Efficacy and safety of fezolinetant for moderate-severe vasomotor symptoms associated with menopause in individuals unsuitable for hormone therapy: phase 3b randomised controlled trial.

Autor:	Schaudig K; Hormone Hamburg, Hamburg, Germany., Wang X; Astellas Pharma Global Development, Northbrook, IL, USA., Bouchard C; Clinique de Recherche en Santé de la Femme, Quebec City, Canada., Hirschberg AL; Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden., Cano A; University of Valencia, Valencia, Spain., Shapiro C M M; University of Toronto, Toronto, ON, Canada., Stute P; Inselspital, Bern, Switzerland., Wu X; Astellas Pharma Global Development, Northbrook, IL, USA., Miyazaki K; Astellas Pharma, Tokyo, Japan., Scrine L; Astellas Pharma Europe, Addlestone, Surrey, UK., Nappi RE; University of Pavia, Pavia, Italy nappi@rossellanappi.com.; Research Center for Reproductive Medicine and Gynecological Endocrinology - Menopause Unit, Fondazione Policlinico IRCCS S Matteo, Pavia, Italy.
Jazyk:	angličtina
Zdroj:	BMJ (Clinical research ed.) [BMJ] 2024 Nov 18; Vol. 387, pp. e079525. Date of Electronic Publication: 2024 Nov 18.
DOI:	10.1136/bmj-2024-079525
Abstrakt:	Objectives: To assess the efficacy and safety of the non-hormonal, neurokinin 3 receptor antagonist, fezolinetant, to treat moderate-severe vasomotor symptoms associated with menopause in individuals unsuitable for hormone therapy. Design: Phase 3b randomised controlled trial. Setting: 16 countries. Participants: 453 individuals aged 40-65 years with moderate-severe vasomotor symptoms associated with menopause who were considered unsuitable candidates for hormone therapy (contraindicated, caution (based on medical history), stoppers (previous discontinuation of hormone therapy), or averse (informed choice not to use hormone therapy)) were randomised to receive fezolinetant (n=227) or placebo (n=226). Intervention: Fezolinetant 45 mg or placebo once daily for 24 weeks. Main Outcome Measures: The primary endpoint was mean change in daily frequency of moderate-severe vasomotor symptoms from baseline to week 24. Secondary endpoints were mean change in symptom severity, sleep disturbance using the Patient-Reported Outcome Measurement Information System Sleep Disturbance Short Form (PROMIS SD-SF) 8b total score, and safety. Results: 370 (81.7%) participants completed the study (fezolinetant=195, placebo group=175). The safety and full analysis sets comprised 452 participants who received at least one dose of study drug. Mean age was 54.5 (standard deviation 4.7) years and most of the participants (435 (96.7%) were white and categorised as either hormone therapy averse (168 (37.2%)) or caution (165 (36.5%)). At week 24, fezolinetant significantly reduced the frequency (least squares mean difference -1.93, 95% confidence interval (CI) -2.64 to -1.22; P<0.001) and severity of vasomotor symptoms (-0.39, -0.57 to -0.21; P<0.001). At week 24, the fezolinetant group had a greater reduction in sleep disturbance (PROMIS SD-SF 8b total score) compared with placebo (-2.5, -3.9 to -1.1; P<0.001). Improvements over placebo were observed as early as week 1. Both groups showed similar incidences of treatment emergent adverse events (TEAEs, 147 (65.0%) in the fezolinetant group, 138 (61.1%) in the placebo group) and serious TEAEs (10 (4.4%) and 8 (3.5%), respectively). The most common TEAEs in the fezolinetant group were covid-19 (30 (13.3%)), headache (20 (8.8%)), and fatigue (13 (5.8%)). Conclusions: Fezolinetant was efficacious and well tolerated over a six month period for treating moderate-severe vasomotor symptoms in individuals considered unsuitable for hormone therapy. These results highlight the utility of fezolinetant as an effective treatment option for those who have contraindications to or choose not to use hormone therapy. Trial Registration: ClinicalTrials.gov NCT05033886; EudraCT 2021-001685-38. Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest and declare: support from Astellas Pharma. KS has received payment or honorariums for lectures, presentations, speakers bureaus, manuscript writing, or educational events from aidhere, Astellas Pharma, Bayer/Jenapharm, Besins Healthcare, Exeltis, Fidia, Gedeon Richter Pharma, Novo Nordisk, Organon, Theramex, Viatris, and Laborarztpraxis Rhein-Main; participates on a data safety monitoring board or advisory board for Astellas, Bayer, Exeltis, Besins Healthcare, and Viatris; is President of the German Menopause Society organises and lectures at conferences for the society; lectures and participates in conferences for the professional association of gynaecologists in Germany; is honorary member for the German Society of Obstetrics and Gynecology and lectures, is president at conferences, and participates on committees for the society. XWang, XWu, and KM are employees of Astellas Pharma. CB has received research grants from Astellas, Incyte, and Mithra; consulting fees from Bayer Pharma, Astellas, and AbCellera; and honorariums for lectures from Pfizer, Lupin, and Orimed. ALH receives consulting fees from Astellas, Besins, and Exeltis; payments or honorariums for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Astellas, Besins, Gedeon Richter, and Bayer; support for attending meetings and/or travel from Astellas and Besins; participates on a data safety monitoring board or advisory board for Exeltis. AC has received payment or honorariums for educational events from Theramex and Astellas; support for attending meetings and travel from Astellas; participates on advisory boards for Astellas and Theramex. MSCM sits on advisory boards for and has received consulting fees and honorariums from Amgen, Aspen, Astellas, BioSyent, Bayer, CCRN, Duchesnay, Eisai, GSK, Idorsia, Merck, Mithra, Novo Nordisk, Organon, Pfizer, Sandoz, and Searchlight; receives support for attending meetings and/or travel from Astellas and The Menopause Society; has a leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, for the International Menopause Society and Terry Fox Research Institute. PS has received grants or contracts from the University of Bern and Swiss National Foundation; consulting fees from Astellas and Theramex; payment or honorariums for lectures, presentations, speakers bureaus, manuscript writing, or educational events for Astellas, Theramex, and Besins Healthcare; leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid for the European Menopause and Andropause Society, Deutsche Menopause Gesellschaft, and Swiss Society for Anti Aging Medicine and Prevention. LS was an employee of Astellas Pharma at the time of development. REN receives grants/contracts from Fidia; consulting fees from Astellas, Bayer Pharma, Besins Healthcare, Fidia, and Theramex; payment or honorariums for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Abbott, Astellas, Exeltis, Fidia, Gedeon Richter, Merck, Novo Nordisk, Shionogi, Theramex, and Viatris; payment for expert testimony from Vichy Laboratories; and is president elect of the International Menopause Society. (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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