A Dose-ranging Study of the Efficacy of ESN364 in Postmenopausal Women Suffering Vasomotor Symptoms (Hot Flashes)

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.

This was a 12-week randomized, double-blind, placebo-controlled, dose-ranging, parallel-group, multi-center study to assess the efficacy of ESN364 in postmenopausal women suffering from vasomotor symptoms (hot flashes).

This study consisted of a screening period (Days -35 to -1, including the screening visit \[Visit 1\] and a minimum 7-day collection of baseline vasomotor symptom frequency and severity assessments), a 12 week treatment period (Day 1 \[Visit 2\] to Week 12 \[Visit 5\]), and a follow up visit (Week 15 \[Visit 6\]) 3 weeks after the last dose of study drug.

The study was performed on an ambulatory basis. The screening visit (Visit 1) occurred up to 35 days prior to randomization. Eligibility was assessed via physical examination, clinical laboratory testing, vital signs, ECG, Pap smear, mammography, and endometrial biopsy. Subjects received an electronic diary to record daily vasomotor symptoms during the duration of the screening period. Subjects who had ≥7 consecutive days of vasomotor symptom recordings participated in the study. Subjects are encouraged to continue recording for the duration of the whole screening period. The electronic diary was reviewed by study site staff on Day 1 (Visit 2) to confirm study eligibility. Subjects were rescreened 1 time upon approval of the medical monitor.

During the treatment period, subjects returned to the study site every 4 weeks for assessments.

The follow-up visit occurred approximately 3 weeks following the last dose of study drug.

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.