Clinical trial NCT04003155: A Study to Find Out if Fezolinetant Helps Reduce Moderate to Severe Hot Flashes in Women Going Through Menopause
Official title: A Phase 3, Randomized, Placebo-controlled, 12-week Double-blind Study, Followed by a Non-Controlled Extension Treatment Period, to Assess the Efficacy and Safety of Fezolinetant in Women Suffering From Moderate to Severe Vasomotor Symptoms (Hot Flashes) Associated With Menopause
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hot Flashes
Keywords: menopause
ESN364
vasomotor symptoms
fezolinetant
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2019-07-01
Enrollment: 527
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 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 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 looks like medicine but did not had 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 was 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 shown 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 was like flipping a coin. The study participants took study treatment for 52 weeks. The first 12 weeks of study treatment are "double-blinded." That means that the study participants and the study doctors did not knew 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 are "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 visited 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 still 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 involves removing a small amount of tissue from the inside lining of the uterus. The tissue was then checked under a microscope. The other test is transvaginal ultrasound. This test 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 may 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 had this test done in the last 12 months had it done at the first study visit. They had it done at the last study visit if they are 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.

Detailed description: This study consisted of a screening period and a 52 week treatment period. Safety follow up occurred 3 weeks after the last dose of study drug.

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.

Primary outcomes:
measure: Change From Baseline in The Mean Frequency of Moderate to Severe VMS at Week 4
timeFrame: Baseline and week 4
measure: Change From Baseline in The Mean Frequency of Moderate to Severe VMS at Week 12
timeFrame: Baseline and week 12
measure: Change From Baseline in The Mean Severity of Moderate to Severe VMS at Week 4
timeFrame: Baseline and week 4
measure: 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 Patient-reported Outcomes Measurement Information System Sleep Disturbance - Short Form 8b (PROMIS SD SF 8b) Total Score at Week 12
timeFrame: Baseline and week 12
measure: Change From Baseline in The Mean Frequency of Moderate, and Severe VMS to Each Study Week Up to Week 12
timeFrame: Baseline and weeks 1, 2, 3, 5, 6, 7, 8, 9, 10 and 11
measure: Change From Baseline in The Mean Severity of Moderate, and Severe VMS to Each Study Week Up to Week 12
timeFrame: Baseline and weeks 1, 2, 3, 5, 6, 7, 8, 9, 10 and 11
measure: Mean Percent Change in The Frequency of Moderate And Severe VMS From Baseline to Each Study Week Up to Week 12
timeFrame: Baseline and weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12
measure: Number of Participants With Percent Reduction of >=50% in the Mean Frequency of Moderate and Severe VMS From Baseline to Each Study Week Up to Week 12
timeFrame: Baseline and weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12
measure: Number of Participants With Mean Percent Reduction of 100% in The Mean Frequency of Moderate, and Severe VMS From Baseline to Each Study Week Up to Week 12
timeFrame: Baseline and weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12
measure: Number of Participants in Each Category of Patient's Global Impression of Change (PGIC) in VMS at Each Visit
timeFrame: Weeks 4, 12, 16, 20, 24, 28, 32, 36, 40, 48, 52 of fezolinetant exposure (weeks 16, 24, 28, 32, 36, 40, 44, 48 and 52 for arms Placebo/Fezolinetant 30 mg and Placebo/Fezolinetant 45 mg)
measure: Change From Baseline in The Mean Frequency of Moderate, and Severe VMS at Week 24
timeFrame: Baseline and 24 weeks of fezolinetant exposure (week 36 for arms Placebo/Fezolinetanat 30 mg and Placebo/Fezolinetant 45 mg)
measure: Change From Baseline in The Mean Severity of Moderate, and Severe VMS at Week 24
timeFrame: Baseline and 24 weeks of fezolinetant exposure (week 36 for arms Placebo/Fezolinetanat 30 mg and Placebo/Fezolinetant 45 mg)
measure: Number of Participants With Adverse Events
timeFrame: From first dose date up to 21 days after last dose (to 55 weeks)
Other outcomes:
Locations:
city: Andalusia
country: United States
facility: SEC Clinical Research
state: Alabama
city: Birmingham
country: United States
facility: Central Research Associates
state: Alabama
city: Ensley
country: United States
facility: Achieve Clinical Research, LLC
state: Alabama
city: Phoenix
country: United States
facility: Elite Clinical Studies, LLC
state: Arizona
city: Tucson
country: United States
facility: Eclipse Clinical Research
state: Arizona
city: Banning
country: United States
facility: Advanced Clinical Research - Rancho Paseo
state: California
city: Canoga Park
country: United States
facility: Hope Clinical Research, LLC
state: California
city: Canoga Park
country: United States
facility: Alliance Research Inc
state: California
city: Huntington Beach
country: United States
facility: Marvel Clinical Research
state: California
city: La Mesa
country: United States
facility: Grossmont Center for Clinical Research
state: California
city: Los Angeles
country: United States
facility: National Research Institute - Panorama
state: California
city: Sacramento
country: United States
facility: Northern California Research
state: California
city: San Diego
country: United States
facility: Precision Research Institute, Inc
state: California
city: New London
country: United States
facility: Coastal Connecticut Research, LLC
state: Connecticut
city: Washington
country: United States
facility: Emerson Clinical Research Institute
state: District of Columbia
city: Coral Springs
country: United States
facility: Precision Clinical Research
state: Florida
city: Cutler Bay
country: United States
facility: American Research Institute, Inc.
state: Florida
city: DeLand
country: United States
facility: Avail Clinical Research, LLC
state: Florida
city: Doral
country: United States
facility: Universal Axon Clinical Research
state: Florida
city: Fleming Island
country: United States
facility: Fleming Island Center for Clinical Research
state: Florida
city: Fort Myers
country: United States
facility: Clinical Physiology Associates
state: Florida
city: Hialeah
country: United States
facility: Vital Pharma Research Inc.
state: Florida
city: Jupiter
country: United States
facility: Health Awareness
state: Florida
city: Kissimmee
country: United States
facility: GYN Research Center
state: Florida
city: Lake City
country: United States
facility: Multi-Specialty Research Associates, Inc.
state: Florida
city: Lake Worth
country: United States
facility: Altus Research
state: Florida
city: Miami
country: United States
facility: Medical Research Center of Miami II
state: Florida
city: Miami
country: United States
facility: Spotlight research center
state: Florida
city: Miami
country: United States
facility: New Age Medical Research Corporation
state: Florida
city: New Port Richey
country: United States
facility: Suncoast Clinical Research, Inc.
state: Florida
city: Orlando
country: United States
facility: Clinical Neuroscience Solutions, Inc
state: Florida
city: Orlando
country: United States
facility: Clinical Neuroscience Solutions, Inc
state: Florida
city: Orlando
country: United States
facility: Cornerstone Research Institute
state: Florida
city: Ponte Vedra
country: United States
facility: St. Johns Center for Clinical Research
state: Florida
city: Port Saint Lucie
country: United States
facility: Health Awareness
state: Florida
city: Sanford
country: United States
facility: International Clinical Research
state: Florida
city: The Villages
country: United States
facility: Premier Medical Associates
state: Florida
city: Atlanta
country: United States
facility: Better Health Greater Life
state: Georgia
city: Buford
country: United States
facility: Gwinnett Research Institute
state: Georgia
city: Columbus
country: United States
facility: IACT Health
state: Georgia
city: Duluth
country: United States
facility: NuDirections Clinical Research
state: Georgia
city: Riverdale
country: United States
facility: Infinite Clinical Trials
state: Georgia
city: Idaho Falls
country: United States
facility: The Healing Sanctuary, LLC
state: Idaho
city: Crowley
country: United States
facility: Avant Research Associates, LLC
state: Louisiana
city: Lake Charles
country: United States
facility: Centex Studies, Inc.
state: Louisiana
city: Saginaw
country: United States
facility: Saginaw Valley Medical Research Group, Llc
state: Michigan
city: Missoula
country: United States
facility: Montana Medical Research Inc
state: Montana
city: Omaha
country: United States
facility: Quality Clinical Research, Inc
state: Nebraska
city: Las Vegas
country: United States
facility: Excel Clinical Research, LLC
state: Nevada
city: Las Vegas
country: United States
facility: Office Of Edmond Pack, Md
state: Nevada
city: Rochester
country: United States
facility: Rochester Clinical Research, Inc.
state: New York
city: Greensboro
country: United States
facility: Unified Women's Clinical Research
state: North Carolina
city: Raleigh
country: United States
facility: Unified Womens Clinical Research
state: North Carolina
city: Raleigh
country: United States
facility: Wake Research Associates, LLC
state: North Carolina
city: Winston-Salem
country: United States
facility: Unified Women's Clinical Research
state: North Carolina
city: Fargo
country: United States
facility: Lillestol Research, LLC
state: North Dakota
city: Cincinnati
country: United States
facility: Velocity Clinical Research
state: Ohio
city: Columbus
country: United States
facility: Complete Healthcare For Women
state: Ohio
city: North Canton
country: United States
facility: Neuro-Behavioral Clinical Research, Inc
state: Ohio
city: Philadelphia
country: United States
facility: Philadelphia Clinical Research, LLC
state: Pennsylvania
city: Lincoln
country: United States
facility: Ocean State Clinical Research Partners
state: Rhode Island
city: Mount Pleasant
country: United States
facility: Coastal Carolina Research Center
state: South Carolina
city: North Charleston
country: United States
facility: Coastal Carolina Research Center
state: South Carolina
city: Summerville
country: United States
facility: Palmetto Clinical Research
state: South Carolina
city: West Columbia
country: United States
facility: Invocare Clinical Research Center
state: South Carolina
city: Memphis
country: United States
facility: Medical Research Center of Memphis LLC
state: Tennessee
city: Murfreesboro
country: United States
facility: International Clinical Research
state: Tennessee
city: Allen
country: United States
facility: Accent Clinical Research Professionals
state: Texas
city: Bryan
country: United States
facility: DiscoveResarch, Inc.
state: Texas
city: Hurst
country: United States
facility: Protenium Clinical Research, LLC
state: Texas
city: Murray
country: United States
facility: EPIC Medical Research
state: Utah
city: Virginia Beach
country: United States
facility: Tidewater Clinical Research, Inc.
state: Virginia
city: Brampton
country: Canada
facility: Site CA15003
state: Ontario
city: Point Claire
country: Canada
facility: Site CA15002
state: Quebec
city: Quebec City
country: Canada
facility: Site CA15006
state: Quebec
city: Quebec
country: Canada
facility: Site CA15001
city: Quebec
country: Canada
facility: Site CA15004
city: Vodnany
country: Czechia
facility: Site CZ42003
state: Jihocesky
city: Olomouc
country: Czechia
facility: Site CZ42001
city: Debrecen
country: Hungary
facility: Site HU36004
city: Kecskemet
country: Hungary
facility: Site HU36001
city: Szekesfeherver
country: Hungary
facility: Site HU36002
city: Katowice
country: Poland
facility: Site PL48012
state: Slaskie
city: Bialystok
country: Poland
facility: Site PL48003
city: Katowice
country: Poland
facility: Site PL48013
city: Katowice
country: Poland
facility: Site PL48004
city: Lublin
country: Poland
facility: Site PL48007
city: Poznan
country: Poland
facility: Site PL48005
city: Swidnik
country: Poland
facility: Site PL48014
city: Warszawa
country: Poland
facility: Site PL48009
city: Warszawa
country: Poland
facility: Site PL48001
city: Sevilla
country: Spain
facility: Site ES34004
city: Wokingham
country: United Kingdom
facility: Site GB44001
state: Berkshire
city: Orpington
country: United Kingdom
facility: Site GB44003
state: Kent
city: Coventry
country: United Kingdom
facility: Site GB44002
state: Warwickshire
city: Middlesex
country: United Kingdom
facility: Site GB44004
Study officials:
affiliation: Astellas Pharma Global Development, Inc.
name: Executive Medical Director
role: STUDY_DIRECTOR
References: