A Study of Fezolinetant to Treat Hot Flashes in Women Going Through Menopause

Study Overview
=================
Brief Summary
-----------------
This study is for women in menopause who have moderate to severe hot flashes. It is for women who are unable to use hormone replacement therapy (HRT). Menopause, a normal part of life, is the time after a woman's last period. Hot flashes often occur during menopause. They can disrupt a woman's daily life. The study medicines (also called investigational products, or IP) are tablets of fezolinetant or placebo. An investigational product means that the product is not yet licensed. In this study, a placebo is a dummy treatment that looks like fezolinetant but does not have any medicine in it. The study will compare fezolinetant with the placebo to learn if fezolinetant reduces the number and severity of hot flashes. Women that want to take part in the study will be given an electronic handheld device with an app to track their hot flashes. Some women may be able to use the app on their own smartphone. In the last 10 days before their next clinic visit, the women will record information about their hot flashes. They can take part in the study if they have an average of 7 or more moderate to severe hot flashes each day. Women will be picked for 1 of 2 treatments (fezolinetant or placebo) by chance alone. Women who take part in the study will take 2 tablets every day for 24 weeks. Treatment will be double-blinded. That means that the women in the study and the study doctors will not know who takes which of the study medicines (fezolinetant or placebo). The women will continue recording information about their hot flashes on the electronic device or their phone. They will also use another device to answer questions about how hot flashes affect their daily life. During the study, the women will visit their study clinic several times for a check-up. This will happen during Weeks 2, 4, 8, 12, 16, 20, 24, and 27. Some women may be able to have home visits instead, from Week 2 to Week 20. At the check-up, they will be asked if they have any medical problems. Other checks will include vital signs (heart rate, temperature and blood pressure) and some blood samples taken for laboratory tests. At some check-ups, the women will have a physical exam. In Week 2 and Week 24, the women will have an ECG to check their heart rhythm. Women who have a uterus will also have a test called a transvaginal ultrasound. A probe is gently placed inside the vagina. Sound waves will create a picture of the organs in the pelvis. This will allow the study doctor to look more closely at the uterus and surrounding organs. The last check-up (at Week 27) will be 3 weeks after they take their last tablets of study medicine (fezolinetant or placebo).

Official Title
-----------------
A Phase 3b, Randomized, Double-blind, Placebo-controlled, 24-week Study to Assess the Efficacy and Safety of Fezolinetant in Menopausal Women Suffering From Moderate to Severe Vasomotor Symptoms (Hot Flashes) and Considered Unsuitable for Hormone Replacement Therapy

Conditions
-----------------
Vasomotor Symptoms

Intervention / Treatment
-----------------
* Drug: fezolinetant
* Drug: placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria : Participant must be seeking treatment or relief for vasomotor symptoms (VMS) associated with menopause and confirmed as menopausal per one of the following criteria at the screening visit: Spontaneous amenorrhea for >= 12 consecutive months Spontaneous amenorrhea for >= 6 months with biochemical criterion of menopause (follicle-stimulating hormone [FSH] > 40 IU/L) Had bilateral oophorectomy >= 6 weeks prior to the screening visit (with or without hysterectomy) Participant has VMS and is unsuitable to receive hormone replacement therapy (HRT) (HRT contraindicated, HRT caution, HRT stoppers and HRT averse participants). Participant has a minimum average of 7 moderate to severe hot flash's (HFs) (VMS) per day as recorded in the electronic diary during the last 10 days prior to randomization. Participant is in good general health as determined on the basis of medical history, general physical examination, laboratory and other medical assessments. Participant has a negative serology panel (including hepatitis B surface antigen, hepatitis C virus antibody and human immunodeficiency virus antibody screens). Had hysterectomy without oophorectomy and who meets the biochemical criterion of menopause (FSH > 40 IU/L). Exclusion Criteria: Participant uses a prohibited therapy for VMS (e.g., prescription, over-the-counter or herbal) prior to screening and for the duration of treatment with investigational product (IP). Participant has known documented substance abuse or alcohol addiction within 6 months of screening. Participant has history of a malignant tumor within the last 5 years, except for basal cell carcinoma. Participant has endometrial thickness > 8 mm on the locally read screening transvaginal ultrasound (TVU) or any clinically significant findings that that would make the participant ineligible. Participant has history of severe allergy, hypersensitivity or intolerance to the IP and/or any of its excipients. Participant has a history of seizures or other convulsive disorders unless well controlled. Participant has a medical condition or chronic disease (including history of neurological [including cognitive], renal, cardiovascular, gastrointestinal, pulmonary [e.g., moderate asthma], endocrine or gynecological disease) or malignancy that could confound interpretation of the study outcome. Participant has any of the following: active liver disease, jaundice, elevated liver aminotransferases at screening (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]), elevated total bilirubin (TBL) or direct bilirubin (DBL) > 1.5 × upper limit of normal (ULN), elevated International Normalized Ratio (INR) > 1.5 (unless participant is receiving anticoagulant therapy) or elevated alkaline phosphatase (ALP). Participants with mildly elevated ALT or AST up to 1.5 × ULN can be enrolled if TBL and DBL are normal. Participants with mildly elevated ALP (up to 1.5 × ULN) can be enrolled if cholestatic liver disease is excluded and no cause other than fatty liver is diagnosed. Participants with Gilbert's syndrome with elevated TBL may be enrolled as long as DBL, hemoglobin and reticulocytes are normal. Participant has creatinine > 1.5 × ULN or estimated glomerular filtration rate using the Modification of Diet in Renal Disease formula <= 59 mL/min per 1.73 m^2 at the screening visit. Participant has a history of suicide attempt or suicidal behavior within the last 12 months. Participant has participated in another interventional study within the last 30 days prior to screening and for the duration of the study. Participant who has been previously enrolled in a clinical study with fezolinetant. Participant is unable or unwilling to complete the study procedures. Participant has any condition makes the participant unsuitable for study participation.

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: fezolinetant<br>Participants will receive 2 tablets of fezolinetant once daily for 24 weeks. | Drug: fezolinetant<br>* oral<br>* Other names: ESN364;|
| Placebo Comparator: placebo fezolinetant<br>Participants will receive 2 tablets of matching placebo once daily for 24 weeks. | Drug: placebo<br>* oral<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change in the frequency of moderate to severe Vasomotor Symptoms (VMS) from baseline to week 24 | Frequency of moderate or severe VMS events will be calculated as the sum of moderate to severe VMS events per day. | Baseline to week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean change in the severity of moderate to severe VMS from baseline to week 24 | The severity of VMS will be calculated using a weighted average of VMS events. | Baseline to week 24 | 
| Mean change in the patient-reported sleep disturbance by the PROMIS SD SF 8b total score from baseline to week 24 | The Patient-reported Outcomes Measurement Information System (PROMIS) is a National Institutes of Health Roadmap initiative designed to improve participant-reported outcome (PRO) measures using state-of-the-science methods. The PROMIS SD SF 8b assesses self-reported sleep disturbance over the past 7 days and includes perceptions of restless sleep; satisfaction with sleep; refreshing sleep; difficulties sleeping, getting to sleep or staying asleep; amount of sleep; and sleep quality. Because it assesses the participant's experience of sleep disturbance, the measure does not focus on specific sleep-disorder symptoms or ask patients to report objective measures of sleep (e.g., total amount of sleep, time to fall asleep and amount of wakefulness during sleep). Responses to each of the 8 items range from 1 to 5, and the range of possible summed raw scores is 8 to 40. Higher scores on the PROMIS SD SF 8b indicate more of the concept measured (disturbed sleep). | Baseline to week 24 | 
| Mean change in the frequency of moderate to severe VMS | Frequency of moderate or severe VMS events will be calculated as the sum of moderate to severe VMS events per day. | Baseline to weeks 1, 4, 8, 12, 16 and 20 | 
| Mean change in the severity of moderate to severe VMS | The severity of VMS will be calculated using a weighted average of VMS events. | Baseline to weeks 1, 4, 8, 12, 16 and 20 | 
| Mean percent change in the frequency of moderate and severe VMS | Frequency of moderate and severe VMS events will be calculated as the sum of moderate or severe VMS events per day. Mean percent change will be reported. | Baseline to weeks 1, 4, 8, 12, 16, 20 and 24 | 
| Percent reduction ≥ 50% in the frequency of moderate and severe VMS | Frequency of moderate and severe VMS events will be calculated as the sum of moderate or severe VMS events per day. Percent reduction ≥ 50% will be reported. | Baseline to weeks 1, 4, 8, 12, 16, 20 and 24 | 
| Percent reduction ≥ 75% in the frequency of moderate and severe VMS | Frequency of moderate and severe VMS events will be calculated as the sum of moderate or severe VMS events per day. Percent reduction ≥ 75% will be reported. | Baseline to weeks 1, 4, 8, 12, 16, 20 and 24 | 
| Percent reduction at 100% in the frequency of moderate and severe VMS | Frequency of moderate and severe VMS events will be calculated as the sum of moderate or severe VMS events per day. Percent reduction 100% will be reported. | Baseline to weeks 1, 4, 8, 12, 16, 20 and 24 | 
| Number of participants with Treatment Emergent Adverse Events (TEAEs) | Adverse events (AEs) will be coded using medical dictionary for regulatory activities (MedDRA). An AE is any untoward medical occurrence in a participant, temporally associated with the use of study Investigational Product (IP), whether or not considered related to the study IP. An AE can therefore be any unfavorable and unintended sign, symptom, or disease (new or exacerbated) temporally associated with the use of study IP. This includes events related to the comparator and events related to the (study) procedures. A TEAE is defined as AE observed after starting administration of the study drug and 21 days after the last dose of study drug. | Up to week 27 | 
| Number of participants with laboratory value abnormalities and/or adverse events (AEs) | Number of participants with potentially clinically significant laboratory values. | Up to week 27 | 
| Number of participants with vital sign abnormalities and/or adverse events (AEs) | Number of participants with potentially clinically significant vital sign values. | Up to week 24 | 
| Number of participants with 12-lead electrocardiogram (ECG) abnormalities and/or Adverse Events (AEs) | Number of participants with potentially clinically significant 12-lead ECG values. | Up to week 24 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ESN364, menopause, fezolinetant, vasomotor symptoms