A Randomized, Placebo-Controlled, Double-Blind, Dose-Ranging, Phase 2b Study to Investigate the Efficacy of ESN364 in Postmenopausal Women Suffering From Vasomotor Symptoms (Hot Flashes)
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 356
- 试验地点
- 3
- 主要终点
- Co-Primary Efficacy Endpoint: Change From Baseline (CFB) in The Mean Frequency of Moderate to Severe Vasomotor Symptoms (VMS) at Week 4
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 40 Years 至 65 Years（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Placebo
Participants received fezolinetant matching placebo capsules orally, BID for a period of 12 weeks.
干预措施: Fezolinetant (Drug)
Fezolinetant 15 mg
Participants received fezolinetant 15 mg capsules orally, BID for a period of 12 weeks.
干预措施: Placebo (Drug)
Fezolinetant 30 mg
Participants received fezolinetant 30 mg capsules orally, BID for a period of 12 weeks.
干预措施: Fezolinetant (Drug)
Fezolinetant 60 mg
Participants received fezolinetant 60 mg capsules orally, BID for a period of 12 weeks.
干预措施: Fezolinetant (Drug)
Fezolinetant 90 mg
Participants received fezolinetant 90 mg capsules orally, BID for a period of 12 weeks.
干预措施: Fezolinetant (Drug)
Fezolinetant 30 mg + Placebo
Participants received fezolinetant 30 mg capsules orally, QD and matching placebo QD for a period of 12 weeks.
干预措施: Fezolinetant (Drug)
Fezolinetant 60 mg + Placebo
Participants received fezolinetant 60 mg capsules orally, QD and matching placebo QD for a period of 12 weeks.
干预措施: Fezolinetant (Drug)
Fezolinetant 120 mg + Placebo
Participants received fezolinetant 120 mg capsules orally, QD and matching placebo QD for a period of 12 weeks.
干预措施: Fezolinetant (Drug)
结局指标
主要结局
Co-Primary Efficacy Endpoint: Change From Baseline (CFB) in The Mean Frequency of Moderate to Severe Vasomotor Symptoms (VMS) at Week 4
时间窗: 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
时间窗: 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
时间窗: 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
时间窗: 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.
次要结局
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- Leeds Sleep Evaluation Questionnaire (LSEQ) Domain Scores at Weeks 4, 8, 12 and 15(Weeks 4, 8, 12, and 15)
- Change From Baseline in Greene Climacteric Scale (GCS) at Weeks 4, 8, 12, and 15(Baseline and weeks 4, 8, 12, and 15)
- Change Over Time From Baseline in Plasma Concentrations of Luteinizing Hormone (LH) at Week 12(Baseline and week 12)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- Change Over Time From Baseline in Plasma Concentrations of Follicle-Stimulating Hormone (FSH) at Week 12(Baseline and week 12)
- 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)
- Change Over Time From Baseline in Plasma Concentrations of Estradiol (E2) at Week 12(Baseline and week 12)
- Change Over Time From Baseline in Plasma Concentrations of Sex Hormone-Binding Globulin (SHBG) at Week 12(Baseline and week 12)