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

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

Detailed Description
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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.

Official Title
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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

Conditions
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Menopause

Intervention / Treatment
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* Drug: Placebo
* Drug: S-equol


Participation Criteria
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Eligibility Criteria
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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.
Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br> <br> |
| Experimental: S-equol 10 mg BID<br>S-equol 20 mg total daily dose | Drug: S-equol<br>* 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)<br>* Other names: AUS-131;|
| Experimental: S-equol 50 mg BID<br>S-equol 100 mg total daily dose | Drug: S-equol<br>* 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)<br>* Other names: AUS-131;|
| Experimental: S-equol 150 mg BID<br>S-equol 300 mg total daily dose | Drug: S-equol<br>* 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)<br>* Other names: AUS-131;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Frequency of Moderate to Severe Vasomotor Symptoms (MSVS) Baseline at Week 4 (2-week 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. | 4 weeks from Baseline (2-week run-in period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Frequency of MSVS From Baseline at Week 4 (1-week 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. | 4 weeks from Baseline (period following first 7 days of 2-week run-in period) | 
| Change From Baseline (Day 0) in the Frequency of MSVS at Week 1 and Week 2 | 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. | 1 and 2 weeks from Baseline (Day 0) | 
| Change From Baseline (Day 0) in the Severity of VMS as Recorded in the Patient Diary at Week 1, Week 2, and Week 4 | 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). | 1, 2, and 4 weeks from Baseline (Day 0) | 
| Change From Baseline (Day 0) in Vaginal pH at Week 2 and Week 4 | 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. | 2 and 4 weeks from Baseline (Day 0) | 
| Change From Baseline in Vaginal Maturation Index at Week 2 and Week 4 | 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. | 2 and 4 weeks from Baseline (Day 0) | 
| Change From Baseline in Estradiol Concentration at Weeks 2 and 4 | The LSMeans refer to overall adjusted mean estradiol concentration. | 2 and 4 weeks from Baseline (Day 0) | 
| Change From Baseline in Progesterone Concentration at Week 2 and Week 4 | No repeated measures ANCOVA results are presented for change from Baseline in progesterone concentrations since the model did not converge. | 2 and 4 weeks from Baseline (Day 0) | 
| Mean Change in the Menopause Rating Scale Total Score From Baseline at Week 4 | 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. | 4 weeks from Baseline (Day 0) | 
| Mean Precentage Change in the Menopause Rating Scale Total Score From Baseline at Week 4 | 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'). | 4 weeks from Baseline (Day 0) |