• Mean change in the frequency of moderate to severe vasomotor symptoms (VMS) from baseline to week 4 [ Time Frame: baseline to week 4 ]
  Frequency of moderate or severe VMS events will be calculated as the sum of moderate or severe VMS events per day.
• Mean change in the frequency of moderate to severe VMS from baseline to week 12 [ Time Frame: baseline to week 12 ]
  Frequency of moderate or severe VMS events will be calculated as the sum of moderate or severe VMS events per day.
• Mean change in the severity of moderate to severe VMS from baseline to week 4 [ Time Frame: baseline to week 4 ]
  The severity of VMS will be calculated using a weighted average of VMS events.
• Mean change in the severity of moderate to severe VMS from baseline to week 12 [ Time Frame: baseline to week 12 ]
  The severity of VMS will be calculated using a weighted average of VMS events.

• Mean change in the Patient-reported Outcomes Measurement Information System Sleep Disturbance - Short Form 8b (PROMIS SD SF 8b) Total Score from baseline to week 12 [ Time Frame: baseline to week 12 ]
  The PROMIS is a National Institutes of Health Roadmap initiative designed to improve PRO measures using state-of-the-science methods. The PROMIS SD SF 8b [PROMIS SD, 2015] 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. 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).
• Mean change in the frequency of moderate to severe VMS from baseline to each week up to week 12 [ Time Frame: baseline to week 1, 2, 3, 5, 6, 7, 8, 9, 10, 11 ]
  Frequency of moderate or severe VMS events will be calculated as the sum of moderate or severe VMS events per day.
• Mean change in the severity of moderate to severe VMS from baseline to each week up to week 12 [ Time Frame: baseline to week 1, 2, 3, 5, 6, 7, 8, 9, 10, 11 ]
  The severity of VMS will be calculated using a weighted average of VMS events.
• Mean percent reduction in the frequency of moderate and severe VMS from baseline to each week up to week 12 [ Time Frame: baseline to week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 ]
  Frequency of moderate and severe VMS events will be calculated as the sum of moderate or severe VMS events per day. Mean percent reduction will be reported.
• Percent reduction ≥ 50% in the frequency of moderate and severe VMS from baseline to each week up to week 12 [ Time Frame: baseline to week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 ]
  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.
• Percent reduction at 100% in the frequency of moderate and severe VMS from baseline to each week up to week 12 [ Time Frame: baseline to week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 ]
  Frequency of moderate and severe VMS events will be calculated as the sum of moderate or severe VMS events per day. Percent reduction at 100% will be reported.
• Mean change in the frequency of moderate to severe VMS from baseline to week 24 [ Time Frame: baseline to week 24 ]
  Frequency of moderate or severe VMS events will be calculated as the sum of moderate or severe VMS events per day.
• Mean change in the severity of moderate to severe VMS from baseline to week 24 [ Time Frame: baseline to week 24 ]
  The severity of VMS will be calculated using a weighted average of VMS events.
• Number of participants with Adverse Events [ Time Frame: Up to 55 weeks ]
  An AE is any untoward medical occurrence in a participant administered a study drug, and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product whether or not considered related to the medicinal product.
• Number of participants with vital sign abnormalities and /or adverse events (AEs) [ Time Frame: Up to 55 weeks ]
  Number of participants with potentially clinically significant vital sign values.
• Number of participants with Transvaginal Ultrasound (TVU) abnormalities and/or Adverse Events (AEs) [ Time Frame: Baseline and 52 weeks ]
  Number of participants with potentially clinically significant TVU abnormalities.
• Number of participants with endometrial biopsy abnormalities and/or Adverse Events (AEs) [ Time Frame: Baseline and 52 weeks ]
  Number of participants with potentially clinically significant endometrial biopsy abnormalities.
• Number of participants with laboratory value abnormalities and/or adverse events (AEs) [ Time Frame: Up to 55 weeks ]
  Number of participants with potentially clinically significant laboratory values.
• Number of participants with electrocardiogram (ECG) abnormalities and/or adverse events (AEs) [ Time Frame: Up to 52 weeks ]
  Number of participants with potentially clinically significant ECG values.
• Score on the Patient Global Impression of Change (PGI-C) in VMS at each visit [ Time Frame: Week 4, 12, 24 and 52 ]
  The Patient Global Impression evaluates the following: (a) patient-perceived severity of a condition (PGI-S) and (2) patient-perceived change from the initiation of treatment (PGI-C). PGI scales will be used to evaluate meaningful within-person changes over time in VMS (PGI-C). The PGI-C VMS asks: "Compared to the beginning of this study, how would you rate your hot flashes (HFs)/night sweats now?" Patient ratings range from (1) much better to (7) much worse.

• Mean change in the Patient-reported Outcomes Measurement Information System Sleep Disturbance - Short Form 8b (PROMIS SD SF 8b) Total Score from baseline to week 12 [ Time Frame: baseline to week 12 ]
  The PROMIS is a National Institutes of Health Roadmap initiative designed to improve PRO measures using state-of-the-science methods. The PROMIS SD SF 8b [PROMIS SD, 2015] 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. 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).
• Mean change in the frequency of moderate to severe VMS from baseline to each week up to week 12 [ Time Frame: baseline to week 1, 2, 3, 5, 6, 7, 8, 9, 10, 11 ]
  Frequency of moderate or severe VMS events will be calculated as the sum of moderate or severe VMS events per day.
• Mean change in the severity of moderate to severe VMS from baseline to each week up to week 12 [ Time Frame: baseline to week 1, 2, 3, 5, 6, 7, 8, 9, 10, 11 ]
  The severity of VMS will be calculated using a weighted average of VMS events.
• Mean percent reduction in the frequency of moderate and severe VMS from baseline to each week up to week 12 [ Time Frame: baseline to week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 ]
  Frequency of moderate and severe VMS events will be calculated as the sum of moderate or severe VMS events per day. Mean percent reduction will be reported.
• Percent reduction ≥ 50% in the frequency of moderate and severe VMS from baseline to each week up to week 12 [ Time Frame: baseline to week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 ]
  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.
• Percent reduction at 100% in the frequency of moderate and severe VMS from baseline to each week up to week 12 [ Time Frame: baseline to week 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 ]
  Frequency of moderate and severe VMS events will be calculated as the sum of moderate or severe VMS events per day. Percent reduction at 100% will be reported.
• Mean change in the frequency of moderate to severe VMS from baseline to week 24 [ Time Frame: baseline to week 24 ]
  Frequency of moderate or severe VMS events will be calculated as the sum of moderate or severe VMS events per day.
• Mean change in the severity of moderate to severe VMS from baseline to week 24 [ Time Frame: baseline to week 24 ]
  The severity of VMS will be calculated using a weighted average of VMS events.

This study is for women in menopause with moderate to severe hot flashes. Menopause, a normal part of aging, is the time of a woman's last period. Hot flashes can interrupt a woman's daily life.

The study treatments are fezolinetant low dose (1 tablet of fezolinetant and 1 placebo tablet) once a day, fezolinetant high dose (2 tablets of fezolinetant) once a day or placebo (2 tablets) once a day. (Placebo is a dummy treatment that looks like medicine but does not have any medicine in it.) The study will compare fezolinetant and placebo after 4 and 12 weeks of dosing. The study will see if fezolinetant reduces the number of hot flashes. And the study will see if fezolinetant reduces the severity of the hot flashes.

Women in the study will receive an electronic handheld device at the first study visit. (It is similar to a smart phone.) Each day of the study, study participants will use this to record their hot flashes. Their record for the 10 days before the start of study treatment will be checked. They can remain in the study if their record shows 7 or 8 moderate to severe hot flashes per day (50 or more per week). Next, they will be picked for 1 of the 2 study treatments (fezolinetant or placebo) by chance alone. It is like flipping a coin.

The study participants will take study treatment for 52 weeks. The first 12 weeks of study treatment are "double-blinded." That means that the study participants and the study doctors do not know who takes which of the study treatments (fezolinetant low dose, fezolinetant high dose or placebo) during that time. The last 40 weeks of study treatment are "noncontrolled." That means that each study participant and the study doctors know which study treatment that study participant takes during that time. Women who take fezolinetant during the first 12 weeks will continue to take the same dose. Women who take placebo during the first 12 weeks will start taking fezolinetant. Their dose will be either low dose or high dose fezolinetant.

At weeks 2, 4, 8, 12, 14, 16 and then once a month, the study participants will go to the hospital or clinic for a check-up. They will be asked about medications, side effects and how they feel. Other checks will include physical exam and vital signs (heart rate, temperature and blood pressure). Blood and urine will be collected for laboratory tests. Study participants will complete questionnaires that are about how hot flashes affect their daily life. Study participants who still have their uterus will have the following 2 tests done at the first and last study visits. One of the 2 tests is endometrial biopsy. This test involves removing a small amount of tissue from the inside lining of the uterus. The tissue is then checked under a microscope. The other test is transvaginal ultrasound. This test uses sound waves to create pictures of the organs in the pelvis. The sound waves are transmitted by a probe (transducer), which is placed inside the vagina. Study participants may have a screening mammogram done at the first and/or last study visit. A mammogram is an x-ray picture of the breasts used to screen for breast cancer. Study participants who did not have this test done in the last 12 months will have it done at the first study visit. They will have it done at the last study visit if they are due for their screening mammogram and their own doctor agrees.

The last check-up at the hospital or clinic will be 3 weeks after the last dose of study treatment.

• Drug: fezolinetant
  administered orally
• Drug: placebo
  administered orally

• Experimental: low dose fezolinetant
  Participants will receive low dose fezolinetant for 52 weeks.
  Intervention: Drug: fezolinetant
• Experimental: high dose fezolinetant
  Participants will receive high dose fezolinetant for 52 weeks.
  Intervention: Drug: fezolinetant
• Placebo Comparator: placebo
  Participants will receive placebo for 12 weeks, after 12 weeks participants will be re-assigned to either low dose or high dose fezolinetant for 40 weeks.
  Intervention: Drug: placebo

Inclusion Criteria:

• Subject has a body mass index ≥ 18 kg/m^2 and ≤ 38 kg/m^2.

• Subject must be seeking treatment or relief for vasomotor symptoms (VMS) associated with menopause and confirmed as menopausal per 1 of the following criteria at the screening visit:

  • Spontaneous amenorrhea for ≥ 12 consecutive months
  • 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.
• Within the 10 days prior to randomization, subject must have a minimum average of 7 to 8 moderate to severe hot flashes (HFs) vasomotor symptoms (VMS) per day, or 50 to 60 per week.
• Subject is 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 electrocardiogram (ECG) within the reference range for the population studied, or showing no clinically relevant deviations.
• Subject has documentation of a normal/negative or no clinically significant findings mammogram (obtained at screening or within the prior 12 months of study enrollment). Appropriate documentation includes a written report or an electronic report indicating normal/negative or no clinically significant mammographic findings.
• Subject is willing to undergo a transvaginal ultrasound (TVU) to evaluate the uterus and ovaries at screening and at week 52 end of treatment (EOT), and for subjects who are withdrawn from the study prior to completion, a TVU at the early discontinuation (ED) visit.
• Subject is willing to undergo an endometrial biopsy at screening and at week 52 (EOT), for subjects with uterine bleeding, and for subjects who are withdrawn from the study prior to completion. The endometrial biopsy obtained at screening must be considered evaluable.
• Subject has documentation of a normal or not clinically significant Papanicolaou (Pap) test (or equivalent cervical cytology) within the previous 12 months or at screening.
• Subject has a negative urine pregnancy test at screening.
• Subject has a negative serology panel (i.e., negative hepatitis B surface antigen, negative hepatitis C virus antibody and negative human immunodeficiency virus antibody screens) at screening.
• Subject agrees not to participate in another interventional study while participating in the present study.

Exclusion Criteria:

• Subject uses a prohibited therapy (strong or moderate cytochrome P450 1A2 [CYP1A2] inhibitors, hormone replacement therapy [HRT], hormonal contraceptive or any treatment for VMS [prescription, over the counter or herbal]) or is not willing to wash out and discontinue use of such drugs for the full duration of study conduct.
• Subject has known substance abuse or alcohol addiction within 6 months of screening.
• Subject has previous or current history of a malignant tumor, except for basal cell carcinoma.

• Subject's systolic blood pressure is ≥ 130 mmHg or diastolic blood pressure is ≥ 80 mmHg based on the average of 2 to 3 readings, on at least 2 different occasions within the screening period.

  • Subjects who do not meet these criteria may be re-assessed after initiation or review of antihypertensive measures.
  • Subjects with a medical history of hypertension can be enrolled once they are medically clear (stable and compliant).
• Subject has history of severe allergy, hypersensitivity or intolerance to drugs in general, including the study drug and any of its excipients.
• Subject has an unacceptable result from the TVU assessment at screening (i.e., full length of endometrial cavity cannot be visualized or presence of a clinically significant finding).
• Subject has an endometrial biopsy confirming presence of disordered proliferative endometrium, endometrial hyperplasia, endometrial cancer or other clinically significant findings at screening.
• Subject has a history within the last 6 months of undiagnosed uterine bleeding.
• Subject has a history of seizures or other convulsive disorders.
• Subject has a medical condition or chronic disease (including history of neurological [including cognitive], hepatic, renal, cardiovascular, gastrointestinal, pulmonary [e.g., moderate asthma], endocrine or gynecological disease) or malignancy that could confound interpretation of the study outcome.
• Subject has active liver disease, jaundice or elevated liver aminotransferases (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]), elevated total or direct bilirubin, elevated international normalized ratio (INR), or elevated alkaline phosphatase (ALP). Patients with mildly elevated ALT or AST up to 1.5 times the upper limit of normal (ULN) can be enrolled if total and direct bilirubin are normal. Patients with mildly elevated ALP (up to 1.5 x ULN) can be enrolled if cholestatic liver disease is excluded and no cause other than fatty liver is diagnosed. Patients with Gilbert's syndrome with elevated total bilirubin may be enrolled as long as direct bilirubin, hemoglobin and reticulocytes are normal.
• Subject has creatinine > 1.5 × ULN; or estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula ≤ 59 mL/min per 1.73 m^2 at screening.
• Subject has a history of suicide attempt or suicidal behavior within the last 12 months or has suicidal ideation within the last 12 months (a response of "yes" to question 4 or 5 on the suicidal ideation portion of the Columbia Suicide Severity Rating Scale [C-SSRS]), or who is at significant risk to commit suicide at screening and at randomization.
• Subject has previously been enrolled in a clinical trial with fezolinetant.
• Subject is participating concurrently in another interventional study or participated in an interventional study within 28 days prior to screening, or received any investigational drug within 28 days or within 5 half-lives prior to screening, whichever is longer.
• Subject is unable or unwilling to complete the study procedures.
• Subject has any condition which makes the subject unsuitable for study participation.
• Subject has had partial or full hysterectomy.