A Study to Find Out if Fezolinetant Helps Reduce Moderate to Severe Hot Flashes in Women Going Through Menopause - 2
Condition: Hot Flashes
MeSH terms: Hot Flashes
Intervention: Fezolinetant; placebo
Intervention description: Oral tablet; Oral Tablet
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 501.0
Sex: Female
Minimum age: 40 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: ESN364; menopause; fezolinetant; vasomotor symptoms

Summary:

      This study was 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 30 mg (1 tablet of fezolinetant and 1 placebo tablet)
      once a day, fezolinetant 45 mg (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 compared fezolinetant and placebo after 4 and 12 weeks of dosing.
      The study evaluated if fezolinetant reduces the number of hot flashes and the study evaluated
      if fezolinetant reduces the severity of the hot flashes.

      Women in the study received an electronic handheld device at the first study visit. (It is
      similar to a smart phone.) Each day of the study, study participants used this to record
      their hot flashes. Their record for the 10 days before the start of study treatment was
      checked. They remained in the study if their record shows 7 or 8 moderate to severe hot
      flashes per day (50 or more per week). Next, they were picked for 1 of the 2 study treatments
      (fezolinetant or placebo) by chance alone. It is like flipping a coin.

      The study participants took study treatment for 52 weeks. The first 12 weeks of study
      treatment was "double-blinded." That means that the study participants and the study doctors
      did not know who took which of the study treatments (fezolinetant 30 mg, fezolinetant 45 mg
      or placebo) during that time. The last 40 weeks of study treatment was "noncontrolled." That
      means that each study participant and the study doctors knew which study treatment that study
      participant took during that time. Women who took fezolinetant during the first 12 weeks
      continued to take the same dose. Women who took placebo during the first 12 weeks took
      fezolinetant. Their dose was either 30 mg or 45 mg fezolinetant.

      At weeks 2, 4, 8, 12, 14, 16 and then once a month, the study participants went to the
      hospital or clinic for a check-up. They were asked about medications, side effects and how
      they felt. Other checks included physical exam and vital signs (heart rate, temperature and
      blood pressure). Blood and urine was collected for laboratory tests. Study participants
      completed questionnaires that were about how hot flashes affect their daily life. Study
      participants who had their uterus had the following 2 tests done at the first and last study
      visits. One of the 2 tests was endometrial biopsy. This test involved removing a small amount
      of tissue from the inside lining of the uterus. The tissue was then checked under a
      microscope. The other test was transvaginal ultrasound. This test used sound waves to create
      pictures of the organs in the pelvis. The sound waves are transmitted by a probe
      (transducer), which was placed inside the vagina. Study participants might 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 had it done at the first study visit. They had done at the last study
      visit if they were due for their screening mammogram and their own doctor agrees.

      The last check-up at the hospital or clinic was 3 weeks after the last dose of study
      treatment.
    

Eligibility criteria:

        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.