A Study to Find Out How Safe Long-term Treatment With Fezolinetant is in Women With Hot Flashes Going Through Menopause
Condition: Hot Flashes
MeSH terms: Hot Flashes
Intervention: fezolinetant; placebo
Intervention description: administered orally; administered orally
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 1831.0
Sex: Female
Minimum age: 40 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: menopause; fezolinetant; ESN364; vasomotor symptoms

Summary:

      This study was for women in menopause with hot flashes. Menopause, a normal part of aging,
      was the time of a woman's last period. Hot flashes can interrupt a woman's daily life.

      The purpose of this study was to find out how safe it is for these women to take fezolinetant
      in long term (up to 52 weeks). To do that, the study looked at the number and severity of the
      "adverse events." Those were the side effects that study participants had while they were in
      the study.

      The study treatments were fezolinetant 30 milligrams (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 was a dummy treatment that looked like medicine but
      did not have any medicine in it.) Women in this study were picked for 1 of the 3 study
      treatments by chance alone. The study participants took study treatment for 52 weeks.

      This study 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).

      At weeks 2 and 4 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 were collected for laboratory tests. At some study visits, study participants
      completed questionnaires that were about their quality of life. At the first and last study
      visits, they had a dual-energy x-ray absorptiometry (DXA for short) test done. To measure
      bone loss in the hips and spine, DXA created pictures of the inside of these areas with
      low-dose x-rays. (The dose was approximately one-tenth of the amount of a normal chest
      x-ray.) Study participants who still had their uterus had 2 more 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. It used sound waves to create
      pictures of the organs in the pelvis. The sound waves were transmitted by a probe
      (transducer), which was placed inside the vagina. Study participants might have had 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 had
      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
      agreed.

      The last check-up at the hospital or clinic was at 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 > 40 IU/L), or

               -  Having had bilateral oophorectomy ≥ 6 weeks prior to the screening visit.

          -  Subject is seeking treatment for relief for VMS associated with menopause.

          -  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 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 mammogram
             findings (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). For subjects who are
             withdrawn from the study prior to completion, a TVU should be collected at the early
             discontinuation (ED) visit.

          -  Subject is willing to undergo an endometrial biopsy at screening and at week 52 (EOT)
             or the ED visit for subjects who are withdrawn from the study prior to completion, and
             any time during the study in the case of uterine bleeding. 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 [CYP] 1A2
             inhibitors, hormone replacement therapy [HRT], hormonal contraceptive, any treatment
             for VMS [prescription, over the counter or herbal]) or is not willing to wash out and
             discontinue such drugs for the full extent of the study.

          -  Subject has a 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 a 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 x 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.

          -  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
             questions 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, as assessed
             at screening and at the time of visit 2 (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 a partial or full hysterectomy.