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A Randomized, Placebo-Controlled, Double-Blind, Phase 2 Study to Select the Optimal Dose(s) of Fezolinetant in Women Suffering from Vasomotor Symptoms (Hot Flashes) Associated with Menopause in Japan (Starlight)

A study to find the best dose of fezolinetant to treat hot flashes in women going through menopause (Starlight)

147

Demographics and baseline characteristics were similar between treatment groups. Most participants were aged < 55 years (70.7%), with a median age of 53.0 years. All participants were Japanese. Most participants were post-menopausal (79.6%), and about a half of participants (46.9%) have had a minimum average of 7 moderate and severe hot flashes (HFs) per day regardless of numbers of mild HFs. The proportion of peri-menopausal participants was lower in the fezolinetant 30 mg group (12.8%) compared with the placebo (27.7%) and fezolinetant 15 mg groups (20.8%).

A total of 240 unique participants signed informed consent and were screened, of which 93 participants failed screening. A total of 147 participants were randomized: 47 participants in the placebo group, 53 in the fezolinetant 15 mg group and 47 in the fezolinetant 30 mg group. All 147 participants took the study intervention. A total of 139 participants completed the 12-week treatment. The most common reason for withdrawal of treatment was "withdrawal by participant" (2.0%). Overall, there were no important differences in frequencies of reason for withdrawal between treatment groups.

The safety results during the study were as follows: - Of the participants, 58.5% and 63.8% of participants in the fezolinetant 15 mg and 30 mg groups, respectively, experienced at least 1 treatment-emergent adverse event (TEAE) compared with 66.0% in the placebo group. The frequency of individual TEAEs was similar across treatment groups. - There were no deaths in the study. - One serious TEAE, urinary bladder polyp, was reported in the fezolinetant 30 mg group. The event was considered as not related to the study drug. No other serious TEAEs were reported. - Two participants in the placebo group and 1 participant in the fezolinetant 15 mg group experienced TEAEs leading to withdrawal of treatment. No TEAEs leading to withdrawal of treatment were reported in the fezolinetant 30 mg group. - No meaningful difference in the frequency of any of the treatment-emergent adverse event of special interest (AESIs), including uterine bleeding were observed across the 3 treatment groups. No treatment-emergent AESIs of endometrial hyperplasia/cancer or disordered proliferative endometrium were reported. - No pregnancies were reported in the study.

Primary Endpoint: - The primary efficacy endpoint (change from baseline to week 8 in mean frequency of mild, moderate and severe VMS per 24 hours) was significantly different from placebo for both fezolinetant treatment groups (15 mg and 30 mg). Participants treated with fezolinetant 15 mg and 30 mg had statistically significant reductions in mean frequency of mild, moderate and severe VMS from baseline to week 8, relative to placebo. Secondary Endpoints: - Participants treated with fezolinetant 15 mg and 30 mg had greater reductions from baseline in mean frequency of mild, moderate and severe VMS compared with placebo after week 1 of treatment with fezolinetant; these greater reductions were maintained throughout the 12-week treatment period. - Transvaginal ultrasound (TVU) was required for all participants to assess endometrial thickness at screening and week 12 or early discontinuation (ED) visit for participants who withdrew from the study except participants who have had a partial (supra-cervical) or full hysterectomy. TVU data were unremarkable and there were no clinically relevant differences in the change from baseline to week 12 in endometrial thickness across all treatment groups. - In general, there were no clinically relevant changes in any of the hematology, coagulation, chemistry or urinalysis parameters. - None of the cases of low platelet values resulted in clinical consequences. - One participant in the fezolinetant 30 mg group had alanine aminotransferase (ALT) levels > 3 x upper limit of normal (ULN). There were no cases of Hy's law. - There were no trends in changes in vital signs. - There were no clinically relevant changes in the quantitative interval measures of the electrocardiogram (ECG) parameters in any of the treatment groups. - Also see Adverse Events section.

Fezolinetant at doses of 15 mg or 30 mg administered orally once daily is efficacious in the treatment of mild, moderate and severe VMS associated with menopause in Japan. The results from this study show that fezolinetant was safe and well tolerated in participants aged between >/= 40 years and </= 65 years. There was no impact on the integrity and interpretation of results for the study due to the coronavirus disease 2019 (COVID-19) pandemic.

May. 01, 2024

Yes

Access to anonymized individual participant level data collected during the study, in addition to supporting clinical documentation, is planned for studies conducted with approved product indications and formulations, as well as products terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Further details on Astellas’ data sharing policy can be found at https://www.clinicaltrials.astellas.com/transparency/. Study-related supporting documentation is redacted and provided if available, such as the protocol and amendments, statistical analysis plan and clinical study report. Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data. Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.

https://jrct.mhlw.go.jp/latest-detail/jRCT2031210334

Wang Xuegong

Astellas Pharma Inc.

2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo

clinicaltrialregistration@astellas.com

Information Center Medical

Astellas Pharma Inc.

2-5-1, Nihonbashi-Honcho, Chuo-ku, Tokyo

+81-120-189-371

clinicaltrialregistration@astellas.com

Complete

Oct. 20, 2021

Interventional

randomized controlled trial

double blind

placebo control

parallel assignment

treatment purpose

1. Subject has a body mass index >= 16 kg/m^2 and =< 38 kg/m^2 at screening visit.
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:
For post-menopausal subjects:
- 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 (with or without hysterectomy)
- For peri-menopausal subjects:
- Skipped menstrual period with amenorrhea for >= 60 days but < 6 consecutive months with biochemical criteria of peri-menopause (follicle-stimulating hormone [FSH] > 25 IU/L); or
- Spontaneous amenorrhea for >= 6 months but < 12 consecutive months with biochemical criteria of peri-menopause (follicle-stimulating hormone [FSH] > 25 IU/L and =< 40 IU/L)
3. Within the 10 days prior to randomization, subject must have a minimum average of 7 mild, moderate and severe hot flashes (VMS) per day.
4. Subject is not pregnant and at least 1 of the following conditions apply:
- Not a woman of childbearing potential (WOCBP)
- WOCBP who agrees to follow the contraceptive guidance from the time of informed consent through at least 21 days after the final study treatment administration.
5. Subject must agree not to breastfeed starting at screening and throughout the study period and for 21 days after the final study treatment administration.
6. Subject must not donate ova starting at first dose of investigational product (IP) and throughout the study period and for 21 days after the final study treatment administration.
7. 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.
8. Subject has documentation of a normal/negative or no clinically significant abnormal findings on breast imaging (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 on breast imaging.
9. Subject is willing to undergo a transvaginal ultrasound (TVU) to evaluate the uterus and ovaries at screening and week 12 (end of treatment), and for subjects who are withdrawn from the study prior to completion, a TVU at the early discontinuation visit. This is not required for subjects who have had a partial (supra-cervical) or full hysterectomy.
10. Subject is willing to undergo 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 and for peri-menopausal subjects in case of menstrual bleeding.
11. Subject has documentation of a normal or not clinically significant abnormal 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 trachelectomy.
12. Subject has a negative urine pregnancy test at screening. Urine pregnancy test is not required for female subjects who are assessed as post-menopausal status.
13. Subject has negative serology panel (i.e. negative hepatitis B surface [HBs] antigen) and negative hepatitis C virus [HCV] antibody) at screening.
14. Subject agrees not to participate in another interventional study while participating in the present study.

1. 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/Chinese medicine]) or is not willing to wash out and discontinue use of such drugs for the full duration of study conduct or it is not medically appropriate to discontinue such drugs for the duration of the study.
2. Subject has known substance abuse or alcohol addiction within 6 months of screening.
3. Subject has a history of a malignant tumor except for non-metastatic basal cell carcinoma of the skin.
4. Subject has uncontrolled hypertension.
5. Subject has a history of severe allergy, hypersensitivity, or intolerance to drugs in general, including the IP and any of its excipients.
6. 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).
7. Subject has a history of an undiagnosed uterine bleeding within the previous 6 months of screening.
8. Subject has a history of seizures or other convulsive disorders.
9. 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.
10. 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 x 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 x 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 direct bilirubin (DBL), hemoglobin and reticulocytes are normal.
11. Subject has 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 m^2 at screening visit.
12. Subject has a previous positive test for the human immunodeficiency virus.
13. 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 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 visit 2.
14. Subject has had previous exposure with fezolinetant.
15. Subject has received an IP within 28 days or 5 half-lives, whichever is longer, prior to screening.
16. Subject is unable or unwilling to complete the study procedures.
17. Subject has any condition which makes the subject unsuitable for study participation.
18. Subject or relative is the investigator or other site staff directly involved in the conduct of the study.
19. Subject is an employee of the sponsor, contract research organizations (CROs) or site management organizations (SMOs).
20. Present or previous history of participation in a study of the IP.

Female

Hot Flush

Women that want to take part in the study will be given an electronic handheld device to track their hot flashes. In the last 10 days before their next clinic visit, the women will record information about their hot flashes. Women will be picked for 1 of 3 treatments (lower or higher dose of fezolinetant, or placebo) by chance alone.
Women who take part in the study will take 2 tablets every day for 12 weeks. Treatment will be double-blinded. That means that the women in the study and the study doctors will not know who takes which of the study medicines (lower or higher dose of fezolinetant, or placebo). The women will continue recording information about their hot flashes on the electronic device. They will also use another device to answer questions about how hot flashes affect their daily life.
During the study, the women will visit their study clinic several times for a check-up. This will happen during weeks 2, 4, 8, 12 and 15. At the check-up, they will be asked if they have any medical problems. Other checks will include some blood samples taken for laboratory tests. At some check-ups, the women will have a physical exam, an ECG to check their heart rhythm, and their vital signs checked (pulse rate, temperature and blood pressure). At the first visit and in week 15, women who have a uterus will also have a test called a transvaginal ultrasound. A probe is gently placed inside the vagina. Sound waves will create a picture of the organs in the pelvis. This will allow the study doctor to look more closely at the uterus and surrounding organs.
The last check-up (at week 15) will be 3 weeks after they take their last tablets of study medicine (lower or higher dose of fezolinetant or placebo).

Mean change in the frequency of mild, moderate and severe vasomotor symptom (VMS) from baseline to Week 8

- Mean change in the frequency of mild, moderate and severe VMS from baseline to each week up to Week 12
- Adverse Events (AEs)
- Change from baseline in endometrial thickness
- Laboratory values
- Vital sign
- Electrocardiogram (ECG)
- Columbia-Suicide Severity Rating Scale (C-SSRS)

+81-3-5543-0196

Sept. 28, 2021

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