A Dose-ranging Study of the Efficacy of ESN364 in Postmenopausal Women Suffering Vasomotor Symptoms (Hot Flashes)
Condition: Menopause; Hot Flashes
MeSH terms: Hot Flashes
Intervention: Fezolinetant; Placebo
Intervention description: Oral Capsule; Oral Capsule
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 356.0
Sex: Female
Minimum age: 40 Years
Maximum age: 65 Years
Healthy volunteers: No
Keywords: Vasomotor symptoms; Menopause; Hot flashes; Perimenopause

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          -  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.

        Exclusion Criteria:

          -  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.