline and visit 3. Treatment group differences are estimated using least squares (LS) means and 95% confidence intervals based on the mean square error from the ANCOVA. LSMeans refer to overall adjusted mean frequency of MSVS.
Time Frame	4 weeks from Baseline (period following first 7 days of 2-week run-in period)

Outcome Measure Data

Analysis Population Description

The analysis population consists of all randomized patients who received at least 1 dose of randomized study drug starting at visit 3, who had at least 1 post-dose efficacy assessment. Missing efficacy data were not imputed.

Arm/Group Title	S-equol 10 mg BID	S-equol 50 mg BID	S-equol 150 mg BID	Placebo
Arm/Group Description	20 mg total daily dose of S-equol	100 mg total daily dose of S-equol	300 mg total daily dose of S-equol	Placebo treatment arm
Measure Participants	42	42	41	42
Baseline (Day 0)	73.0	71.4	69.5	67.9
Week 4	40.0	45.5	37.1	40.2
Change from Baseline at Week 4	-30.2	-24.9	-32.6	-27.6
LSMean	40.04	44.99	38.60	40.23

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	S-equol 10 mg BID, S-equol 50 mg BID, S-equol 150 mg BID, Placebo
	Comments	# of MSVS per week at each protocol visits = (# of Moderate+Severe hot flushes)/(Current protocol visit date-Previous protocol visit date (days)) x 7 1-week period = remaining days of the period since the last visit (i.e. period following first 7 days, as per CRF)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7364
	Comments	P-value was not adjusted for multiple comparisons and the a priori threshold for statistical significance was P <0.05.
	Method	ANCOVA
	Comments	Model: Week 4 = Baseline (MSVS) + Treatment + Site Difference Between Means: S-equol treatment group - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	S-equol 10 mg BID, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	-0.19
	Confidence Interval	(2-Sided) 95%; -12.38 to 12.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	S-equol 50 mg BID, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	4.77
	Confidence Interval	(2-Sided) 95%; -6.94 to 16.48
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	S-equol 150 mg BID, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	-1.63
	Confidence Interval	(2-Sided) 95%; -13.41 to 10.15
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change From Baseline (Day 0) in the Frequency of MSVS at Week 1 and Week 2
Description	The frequency of MSVS per week, at each of the protocol visits, was calculated as follows, for each patient: [# of Moderate+Severe hot flushes)/(Current protocol visit date-Previous protocol visit date (days)] * 7. The ANCOVA procedure tested the following hypotheses: H0: μ1 = μp versus HA: μ1 ≠ μp, where μ1 and μp denote the mean frequency of MSVS, adjusted for Baseline MSVS values, in the treatment and placebo groups, respectively. LSMeans refer to the overall adjusted mean frequecy of MSVS.
Time Frame	1 and 2 weeks from Baseline (Day 0)

Outcome Measure Data

Analysis Population Description

The analysis population consists of all randomized patients who received at least 1 dose of randomized study drug starting at visit 3, who had at least 1 post-dose efficacy assessment. Missing efficacy data were not imputed.

Arm/Group Title	S-equol 10 mg BID	S-equol 50 mg BID	S-equol 150 mg BID	Placebo
Arm/Group Description	20 mg total daily dose of S-equol	100 mg total daily dose of S-equol	300 mg total daily dose of S-equol	Placebo treatment arm
Measure Participants	42	42	41	42
Week 1	53.6	63.1	54.4	54.1
Change from Baseline at Week 1	-19.9	-6.7	-15.9	-13.8
Week 1, LSMean	50.95	64.41	56.03	54.72
Week 2	47.3	54.3	51.0	50.0
Change from Baseline at Week 2	-23.3	-14.8	-19.4	-17.9
Week 2, LSMean	43.96	54.22	51.56	50.66

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	S-equol 10 mg BID, S-equol 50 mg BID, S-equol 150 mg BID, Placebo
	Comments	# of MSVS per week at each protocol visits = (# of Moderate+Severe hot flushes)/(Current protocol visit date-Previous protocol visit date (days)) x 7.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1217
	Comments	P-value was not adjusted for multiple comparisons and the a priori threshold for statistical significance was P <0.05. Treatment effect averaged across Weeks 1 and 2.
	Method	Repeated measures ANCOVA
	Comments	Mixed Model: MSVS = Baseline (MSVS) + Treatment + Site + Weeks + Treatment x Weeks Difference Between Means: S-equol treatment group - Placebo

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	S-equol 10 mg BID, Placebo
	Comments	Week 1, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	-3.77
	Confidence Interval	() 95%; -12.69 to 5.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	S-equol 50 mg BID, Placebo
	Comments	Week 1, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	9.69
	Confidence Interval	(2-Sided) 95%; 0.79 to 18.60
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	S-equol 150 mg BID, Placebo
	Comments	Week 1, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	1.31
	Confidence Interval	(2-Sided) 95%; -7.73 to 10.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	S-equol 10 mg BID, Placebo
	Comments	Week 2, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	-6.70
	Confidence Interval	(2-Sided) 95%; -18.36 to 4.96
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	S-equol 50 mg BID, Placebo
	Comments	Week 2, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	3.56
	Confidence Interval	(2-Sided) 95%; -8.01 to 15.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	S-equol 150 mg BID, Placebo
	Comments	Week 2, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 95%; -10.77 to 12.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change From Baseline (Day 0) in the Severity of VMS as Recorded in the Patient Diary at Week 1, Week 2, and Week 4
Description	The severity of vasomotor symptoms per week at each of the protocol visits was calculated for each patient as follows: [(Sum of scores of Mild, Moderate, Severe hot flushes)/(Current protocol visit date - Previous protocol visit date (days)] * 7, where severity of vasomotor symptoms were scored as: 1 = mild, 2 = moderate and 3 = severe. Higher values represented worse severity. LSMeans refer to the overall adjusted mean severity of VMS. Hot Flush Classification: Mild: sensation of heat without sweating; Moderate: sensation of heat with sweating, able to continue activity; Severe: sensation of heat with sweating, causing cessation of activity. Patients recorded the number of hot flushes (day and night) in their diaries related to the severity (mild/moderate/severe).
Time Frame	1, 2, and 4 weeks from Baseline (Day 0)

Outcome Measure Data

Analysis Population Description

The analysis population consists of all randomized patients who received at least 1 dose of randomized study drug starting at visit 3, who had at least 1 post-dose efficacy assessment. Missing efficacy data were not imputed.

Arm/Group Title	S-equol 10 mg BID	S-equol 50 mg BID	S-equol 150 mg BID	Placebo
Arm/Group Description	20 mg total daily dose of S-equol	100 mg total daily dose of S-equol	300 mg total daily dose of S-equol	Placebo treatment arm
Measure Participants	42	42	41	42
Baseline (Day 0)	188.6	177.1	175.6	172.8
Week 1	139.0	160.4	133.6	136.0
Change from Baseline at Week 1	-49.5	-17.5	-41.8	-36.8
Week 1, LSMean	130.93	162.94	139.36	137.27
Week 2	122.0	140.1	126.2	128.7
Change from Baseline at Week 2	-60.4	-35.3	-49.4	-44.1
Week 2, LSMean	113.86	138.73	129.34	130.00
Week 4	110.5	120.3	99.5	101.6
Change from Baseline at Week 4	-75.5	-56.8	-76.2	-71.2
Week 4, LSMean	101.27	119.11	101.67	102.96

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	S-equol 10 mg BID, S-equol 50 mg BID, S-equol 150 mg BID, Placebo
	Comments	Severity of VMS per week at each protocol visits = (Sum of scores of Mild, Moderate, Severe hot flushes)/(Current protocol visit date-Previous protocol visit date (days)) x 7, where severity of vasomotor symptoms are scored as: 1 = mild, 2 = moderate and 3 = severe.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1609
	Comments	P-value was not adjusted for multiple comparisons and the a priori threshold for statistical significance was P <0.05. Treatment effect averaged across Weeks 1, 2 and 4.
	Method	Repeated measures ANCOVA
	Comments	Mixed Model: Severity of VMS = Baseline (severity of VMS) + Treatment + Site + Weeks + Treatment x Weeks

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	S-equol 10 mg BID, Placebo
	Comments	Week 1, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	-6.34
	Confidence Interval	(2-Sided) 95%; -26.41 to 13.73
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	S-equol 50 mg BID, Placebo
	Comments	Week 1, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	25.67
	Confidence Interval	(2-Sided) 95%; 5.64 to 45.69
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	S-equol 150 mg BID, Placebo
	Comments	Week 1, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	2.09
	Confidence Interval	(2-Sided) 95%; -18.21 to 22.39
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	S-equol 10 mg BID
	Comments	Week 2, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	-16.14
	Confidence Interval	(2-Sided) 95%; -43.29 to 11.01
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	S-equol 50 mg BID, Placebo
	Comments	Week 2, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	8.73
	Confidence Interval	(2-Sided) 95%; -18.19 to 35.65
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	S-equol 150 mg BID, Placebo
	Comments	Week 2, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	-0.65
	Confidence Interval	(2-Sided) 95%; -27.80 to 26.50
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	S-equol 10 mg BID, Placebo
	Comments	Week 4, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	-1.69
	Confidence Interval	(2-Sided) 95%; -28.68 to 25.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	S-equol 50 mg BID, Placebo
	Comments	Week 4, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	16.15
	Confidence Interval	(2-Sided) 95%; -10.40 to 42.71
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	S-equol 150 mg BID, Placebo
	Comments	Week 4, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	-1.29
	Confidence Interval	(2-Sided) 95%; -28.18 to 25.60
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline (Day 0) in Vaginal pH at Week 2 and Week 4
Description	The pH scale measures how acidic or basic a substance is. The pH scale ranges from 0 to 14. A pH of 7 is neutral. A pH less than 7 is acidic. A pH greater than 7 is basic. The pH scale is logarithmic and as a result, each whole pH value below 7 is ten times more acidic than the next higher value. Normal vaginal pH is 3.8 to 4.5, slightly acidic. The LSMeans refer to overall adjusted mean pH.
Time Frame	2 and 4 weeks from Baseline (Day 0)

Outcome Measure Data

Analysis Population Description

The analysis population consists of all randomized patients who received at least 1 dose of randomized study drug starting at visit 3, who had at least 1 post-dose efficacy assessment. Missing efficacy data were not imputed.

Arm/Group Title	S-equol 10 mg BID	S-equol 50 mg BID	S-equol 150 mg BID	Placebo
Arm/Group Description	20 mg total daily dose of S-equol	100 mg total daily dose of S-equol	300 mg total daily dose of S-equol	Placebo treatment arm
Measure Participants	42	42	41	42
Baseline (Day 0)	5.5	5.5	5.8	5.7
Week 2	5.4	5.4	5.8	5.8
Change from Baseline at Week 2	-0.1	-0.1	-0.0	0.0
Week 2, LSMean	5.51	5.49	5.75	5.72
Week 4	5.4	5.5	5.6	5.8
Change from Baseline at Week 4	-0.2	-0.0	-0.3	0.0
Week 4, LSMean	5.48	5.61	5.50	5.74

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	S-equol 10 mg BID, S-equol 50 mg BID, S-equol 150 mg BID, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2211
	Comments	P-value was not adjusted for multiple comparisons and the a priori threshold for statistical significance was P <0.05. Treatment effect averaged across Weeks 2 and 4.
	Method	Repeated measures ANCOVA
	Comments	Mixed Model: (Vaginal pH) = Baseline (Vaginal pH) + Treatment + Site + Weeks + Treatment x Weeks

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	S-equol 10 mg BID, Placebo
	Comments	Week 2, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	-0.21
	Confidence Interval	(2-Sided) 95%; -0.53 to 0.12
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	S-equol 50 mg BID, Placebo
	Comments	Week 2, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	-0.23
	Confidence Interval	(2-Sided) 95%; -0.55 to 0.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	S-equol 150 mg BID, Placebo
	Comments	Week 2, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	0.03
	Confidence Interval	(2-Sided) 95%; -0.28 to 0.35
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	S-equol 10 mg BID, Placebo
	Comments	Week 4, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	-0.26
	Confidence Interval	(2-Sided) 95%; -0.54 to 0.02
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	S-equol 50 mg BID, Placebo
	Comments	Week 4, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	-0.13
	Confidence Interval	(2-Sided) 95%; -0.40 to 0.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	S-equol 150 mg BID, Placebo
	Comments	Week 4, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	-0.24
	Confidence Interval	(2-Sided) 95%; -0.51 to 0.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline in Vaginal Maturation Index at Week 2 and Week 4
Description	The Vaginal Maturation Index was calculated by examining the maturation of the vaginal epithelium as adjudged by the cell types exfoliated. Parabasal cells are the least mature cells, intermediate cells display mild maturation, and superficial cells display the most maturity. The cell count is expressed as a percentage. The Vaginal Maturation Index was calculated as: 0.2*(parabasal cells, %)+0.6*(intermediate cells, %)+1.0*(superficial cells, %). This method is described in Menopause 2005;12(6):708-15. The index serves as an objective means of evaluating hormonal secretion or response; lower values indicate more immature cells on the surface (atrophy), while higher values indicate more mature epithelium. The LSMeans refer to overall adjusted mean percent of cells counted.
Time Frame	2 and 4 weeks from Baseline (Day 0)

Outcome Measure Data

Analysis Population Description

The analysis population consists of all randomized patients who received at least 1 dose of randomized study drug starting at visit 3, who had at least 1 post-dose efficacy assessment. Missing efficacy data were not imputed.

Arm/Group Title	S-equol 10 mg BID	S-equol 50 mg BID	S-equol 150 mg BID	Placebo
Arm/Group Description	20 mg total daily dose of S-equol	100 mg total daily dose of S-equol	300 mg total daily dose of S-equol	Placebo treatment arm
Measure Participants	42	42	41	42
Baseline (Day 0)	52.6	55.7	50.9	43.5
Week 2	54.5	54.3	50.8	47.0
Change from Baseline at Week 2	-0.7	-1.3	0.6	3.9
Week 2, LSMean	50.89	50.89	50.88	52.47
Week 4	56.5	51.7	51.3	48.1
Change from Baseline at Week 4	1.7	-3.7	0.3	5.2
Week 4, LSMean	53.58	47.75	51.01	53.26

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	S-equol 10 mg BID, S-equol 50 mg BID, S-equol 150 mg BID, Placebo
	Comments	Vaginal maturation index = 0.2 x (% parabasal cells) + 0.6 x(% intermediate cells) + 1.0 x (% superficial cells)
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.6375
	Comments	P-value was not adjusted for multiple comparisons and the a priori threshold for statistical significance was P <0.05. Treatment effect averaged across Weeks 2 and 4.
	Method	Repeated measures ANCOVA
	Comments	Mixed Model: (Vaginal Maturation Index) = Baseline (Vaginal Maturation Index) + Treatment + Site + Weeks + Treatment x Weeks

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	S-equol 10 mg BID, Placebo
	Comments	Week 2, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	-1.58
	Confidence Interval	(2-Sided) 95%; -9.57 to 6.42
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	S-equol 50 mg BID, Placebo
	Comments	Week 2, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	-1.58
	Confidence Interval	(2-Sided) 95%; -9.63 to 6.46
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	S-equol 150 mg BID
	Comments	Week 2, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	-1.59
	Confidence Interval	(2-Sided) 95%; -9.66 to 6.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	S-equol 10 mg BID, Placebo
	Comments	Week 4, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	-0.31
	Confidence Interval	(2-Sided) 95%; -6.73 to 6.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	S-equol 50 mg BID, Placebo
	Comments	Week 4, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	-6.14
	Confidence Interval	(2-Sided) 95%; -12.36 to 0.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	S-equol 150 mg BID, Placebo
	Comments	Week 4, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	-2.88
	Confidence Interval	(2-Sided) 95%; -9.05 to 3.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline in Estradiol Concentration at Weeks 2 and 4
Description	The LSMeans refer to overall adjusted mean estradiol concentration.
Time Frame	2 and 4 weeks from Baseline (Day 0)

Outcome Measure Data

Analysis Population Description

The analysis population consists of all randomized patients who received at least 1 dose of randomized study drug starting at visit 3, who had at least 1 post-dose efficacy assessment. Missing efficacy data were not imputed.

Arm/Group Title	S-equol 10 mg BID	S-equol 50 mg BID	S-equol 150 mg BID	Placebo
Arm/Group Description	20 mg total daily dose of S-equol	100 mg total daily dose of S-equol	300 mg total daily dose of S-equol	Placebo treatment arm
Measure Participants	42	42	41	42
Baseline (Day 0)	79.0	65.7	66.1	59.6
Week 2	117.3	72.2	68.1	62.1
Change from Baseline at Week 2	40.2	6.7	2.0	2.5
Week 2, LSMean	104.93	73.22	65.03	69.61
Week 4	114.0	82.8	60.0	70.4
Change from Baseline at Week 4	37.5	20.3	-6.7	10.7
Week 4, LSMean	100.89	86.56	56.03	78.77

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	S-equol 10 mg BID, S-equol 50 mg BID, S-equol 150 mg BID, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0681
	Comments	P-value is adjusted for multiple comparisons and the a priori threshold for statistical significance was P <0.05. Treatment effect averaged across Weeks 2 and 4.
	Method	Repeated measures ANCOVA
	Comments	Mixed Model: (Estradiol) = Baseline (Estradiol) + Treatment + Site + Weeks + Treatment x Weeks

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	S-equol 10 mg BID, Placebo
	Comments	Week 2, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	35.32
	Confidence Interval	(2-Sided) 95%; 1.75 to 68.90
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	S-equol 50 mg BID, Placebo
	Comments	Week 2, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	3.61
	Confidence Interval	(2-Sided) 95%; -29.12 to 36.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	S-equol 150 mg BID, Placebo
	Comments	Week 2, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	-4.58
	Confidence Interval	(2-Sided) 95%; -37.39 to 28.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	S-equol 10 mg BID, Placebo
	Comments	Week 4, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	22.12
	Confidence Interval	(2-Sided) 95%; -23.56 to 67.80
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	S-equol 50 mg BID, Placebo
	Comments	Week 4, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	7.80
	Confidence Interval	(2-Sided) 95%; -36.70 to 52.29
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	S-equol 150 mg BID, Placebo
	Comments	Week 4, Treatment Effect
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	Pair-wise comparisons
	Comments
Method of Estimation	Estimation Parameter	LS means difference
	Estimated Value	-22.74
	Confidence Interval	(2-Sided) 95%; -67.44 to 21.96
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline in Progesterone Concentration at Week 2 and Week 4
Description	No repeated measures ANCOVA results are presented for change from Baseline in progesterone concentrations since the model did not converge.
Time Frame	2 and 4 weeks from Baseline (Day 0)

Outcome Measure Data

Analysis Population Description

The analysis population consists of all randomized patients who received at least 1 dose of randomized study drug starting at visit 3, who had at least 1 post-dose efficacy assessment. Missing efficacy data were not imputed.

Arm/Group Title	S-equol 10 mg BID	S-equol 50 mg BID	S-equol 150 mg BID	Placebo
Arm/Group Description	20 mg total daily dose of S-equol	100 mg total daily dose of S-equol	300 mg total daily dose of S-equol	Placebo treatment arm
Measure Participants	42	42	41	42
Baseline (Day 0)	1.1	1.1	1.3	1.1
Week 2	1.2	1.3	1.1	1.0
Change from Baseline at Week 2	0.0	0.1	-0.2	-0.0
Week 4	7.0	1.1	1.4	1.1
Change from Baseline at Week 4	5.9	-0.0	0.1	-0.0

9. Secondary Outcome

Title	Mean Change in the Menopause Rating Scale Total Score From Baseline at Week 4
Description	MRS consists of 11 menopause symptoms. The scoring scheme is simple, i.e., the score increases point by point with increasing severity of subjectively perceived symptoms in each of the 11 items (severity 0 [no complaints] 4 scoring points [extremely severe symptoms]). The respondent provides her personal perception by checking one of 5 possible boxes of "severity" for each of the items. The composite score (total score) is the sum of the 11 item scores, which can range from 0 (no symptoms) to 44 (extremely severe symptoms). Low total scores represent less severe menopause symptoms while higher scores represent more severe symptoms.
Time Frame	4 weeks from Baseline (Day 0)

Outcome Measure Data

Analysis Population Description

The analysis population consists of all randomized patients who received at least 1 dose of randomized study drug starting at visit 3, who had at least 1 post-dose efficacy assessment. Missing efficacy data were not imputed.

Arm/Group Title	S-equol 10 mg BID	S-equol 50 mg BID	S-equol 150 mg BID	Placebo
Arm/Group Description	20 mg total daily dose of S-equol	100 mg total daily dose of S-equol	300 mg total daily dose of S-equol	Placebo treatment arm
Measure Participants	42	42	41	42
Baseline (Day 0)	16.9	17.3	15.7	14.5
Week 4	11.5	10.8	9.7	9.9
Change from Baseline at Week 4	-5.3	-6.4	-6.0	-4.6

10. Post-Hoc Outcome

Title	Change From Baseline in Menopause Rating Scale (MRS) - Sum of 3 Symptoms (Irritability, Dry Vagina, Joint/Muscular Discomfort)
Description	Note: Each MRS symptoms is assigned a score from 0 to 4 (0 = 'None' and 4 = 'Extremely severe'). Scores for Symptoms 5, 10, and 11 on the MRS were summed and analyzed. Total summed scores ranged from 0 to 12, with higher scores representing more severe symptoms.
Time Frame	4 weeks from Baseline (Day 0)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	S-equol 10 mg BID	S-equol 50 mg BID	S-equol 150 mg BID	Placebo
Arm/Group Description	20 mg total daily dose of S-equol	100 mg total daily dose of S-equol	300 mg total daily dose of S-equol	Placebo treatment arm
Measure Participants	42	42	41	42
Baseline (Day 0)	4.0	4.2	4.0	3.4
Week 4	2.8	2.8	2.5	2.9
Change from Baseline at Week 4	-1.3	-1.5	-1.5	-0.5

11. Post-Hoc Outcome

Title	Percentage Change From Baseline in Menopause Rating Scale (MRS) - Sum of 3 Symptoms (Irritability, Dry Vagina, Joint/Muscular Discomfort)
Description	Percentage change from Baseline at Week 4 = (Week 4 value - Day 0 value)/(Day 0 value) x 100. Note: Each MRS symptoms is assigned a score from 0 to 4 (0 = 'None' and 4 = 'Extremely severe').
Time Frame	4 weeks from Baseline (Day 0)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	S-equol 10 mg BID	S-equol 50 mg BID	S-equol 150 mg BID	Placebo
Arm/Group Description	20 mg total daily dose of S-equol	100 mg total daily dose of S-equol	300 mg total daily dose of S-equol	Placebo treatment arm
Measure Participants	42	42	41	42
Mean (95% Confidence Interval) [Percentage Change]	-29.1	-32.7	-30.2	-0.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	S-equol 10 mg BID, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0475
	Comments	P-value was not adjusted for multiple comparisons and the a priori threshold for statistical significance was P <0.05.
	Method	Wilcoxon (Mann-Whitney)
	Comments	Wilcoxon Mann-Whitney test: S-equol treatment group versus Placebo: Percentage Change from Baseline at Week 4

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	S-equol 50 mg BID, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0258
	Comments	P-value was not adjusted for multiple comparisons and the a priori threshold for statistical significance P <0.05.
	Method	Wilcoxon (Mann-Whitney)
	Comments	Wilcoxon Mann-Whitney test: S-equol treatment group versus Placebo: Percentage Change from Baseline at Week 4

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	S-equol 150 mg BID, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0281
	Comments	P-value was not adjusted for multiple comparisons and the a priori threshold for statistical significance was P <0.05.
	Method	Wilcoxon (Mann-Whitney)
	Comments	Wilcoxon Mann-Whitney test: S-equol treatment group versus Placebo: Percentage Change from Baseline at Week 4

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	S-equol 10 mg BID, S-equol 50 mg BID, S-equol 150 mg BID, Placebo
	Comments	All three S-equol treatment arms were aggregated and compared to placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0645
	Comments
	Method	Kruskal-Wallis
	Comments

12. Post-Hoc Outcome

Title	Change From Baseline in Menopause Rating Scale (MRS) - Sum of 3 Symptoms (Irritability, Dry Vagina, Joint/Muscular Discomfort) - S-equol Groups Combined
Description	The following analysis shows the results when the S-equol groups (S-equol 20 mg total daily dose, 100 mg total daily dose, and 300 mg total daily dose) are combined and regarded as a single treatment group. Note: Each MRS symptoms was assigned a score from 0 to 4 (0 = 'None' and 4 = 'Extremely severe'
Time Frame	4 weeks from Baseline (Day 0)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	S-equol Groups Combined	Placebo
Arm/Group Description	The S-equol groups (S-equol 20 mg total daily dose, 100 mg total daily dose, and 300 mg total daily dose) were combined and regarded as a single treatment group.	Placebo treatment arm
Measure Participants	125	42
Baseline (Day 0)	4.1	3.4
Week 4	2.7	2.9
Change from Baseline at Week 4	-1.4	0.0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	S-equol 10 mg BID, S-equol 50 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0097
	Comments	P-value is adjusted for multiple comparisons and the a priori threshold for statistical significance was P <0.05.
	Method	Wilcoxon (Mann-Whitney)
	Comments	Wilcoxon Mann-Whitney test: S-equol groups combined versus Placebo: Change from Baseline at Week 4

13. Secondary Outcome

Title	Mean Precentage Change in the Menopause Rating Scale Total Score From Baseline at Week 4
Description	Percentage change from Baseline at Week 4 = (Week 4 value - Day 0 value)/(Day 0 value) x 100. Note: MRS consists of 11 symptoms, where each symptom is assigned a score from 0 to 4 (0 = 'None' and 4 = 'Extremely severe').
Time Frame	4 weeks from Baseline (Day 0)

Outcome Measure Data

Analysis Population Description

The analysis population consists of all randomized patients who received at least 1 dose of randomized study drug starting at visit 3, who had at least 1 post-dose efficacy assessment. Missing efficacy data were not imputed.

Arm/Group Title	S-equol 10 mg BID	S-equol 50 mg BID	S-equol 150 mg BID	Placebo
Arm/Group Description	20 mg total daily dose of S-equol	100 mg total daily dose of S-equol	300 mg total daily dose of S-equol	Placebo treatment arm
Measure Participants	42	42	41	42
Mean (95% Confidence Interval) [Percentage Change]	-36.7	-37.4	-30.6	-27.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	S-equol 10 mg BID, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4352
	Comments	P-value was not adjusted for multiple comparisons and the a priori threshold for statistical significance was P <0.05.
	Method	Wilcoxon (Mann-Whitney)
	Comments	Wilcoxon Mann-Whitney test: S-equol treatment group versus Placebo: Percentage Change from Baseline at Week 4

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	S-equol 50 mg BID, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2600
	Comments	P-value was not adjusted for multiple comparisons and the a priori threshold for statistical significance was P <0.05.
	Method	Wilcoxon (Mann-Whitney)
	Comments	Wilcoxon Mann-Whitney test: S-equol treatment group versus Placebo: Percentage Change from Baseline at Week 4

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	S-equol 150 mg BID, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7037
	Comments	P-value was not adjusted for multiple comparisons and the a priori threshold for statistical significance was P <0.05.
	Method	Wilcoxon (Mann-Whitney)
	Comments	Wilcoxon Mann-Whitney test: S-equol treatment group versus Placebo: Percentage Change from Baseline at Week 4

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	S-equol 10 mg BID, S-equol 50 mg BID, S-equol 150 mg BID, Placebo
	Comments	All three S-equol treatment arms were aggregated and compared to placebo.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7155
	Comments
	Method	Kruskal-Wallis
	Comments

14. Post-Hoc Outcome

Title	Change From Baseline in Menopause Rating Scale (MRS) - Dryness of Vagina- S-equol Groups Combined
Description	The following analysis pre-specified the combining of all S-equol groups (S-equol 20 mg total daily dose, 100 mg total daily dose, and 300 mg total daily dose) into a single treatment group. The results from the Wilcoxon-Mann-Whitney test (pair-wise test), based on the change from Baseline at Week 4, are presented. Note: Dryness of Vagina was assigned a score from 0 to 4 (0 = 'None' and 4 = 'Extremely severe'
Time Frame	4 weeks from Baseline (Day 0)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	S-equol Groups Combined	Placebo
Arm/Group Description	The S-equol groups (S-equol 20 mg total daily dose, 100 mg total daily dose, and 300 mg total daily dose) were combined and regarded as a single treatment group.	Placebo treatment arm
Measure Participants	125	42
Baseline (Day 0)	1.5	1.5
Week 4	1.1	1.4
Change from Baseline at Week 4	-0.4	-0.1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	S-equol 10 mg BID, S-equol 50 mg BID
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0381
	Comments	P-value is adjusted for multiple comparisons and the a priori threshold for statistical significance was P <0.05.
	Method	Wilcoxon (Mann-Whitney)
	Comments	Wilcoxon Mann-Whitney test: S-equol groups combined versus Placebo: Change from Baseline at Week 4

Adverse Events

Time Frame	Adverse events were collected from the time of signing of the informed consent document through the follow-up visit or early termination visit (whichever occurred first).
Adverse Event Reporting Description	An adverse event was followed to a satisfactory resolution, until it became stable, or until it could be explained by another known cause(s) and clinical judgment indicated that further evaluation was not warranted, or 30 days from the date of last study drug dose for adverse events not related to study drug.
Arm/Group Title	S-equol 10 mg BID		S-equol 50 mg BID		S-equol 150 mg BID		Placebo
Arm/Group Description	20 mg total daily dose of S-equol		100 mg total daily dose of S-equol		300 mg total daily dose of S-equol		Placebo treatment arm
All Cause Mortality
	S-equol 10 mg BID		S-equol 50 mg BID		S-equol 150 mg BID		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	S-equol 10 mg BID		S-equol 50 mg BID		S-equol 150 mg BID		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/43 (2.3%)		0/42 (0%)		1/42 (2.4%)		0/42 (0%)
Injury, poisoning and procedural complications
Ankle Fracture	0/43 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pleurisy	1/43 (2.3%)	1	0/42 (0%)	0	0/42 (0%)	0	0/42 (0%)	0
Pulmonary Embolism	0/43 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0
Other (Not Including Serious) Adverse Events
	S-equol 10 mg BID		S-equol 50 mg BID		S-equol 150 mg BID		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/43 (46.5%)		20/42 (47.6%)		17/42 (40.5%)		15/42 (35.7%)
Cardiac disorders
Atrial Fibrillation	0/43 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0
Cardiac Disorder	0/43 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0
Eye disorders
Conjunctivitis	0/43 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Gastrointestinal disorders
Abdominal Discomfort	0/43 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Abdominal Distension	0/43 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0
Abdominal Pain	0/43 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Abdominal Pain Upper	1/43 (2.3%)	2	0/42 (0%)	0	0/42 (0%)	0	0/42 (0%)	0
Abnormal Feces	0/43 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Constipation	4/43 (9.3%)	4	0/42 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0
Diarrhea	3/43 (7%)	3	0/42 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1
Dry Mouth	0/43 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0
Dyspepsia	2/43 (4.7%)	2	0/42 (0%)	0	0/42 (0%)	0	3/42 (7.1%)	3
Flatulence	0/43 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0
Hemorrhoids	1/43 (2.3%)	1	0/42 (0%)	0	0/42 (0%)	0	0/42 (0%)	0
Nausea	5/43 (11.6%)	7	3/42 (7.1%)	3	3/42 (7.1%)	3	1/42 (2.4%)	1
Toothache	1/43 (2.3%)	1	0/42 (0%)	0	0/42 (0%)	0	0/42 (0%)	0
Vomiting	1/43 (2.3%)	1	0/42 (0%)	0	0/42 (0%)	0	0/42 (0%)	0
General disorders
Asthenia	0/43 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Chest Pain	0/43 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0
Fatigue	0/43 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Injection Site Pain	0/43 (0%)	0	0/42 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1
Irritability	0/43 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Immune System Disorders	1/43 (2.3%)	1	0/42 (0%)	0	0/42 (0%)	0	0/42 (0%)	0
Seasonal Allergy	1/43 (2.3%)	1	0/42 (0%)	0	0/42 (0%)	0	0/42 (0%)	0
Infections and infestations
Fungal Infection	0/43 (0%)	0	1/42 (2.4%)	1	1/42 (2.4%)	1	0/42 (0%)	0
Gastroenteritis	1/43 (2.3%)	1	0/42 (0%)	0	0/42 (0%)	0	0/42 (0%)	0
Gingival Infection	1/43 (2.3%)	1	0/42 (0%)	0	0/42 (0%)	0	0/42 (0%)	0
Influenza	0/43 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Lower Respiratory Tract Infection	0/43 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0
Nail Infection	1/43 (2.3%)	1	0/42 (0%)	0	0/42 (0%)	0	0/42 (0%)	0
Nasopharyngitis	1/43 (2.3%)	1	1/42 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Oral Herpes	0/43 (0%)	0	0/42 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1
Rhinitis	1/43 (2.3%)	1	0/42 (0%)	0	0/42 (0%)	0	0/42 (0%)	0
Sinusitis	0/43 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0
Upper Respiratory Tract Infection	2/43 (4.7%)	2	2/42 (4.8%)	2	6/42 (14.3%)	6	2/42 (4.8%)	2
Urinary Tract Infection	2/43 (4.7%)	2	2/42 (4.8%)	2	3/42 (7.1%)	3	0/42 (0%)	0
Vaginal Infection	0/43 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Injury, poisoning and procedural complications
Arthropod Bite	0/43 (0%)	0	1/42 (2.4%)	2	0/42 (0%)	0	0/42 (0%)	0
Contusion	1/43 (2.3%)	1	0/42 (0%)	0	0/42 (0%)	0	0/42 (0%)	0
Joint Sprain	0/43 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1	1/42 (2.4%)	1
Mouth Injury	0/43 (0%)	0	0/42 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1
Muscle Strain	0/43 (0%)	0	0/42 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1
Procedural Hypertension	0/43 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0
Investigations
Alanine Aminotransferase Increased	0/43 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Blood Glucose Increased	0/43 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Blood Lactate Dehydrogenase Increased	0/43 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0
Blood Triglycerides Increased	0/43 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Estradiol Increased	1/43 (2.3%)	1	1/42 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Smear Cervix Abnormal	1/43 (2.3%)	1	0/42 (0%)	0	0/42 (0%)	0	0/42 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	2/43 (4.7%)	2	0/42 (0%)	0	0/42 (0%)	0	0/42 (0%)	0
Back Pain	0/43 (0%)	0	0/42 (0%)	0	0/42 (0%)	0	2/42 (4.8%)	2
Bursitis	0/43 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Nervous system disorders
Dizziness	1/43 (2.3%)	1	0/42 (0%)	0	0/42 (0%)	0	0/42 (0%)	0
Headache	1/43 (2.3%)	1	3/42 (7.1%)	3	1/42 (2.4%)	1	2/42 (4.8%)	2
Migraine	1/43 (2.3%)	1	1/42 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Sciatica	0/43 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Psychiatric disorders
Anxiety	0/43 (0%)	0	0/42 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1
Insomnia	1/43 (2.3%)	1	0/42 (0%)	0	0/42 (0%)	0	0/42 (0%)	0
Mood Swings	0/43 (0%)	0	0/42 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1
Renal and urinary disorders
Glycosuria	0/43 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Reproductive system and breast disorders
Breast Tenderness	1/43 (2.3%)	1	0/42 (0%)	0	0/42 (0%)	0	0/42 (0%)	0
Cervical Dysplasia	1/43 (2.3%)	1	0/42 (0%)	0	0/42 (0%)	0	0/42 (0%)	0
Endometrial Hypertrophy	2/43 (4.7%)	2	3/42 (7.1%)	3	0/42 (0%)	0	0/42 (0%)	0
Vaginal Discharge	0/43 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1	1/42 (2.4%)	1
Vaginal Hemorrhage	1/43 (2.3%)	2	1/42 (2.4%)	1	0/42 (0%)	0	1/42 (2.4%)	1
Vulvovaginal Erythema	0/43 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dry Throat	0/43 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Oropharyngeal Pain	0/43 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0
Skin and subcutaneous tissue disorders
Actinic Keratosis	0/43 (0%)	0	0/42 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1
Dermatitis Contact	0/43 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0	1/42 (2.4%)	1
Pruritus	0/43 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Rash Macular	0/43 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0
Rash Pruritic	0/43 (0%)	0	0/42 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0
Skin Hypertrophy	0/43 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Urticaria	0/43 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0
Vascular disorders
Hot Flush	0/43 (0%)	0	1/42 (2.4%)	1	0/42 (0%)	0	0/42 (0%)	0

Limitations/Caveats

Per-protocol, an ANOVA model was to be used for the primary efficacy analysis. However using statistical adjustment of baseline values, ANCOVA could be more a more powerful analysis (Vickers AJ. BMC Med Res Methodology. 2001;1:6. Epub 2001 Jun 28).

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.