Clinical trial NCT04451226: A Study to Assess the Safety and Tolerability of Fezolinetant in Women Seeking Treatment for Relief of Vasomotor Symptoms (VMS) Associated With Menopause
Official title: A Single-Arm Phase 3 Clinical Study to Investigate the Long-Term Safety of Fezolinetant in Women in China Suffering From Vasomotor Symptoms (Hot Flashes) Associated With Menopause
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hot Flashes
Keywords: Vasomotor Symptoms
menopause
fezolinetant
ESN364
Lead sponsor: Astellas Pharma Inc
Sponsor class: INDUSTRY
First posted: 2020-06-30
Enrollment: 150
Sex: FEMALE
Minimum age (years): 40
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study is for women in menopause with 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 purpose of this study is to find out how safe it is for these women to take fezolinetant long term (up to 52 weeks). To do that, the study will look at the number and severity of the "adverse events." Those are the side effects that study participants have while they are in the study. The study treatment is fezolinetant (1 tablet of fezolinetant) once a day. The study participants will take study treatment for 52 weeks. At weeks 2 and 4 and then once a month, the study participants will go the hospital or clinic for a check-up. They will be asked about medications, side effects and how they feel. Other checks will include physical exam and vital signs (heart rate, temperature and blood pressure). Blood and urine will be collected for laboratory tests. At some study visits, study participants will complete questionnaires that are about their quality of life. Study participants who still have their uterus will have 2 more tests done at the first and last study visits. One of the 2 tests is endometrial biopsy. This test involves removing a small amount of tissue from the inside lining of the uterus. The tissue is then checked under a microscope. The other test is transvaginal ultrasound. It uses sound waves to create pictures of the organs in the pelvis. The sound waves are transmitted by a probe (transducer), which is 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 have this test done in the last 12 months will have it done at the first study visit. They will have 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 will be 3 weeks after the last dose of study treatment.

Detailed description: The study will consist of a screening period, a 52-week treatment period and a follow-up visit, 3 weeks after the last dose of study drug.

Eligibility criteria: Inclusion Criteria:

* Subject has a body mass index ≥ 16 kg/m\^2 and ≤ 38 kg/m\^2 at the screening visit.
* Subject confirmed as menopausal per 1 of the following criteria at the screening visit:

O Subject has spontaneous amenorrhea for \>= 12 consecutive months O Spontaneous amenorrhea for ≥ 6 months with biochemical criteria of menopause (follicle-stimulating hormone \[FSH\] \> 40 International Units per Liter \[IU/L\], or O Having had bilateral oophorectomy ≥ 6 weeks prior to the screening visit (with or without hysterectomy).

O FSH \> 40 IU/L if subjects received hysterectomy but still have ovary

* Subject is seeking treatment for relief for VMS associated with menopause.
* 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 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 abnormal findings on mammogram (or echo) (e.g., \<BI-RADS class 4; obtained at screening or within the prior 12 months of screening). Appropriate documentation includes a written report or an electronic report indicating normal/negative or no clinically significant abnormal 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). For subjects who are withdrawn from the study prior to completion, a TVU should be collected at the early discontinuation (ED) visit. This is not required for subjects who have had a partial (supra-cervical) or full hysterectomy.
* Subject is willing to undergo an endometrial biopsy at screening and at week 52 (end of treatment) or the ED visit if endometrial thickness \> 4 millimeter (mm) indicated by TVU; and subject is willing to undergo an endometrial biopsy at any time during the study in the case of uterine bleeding. This is not required for subjects who have had a partial (supra-cervical) or full hysterectomy. A biopsy with insufficient material for evaluation, or unevaluable material, is acceptable provided the endometrial thickness is no greater than 8 mm.
* Subject has documentation of a normal or not clinically significant abnormal Papanicolaou (Pap) test (or equivalent cervical cytology) within the previous 12 months of screening or at screening. This is not required for subjects who have had a full hysterectomy.
* Subject has a negative urine pregnancy test at screening.
* Subject has a negative serology panel (including hepatitis B virus surface antigen \[HBs\] and hepatitis C virus antibody \[anti-HCV\], and human immunodeficiency virus \[HIV\]) 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 and moderate cytochrome P450 \[CYP\] 1A2 inhibitors, hormone replacement therapy \[HRT\], hormonal contraceptive, any treatment for VMS \[prescription, over the counter or herbal\]) or is not willing to wash out and discontinue such drugs for the full extent of the study.
* Subject has a known substance abuse or alcohol addiction within 6 months of screening.
* Subject has a history of a malignant tumor, except for non-metastatic basal cell carcinoma of the skin.
* Subject has uncontrolled hypertension, defined as systolic blood pressure \>= 140 millimeters of mercury (mmHg) or diastolic blood pressure as \>= 90 mmHg based on an average of 2 to 3 readings within the screening period.

O Subjects with a medical history of hypertension who are well controlled may be enrolled.

O Subjects who do not meet the criteria may, be re-assessed after initiation or review of antihypertensive measures.

* Subject has a history of severe allergy, hypersensitivity, or intolerance to drugs in general, including the study drug and any of its excipients.
* For subjects with a uterus: 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 abnormal finding.
* For subjects with an endometrial thickness \> 4 mm as indicated by TVU at screening: Subject has an endometrial biopsy confirming presence of disordered proliferative endometrium, endometrial hyperplasia, endometrial cancer, or other clinically significant abnormal findings in the at screening. A biopsy with insufficient material for evaluation, or unevaluable material is acceptable provided the endometrial thickness is no greater than 8 mm.
* Subject has a history of an undiagnosed uterine bleeding within the last 6 months of screening.
* 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) at screening. Subject with mildly elevated ALT or AST up to 1.5 × the upper limit of normal (ULN) can be enrolled if total and direct bilirubin are normal. Subject with mildly elevated ALP (up to 1.5 × ULN) can be enrolled if cholestatic liver disease is excluded and no cause other than fatty liver is diagnosed. Subject with Gilbert's syndrome with elevated total bilirubin (TBL) may be enrolled as long as hemolysis is ruled out (i.e., direct bilirubin (DBL), 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 milliliter per minute per 1.73 meter square (mL/min/1.73 m\^2) at the screening visit.
* Subject has a history of suicide attempt or suicidal behavior within the prior to 12 months of study enrollment or has suicidal ideation within the prior to 12 months of study enrollment (a response of "yes" to questions 4 or 5 on the suicidal ideation portion of the C-SSRS), or who is at significant risk to commit suicide at screening and at visit 2.
* Subject has previously been enrolled in a clinical trial with fezolinetant.
* Subject has received an investigational study drug within 28 days or 5 half-lives, whichever is longer, prior to screening.
* Subject is unable or unwilling to complete the study procedures.
* Subject has any condition which, makes the subject unsuitable for study participation.

Primary outcomes:
measure: Number of Participants With Adverse Events
timeFrame: Up to 55 weeks
measure: Number of Participants With Adverse Events Based on Severity
timeFrame: Up to 55 weeks
Secondary outcomes:
measure: Change From Baseline in Endometrial Thickness
timeFrame: Baseline and 52 weeks
measure: Percentage of Participants With Endometrial Hyperplasia and/or Endometrial Cancer
timeFrame: Up to 52 weeks
measure: Number of Participants With Vital Sign Abnormalities and/or Adverse Events (AEs)
timeFrame: Up to 55 weeks
measure: Number of Participants With Laboratory Value Abnormalities and/or Adverse Events (AEs)
timeFrame: Up to 55 weeks
measure: Number of Participants With Suicidal Ideation and/or Behavior as Assessed by Columbia-Suicide Severity Rating Scale (C-SSRS)
timeFrame: Up to 55 weeks
measure: Number of Participants With Electrocardiogram (ECG) Abnormalities and/or Adverse Events (AEs)
timeFrame: Up to 52 weeks
measure: Change From Baseline in Bone Specific Alkaline Phosphatase (BSAP) Levels
timeFrame: Baseline, week 52 and week 55
measure: Change From Baseline in Procollagen Type 1 Amino-terminal Propeptide (P1NP) Levels
timeFrame: Baseline, week 52 and week 55
measure: Change From Baseline in Carboxy-terminal Telopeptide of Type I Collagen (CTX) Levels
timeFrame: Baseline, week 52 and week 55
measure: Change From Baseline in Serum Concentration of Sex Hormones
timeFrame: Baseline, week 4, week 12, week 24 , week 52 and week 55
measure: Change From Baseline in Sex Hormone-Binding Globulin (SHBG)
timeFrame: Baseline, week 4, week 12, week 24 , week 52 and week 55
measure: Pharmacokinetics (PK) of Fezolinetant in Plasma: Concentration
timeFrame: Week 4, week 12, week 24 and week 52
measure: Pharmacokinetics (PK) of Fezolinetant Metabolite ES259564 in Plasma: Concentration
timeFrame: Week 4, week 12, week 24 and week 52
Other outcomes:
Locations:
city: Beijing
country: China
facility: Site CN86002
city: Beijing
country: China
facility: Site CN86015
city: Beijing
country: China
facility: Site CN86029
city: Chengdu
country: China
facility: Site CN86032
city: Guangzhou
country: China
facility: Site CN86001
city: Guangzhou
country: China
facility: Site CN86019
city: Guangzhou
country: China
facility: Site CN86022
city: Guangzhou
country: China
facility: Site CN86040
city: Guangzhou
country: China
facility: Site CN86042
city: Hangzhou
country: China
facility: Site CN86008
city: Hangzhou
country: China
facility: Site CN86012
city: Hunan
country: China
facility: Site CN86005
city: Jiangsu
country: China
facility: Site CN86039
city: Jinlin
country: China
facility: Site CN86010
city: Kunming
country: China
facility: Site CN86020
city: Liuzhou
country: China
facility: Site CN86037
city: Nanjing
country: China
facility: Site CN86006
city: Nanjing
country: China
facility: Site CN86007
city: Nanning
country: China
facility: Site CN86018
city: Ningxia Hui Nationality Autonomous Region
country: China
facility: Site CN86034
city: Shanghai
country: China
facility: Site CN86009
city: Shanxi
country: China
facility: Site CN86011
city: Shenzhen
country: China
facility: Site CN86004
city: Shijiazhuang
country: China
facility: Site CN86028
city: Suzhou
country: China
facility: Site CN86026
city: Taiyuan
country: China
facility: Site CN86038
city: Tianjin
country: China
facility: Site CN86030
city: Tianjin
country: China
facility: Site CN86036
city: Wuhan
country: China
facility: Site CN86025
Study officials:
affiliation: Astellas Pharma China, Inc.
name: Medical Director
role: STUDY_DIRECTOR
References: