What is the role of hormone therapy and fezolinetant (Veozah) for hot flashes or menopause?

What information is available on menopause, including the use of hormone therapy and fezolinetant (Veozah) for hot flashes, and whether guidelines recommend these agents?

Comment by InpharmD Researcher

The North American Menopause Society (NAMS) 2023 position statement assigns Level I recommendation to fezolinetant for managing vasomotor symptoms (VMS). While no direct comparisons exist with other therapies, landmark trials (SKYLIGHT 1 and 2) show fezolinetant’s efficacy and safety relative to placebo, maintained for up to 52 weeks. Indirect evidence suggests it outperforms available nonhormonal treatments for moderate to severe VMS.

Background

The 2014 practice bulletin by the American College of Obstetricians and Gynecologists and the 2015 Endocrine Society guidelines do not mention fezolinetant (Veozah) or neurokinin 3 receptor antagonist for symptom management of menopause; however, both references were released prior to the fezolinetant’s 2023 FDA approval. [1], [2]

A 2023 position statement from The North American Menopause Society (NAMS) comprehensively reviewed and updated evidence-based recommendations for nonhormonal management of menopause-associated vasomotor symptoms (VMS), integrating data published since the 2015 guidance. Key findings emphasized that cognitive-behavioral therapy, clinical hypnosis, selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors, gabapentin, and fezolinetant (Level I evidence; good and consistent scientific evidence) significantly reduced VMS. [3]

Therapy recommendations are based on advancements in understanding the physiology of VMS, particularly the role of KNDy neurons (producing kisspeptin, neurokinin B, and dynorphin) in the hypothalamus. These neurons influence the secretion of gonadotrophin-releasing hormone (GnRH), and their hyperactivity is linked to VMS. Fezolinetant is an FDA-approved therapy targeting neurokinin B receptors to alleviate VMS, including hot flashes. It has been shown to be effective compared to placebo, with benefits observed within 12 weeks of use with an overall favorable safety profile. As only two FDA-approved, paroxetine mesylate 7.5 mg daily and fezolinetant 45 mg daily, are indicated for VMS, direct head-to-head trials among nonhormone prescription therapies or hormone therapies are lacking. While early evidence suggests these therapies may improve quality of life and sleep disturbances related to VMS, more research is needed on their effects on mood, sexual, cardiovascular, metabolic, and bone health. Higher doses of these agents seem to affect luteinizing hormone (LH) levels but not estradiol in postmenopausal women. Further investigation is required to understand their comprehensive physiological impacts. [3]

A 2024 systematic review and Bayesian network meta-analysis evaluated the relative efficacy of fezolinetant 45 mg, hormone therapy (HT), and non-hormone therapy (non-HT) interventions in managing moderate to severe vasomotor symptoms (VMS) associated with menopause. As there are no current head-to-head studies comparing fezolinetant to available HT and non-HTs, the analysis incorporated data from two phase 3 randomized controlled trials (SKYLIGHT 1 and SKYLIGHT 2; see Tables 1 and 2, respectively) of fezolinetant, alongside 23 comparator publications encompassing phase 3 or 4 trials, all of which were considered well-conducted randomized controlled trials (RCTs), provided level 1 evidence, and had a low risk for selection bias. Outcomes were assessed using fixed-effect Bayesian models focusing on three endpoints at 12 weeks: mean reduction in VMS frequency, changes in VMS severity, and responder rates defined by a ≥75% reduction in VMS frequency from baseline. Data synthesis included 27 HT regimens, six non-HT regimens, placebo comparators, and direct and indirect comparisons across the network. Results highlighted that fezolinetant 45 mg demonstrated no significant differences in reducing daily VMS frequency versus most HT regimens, including standard-dose estradiol (E2) and conjugated estrogen (CE) therapies administered orally, transdermally, or topically. Notably, fezolinetant was significantly more effective than all evaluated non-HT regimens, including paroxetine 7.5 mg (mean difference [MD] 1.66; 95% confidence interval [CI] 0.63 to 2.71), desvenlafaxine 50-200 mg (MD 1.12; 95% CI 0.10 to 2.13 to MD 2.16; 95% CI 0.90 to 3.40), and gabapentin ER 1800 mg daily (MD 1.63; 95% CI 0.48 to 2.81), as well as placebo. For VMS severity, fezolinetant 45 mg was less effective than tibolone 2.5 mg, an HT regimen unavailable in the United States, but outperformed desvenlafaxine 50 mg (MD 0.28; 95% CI 0.07 to 0.48) and placebo. Regarding ≥75% responder rates, fezolinetant 45 mg was comparable to most HT regimens but was surpassed by tibolone 2.5 mg and CE 0.625 mg/bazedoxifene (20 mg); however, superior efficacy was observed over desvenlafaxine 50 mg (MD 0.43; 95% CI 0.24 to 0.75) and placebo. These findings offer critical insights into the relative positioning of fezolinetant as a non-hormonal alternative for individualized management of VMS, particularly for patients contraindicated for or unwilling to use HT. [4]

Literature Review

A search of the published medical literature revealed 5 studies investigating the researchable question:

What information is available on menopause, including the use of hormone therapy and fezolinetant (Veozah) for hot flashes, and whether guidelines recommend these agents?

Level of evidence

A - Multiple high-quality studies with consistent results Read more→

Please see Tables 1-5 for your response.

Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study
Design	Phase 3 randomized, double-blind, placebo-controlled trial N= 527
Objective	to evaluate the efficacy of fezolinetant versus placebo on the frequency and severity of moderate-to-severe vasomotor symptoms
Study Groups	Fezolinetant 30 mg (n= 174) Fezolinetant 45 mg (n= 173) Placebo (n= 175)
Inclusion Criteria	Women aged 40-65 years, BMI of 18–38 kg/m², an average of ≥7 moderate-to-severe hot flashes per day, spontaneous amenorrhea for at least 12 consecutive months or at least 6 months with biochemical criteria of menopause, or bilateral oophorectomy at least 6 weeks before the screening visit
Exclusion Criteria	Women who had used hormone therapy for hot flashes or night sweats within the past 12 weeks, history of breast cancer, significant uncontrolled medical conditions
Methods	Eligible participants were randomized (1:1:1) to placebo, fezolinetant 30 mg once daily, or fezolinetant 45 mg once daily for 12 weeks. Participants who completed the 12-week placebo-controlled phase entered a 40-week extension. Women on fezolinetant continued their dose, while those on placebo were rerandomized to either 30 mg or 45 mg of fezolinetant.
Duration	Between July 11, 2019, and Aug 11, 2021, 2205 12-week double-blind phase followed by a 40-week active treatment extension phase, totaling 52 weeks of treatment
Outcome Measures	Primary: Frequency and severity of vasomotor symptoms Secondary: Improvements in quality of life measured by the MENQOL, sleep disturbances measured by the PROMIS SD SF 8
Baseline Characteristics		Placebo (n= 175)	Fezolinetant 30 mg (n= 174)	Fezolinetant 45 mg (n= 173)
	Age (SD), years	54.7 (4.8)	54.2 (4.9)	54.2 (5.1)
	Race Black White	28 (16%) 142 (81%)	21 (12%) 148 (86%)	26 (15%) 141 (82%)
	BMI (SD), kg/m²	28.19 (4.28)	28.14 (4.83)	28.28 (4.35)
	Smoking status Current Former or never	22 (13%) 153 (87%)	22 (13%) 152 (87%)	22 (13%) 151 (87%)
	Time since onset of hot flashes (SD), months	81.9 (73.6)	77.4 (66.3)	71.9 (59.3)
	Amenorrhoea	170 (97%)	170 (98%)	171 (99%)
	Hysterectomy	124 (71%)	113 (65%)	117 (68%)
	Oophorectomy	137 (78%)	137 (79%)	136 (79%)
	Previously used hormone therapy for hot flashes or night sweats	33 (19%)	31 (18%)	30 (18%)
Results	Endpoint	Fezolinetant 30 mg	Fezolinetant 45 mg
	Frequency of vasomotor symptoms at Week 4 Difference in change in least squares mean (LSM) compared to placebo	–1.87 [SE 0.42]; p< 0.001	–2.07 [SE 0.42]; p< 0.001
	Frequency of vasomotor symptoms at Week 12 Difference in change in LSM compared to placebo	–2.39 [SE 0.44]; p< 0.001],	–2.55 [SE 0.43]; p< 0.001]
	Severity of vasomotor symptoms at Week 4 Difference in change in LSM compared to placebo	–0.15 [SE 0.06]; p= 0.012	–0.19 [SE 0.06]; p= 0.002
	Severity of vasomotor symptoms at Week 12 Difference in change in LSM compared to placebo	–0.24 [SE 0.08]; p= 0.002	–0.20 [SE 0.08]; p= 0.007
	Clinically meaningful improvement in quality of life as measured by the MENQOL, yet no significant improvements in PROMIS SD SF 8b in fezolinetant groups at 12 weeks.
Adverse Events	Common Adverse Events: Common treatment-emergent adverse events (TEAEs): Headache (5% fezolinetant 30 mg vs. 6% fezolinetant 45 mg vs. 7% placebo)
	Serious Adverse Events: Serious TEAEs: 1% vs. 1% vs. 1%
	Percentage that Discontinued due to Adverse Events: TEAEs causing permanent discontinuation of study drug: 6% vs. 2% vs. 5%. Drug-related TEAEs causing permanent discontinuation of study drug: 3% vs. 2% vs. 4%
Study Author Conclusions	Data support the clinical use of fezolinetant as a non-hormonal treatment for vasomotor symptoms associated with menopause. The study was placebo-controlled for 12 weeks followed by a 40-week blinded extension to assess the maintenance of effect. Furthermore, the population studied was diverse and representative of the potential target population for fezolinetant therapy. Further characterisation of the benefit of fezolinetant on quality of life, including on symptoms of mood and sexual wellbeing, merits investigation.
InpharmD Researcher Critique	Vasomotor symptoms showed significant improvement within the first week of treatment, sustained through week 12 and up to 52 weeks without tachyphylaxis. This study was not designed to compare active doses, and further research on additional menopausal symptoms like mood and sexual well-being could offer a more complete understanding of treatment benefits.

References:
[1] Lederman S, Ottery FD, Cano A, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. Lancet 2023;401(10382):1091-102.

Efficacy and Safety of Fezolinetant in Moderate to Severe Vasomotor Symptoms Associated With Menopause: A Phase 3 RCT
Design	Multinational, randomized, double-blind, placebo-controlled, multicenter, phase 3 trial (SKYLIGHT 2 trial) N= 501
Objective	To assess the efficacy and safety of fezolinetant for the treatment of moderate to severe vasomotor symptoms (VMS) associated with menopause
Study Groups	Fezolinetant 30 mg (n= 166) Fezolinetant 45 mg (n= 167) Placebo (n= 167)
Inclusion Criteria	Women aged 40 to 65 years, confirmed menopausal status, seeking treatment for VMS, with a minimum average of 7 moderate to severe VMS/day
Exclusion Criteria	Use of CYP1A2 inhibitors, hormone replacement therapy, history of malignant tumors, uncontrolled hypertension, active liver disease, and other significant medical conditions
Methods	Participants were randomized to receive once-daily placebo, fezolinetant 30 mg, or fezolinetant 45 mg for 12 weeks, followed by a 40-week active treatment extension. Efficacy was assessed using daily VMS diaries and the Patient-Reported Outcomes Measurement Information System Sleep Disturbance – Short Form 8b (PROMIS SD SF 8b) scores.
Duration	12-week double-blind period followed by 40-week active treatment extension
Outcome Measures	Primary: Mean change in daily frequency and severity of moderate to severe VMS from baseline to weeks 4 and 12 Secondary: Mean change in PROMIS SD SF 8b total score from baseline to week 12
Baseline Characteristics		Placebo (n= 167)	Fezolinetant 30 mg (n= 166)	Fezolinetant 45 mg (n= 167)
	Age, years	54.7 ± 4.6	53.9 ± 4.9	54.3 ± 5.4
	White	80.2%	78.9%	79.0%
	Weight, kg	74.57 (46.2–125.0)	75.33 (48.0–108.4)	74.62 (45.0–107.4)
	Time since onset of VMS, mo	81.9 (3-364)	76.2 (3-370)	81.7 (2-396)
	Amenorrhea	159 ± 95.2	163 ± 98.2	162 ± 97.0
	Hysterectomy	51 ± 30.5	53 ± 31.9	56 ± 33.5
	Oophorectomy	37 ± 22.2	34 ± 20.5	38 ± 22.8
Results	Efficacy endpoint	Placebo (n= 167)	Fezolinetant 30 mg (n= 166)	Fezolinetant 45 mg (n= 167)
	Frequency of daily moderate to severe VMS Week 4 Week 12	8.08 ± 6.50 6.73 ± 7.58	5.79 ± 6.02* 4.80 ± 5.59*	5.67 ± 7.29* 4.49 ± 5.39*
	Severity of daily moderate to severe VMS Week 4 Week 12	2.11 ± 0.56 1.95 ± 0.68	1.97 ± 0.65* 1.84 ± 0.79*	1.80 ± 0.74* 1.66 ± 0.79*
	Change from baseline in PROMIS SD SF 8b score Week 4 Week 12	-2.6 -3.4	-3.9 -4.1	-5.3* -5.5*
	Safety endpoints Drug-related TEAE Drug-related serious TEAE Drug-related TEAE leading to drug discontinuation TEAEs Upper respiratory tract infection Headache Dry mouth Arthralgia Diarrhea Nasopharyngitis Nausea Weight increase Depression Liver test elevation Wakefulness Uterine bleeding Bone fractures Thrombocytopenia	11 (6.6%) 0 0 7 (4.2%) 4 (2.4%) 0 1 (0.6%) 4 (2.4%) 4 (2.4%) 0 1 (0.6%) 4 (2.4%) 0 1 (0.6%) 1 (0.6) 1 (0.6) 0	24 (14.5%) 0 1 (0.6%) 5 (3.0%) 5 (3.0%) 4 (2.4%) 5 (3.0%) 1 (0.6%) 3 (1.8%) 3 (1.8%) 5 (3.0%) 3 (1.8%) 2 (1.2%) 3 (1.8%) 1 (0.6) 1 (0.6) 2 (1.2%)	25 (15.0%) 0 5 (3.0%) 5 (3.0%) 6 (3.6%) 4 (2.4%) 1 (0.6%) 2 (1.2%) 0 4 (2.4%) 1 (0.6%) 1 (0.6%) 3 (1.8%) 1 (0.6%) 1 (0.6%) 0 0
	*When compared to placebo, statistically significant p-value (p< 0.05) No deaths were reported in this study
Adverse Events	See results
Study Author Conclusions	Daily fezolinetant 30 and 45 mg were efficacious and well tolerated for treating moderate to severe VMS associated with menopause, with rapid onset of effect and sustained efficacy over 52 weeks.
InpharmD Researcher Critique	The study was well-designed with a robust sample size and clear endpoints. However, the absence of a placebo group beyond 12 weeks limits long-term comparative conclusions. Additionally, other menopause symptoms were not assessed.

References:
[1] Johnson KA, Martin N, Nappi RE, et al. Efficacy and Safety of Fezolinetant in Moderate to Severe Vasomotor Symptoms Associated With Menopause: A Phase 3 RCT. J Clin Endocrinol Metab. 2023;108(8):1981-1997. doi:10.1210/clinem/dgad058

Effect of Fezolinetant on Sleep Disturbance and Impairment During Treatment of Vasomotor Symptoms due to Menopause
Design	SKYLIGHT 1 and 2, were both phase 3, multinational, randomized, placebo-controlled, double-blind trials N= 1,022
Objective	To assess the effect of fezolinetant on patient-reported sleep disturbance and impairment in individuals with vasomotor symptoms (VMS) using pooled data from the SKYLIGHT 1 and 2 studies
Study Groups	Fezolinetant 30 mg (339 participants) Fezolinetant 45 mg (341 participants) Placebo (n= 342)
Inclusion Criteria	Individuals aged 40-65 years, assigned female at birth, seeking treatment for moderate-to-severe VMS, BMI 18-38 kg/m2, confirmed postmenopausal status
Exclusion Criteria	Previous or current malignant tumors, hypertension, active liver disease, jaundice, elevated liver aminotransferases, elevated bilirubin, elevated international normalized ratio, or elevated alkaline phosphatase
Methods	Participants were randomized to receive placebo, fezolinetant 30 mg, or fezolinetant 45 mg once daily for 12 weeks. Sleep disturbance and impairment were assessed using Patient-Reported Outcomes Measurement Information System Sleep Disturbance – Short Form 8b (PROMIS SD SF 8b), PROMIS Sleep-Related Impairment – Short Form 8a (PROMIS SRI SF 8a), and Patient Global Impression of Change/Severity in Sleep Disturbance (PGI-C SD and PGI-S SD).
Duration	12 week treatment period
Outcome Measures	Primary: PROMIS SD SF 8b, PROMIS SRI SF 8a Secondary: PGI-C SD, PGI-S SD
Baseline Characteristics		Placebo (n= 342)	Fezolinetant 30 mg (n= 339)	Fezolinetant 45 mg (n= 341)
	Age, years	54.7 ± 4.7	54.0 ± 4.9	54.3 ± 5.3
	White	276 (80.7%)	278 (82.2%)	274 (80.4%)
	BMI, kg/m2	28.2 ± 4.6	28.0 ± 4.7	28.1 ± 4.4
	Time since onset of hot flashes, mo (range)	81.9 (2–422)	76.7 ± (3–370)	76.9 ± (1–396)
	Hysterectomy	102 (29.8%)	113 (33.3%)	113 (33.1%)
Results	Endpoint	Placebo (n= 342)	Fezolinetant 30 mg (n= 339)	Fezolinetant 45 mg (n= 341)
	ROMIS SD SF 8b (sleep disturbance) Week 4 LS mean change (95% CI) Week 12 LS mean chnage (95% CI)	–2.5 (–3.2 to –1.7) –3.3 (–4.0 to –2.6)	–3.6 (–4.3 to –2.9) –3.9 (–4.7 to –3.2)	–4.7 (–5.4 to –4.0) –4.8 (–5.5 to –4.1)
	PROMIS SRI SF 8a (sleep impairment) Week 4 LS mean change (95% CI) Week 12 LS mean chnage (95% CI)	–2.7 (–3.3 to 2.0) –3.1 (–3.8 to 2.4)	–3.3 (–4.0 to –2.7) –4.2 (–5.0 to –3.5)	–4.4 (–5.1 to –3.8) –4.4 (–5.1 to –3.7)
	Abbreviations: LS, least squares; CI, confidence interval PGI-C SD: At week 12, 33.6% of the placebo group felt much/moderately better versus 40.1% and 51.0% of the fezolinetant 30 mg and 45 mg groups, respectively PGI-S SD: At week 12, 44% of the placebo group had severe/moderate problems versus 41.1% and 36.6% of the fezolinetant 30 mg and 45 mg groups, respectively
Adverse Events	Not assessed
Study Author Conclusions	Fezolinetant had a beneficial effect on four measures of sleep disturbance and impairment following treatment for VMS. The findings demonstrate the potential utility of fezolinetant as an effective treatment for individuals with VMS due to menopause.
InpharmD Researcher Critique	The study's strengths include the use of large, phase 3 trials and multiple patient-reported outcome tools. Limitations include the short 12-week placebo-controlled period and lack of stratification for baseline sleep disturbance. The study did not control for the use of sleep medications and relied on patient-reported outcomes without wearable technology.

References:
[1] Shapiro C M M, Cano A, Nappi RE, et al. Effect of fezolinetant on sleep disturbance and impairment during treatment of vasomotor symptoms due to menopause. Maturitas. 2024;186:107999.

Fezolinetant impact on health-related quality of life for vasomotor symptoms due to the menopause: Pooled data from SKYLIGHT 1 and SKYLIGHT 2 randomised controlled trials
Design	Pooled analysis of two double-blind, placebo-controlled phase 3 trials (SKYLIGHT 1 and 2) N= 1022
Objective	To assess the effect of fezolinetant treatment on health-related quality of life (HRQoL) for vasomotor symptoms (VMS) due to menopause
Study Groups	Placebo (n= 342) Fezolinetant 30 mg (n= 339) Fezolinetant 45 mg (n= 341)
Inclusion Criteria	Women aged 40-65 years, genetically female at birth, with moderate-to-severe VMS (≥7 hot flushes/day), BMI 18-38 kg/m2, confirmed postmenopausal status
Exclusion Criteria	Previous/current malignant tumors, hypertension, active liver disease, elevated liver enzymes, use of prohibited VMS therapies, prior participation in fezolinetant trials
Methods	Eligible patients were randomized to 12-week double-blind treatment with a placebo or fezolinetant (30 or 45 mg daily). Completers entered a 40-week active extension with fezolinetant.
Duration	July 2019 to August 2021 (SKYLIGHT 1); July 2019 to April 2021 (SKYLIGHT 2) 12-week double-blind treatment period followed by a 40-week active extension period
Outcome Measures	Mean changes in MENQoL total and domain scores, WPAI-VMS domain scores, Patient Global Impression of Change in VMS (PGI-C VMS) responses, percentage achieving PGI-C VMS 'much better' response
Baseline Characteristics	Parameter	Placebo (n=342)	Fezolinetant 45 mg (n=341)	Fezolinetant 30 mg (n=339)	Total (N=1022)
	Ethnicity Hispanic or Latina Not Hispanic or Latina	78 (22.9%) 262 (77.1%)	89 (26.1%) 252 (73.9%)	76 (22.4%) 263 (77.6%)	243 (23.8%) 777 (76.2%)
	Race White Black	276 (80.7%) 59 (17.3)	274 (80.4%) 59 (17.3)	278 (82.2%) 56 (16.6)	828 (81.1%) 174 (17.0)
	Age, mean (SD), years	54.7 (4.7)	54.3 (5.3)	54.0 (4.9)	54.3 (5.0)
	Weight, mean (range), kg	74.5 (46.2–125.0)	75.2 (45.0–110.6)	75.2 (42.0–121.2)	75.0 (42.0–125.0)
	Current smoker	57 (16.7%)	57 (16.7%)	55 (16.2%)	169 (16.5%)
	Time since onset of VMS, mean (range), months	81.9 (2–422)	76.9 (1–396)	76.7 (3–370)	78.5 (1–422)
	Amenorrhoea	329 (96.2%)	334 (97.9%)	332 (97.9%)	995 (97.4%)
	Hysterectomy	102 (29.8%)	113 (33.1%)	113 (33.1%)	328 (32.1%)
	Oophorectomy	75 (21.9%)	76 (22.3%)	70 (20.6%)	221 (21.6%)
Results	Outcome	Placebo	Fezolinetant 30 mg	Fezolinetant 45 mg
	MENQoL Total Score Reduction at Week 4	-0.57 (95% CI -0.75 to -0.39)	-0.46 (95% CI -0.64 to -0.27); p<0.001	-0.57 (95% CI -0.75 to -0.39); p<0.001
	MENQoL Total Score Reduction at Week 12	-0.47 (95% CI -0.66 to -0.28)	-0.32 (95% CI -0.51 to -0.12); p= 0.001	-0.47 (95% CI -0.66 to -0.28); p<0.001
	PGI-C VMS Responders at Week 4	18.3%	36.4%	43.9%
	PGI-C VMS Responders at Week 12	23.9%	42.5%	47.5%
Adverse Events	N/A
Study Author Conclusions	Fezolinetant treatment improved overall quality of life and work productivity in women with moderate-to-severe VMS, with a high proportion feeling 'much better' compared to placebo.
InpharmD Researcher Critique	This prespecified pooled analysis does not control the type I error rate, so p-values do not confer statistical significance. It relies on PROMs without wearable monitors and excludes class III obesity (morbid obesity) patients.

References:
[1] Cano A, Nappi RE, Santoro N, et al. Fezolinetant impact on health-related quality of life for vasomotor symptoms due to the menopause: Pooled data from SKYLIGHT 1 and SKYLIGHT 2 randomised controlled trials. BJOG. 2024;131(9):1296-1305. doi:10.1111/1471-0528.17773

Efficacy and safety of fezolinetant for moderate-severe vasomotor symptoms associated with menopause in individuals unsuitable for hormone therapy: phase 3b randomised controlled trial
Design	Phase 3b randomized controlled trial with N= 453
Objective	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
Study Groups	Fezolinetant (n= 227) Placebo (n= 226)
Inclusion Criteria	Individuals aged 40-65 years with moderate-severe vasomotor symptoms associated with menopause, unsuitable for hormone therapy (contraindicated, caution, stoppers, or averse)
Exclusion Criteria	Not explicitly stated
Methods	Eligible participants were randomized to receive fezolinetant 45 mg or placebo once daily for 24 weeks. The study used interactive response technology and stratified participants by smoking status.
Duration	Between 8 November 2021 and 20 April 2023 24 weeks of treatment
Outcome Measures	Primary: Mean change in daily frequency of moderate-severe vasomotor symptoms from baseline to week 24 Secondary: Mean change in symptom severity, sleep disturbance using PROMIS SD-SF 8b total score, and safety
Baseline Characteristics		Fezolinetant (n= 226)	Placebo (n= 226)	Total (n= 452)
	Mean (SD) age, years	54.9 (4.8)	54.1 (4.6)	54.5 (4.7)
	Mean (SD) weight, kg	74.2 (12.6)	72.6 (13.2)	73.4 (12.9)
	Mean (SD) BMI, kg/m²	27.42 (4.33)	26.98 (4.52)	27.20 (4.43)
	BMI category <25 ≥25	67 (29.6%) 159 (70.4%)	85 (37.6%) 141 (62.4%)	152 (33.6%) 300 (66.4%)
	Race White Other	217 (96.0%) 9 (4.0%)	218 (97.3%) 6 (2.7%)	435 (96.7%) 15 (3.3%)
	Categories for hormone therapy unsuitability Contraindicated Caution Stoppers Averse	27 (11.9%) 74 (32.7%) 32 (14.2%) 93 (41.2%)	23 (10.2%) 91 (40.3%) 37 (16.4%) 75 (33.2%)	50 (11.1%) 165 (36.5%) 69 (15.3%) 168 (37.2%)
	Smoking status Current Former/never	36 (15.9%) 190 (84.1%)	35 (15.5%) 191 (84.5%)	71 (15.7%) 381 (84.3%)
Results		Fezolinetant (n= 226)				Placebo (n= 226)
	Primary: Frequency of moderate-severe vasomotor symptoms at Week 24
	Change from baseline: Mean (SD) events daily	–8.15 (4.43)				–6.09 (4.19)
	Least squares mean (SE)	–8.13 (0.25)				–6.20 (0.26)
	Least squares mean (SE) difference; P value		–1.93 (0.36); <0.001
	Secondary: Severity of moderate-severe vasomotor symptoms at Week 24
	Change from baseline: Mean (SD) severity: –0.99 (0.97)	–0.99 (0.97)				–0.54 (0.80)
	Least squares mean (SE)	–1.01 (0.06)				–0.62 (0.06)
	Least squares mean (SE) difference; P value		–0.39 (0.09); <0.001
	Secondary: Change from baseline in PROMIS SD-SF 8b total score to Week 24
	Change from baseline: Mean (SD) score	–7.3 (7.7)				–4.6 (8.1)
	Least squares mean (SE)	–7.0 (0.5)				–4.5 (0.5)
	Least squares mean (SE) difference; unadjusted P value				–2.5 (0.7); <0.001
Adverse Events	Drug-related treatment-emergent adverse events (TEAEs): 17.3% fezolinetant vs. 11.1% placebo. Drug-related serious TEAEs: 0.4% vs. 0%. Drug-related TEAE leading to withdrawal of treatment: 3.1% vs. 3.1% The most common TEAEs in the fezolinetant group were covid-19 (13.3%), headache (8.8%), and fatigue (5.8%).
Study Author 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.
InpharmD Researcher Critique	The study adds to the evidence supporting fezolinetant's efficacy and safety, with a longer placebo control period than previous studies. However, the study population was predominantly white, suggesting a need for further research in more diverse populations.

References:
[1] Schaudig K, Wang X, Bouchard C, et al. Efficacy and safety of fezolinetant for moderate-severe vasomotor symptoms associated with menopause in individuals unsuitable for hormone therapy: phase 3b randomised controlled trial [published correction appears in BMJ. 2024 Nov 27;387:q2623. doi:10.1136/bmj.q2623]. BMJ. 2024;387:e079525. Published 2024 Nov 18. doi:10.1136/bmj-2024-079525