Clinical trial NCT03192176: A Dose-ranging Study of the Efficacy of ESN364 in Postmenopausal Women Suffering Vasomotor Symptoms (Hot Flashes)
Official title: A Randomized, Placebo-Controlled, Double-Blind, Dose-Ranging, Phase 2b Study to Investigate the Efficacy of ESN364 in Postmenopausal Women Suffering From Vasomotor Symptoms (Hot Flashes)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Menopause
Hot Flashes
Keywords: Vasomotor symptoms
Menopause
Hot flashes
Perimenopause
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2017-06-19
Enrollment: 356
Sex: FEMALE
Minimum age (years): 40
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Detailed description: 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.

Primary outcomes:
measure: Co-Primary Efficacy Endpoint: Change From Baseline (CFB) in The Mean Frequency of Moderate to Severe Vasomotor Symptoms (VMS) at Week 4
timeFrame: Baseline and week 4
measure: Co-Primary Efficacy Endpoint: Change From Baseline in The Mean Frequency of Moderate to Severe VMS at Week 12
timeFrame: Baseline and week 12
measure: Co-Primary Efficacy Endpoint: Change From Baseline in The Mean Severity of Moderate to Severe VMS at Week 4
timeFrame: Baseline and week 4
measure: Co-Primary Efficacy Endpoint: Change From Baseline in The Mean Severity of Moderate to Severe VMS at Week 12
timeFrame: Baseline and week 12
Secondary outcomes:
measure: Change From Baseline in The Mean Frequency of Mild, Moderate, and Severe VMS to Each Study Week
timeFrame: Baseline and weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
measure: Change From Baseline in The Mean Frequency of Moderate and Severe VMS to Each Study Week
timeFrame: Baseline and weeks 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 13, 14 and 15
measure: Change From Baseline in The Mean Severity of Mild, Moderate, and Severe VMS to Each Study Week
timeFrame: Baseline and weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
measure: Change From Baseline in The Mean Severity of Moderate and Severe VMS to Each Study Week
timeFrame: Baseline and weeks 1, 2, 3, 5, 6, 7, 8, 9, 10, 11, 13, 14 and 15
measure: Change From Baseline in The Hot Flash Score of Mild, Moderate, and Severe VMS to Each Study Week
timeFrame: Baseline and weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
measure: Change From Baseline in The Hot Flash Score of Moderate and Severe VMS to Each Study Week
timeFrame: Baseline and weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
measure: Mean Percent Reduction of Mild, Moderate, And Severe Vasomotor Symptoms From Baseline to Each Study Week
timeFrame: Baseline and weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
measure: Mean Percent Reduction of Moderate And Severe Vasomotor Symptoms From Baseline to Each Study Week
timeFrame: Baseline and weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
measure: Number of Participants With Mean Percent Reduction of 50% in The Mean Frequency of Mild, Moderate, and Severe VMS From Baseline to Each Study Week
timeFrame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, and 15
measure: Number of Participants With Mean Percent Reduction of 70% in The Mean Frequency of Mild, Moderate, and Severe VMS From Baseline to Each Study Week
timeFrame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
measure: Number of Participants With Mean Percent Reduction of 90% in The Mean Frequency of Mild, Moderate, and Severe VMS From Baseline to Each Study Week
timeFrame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
measure: Number of Participants With Mean Percent Reduction of 100% in The Mean Frequency of Mild, Moderate, and Severe VMS From Baseline to Each Study Week
timeFrame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
measure: Number of Participants With Mean Percent Reduction of 50% in The Mean Frequency of Moderate and Severe Vasomotor Symptoms From Baseline to Each Study Week
timeFrame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
measure: Number of Participants With Mean Percent Reduction of 70% in The Mean Frequency of Moderate and Severe Vasomotor Symptoms From Baseline to Each Study Week
timeFrame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
measure: Number of Participants With Mean Percent Reduction of 90% in The Mean Frequency of Moderate and Severe Vasomotor Symptoms From Baseline to Each Study Week
timeFrame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
measure: Number of Participants With Mean Percent Reduction of 100% in The Mean Frequency of Moderate and Severe Vasomotor Symptoms From Baseline to Each Study Week
timeFrame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
measure: Number of Participants With Absolute Reduction of 2 in Mean Number of Mild, Moderate and Severe VMS Per Day From Baseline to Each Study Week
timeFrame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
measure: Number of Participants With Absolute Reduction of 3 in Mean Number of Mild, Moderate and Severe VMS Per Day From Baseline to Each Study Week
timeFrame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
measure: Number of Participants With Absolute Reduction of 4 in Mean Number of Mild, Moderate and Severe VMS Per Day From Baseline to Each Study Week
timeFrame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
measure: Number of Participants With Absolute Reduction of 5 in Mean Number of Mild, Moderate and Severe VMS Per Day From Baseline to Each Study Week
timeFrame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
measure: Number of Participants With Absolute Reduction of 2 in Mean Number of Moderate and Severe VMS Per Day From Baseline to Each Study Week
timeFrame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
measure: Number of Participants With Absolute Reduction of 3 in Mean Number of Moderate and Severe VMS Per Day From Baseline to Each Study Week
timeFrame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
measure: Number of Participants With Absolute Reduction of 4 in Mean Number of Moderate and Severe VMS Per Day From Baseline to Each Study Week
timeFrame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
measure: Number of Participants With Absolute Reduction of 5 in Mean Number of Moderate and Severe VMS Per Day From Baseline to Each Study Week
timeFrame: Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 and 15
measure: Change From Baseline in Hot Flash-Related Daily Interference Scale (HFRDIS) at Weeks 4, 8, 12, and 15
timeFrame: Baseline and weeks 4, 8, 12, and 15
measure: Leeds Sleep Evaluation Questionnaire (LSEQ) Domain Scores at Weeks 4, 8, 12 and 15
timeFrame: Weeks 4, 8, 12, and 15
measure: Change From Baseline in Greene Climacteric Scale (GCS) at Weeks 4, 8, 12, and 15
timeFrame: Baseline and weeks 4, 8, 12, and 15
measure: Change From Baseline in Menopause-Specific Quality of Life (MENQoL) at Weeks 4, 8, 12, and 15
timeFrame: Baseline and weeks 4, 8, 12, and 15
measure: Change Over Time From Baseline in Plasma Concentrations of Luteinizing Hormone (LH) at Week 12
timeFrame: Baseline and week 12
measure: Change Over Time From Baseline in Plasma Concentrations of Follicle-Stimulating Hormone (FSH) at Week 12
timeFrame: Baseline and week 12
measure: Change Over Time From Baseline in Plasma Concentrations of Estradiol (E2) at Week 12
timeFrame: Baseline and week 12
measure: Change Over Time From Baseline in Plasma Concentrations of Sex Hormone-Binding Globulin (SHBG) at Week 12
timeFrame: Baseline and week 12
Other outcomes:
Locations:
city: Anniston
country: United States
facility: Research Site
state: Alabama
city: Birmingham
country: United States
facility: Research Site
state: Alabama
city: Phoenix
country: United States
facility: Research Site
state: Arizona
city: Los Angeles
country: United States
facility: Research Site
state: California
city: Oceanside
country: United States
facility: Research Site
state: California
city: Panorama City
country: United States
facility: Research Site
state: California
city: Sacramento
country: United States
facility: Research Site 052
state: California
city: Sacramento
country: United States
facility: Research Site 058
state: California
city: San Diego
country: United States
facility: Research Site
state: California
city: Thousand Oaks
country: United States
facility: Research Site
state: California
city: Valley Village
country: United States
facility: Research Site
state: California
city: Denver
country: United States
facility: Research Site
state: Colorado
city: Milford
country: United States
facility: Research Site
state: Connecticut
city: Crystal River
country: United States
facility: Research Site
state: Florida
city: DeLand
country: United States
facility: Research Site
state: Florida
city: Jupiter
country: United States
facility: Research Site
state: Florida
city: Lake Worth
country: United States
facility: Research Site
state: Florida
city: Miami
country: United States
facility: Research Site
state: Florida
city: Ormond Beach
country: United States
facility: Research Site
state: Florida
city: Port Saint Lucie
country: United States
facility: Research Site
state: Florida
city: Atlanta
country: United States
facility: Research Site
state: Georgia
city: Norcross
country: United States
facility: Research Site
state: Georgia
city: Meridian
country: United States
facility: Research Site
state: Idaho
city: Champaign
country: United States
facility: Research Site
state: Illinois
city: Marrero
country: United States
facility: Research Site
state: Louisiana
city: Elkridge
country: United States
facility: Research Site
state: Maryland
city: Watertown
country: United States
facility: Research Site
state: Massachusetts
city: Lincoln
country: United States
facility: Research Site
state: Nebraska
city: Norfolk
country: United States
facility: Research Site
state: Nebraska
city: Las Vegas
country: United States
facility: Research Site
state: Nevada
city: New York
country: United States
facility: Research Site
state: New York
city: Williamsville
country: United States
facility: Research Site
state: New York
city: Cincinnati
country: United States
facility: Research Site
state: Ohio
city: Cleveland
country: United States
facility: Research Site
state: Ohio
city: Columbus
country: United States
facility: Research Site
state: Ohio
city: Columbus
country: United States
facility: Research Site
state: Ohio
city: Oklahoma City
country: United States
facility: Research Site
state: Oklahoma
city: Philadelphia
country: United States
facility: Research Site
state: Pennsylvania
city: Mount Pleasant
country: United States
facility: Research Site
state: South Carolina
city: Clarksville
country: United States
facility: Research Site
state: Tennessee
city: Kingsport
country: United States
facility: Research Site
state: Tennessee
city: Houston
country: United States
facility: Research Site
state: Texas
city: Hurst
country: United States
facility: Research Site
state: Texas
city: Lampasas
country: United States
facility: Research Site
state: Texas
city: Plano
country: United States
facility: Research Site
state: Texas
city: San Antonio
country: United States
facility: Research Site
state: Texas
city: Riverton
country: United States
facility: Research Site
state: Utah
city: Charlottesville
country: United States
facility: Research Site
state: Virginia
city: Vienna
country: United States
facility: Research Site
state: Virginia
city: Seattle
country: United States
facility: Research Site
state: Washington
city: Spokane
country: United States
facility: Research Site
state: Washington
Study officials:
affiliation: Astellas Pharma Global Development, Inc.
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Fraser GL, Lederman S, Waldbaum A, Kroll R, Santoro N, Lee M, Skillern L, Ramael S. A phase 2b, randomized, placebo-controlled, double-blind, dose-ranging study of the neurokinin 3 receptor antagonist fezolinetant for vasomotor symptoms associated with menopause. Menopause. 2020 Apr;27(4):382-392. doi: 10.1097/GME.0000000000001510.