A Dose-ranging Study of the Efficacy of ESN364 in Postmenopausal Women Suffering Vasomotor Symptoms (Hot Flashes)

Phase 2

Completed

Conditions: Hot Flashes
Menopause

Interventions: Drug: Fezolinetant
Drug: Placebo

Registration Number: NCT03192176

Lead Sponsor: Astellas Pharma Global Development, Inc.

Brief Summary: This study determined the effects of different doses and dosing regimens of ESN364 on the frequency and severity of hot flashes. The treatment was administered for 12 weeks to postmenopausal women, aged 40 to 65, suffering at least 50 moderate to severe hot flashes per week.

Detailed Description: This was a 12-week randomized, double-blind, placebo-controlled, dose-ranging, parallel-group, multi-center study to assess the efficacy of ESN364 in postmenopausal women suffering from vasomotor symptoms (hot flashes).

This study consisted of a screening period (Days -35 to -1, including the screening visit \[Visit 1\] and a minimum 7-day collection of baseline vasomotor symptom frequency and severity assessments), a 12 week treatment period (Day 1 \[Visit 2\] to Week 12 \[Visit 5\]), and a follow up visit (Week 15 \[Visit 6\]) 3 weeks after the last dose of study drug.

The study was performed on an ambulatory basis. The screening visit (Visit 1) occurred up to 35 days prior to randomization. Eligibility was assessed via physical examination, clinical laboratory testing, vital signs, ECG, Pap smear, mammography, and endometrial biopsy. Subjects received an electronic diary to record daily vasomotor symptoms during the duration of the screening period. Subjects who had ≥7 consecutive days of vasomotor symptom recordings participated in the study. Subjects are encouraged to continue recording for the duration of the whole screening period. The electronic diary was reviewed by study site staff on Day 1 (Visit 2) to confirm study eligibility. Subjects were rescreened 1 time upon approval of the medical monitor.

During the treatment period, subjects returned to the study site every 4 weeks for assessments.

The follow-up visit occurred approximately 3 weeks following the last dose of study drug.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 356

Inclusion Criteria

Women >40 years and ≤65 years of age at the screening visit;
A body mass index between 18 kg/sqm to 38 kg/sqm (extremes included);
Spontaneous amenorrhea for ≥12 consecutive months; or spontaneous amenorrhea for ≥6 months with biochemical criteria of menopause (follicle-stimulating hormone [FSH] >40 IU/L); or having had bilateral oophorectomy ≥6 weeks prior to the screening visit (with or without hysterectomy);
At least 50 moderate to severe vasomotor symptoms per week (ie, 7 consecutive days), as recorded in the daily diary during the screening period;
In good general health as determined on the basis of medical history and general physical examination, including a bimanual clinical pelvic examination and clinical breast examination devoid of relevant clinical findings, performed at the screening visit; hematology and biochemistry parameters, pulse rate and/or blood pressure, and ECG within the reference range for the population studied, or showing no clinically relevant deviations, as judged by the Investigator;
Women >40 years of age who have documentation of a normal/negative or no clinically significant findings mammogram (obtained at Screening or within the prior 9 months of trial enrollment.) Appropriate documentation includes a written report or an electronic report indicating normal/negative or no clinically significant mammographic findings;
Willing to undergo a transvaginal ultrasound to assess endometrial thickness at Screening and at Week 12 (end-of-treatment, - and subjects) who are withdrawn from the study prior to completion, at the Early Termination (ET) Visit. This is not required for subjects who have had a partial (supracervical) or full hysterectomy;
Willing to undergo an endometrial biopsy at Screening (in the event that the subject's transvaginal ultrasound shows endometrial thickness ≥4 mm) and at Week 12 (end--of--treatment) - all subjects), for subjects with uterine bleeding, and for subjects who are withdrawn from the study prior to completion, at the ET Visit if study drug exposure is ≥10 weeks. This is not required for subjects who have had a partial (supracervical) or full hysterectomy;
Negative alcohol breath test and negative urine test for selected drugs of abuse (amphetamines, tricyclic antidepressants, cocaine, or opiates) at the screening visit;
Negative urine pregnancy test;
Negative serology panel (including hepatitis B surface antigen, hepatitis C virus antibody, and human immunodeficiency virus antibody screens);
Informed Consent Form signed voluntarily before any study-related procedure is performed, indicating that the subject understands the purpose of and procedures required for the study and is willing to participate in the study; and
Documentation of a normal Pap smear (or equivalent cervical cytology) or of no clinical significance in the opinion of the Investigator within the previous 9 months or at Screening.

Exclusion Criteria

Use of a prohibited therapy (hormone therapy, hormonal contraceptive, or vasomotor symptom medication [prescription, over the counter, or herbal]) or not willing to wash out drugs
History (in the past year) or presence of drug or alcohol abuse;
Previous or current history of a malignant tumor, except for basal cell carcinoma;
Uncontrolled hypertension and a systolic blood pressure ≥140 mmHg and/or a diastolic blood pressure ≥90 mmHg;
Judged by the Investigator to be unsuited to participate in the study based on findings observed during physical examination, vital sign assessment, or 12-lead electrocardiogram (ECG);
History of severe allergy, hypersensitivity, or intolerance to drugs in general, including the study drug and any of its excipients;
Exclusion criterion 7 has been removed in Amendment 1;
An unacceptable result from endometrial biopsy (performed when endometrial thickness is ≥ 4mm measured by transvaginal ultrasound) of endometrial hyperplasia, endometrial cancer, or inadequate specimen at Screening (1 repeat biopsy permitted if technically possible);
History of endometrial hyperplasia or uterine/endometrial cancer;
History of unexplained uterine bleeding;
History of seizures or other convulsive disorders;
Medical condition or chronic disease (including history of neurological [including cognitive], hepatic, renal, cardiovascular, gastrointestinal, pulmonary [eg, moderate asthma], endocrine, or gynecological disease) or malignancy that could confound interpretation of the study outcome;
Presence or sequelae of gastrointestinal, liver, kidney, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion (ADME) mechanisms of drugs as judged by the Investigator;
Active liver disease or jaundice, or values of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) >1.5 x the upper limit of normal (ULN); or total bilirubin >1.5 x ULN; or creatinine >1.5 x ULN; or estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula ≤59 mL/min/1.73 sqm at the screening visit;
Concurrent participation in another interventional study (or participation within 3 months prior to screening in this study);
Suicide attempt in the past 3 years;
Unable or unwilling to complete the study procedures; or
Subject is the Investigator or any sub-Investigator, research assistant, pharmacist, study coordinator, or other staff or relative thereof, who is directly involved in the conduct of the study.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Fezolinetant 30 mg + Placebo	Fezolinetant	Participants received fezolinetant 30 mg capsules orally, QD and matching placebo QD for a period of 12 weeks.
Placebo	Fezolinetant	Participants received fezolinetant matching placebo capsules orally, BID for a period of 12 weeks.
Fezolinetant 15 mg	Placebo	Participants received fezolinetant 15 mg capsules orally, BID for a period of 12 weeks.
Fezolinetant 30 mg	Fezolinetant	Participants received fezolinetant 30 mg capsules orally, BID for a period of 12 weeks.
Fezolinetant 60 mg	Fezolinetant	Participants received fezolinetant 60 mg capsules orally, BID for a period of 12 weeks.
Fezolinetant 60 mg + Placebo	Fezolinetant	Participants received fezolinetant 60 mg capsules orally, QD and matching placebo QD for a period of 12 weeks.
Fezolinetant 90 mg	Fezolinetant	Participants received fezolinetant 90 mg capsules orally, BID for a period of 12 weeks.
Fezolinetant 120 mg + Placebo	Fezolinetant	Participants received fezolinetant 120 mg capsules orally, QD and matching placebo QD for a period of 12 weeks.

Primary Outcome Measures

Name	Time	Method
Co-Primary Efficacy Endpoint: Change From Baseline (CFB) in The Mean Frequency of Moderate to Severe Vasomotor Symptoms (VMS) at Week 4	Baseline and week 4	The frequency of moderate to severe VMS was the number of moderate to severe VMS per 24 hours. A daily frequency and severity per week was derived by taking the mean of the data over 7 days. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed).
Co-Primary Efficacy Endpoint: Change From Baseline in The Mean Frequency of Moderate to Severe VMS at Week 12	Baseline and week 12	The frequency of moderate to severe VMS was the number of moderate to severe VMS per 24 hours. A daily frequency and severity per week was derived by taking the mean of the data over 7 days. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed).
Co-Primary Efficacy Endpoint: Change From Baseline in The Mean Severity of Moderate to Severe VMS at Week 4	Baseline and week 4	Severity of moderate to severe VMS per day was calculated as follows: \[(number of moderate VMS × 2) + (number of severe VMS × 3)\]/number of daily moderate/severe VMS. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed). Severity was zero for participants that had no moderate or severe VMS. Higher score indicates greater severity.
Co-Primary Efficacy Endpoint: Change From Baseline in The Mean Severity of Moderate to Severe VMS at Week 12	Baseline and week 12	Severity of moderate to severe VMS per day was calculated as follows: \[(number of moderate VMS × 2) + (number of severe VMS × 3)\]/number of daily moderate/severe VMS. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed). Severity was zero for participants that had no moderate or severe VMS. Higher scores indicates greater severity.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Absolute Reduction of 3 in Mean Number of Mild, Moderate and Severe VMS Per Day From Baseline to Each Study Week	Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	The frequency of mild, moderate and severe VMS was the number of mild, moderate and severe VMS per 24 hours. A daily frequency and severity per week was derived by taking the mean of the data over 7 days. Mild VMS was defined as sensation of heat without sweating/dampness. If at night, participant does not wake up but later notices damp sheets or clothing. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed).
Number of Participants With Absolute Reduction of 4 in Mean Number of Mild, Moderate and Severe VMS Per Day From Baseline to Each Study Week	Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	The frequency of mild, moderate and severe VMS was the number of mild, moderate and severe VMS per 24 hours. A daily frequency and severity per week was derived by taking the mean of the data over 7 days. Mild VMS was defined as sensation of heat without sweating/dampness. If at night, participant does not wake up but later notices damp sheets or clothing. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed).
Number of Participants With Absolute Reduction of 2 in Mean Number of Moderate and Severe VMS Per Day From Baseline to Each Study Week	Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	The frequency of moderate to severe VMS was the number of moderate to severe VMS per 24 hours. A daily frequency and severity per week was derived by taking the mean of the data over 7 days. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed).
Number of Participants With Absolute Reduction of 4 in Mean Number of Moderate and Severe VMS Per Day From Baseline to Each Study Week	Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	The frequency of moderate to severe VMS was the number of moderate to severe VMS per 24 hours. A daily frequency and severity per week was derived by taking the mean of the data over 7 days. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed).
Number of Participants With Absolute Reduction of 5 in Mean Number of Moderate and Severe VMS Per Day From Baseline to Each Study Week	Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	The frequency of moderate to severe VMS was the number of moderate to severe VMS per 24 hours. A daily frequency and severity per week was derived by taking the mean of the data over 7 days. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed).
Mean Percent Reduction of Mild, Moderate, And Severe Vasomotor Symptoms From Baseline to Each Study Week	Baseline and weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	The frequency of mild, moderate and severe VMS was the number of mild, moderate and severe VMS per 24 hours. A daily frequency and severity per week was derived by taking the mean of the data over 7 days. Mild VMS was defined as sensation of heat without sweating/dampness. If at night, subject does not wake up but later notices damp sheets or clothing. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed).
Change From Baseline in The Hot Flash Score of Mild, Moderate, and Severe VMS to Each Study Week	Baseline and weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	The hot flash score per 24h (or 12 h day time or 12 h night time) of VMS (mild, moderate, and severe) is calculated as follows: (number of mild VMS x 1) + (number of moderate VMS x 2) + (number of severe VMS x 3). Mild VMS was defined as sensation of heat without sweating/dampness. If at night, participant did not wake up but later noticed damp sheets or clothing. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed). Higher score indicates greater severity.
Change From Baseline in The Hot Flash Score of Moderate and Severe VMS to Each Study Week	Baseline and weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	The hot flash score per 24h of moderate and severe VMS is calculated as follows: (number of moderate VMS x 2) + (number of severe VMS x 3). Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed). VMS. Baseline is the average frequency of 24h vasomotor symptom from 7 non-missing days prior to Day 1. Higher score indicates greater severity.
Number of Participants With Mean Percent Reduction of 70% in The Mean Frequency of Moderate and Severe Vasomotor Symptoms From Baseline to Each Study Week	Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	The frequency of moderate to severe VMS was the number of moderate to severe VMS per 24 hours. A daily frequency and severity per week was derived by taking the mean of the data over 7 days. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed).
Number of Participants With Mean Percent Reduction of 90% in The Mean Frequency of Moderate and Severe Vasomotor Symptoms From Baseline to Each Study Week	Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	The frequency of moderate to severe VMS was the number of moderate to severe VMS per 24 hours. A daily frequency and severity per week was derived by taking the mean of the data over 7 days. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed).
Number of Participants With Mean Percent Reduction of 100% in The Mean Frequency of Moderate and Severe Vasomotor Symptoms From Baseline to Each Study Week	Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	The frequency of moderate to severe VMS was the number of moderate to severe VMS per 24 hours. A daily frequency and severity per week was derived by taking the mean of the data over 7 days. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed).
Number of Participants With Absolute Reduction of 2 in Mean Number of Mild, Moderate and Severe VMS Per Day From Baseline to Each Study Week	Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	The frequency of mild, moderate and severe VMS was the number of mild, moderate and severe VMS per 24 hours. A daily frequency and severity per week was derived by taking the mean of the data over 7 days. Mild VMS was defined as sensation of heat without sweating/dampness. If at night, participant does not wake up but later notices damp sheets or clothing. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed).
Number of Participants With Mean Percent Reduction of 90% in The Mean Frequency of Mild, Moderate, and Severe VMS From Baseline to Each Study Week	Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	The frequency of mild, moderate and severe VMS was the number of mild, moderate and severe VMS per 24 hours. A daily frequency and severity per week was derived by taking the mean of the data over 7 days. Mild VMS was defined as sensation of heat without sweating/dampness. If at night, participant does not wake up but later notices damp sheets or clothing. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed).
Change From Baseline in The Mean Severity of Mild, Moderate, and Severe VMS to Each Study Week	Baseline and weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	Severity of mild, moderate \& severe VMS per day was calculated as follows \[(number of mild VMS × 1) + (number of moderate VMS × 2) + (number of severe VMS × 3)\]/number of daily mild/moderate/severe VMS Mild VMS was defined as sensation of heat without sweating/dampness. If at night, participant did not wake up but later noticed damp sheets or clothing. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot \& was sweating \& needed to take action Severity was zero for participants that had no moderate or severe VMS. Higher score indicates greater severity.
Change From Baseline in The Mean Severity of Moderate and Severe VMS to Each Study Week	Baseline and weeks 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 13, 14 and 15	Severity of moderate to severe VMS per day was calculated as follows: \[(number of moderate VMS × 2) + (number of severe VMS × 3)\]/number of daily moderate/severe VMS. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed). Severity was zero for patients that had no moderate or severe VMS. Higher score indicates greater severity.
Change From Baseline in Menopause-Specific Quality of Life (MENQoL) at Weeks 4, 8, 12, and 15	Baseline and weeks 4, 8, 12, and 15	The MENQoL is self-administered and consists of a total of 29 items in a Likert-scale format. Each item assesses the impact of 1 of 4 domains of menopausal symptoms, as experienced over the last month: vasomotor (items 1 to 3), psychosocial (items 4 to 10), physical (items 11 to 26), and sexual (items 27 to 29). Items pertaining to a specific symptom are rated as present or not present, and if present, how bothersome on a 0 (not bothersome) to 6 (extremely bothersome) scale. Means are computed for each subscale by dividing the sum of the domain's items by the number of items within that domain. Non-endorsement of an item is scored a "1" and endorsement a "2," plus the number of the particular rating, so that the possible score on any item ranges from 1 to 8. Higher scores indicate that menopause symptoms are more bothersome.
Number of Participants With Mean Percent Reduction of 50% in The Mean Frequency of Mild, Moderate, and Severe VMS From Baseline to Each Study Week	Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15	The frequency of mild, moderate and severe VMS was the number of mild, moderate and severe VMS per 24 hours. A daily frequency and severity per week was derived by taking the mean of the data over 7 days. Mild VMS was defined as sensation of heat without sweating/dampness. If at night, participant does not wake up but later notices damp sheets or clothing. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed).
Change From Baseline in Hot Flash-Related Daily Interference Scale (HFRDIS) at Weeks 4, 8, 12, and 15	Baseline and weeks 4, 8, 12, and 15	The HFRDIS is a 10-item scale that measures a woman's perceptions of the degree to which VMS interfere with 9 daily life activities (work, social activities, leisure, sleep, mood, concentration, relations with others, sexuality, and enjoying life); the tenth item measures interference with overall quality of life. This scale was modeled after items on the Brief Pain Inventory and Brief Fatigue Inventory, which assess the extent to which pain or fatigue interfere with daily life. Participants were asked to rate the extent to which VMS had interfered with each item during the previous 2-week time interval using a 0 (do not interfere) to 10 (completely interfere) scale. Overall mean score is the average of individual item scores (sum of items/10).
Leeds Sleep Evaluation Questionnaire (LSEQ) Domain Scores at Weeks 4, 8, 12 and 15	Weeks 4, 8, 12, and 15	The LSEQ is a 10-item self-rated questionnaire that assesses a participants aspects of sleep and early morning behavior. The questions are grouped into 4 chronological areas: ease of getting to sleep, perceived quality of sleep, ease of awaking from sleep, and integrity of early morning behavior following wakefulness. The LSEQ is a visual analog scale that requires respondents to place marks on a group of 10 cm lines. Lines extend between extremes like "more difficult than usual" and "easier than usual." Responses are measured using a 100 mm scale and are averaged to a score for each domain. Higher scores indicates better sleep and better early morning behavior.
Change From Baseline in Greene Climacteric Scale (GCS) at Weeks 4, 8, 12, and 15	Baseline and weeks 4, 8, 12, and 15	The GCS is a 21-item scale that provides a brief but comprehensive and valid measure of climacteric symptomatology. Each item is rated by the participant according to its severity using a 4-point rating scale from 0 (none) to 3 (severe). The first 20 items of the scale combine into 3 main independent symptom measures by summing up the individual item scores: psychological symptoms (items 1 to 11; score 0 to 33), physical symptoms (items 12 to 18; score 0 to 21), and VMS (items 19 to 20; score 0 to 6). Item 21 is a probe for sexual dysfunction. The total score can range from 0 to 63. Higher scores indicate worse symptoms.
Change Over Time From Baseline in Plasma Concentrations of Luteinizing Hormone (LH) at Week 12	Baseline and week 12	Change was calculated as the post-baseline measurement minus the baseline measurement. Baseline was the last measurement taken prior to initial study drug administration.
Change From Baseline in The Mean Frequency of Mild, Moderate, and Severe VMS to Each Study Week	Baseline and weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	The frequency of mild, moderate and severe VMS was the number of mild, moderate and severe VMS per 24 hours. A daily frequency and severity per week was derived by taking the mean of the data over 7 days. Mild VMS was defined as sensation of heat without sweating/dampness. If at night, subject does not wake up but later notices damp sheets or clothing. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed).
Change From Baseline in The Mean Frequency of Moderate and Severe VMS to Each Study Week	Baseline and weeks 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 13, 14 and 15	The frequency of moderate to severe VMS was the number of moderate to severe VMS per 24 hours. A daily frequency and severity per week was derived by taking the mean of the data over 7 days. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed).
Mean Percent Reduction of Moderate And Severe Vasomotor Symptoms From Baseline to Each Study Week	Baseline and weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	The frequency of moderate to severe VMS was the number of moderate to severe VMS per 24 hours. A daily frequency and severity per week was derived by taking the mean of the data over 7 days. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed).
Number of Participants With Mean Percent Reduction of 70% in The Mean Frequency of Mild, Moderate, and Severe VMS From Baseline to Each Study Week	Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	The frequency of mild, moderate and severe VMS was the number of mild, moderate and severe VMS per 24 hours. A daily frequency and severity per week was derived by taking the mean of the data over 7 days. Mild VMS was defined as sensation of heat without sweating/dampness. If at night, participant does not wake up but later notices damp sheets or clothing. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed).
Number of Participants With Mean Percent Reduction of 50% in The Mean Frequency of Moderate and Severe Vasomotor Symptoms From Baseline to Each Study Week	Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	The frequency of moderate to severe VMS was the number of moderate to severe VMS per 24 hours. A daily frequency and severity per week was derived by taking the mean of the data over 7 days. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed).
Number of Participants With Absolute Reduction of 5 in Mean Number of Mild, Moderate and Severe VMS Per Day From Baseline to Each Study Week	Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	The frequency of mild, moderate and severe VMS was the number of mild, moderate and severe VMS per 24 hours. A daily frequency and severity per week was derived by taking the mean of the data over 7 days. Mild VMS was defined as sensation of heat without sweating/dampness. If at night, participant does not wake up but later notices damp sheets or clothing. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed).
Number of Participants With Absolute Reduction of 3 in Mean Number of Moderate and Severe VMS Per Day From Baseline to Each Study Week	Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	The frequency of moderate to severe VMS was the number of moderate to severe VMS per 24 hours. A daily frequency and severity per week was derived by taking the mean of the data over 7 days. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed).
Change Over Time From Baseline in Plasma Concentrations of Follicle-Stimulating Hormone (FSH) at Week 12	Baseline and week 12	Change was calculated as the post-baseline measurement minus the baseline measurement. Baseline was the last measurement taken prior to initial study drug administration.
Number of Participants With Mean Percent Reduction of 100% in The Mean Frequency of Mild, Moderate, and Severe VMS From Baseline to Each Study Week	Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15	The frequency of mild, moderate and severe VMS was the number of mild, moderate and severe VMS per 24 hours. A daily frequency and severity per week was derived by taking the mean of the data over 7 days. Mild VMS was defined as sensation of heat without sweating/dampness. If at night, participant does not wake up but later notices damp sheets or clothing. Moderate VMS was defined as sensation of heat with sweating/dampness, but was able to continue activity. If at night, participant woke up because she was feeling hot and/or was sweating, but no action was necessary other than rearranging the bed sheets. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. If at night, participant woke up hot and was sweating and needed to take action (e.g., remove layers of clothes, open the window, or get out of bed).
Change Over Time From Baseline in Plasma Concentrations of Estradiol (E2) at Week 12	Baseline and week 12	Change was calculated as the post-baseline measurement minus the baseline measurement. Baseline was the last measurement taken prior to initial study drug administration. The analysis value for Estradiol was imputed as 73.4/2 = 36.7 when result was \< 73.4.
Change Over Time From Baseline in Plasma Concentrations of Sex Hormone-Binding Globulin (SHBG) at Week 12	Baseline and week 12	Change was calculated as the post-baseline measurement minus the baseline measurement. Baseline was the last measurement taken prior to initial study drug administration.

Trial Locations

Locations (3): Research Site 052
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Sacramento, California, United States
Research Site 058
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Sacramento, California, United States
Research Site
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Spokane, Washington, United States