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Research

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

BMJ 2024; 387 doi: https://doi.org/10.1136/bmj-2024-079525 (Published 18 November 2024) Cite this as: BMJ 2024;387:e079525

Linked Editorial

Non-hormonal management of vasomotor symptoms of menopause

This article has a correction. Please see:

  1. Katrin Schaudig, gynaecologist1,
  2. Xuegong Wang, senior medical director2,
  3. Céline Bouchard, professor3,
  4. Angelica Lindén Hirschberg, professor4,
  5. Antonio Cano, professor5,
  6. Marla Shapiro C M, professor6,
  7. Petra Stute, professor7,
  8. Xi Wu, statistical science lead2,
  9. Kentaro Miyazaki, executive director8,
  10. Ludmila Scrine, senior director9,
  11. Rossella E Nappi, professor1011
  1. 1Hormone Hamburg, Hamburg, Germany
  2. 2Astellas Pharma Global Development, Northbrook, IL, USA
  3. 3Clinique de Recherche en Santé de la Femme, Quebec City, Canada
  4. 4Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
  5. 5University of Valencia, Valencia, Spain
  6. 6University of Toronto, Toronto, ON, Canada
  7. 7Inselspital, Bern, Switzerland
  8. 8Astellas Pharma, Tokyo, Japan
  9. 9Astellas Pharma Europe, Addlestone, Surrey, UK
  10. 10University of Pavia, Pavia, Italy
  11. 11Research Center for Reproductive Medicine and Gynecological Endocrinology – Menopause Unit, Fondazione Policlinico IRCCS S Matteo, Pavia, Italy
  1. Correspondence to: R E Nappi nappi{at}rossellanappi.com
  • Accepted 25 September 2024

Abstract

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.

Figure1

Introduction

Vasomotor symptoms, comprising hot flushes and night sweats, are the most common and bothersome symptoms associated with menopause.12 Up to 80% of women experience vasomotor symptoms during menopause.12 Moderate-severe symptoms occur in 11-46% of women older than 40 years,345 with a median total duration around 7.4 years,6 whereas the severity of vasomotor symptoms associated with menopause varies throughout the course of menopause and among women.345

Although vasomotor symptoms are common and often severe enough to warrant medical treatment, approved and effective non-hormonal treatments are limited. Hormone therapy is effective but not appropriate for everyone.7 Treatment is contraindicated in women with a history of breast cancer, uterine cancer, active liver disease, or thromboembolic diseases, and caution is advised in those with comorbidities such as cardiovascular disease, diabetes, and raised triglyceride levels.8 Hormone therapy is not suitable for many women, and some choose not to use it.9

Contraindications to hormone therapy in daily practice is important. Individuals may require counselling from their doctor or other healthcare professionals, and risk factors can complicate the treatment decision making process. In addition to having contraindications, many individuals are cautious about or would prefer to not use hormone therapy, despite being suitable candidates for treatment. Reasons for not wanting to use treatment can include worries about side effects or long term risks of treatment, or acceptance that menopause is a transitory, self-limiting condition that does not require treatment.10 The US Food and Drug Administration has approved low dose paroxetine, a selective serotonin reuptake inhibitor (SSRI), as the only non-hormonal alternative, which offers modest relief of vasomotor symptoms associated with menopause and carries a black box warning for suicidal thoughts and behaviour and other side effects.11 Alternative non-hormonal drug options include other SSRIs and serotonin and norepinephrine reuptake inhibitors, which are prescribed for up to one fifth of women with vasomotor symptoms.1213 The α adrenergic agonist clonidine and neuromodulators such as gabapentin and pregabalin are also non-hormonal options for treating vasomotor symptoms, although they are not globally approved for such management.814 The Menopause Society does not recommend clonidine owing to adverse events or pregabalin because of the potential for misuse as a schedule V controlled substance. Gabapentin includes black box warnings for rare suicidal thoughts or behaviours.14 Nutraceutical options for vasomotor symptoms associated with menopause, such as phytoestrogens and herbal derivatives, are widely available as an alternative to hormone therapy, but evidence of their efficacy is limited.15 None of these other potential treatments is approved globally to manage vasomotor symptoms. A substantial unmet need therefore exists for safe and effective options for non-hormonal treatment of vasomotor symptoms associated with menopause.1617

Fezolinetant, an oral, non-hormonal, neurokinin 3 receptor antagonist, is a treatment option for moderate-severe vasomotor symptoms, and it is approved in many countries, including the US, Europe, and Australia at a dose of 45 mg once daily.1819202122 Fezolinetant blocks neurokinin B signalling, normalising kisspeptin, neurokinin B, and dynorphin neuron activity in the thermoregulatory centre of the brain to reduce the frequency and severity of vasomotor symptoms.2324 Fezolinetant was shown to be efficacious and well tolerated for treating moderate-severe vasomotor symptoms associated with menopause in phase 3 studies SKYLIGHT 1 and SKYLIGHT 2,2526 which both included a 12 week placebo control period followed by active treatment extension to 52 weeks. To further investigate the clinical benefits of fezolinetant for the treatment of moderate-severe vasomotor symptoms, we performed a phase 3b trial (DAYLIGHT), which included a 24 week placebo control period and enrolled a population considered unsuitable for hormone therapy.

Methods

Study design, objectives, and participants

The present study was a phase 3b, randomised, double blind, placebo controlled trial to assess the efficacy and safety of fezolinetant for treating moderate-severe vasomotor symptoms associated with menopause in individuals considered unsuitable for hormone therapy. Written informed consent was obtained from all participants before any study related procedures. We aimed to evaluate the efficacy of fezolinetant 45 mg versus placebo once daily on the frequency (primary endpoint) and severity (secondary) of moderate-severe vasomotor symptoms and patient reported sleep disturbance (secondary) associated with menopause. Participants were provided with a reference guide for severity of symptoms: mild—sensation of heat without sweating; moderate—sensation of heat with sweating, able to continue activity; and severe—sensation of heat with sweating, unable to continue activity.

Individuals aged 40-65 years with moderate-severe vasomotor symptoms associated with menopause and considered unsuitable candidates for hormone therapy were randomised 1:1 using interactive response technology to fezolinetant 45 mg or placebo once daily and stratified by smoking status (current and non-smoker (former or never)). Categories for hormone unsuitability were defined based on contraindicated; caution (based on medical history); stoppers (previous discontinuation of hormone therapy owing to lack of efficacy, side effects, or medical advice); or averse (informed choice not to use hormone therapy after discussion with a clinician) (see supplementary table 1).

Endpoints

The primary efficacy endpoint was mean change in the frequency of moderate-severe vasomotor symptoms from baseline to week 24. The key secondary efficacy endpoint was mean change in severity of moderate-severe vasomotor symptoms from baseline to week 24. The selected secondary endpoint was mean change in the Patient-Reported Outcome Measurement Information System (PROMIS) Sleep Disturbance Short Form 8b total score from baseline to week 24. PROMIS is a set of patient centred instruments that evaluates physical, mental, and social health.27 PROMIS Sleep Disturbance Short Form 8b was developed from PROMIS to assess sleep disturbance, and it evaluates difficulties and problems with falling asleep, staying asleep, and getting enough sleep, as well as perceptions of the quality and satisfaction of sleep. Exploratory endpoints included two Patient Global Impression of Change measures, one for vasomotor symptoms and one for sleep disturbance, and menopause specific quality of life, measured at baseline and weeks 4, 12, 16, and 24. The Patient Global Impression of Change in Sleep Disturbance is a patient reported one item questionnaire that asks participants to rate the severity of any problems during nighttime sleeping using a scale from 1 (no problems) to 4 (severe problems). The questionnaire asks participants to rate how well they were sleeping at that timepoint compared with the start of the study, using a scale from 1 (much better) to 7 (much worse). Similarly, using the same scale the Patient Global Impression of Change in Vasomotor Symptoms asks participants to rate the severity of their vasomotor symptoms compared with the start of the study.

Safety was assessed based on treatment emergent adverse events (TEAEs). A TEAE was defined as an adverse event observed between start of the study drug and up to 21 days after the last dose. Safety follow-up visits were scheduled for three weeks from the last dose. The number and percentage of participants with TEAEs, drug related TEAEs, serious TEAEs, drug related serious TEAEs, TEAEs leading to withdrawal of the study intervention, and drug related TEAEs leading to withdrawal of study intervention were summarised by system organ class, Medical Dictionary for Regulatory Activities version 25.0 preferred term, and treatment group. We also summarised the number and percentage of TEAEs by severity and causality. Participants who discontinued treatment early were asked to remain in the study and continue to complete the daily electronic diary of vasomotor symptoms and electronic patient reported outcome assessments as scheduled to week 24. They were monitored for adverse events, serious adverse events, and use of concomitant drugs to week 27.

Liver function and liver injury were evaluated as part of standard monitoring investigations, including previous phase 3 studies2526 of fezolinetant. An independent panel of three liver experts (liver safety monitoring panel) evaluated participants for potential drug induced liver injury who met the criterion of alanine transaminase (ALT) or aspartate aminotransferase (AST) greater than three times the upper limit of normal (ULN) or total bilirubin more than twice the ULN.

Transvaginal ultrasonography was required for all participants to assess endometrial thickness at screening and week 24 or end of treatment, or at the early discontinuation visit for participants who stopped prematurely.

Statistical analysis

All safety analyses were performed using the safety analysis set, defined as all participants who were randomised and received at least one dose of study intervention. All primary, secondary, and exploratory efficacy analyses were performed using the full analysis set, defined as all participants who were randomised and received at least one dose of study intervention. For both sets, participants were analysed according to the treatment group to which they were randomised.

For a pairwise comparison of the primary endpoint using a two sample t test at a two sided 5% α, we determined that 220 participants in each group would provide at least 80% power to detect a difference from placebo of –1.8, assuming a standard deviation (SD) of 5.6. This size was calculated assuming that about 30% of participants might discontinue the study prematurely. For a pairwise comparison of the key secondary endpoint using a two sample t test at a two sided 5% α, estimated power was calculated as 31% and 59% with 220 participants in each group to detect a difference from placebo of –0.2 and –0.3, respectively, assuming a SD of 1.2. The α statistic was only applied to the key secondary endpoint if the primary endpoint was statistically significant at the 5% level.

We performed a mixed model for repeated measures analysis with a missing at random assumption on change in the average daily frequency (or severity) of moderate-severe vasomotor symptoms from baseline to week 24. For the primary and key secondary efficacy endpoints, the primary analysis method was a mixed model for repeated measures using change from baseline as the dependent variable; treatment group, week, and smoking status (current v former or never) as factors; baseline weight and baseline value as covariates; and treatment group by week and baseline value by week as interaction terms. From this analysis, comparisons between fezolinetant and placebo were calculated based on least squares mean contrasts using a two sided 95% confidence interval. PROMIS Sleep Disturbance Short Form 8b total score was analysed using a similar method; however, P values were not controlled for multiplicity.

Patient and public involvement

Public and patient involvement was initiated following the optional exit interviews available to participants and study coordinators after the phase 2 dose finding study (NCT03192176). The interviews were largely focused on the technology used in the study. The technology was revised based on the participant’s feedback. The same participants were asked to re-evaluate the electronic vasomotor symptoms diary for improvement before initiation of the phase 3 studies, including DAYLIGHT, to confirm the changes made were effective.

Results

Baseline characteristics

The study was conducted between 8 November 2021 and 20 April 2023 at 69 centres in 16 countries (Canada, the Netherlands, Belgium, France, Spain, Finland, Hungary, Italy, Czech Republic, UK, Denmark, Sweden, Norway, Poland, Germany, and Turkey). Overall, the centres randomised 453 participants (fezolinetant n=227, placebo n=226), with 370 (81.7%) completing the study (195 and 175, respectively) (fig 1). The safety analysis and full analysis sets, defined as all participants who were randomised and received at least one dose of study drug, comprised 452 participants (fezolinetant n=226, placebo n=226), as one participant randomised to the fezolinetant group did not receive study drug. Of these, 387 (85.6%) participants completed the 24 week treatment period. Results are presented for the 452 participants in the safety and full analysis sets.

Fig 1
Fig 1

Flow chart of participants through study. Safety and full analysis sets were defined as all participants who were randomised and received at least one dose of study drug

Eighty two (18.1%) participants discontinued treatment owing to adverse events (n=25, 5.5%), loss to follow-up (n=5, 1.1%), protocol deviation (n=2, 0.4%), withdrawal from study (n=47, 10.4%), and other reasons (n=3, 0.7%). Of the 47 (10%) participants who withdrew from treatment, 17 (8%) were assigned to fezolinetant and 30 (13%) to placebo. All five participants lost to follow-up were in the placebo group; one participant completed treatment with the last dose in week 24 but did not return for the safety follow-up, and the other four participants discontinued early but no reason was provided. Mean (SD) age was 54.5 (4.7) years, and most of the participants were white (n=435, 96.7%) (table 1). Most participants were categorised as either hormone therapy averse (n=168, 37.2%) or caution (n=165, 36.5%); the remainder were contraindicated (n=50, 11.1%) or stoppers (n=69, 15.3%). Mean (SD) overall drug use was 150.8 (44.6) days. Baseline personal characteristics were generally similar between the two treatment groups.

Table 1

Baseline characteristics of participants. Values are number (percentage) unless stated otherwise

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Primary endpoint

In the 226 participants assigned to fezolinetant, mean frequency of vasomotor symptoms reduced from 10.58 (SD 3.57) events daily at baseline to 2.61 (3.14) at week 24 (fig 2). In the 226 participants assigned to placebo, mean frequency of vasomotor symptoms reduced from 10.75 (SD 4.08) events daily at baseline to 4.67 (4.80) at week 24. Fezolinetant significantly reduced the frequency of vasomotor symptoms compared with placebo at week 24 (least squares mean difference –1.93, 95% confidence interval (CI) –2.64 to –1.22; P<0.001) (table 2). At week 24 the least squares mean percentage change from baseline was –75.66% (95% CI –80.13% to –71.19%) for fezolinetant and –59.12% (–63.71% to –54.52%) for placebo. This significant reduction in frequency of vasomotor symptoms started on day 1 (see supplementary figure S1) and continued to week 24 (fig 2).

Fig 2
Fig 2

Daily change in frequency of moderate-severe vasomotor symptoms associated with menopause from baseline to week 24. SE=standard error; VMS=vasomotor symptoms

Table 2

Change from baseline in primary and secondary endpoints

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Secondary endpoints

In the 226 participants assigned to fezolinetant, severity of vasomotor symptoms reduced from a mean 2.43 (SD 0.36) at baseline to 1.43 (0.97) at week 24 (fig 3). In the 226 participants assigned to placebo, severity of vasomotor symptoms reduced from a mean 2.41 (0.34) at baseline to 1.87 (0.82) at week 24. The week 24 difference in symptom severity between fezolinetant and placebo was significant (least squares mean difference –0.39, 95% CI –0.57 to –0.21; P<0.001) (table 2). Participants receiving fezolinetant also had a greater reduction in total scores on the PROMIS Sleep Disturbance Short Form 8b compared with the placebo group (least mean squares mean difference –2.5, –3.9 to –1.1; P<0.001) (table 2).

Fig 3
Fig 3

Daily change in mean severity of moderate-severe vasomotor symptoms associated with menopause from baseline to week 24. SE=standard error; VMS=vasomotor symptoms

Exploratory endpoints

At week 24, the most common response on the Patient Global Impression of Change in Vasomotor Symptoms in participants receiving fezolinetant was “much better” (n=123, 62.4% v n=71, 39.9%, fezolinetant v placebo groups, respectively, P<0.001) (table 3 and fig 4). Similarly, at week 24, the most common response on the Patient Global Impression of Change in Sleep Disturbance in participants receiving fezolinetant was “much better” (n=74, 37.6% v n=42, 23.6%, fezolinetant v placebo groups, respectively, P<0.001) (table 3, figure 4). Participants receiving fezolinetant also had greater reductions from baseline (improvements) in mean menopause specific quality of life total score relative to placebo at week 24 (least squares mean difference –0.44, –0.69 to –0.18; P<0.001) (table 3).

Table 3

Change from baseline in exploratory endpoints. Values are number* (percentage) unless stated otherwise

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Fig 4
Fig 4

Distribution of PGI-C VMS and PGI-C SD at week 24 in individuals with moderate-severe vasomotor symptoms associated with menopause. NA=not available; PGI-C SD=Patient Global Impression of Change in Sleep Disturbance; PGI-C VMS=Patient Global Impression of Change in Vasomotor Symptoms

Safety

No differences were found in incidence of TEAEs (fezolinetant: n=147, 65.0%; placebo: n=138, 61.1%) and serious TEAEs (n=10, 4.4%; n=8, 3.5%, respectively) between the groups (table 4). The most common TEAEs in the fezolinetant group were covid-19 (n=30, 13.3%), headache (n=20, 8.8%), and fatigue (n=13, 5.8%) (table 5). The most common TEAEs in the placebo group were covid-19 (n=29, 12.8%), headache (n=21, 9.3%), and nasopharyngitis (n=11, 4.9%). There was one (0.4%) reported TEAE of system organ class neoplasms benign, malignant, and unspecified (including cysts and polyps) of mild severity in the placebo group, which was considered unrelated to placebo, and no TEAEs of this system organ class reported in the fezolinetant group.

Table 4

Overview of TEAEs

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Table 5

Most common TEAEs occurring in ≥2% of participants in the fezolinetant group

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Increases in abnormal liver test results were reported for 10 (4.4%) participants in the fezolinetant group and six (2.7%) in the placebo group (table 6). For liver safety assessments, three (1.3%) participants in the fezolinetant group showed ALT levels three times the ULN (table 7). The liver safety monitoring panel concluded a causal association was possible in one of the participants and unlikely in the other two participants. No participants showed AST levels three times the ULN or total bilirubin twice the ULN. While there were transient or isolated increases in transaminase levels during the study, no participants had drug induced liver injury according to Hy’s law.28

Table 6

TEAEs of special interest

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Table 7

Liver safety assessments

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TEAEs of special interest included uterine bleeding, which was reported for six (2.7%) participants in the fezolinetant group and 10 (4.4%) in the placebo group (table 6). None of these events was considered serious. In six of 10 participants in the placebo group and four of six in the fezolinetant group, these events were reported as vaginal or postmenopausal bleedings. Eight participants had 11 study drug related events of vaginal or postmenopausal bleeding. Most of these events resolved with no action or resolved after withdrawal of the study intervention, and the outcome of one event (vaginal haemorrhage) was unknown with no action taken. Other TEAEs of special interest included endometrial hyperplasia, cancer, and disordered proliferative endometrium, which was reported by one (0.4%) participant in the fezolinetant group and two (0.9%) participants in the placebo group. All three of these events were preferred terms of endometrial thickening measured with transvaginal ultrasound and non-serious, none were related to cancer, and all three were considered study drug related. Thrombocytopenia was a TEAE of special interest and reported in no participants in the fezolinetant group and one (0.4%) participant in the placebo group. It was not considered serious or related to the use of placebo.

Discussion

The findings of this study support evidence792930 that fezolinetant is an effective treatment option for individuals with moderate-severe vasomotor symptoms associated with menopause who cannot or choose not to use hormone therapy. This study provided placebo controlled efficacy data over a 24 week period, compared with 12 weeks in the SKYLIGHT studies.2526 Frequency and severity of moderate-severe vasomotor symptoms at week 24 showed statistically significant improvements with fezolinetant 45 mg compared with placebo once daily, a sustained treatment effect over a longer period than in previous studies. In addition to these findings, a greater reduction in patient reported sleep disturbance (PROMIS Sleep Disturbance Short Form 8b total score) was seen in the fezolinetant compared with placebo group.

Comparison with other studies

Improvements in frequency of moderate-severe vasomotor symptoms in the fezolinetant group compared with placebo were observed as early as day 1, consistent with efficacy results in phase 3 studies SKYLIGHT 1 and SKYLIGHT 2.2526 The available safety data appeared generally consistent with the known safety profile for fezolinetant, including data from phase 3 placebo controlled trials showing that fezolinetant is well tolerated for as much as 52 weeks.252631 The incidence of serious TEAEs from baseline to week 24 was low. No safety signals of concern were observed, including liver safety, in the fezolinetant group, and no drug induced liver injury was observed in any study participants. Some participants experienced an increase in transaminase levels, which overall were not serious, and asymptomatic liver test abnormalities, captured through protocol specified routine testing. Three participants in the fezolinetant group had raised ALT levels three times the ULN; none of them was accompanied by bilirubin levels twice the ULN. The liver safety monitoring panel concluded that a causal association was possible in one participant and unlikely in the other two participants.

Strengths and weaknesses of this study

The findings of this study add to a large body of data showing a positive benefit-risk profile for fezolinetant and the potential of this drug to address an important unmet need for individuals with moderate-severe vasomotor symptoms associated with menopause. The study included a longer placebo control period (24 weeks) than previous phase 3 studies, and a large defined patient population unsuitable for current hormone therapy (ie, hormone therapy contraindicated, caution, stoppers, and averse).2526 A potential limitation of this study was that participants were from 16 countries (Canada, the Netherlands, Belgium, France, Spain, Finland, Hungary, Italy, Czech Republic, UK, Denmark, Sweden, Norway, Poland, Germany, and Turkey), with most self-identifying as white. Further studies of fezolinetant in global populations with diverse ethnicity or races would be of interest.

Conclusion

The findings of this study support the utility of fezolinetant as an effective non-hormonal treatment option for individuals who cannot or choose not to use hormone therapy for the management of moderate-severe vasomotor symptoms associated with menopause.

What is already known on this topic

  • Hormone therapy is an effective treatment for vasomotor symptoms associated with menopause

  • Treatment is not always appropriate, however, and hormone therapy is unsuitable for many individuals

  • Fezolinetant, an oral, non-hormonal, neurokinin 3 receptor antagonist treatment option for moderate-severe vasomotor symptoms, is approved in many countries, including the US, Europe, and Australia, at a dose of 45 mg once daily

What this study adds

  • Fezolinetant 45 mg once daily was efficacious and well tolerated as a treatment for moderate-severe vasomotor symptoms in individuals considered unsuitable candidates for hormone therapy

  • Improvements in moderate-severe vasomotor symptoms were observed as early as week 1, with sustained benefit throughout the 24 week treatment period

  • No safety signals of concern, including drug induced liver injury, were observed

Ethics statements

Ethical approval

This study was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice, and International Council for Harmonisation guidelines. An independent ethics committee or institutional review board reviewed ethical, scientific, and medical appropriateness of the study before data collection at each site: Canada: Advarra IRB (Ontario, Canada); Netherlands: Medical Research Ethics Committees United (MEC-U), St Antonius Ziekenhuis (Nieuwegein, Netherlands); Belgium: EC of UZ Gent, Medical Ethics Committee, University Hospital Gent (Gent, Belgium); France: Comité de Protection des Personnes Sud-Ouest et Outre-Mer 1, Regional Health Agency (Toulouse, France); Spain: EC Gregorio Marañón, Secretaría Técnica CEIm, Fundación para la Investigación Biomédica Hospital Gregorio Marañón, Pabellón de Gobierno (Madrid, Spain); Finland: Ethics Committee of Hospital District of Northern Savo, Kuopio University Hospital (Kuopio, Finland); Hungary: Medical Research Council (Budapest, Hungary); Italy: CEC, Comitato Etico Referente Area di Pavia Fondazione IRCCS Policlinico “San Matteo” (Pavia, Italy); Czech Republic: Etická komise pro multicentrická klinická hodnocení Fakultní nemocnice, Královské Vinohrady (Prague, Czech Republic); UK: London – Westminster Research Ethics Committee (Nottingham, UK); Denmark: Den Videnskabsetiske Komité for Region Nordjylland Regionssekretariatet (Aalborg, Denmark); Sweden: Etikprövningsmyndigheten (Uppsala, Sweden); Norway: REK sør-øst (Oslo, Norway); Poland: Komisja Bioetyczna przy Okregowej Izbie Lekarskiej w Lublinie (Lublin, Poland); Germany: Ethikkommission der Fakultät für Medizin der Technischen Universität (Munich, Germany); Turkey: Ankara University Tip Fakultesi, Clinical Trial Ethics Committee (Ankara, Turkey). Written informed consent was obtained from all participants before any study related procedures.

Data availability statement

Researchers may request access to anonymised participant level data, trial level data, and protocols from Astellas sponsored clinical trials at www.clinicalstudydatarequest.com. For the Astellas criteria on data sharing, see https://clinicalstudydatarequest.com/Study-Sponsors/Study-Sponsors-Astellas.aspx.

Acknowledgments

We thank the DAYLIGHT study investigators, staff, and all participants who took part in the study. Yien Liu, from Envision Pharma (Fairfield, CT) provided medical writing support, funded by the study sponsor.

Footnotes

  • Contributors: All authors contributed to the conception or design of the study; the acquisition, analysis, or interpretation of the data; drafting of the manuscript; or reviewing of the manuscript for important intellectual content. The authors also provided final approval of the version to be submitted and agree to be accountable for all aspects of the manuscript. KS is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding: This study was funded by Astellas Pharma. All authors can confirm their independence from the funder, and all authors, external and internal, had full access to all the data (including statistical reports and tables) in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis.

  • 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.

  • Transparency: The manuscript’s guarantor (KS) affirms that the manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

  • Dissemination to participants and related patient and public communities: The clinical study report synopsis and plain language summary have been posted on the Astellas clinical trials website (https://www.clinicaltrials.astellas.com). In addition, the plain language summary has been posted on the multi-sponsor website, trial results summaries (https://www.trialsummaries.com/Home/LandingPage). DAYLIGHT findings have been submitted as part of the evidence base for health technology assessment processes, which include critical participation and input from individuals with vasomotor symptoms associated with menopause.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

http://creativecommons.org/licenses/by-nc/4.0/

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

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