Clinical trial NCT04003142: A Study to Find Out if Fezolinetant Helps Reduce Moderate to Severe Hot Flashes in Women Going Through Menopause - 2
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: ESN364
menopause
fezolinetant
vasomotor symptoms
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2019-07-01
Enrollment: 501
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 are fezolinetant 30 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 is a dummy treatment that looks like medicine but does not have 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 is 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 shows 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 is like flipping a coin.

The study participants took study treatment for 52 weeks. The first 12 weeks of study treatment 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) during that time. The last 40 weeks of study treatment was "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 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 was collected for laboratory tests. Study participants completed questionnaires that were about how hot flashes affect their daily life. Study participants who 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 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. This test used sound waves to create pictures of the organs in the pelvis. The sound waves are transmitted by a probe (transducer), which was placed inside the vagina. Study participants might 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 have 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 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 Vasomotor Symptoms 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: 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/Fezolinetant 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/Fezolinetant 30 mg and Placebo/Fezolinetant 45 mg)
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, 44, 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: Number of Participants With Adverse Events
timeFrame: From first dose date up to 21 days after last dose (up to 55 weeks)
Other outcomes:
Locations:
city: Mesa
country: United States
facility: Mesa Obstetricians and Gynecologists
state: Arizona
city: Phoenix
country: United States
facility: Precision Trials
state: Arizona
city: Tucson
country: United States
facility: Visions Clinical Research - Tuscon
state: Arizona
city: Oceanside
country: United States
facility: Excell Research
state: California
city: Pomona
country: United States
facility: Dream Team Clinical Research, LLC
state: California
city: Sacramento
country: United States
facility: Clinical Trials Research
state: California
city: San Diego
country: United States
facility: Wake Research Associates, LLC
state: California
city: San Diego
country: United States
facility: Women's Healthcare Affiliates
state: California
city: Valley Village
country: United States
facility: Bayview Research Group
state: California
city: Denver
country: United States
facility: Downtown Women's Health Care
state: Colorado
city: Denver
country: United States
facility: Horizons Clincial Research Center LLC
state: Colorado
city: Lakewood
country: United States
facility: Physicians' Research Options/Red Rocks OB/GYN
state: Colorado
city: Boynton Beach
country: United States
facility: Helix Biomedics
state: Florida
city: Cape Coral
country: United States
facility: Renaissance Research and Medical Group, Inc.
state: Florida
city: Crystal River
country: United States
facility: Nature Coast Clinical Research
state: Florida
city: Melbourne
country: United States
facility: Bioclinica Research, Melbourne
state: Florida
city: Miami
country: United States
facility: LCC Medical Research Institute, LLC
state: Florida
city: Miami
country: United States
facility: Suncoast Clinical Research, Inc.
state: Florida
city: Miami
country: United States
facility: Suncoast Research
state: Florida
city: Miami
country: United States
facility: Medical Health Center & Research
state: Florida
city: North Miami
country: United States
facility: Healthcare Clinical Data Inc
state: Florida
city: Ocoee
country: United States
facility: Sensible Healthcare LLC
state: Florida
city: Orlando
country: United States
facility: Bioclinica Research
state: Florida
city: Ormond Beach
country: United States
facility: Ormond Medical Arts Pharmaceutical Research Center
state: Florida
city: Port Orange
country: United States
facility: Progressive Medical Research
state: Florida
city: Saint Petersburg
country: United States
facility: Meridien Research
state: Florida
city: Sarasota
country: United States
facility: Physician Care Clinical Research, LLC
state: Florida
city: Tampa
country: United States
facility: GCP Clinical Research, LLC
state: Florida
city: West Palm Beach
country: United States
facility: Comprehensive Clinical Development
state: Florida
city: Winter Haven
country: United States
facility: Clinical Research of Central Florida
state: Florida
city: Atlanta
country: United States
facility: Georgia Research for Women
state: Georgia
city: Atlanta
country: United States
facility: Agile Clinical Research Trials, LLC
state: Georgia
city: Decatur
country: United States
facility: iResearch Atlanta LLC
state: Georgia
city: Sandy Springs
country: United States
facility: WR-Mount Vernon Clinical Research
state: Georgia
city: Snellville
country: United States
facility: Georgia Clinical Research
state: Georgia
city: Blackfoot
country: United States
facility: Elite Clinical Trials
state: Idaho
city: Nampa
country: United States
facility: ASR, LLC-Advanced Specialty Research
state: Idaho
city: Oak Brook
country: United States
facility: Affinity Clinical Research Institute
state: Illinois
city: Wichita
country: United States
facility: Cypress Medical Research Center
state: Kansas
city: Marrero
country: United States
facility: Praetorian Pharmaceutical Research
state: Louisiana
city: Metairie
country: United States
facility: Southern Clinical Research Associates
state: Louisiana
city: New Orleans
country: United States
facility: Women Under Study, LLC
state: Louisiana
city: Baltimore
country: United States
facility: Pharmasite Research Inc
state: Maryland
city: Las Vegas
country: United States
facility: Clinical Research Center of Nevada (CRCN)
state: Nevada
city: Las Vegas
country: United States
facility: Dr.R. Garn Mabey, MD,Office Of
state: Nevada
city: Berlin
country: United States
facility: Hassman Research Institute, LLC
state: New Jersey
city: Albuquerque
country: United States
facility: Albuquerque Clinical Trials, Inc.
state: New Mexico
city: Albuquerque
country: United States
facility: Bosque Women's Care
state: New Mexico
city: West Seneca
country: United States
facility: Circuit Clinical
state: New York
city: Charlotte
country: United States
facility: Premier Gynecology & Wellness
state: North Carolina
city: Greensboro
country: United States
facility: Medication Management, LLC
state: North Carolina
city: Englewood
country: United States
facility: Hwc Women's Research Center
state: Ohio
city: Erie
country: United States
facility: OB/GYN Associates of Erie
state: Pennsylvania
city: Jenkintown
country: United States
facility: Dr. Marvin Kalafer MD, Office Of
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Research Protocol Management Specialists
state: Pennsylvania
city: Memphis
country: United States
facility: Clinical Neuroscience Solutions, Inc
state: Tennessee
city: Carrollton
country: United States
facility: The Clinical Research Center, LLC
state: Texas
city: Houston
country: United States
facility: Advances in Health
state: Texas
city: Houston
country: United States
facility: Centex Studies, Inc.
state: Texas
city: Lampasas
country: United States
facility: FMC Science
state: Texas
city: Plano
country: United States
facility: ClinRx Research
state: Texas
city: Riverton
country: United States
facility: Granger Medical Clinic
state: Utah
city: Salt Lake City
country: United States
facility: Wasatch Clinical Research, LLC
state: Utah
city: Seattle
country: United States
facility: Seattle Women's: Health, Research, Gynecology
state: Washington
city: Spokane
country: United States
facility: North Spokane Women's Health
state: Washington
city: Sarnia
country: Canada
facility: Site CA15006
state: Ontario
city: Toronto
country: Canada
facility: Site CA15009
state: Ontario
city: Levis
country: Canada
facility: Site CA15007
state: Quebec
city: Sherbrooke
country: Canada
facility: Site CA15002
state: Quebec
city: Victoriaville
country: Canada
facility: Site CA15001
state: Quebec
city: Quebec
country: Canada
facility: Site CA15008
city: Pisek
country: Czechia
facility: Site CZ42007
city: Praha 2
country: Czechia
facility: Site CZ42006
city: Praha 9
country: Czechia
facility: Site CZ42004
city: Tabor 3
country: Czechia
facility: Site CZ42005
city: Vsetin
country: Czechia
facility: Site CZ42003
city: Riga
country: Latvia
facility: Site LV37101
city: Riga
country: Latvia
facility: Site LV37103
city: Bydgoszcz
country: Poland
facility: Site PL48001
city: Elblag
country: Poland
facility: Site PL48013
city: Katowice
country: Poland
facility: Site PL48009
city: Krakow
country: Poland
facility: Site PL48011
city: Lublin
country: Poland
facility: Site PL48002
city: Lublin
country: Poland
facility: Site PL48012
city: Piaseczno
country: Poland
facility: Site PL48004
city: Poznan
country: Poland
facility: Site PL48006
city: Szczecin
country: Poland
facility: Site PL48005
city: Warsaw
country: Poland
facility: Site PL48010
city: Warszawa
country: Poland
facility: Site PL48003
city: Aravaca
country: Spain
facility: Site ES34003
city: Centelles
country: Spain
facility: Site ES34002
city: Madrid
country: Spain
facility: Site ES34001
city: Shipley
country: United Kingdom
facility: Site GB44001
Study officials:
affiliation: Astellas Pharma Global Development, Inc.
name: Executive Medical Director
role: STUDY_DIRECTOR
References: