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    Clinical Trial Results:
    A Phase 3b, Randomized, Double-blind, Placebo-controlled, 24-week Study to Assess the Efficacy and Safety of Fezolinetant in Menopausal Women Suffering from Moderate to Severe Vasomotor Symptoms (Hot Flashes) and Considered Unsuitable for Hormone Replacement Therapy

    Summary
    EudraCT number
    		 2021-001685-38
    Trial protocol
    		 CZ   ES   IT   HU   FI   NL   NO   DE   PL   DK   BE   SK   BG  
    Global end of trial date
    20 Apr 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Mar 2024
    First version publication date
    31 Mar 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    2693-CL-0312
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05033886
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Global Development, Inc. (APGD)
    Sponsor organisation address
    1 Astellas Way, Northbrook, Illinois, United States, 60062
    Public contact
    Clinical Trial Transparency, Astellas Pharma Global Development, Inc., 60062 8008887704, astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Transparency, Astellas Pharma Global Development, Inc. (APGD), 60062 8008887704, astellas.resultsdisclosure@astellas.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    20 Apr 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Apr 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of fezolinetant 45 milligram (mg) versus placebo on the frequency of moderate to severe Vasomotor Symptoms (VMS) from baseline to week 24
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Nov 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Canada: 86
    Country: Number of subjects enrolled
    Czechia: 44
    Country: Number of subjects enrolled
    Denmark: 32
    Country: Number of subjects enrolled
    Finland: 4
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 23
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Hungary: 24
    Country: Number of subjects enrolled
    Netherlands: 12
    Country: Number of subjects enrolled
    Norway: 4
    Country: Number of subjects enrolled
    Poland: 94
    Country: Number of subjects enrolled
    Spain: 42
    Country: Number of subjects enrolled
    Sweden: 13
    Country: Number of subjects enrolled
    Türkiye: 16
    Country: Number of subjects enrolled
    United Kingdom: 47
    Worldwide total number of subjects
    453
    EEA total number of subjects
    304
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    447
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Female participants aged ≥ 40 and ≤ 65 years suffering from moderate to severe VMS associated with menopause and unsuitable Hormone Replacement Therapy (HRT) and those who met inclusion criteria and none of the exclusion criteria were enrolled.

    Pre-assignment
    Screening details
    		 Prior to randomization, participants had a screening period during which a maximum 21-day collection of baseline VMS frequency and severity assessments were performed. Participants were stratified by smoking status (Current versus former or never).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Fezolinetant
    Arm description
    		 Participants received fezolinetant 45 milligrams (mg) (one 30 mg tablet and one 15 mg tablet) orally once daily for 24 weeks of treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Fezolinetant
    Investigational medicinal product code
    ESN364
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet administered orally once daily for 24 weeks.

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo matched to fezolinetant tablets orally once daily for 24 weeks of treatment.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet administered orally once daily for 24 weeks.

    Number of subjects in period 1
    		Fezolinetant Placebo
    Started
    227
    226
    Completed
    202
    185
    Not completed
    25
    41
         Consent withdrawn by subject
    19
    33
         Randomized but not treated
    1
    -
         Adverse event, non-fatal
    2
    2
         Miscellaneous
    2
    -
         Lost to follow-up
    -
    5
         Protocol deviation
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Fezolinetant
    Reporting group description
    		 Participants received fezolinetant 45 milligrams (mg) (one 30 mg tablet and one 15 mg tablet) orally once daily for 24 weeks of treatment.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo matched to fezolinetant tablets orally once daily for 24 weeks of treatment.

    Reporting group values
    		 Fezolinetant Placebo Total
    Number of subjects
    		 227 226 453
    Age categorical
    Units: Subjects
    Age
    Units: years
        arithmetic mean (standard deviation)
    		 54.9 ( 4.8 ) 54.1 ( 4.6 ) -
    Sex
    Units: Subjects
        Female
    		 227 226 453
    Race
    Units: Subjects
        Asian
    		 1 5 6
        Black or African American
    		 4 0 4
        Missing
    		 0 2 2
        More Than One Race
    		 3 0 3
        Other
    		 1 1 2
        White
    		 218 218 436
    Smoking status
    Current versus former or never smoking status was a stratification factor for randomization.
    Units: Subjects
        Current
    		 36 35 71
        Former/Never
    		 191 191 382
    Frequency of Moderate to Severe VMS per 24 hour
    The frequency of moderate to severe VMS was the number of moderate to severe VMS per 24 hours. Baseline was the average number of moderate to severe VMS per 24 hours based on the non-missing values in the 10 days immediately prior to randomization. Number of participants analyzed is 226 and 226 for fezolinetant and placebo, respectively. One participant was randomized but was not included in the analysis as the participant did not receive study medication.
    Units: VMS per day
        arithmetic mean (standard deviation)
    		 10.58 ( 3.57 ) 10.75 ( 4.08 ) -

    End points

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    End points reporting groups
    Reporting group title
    Fezolinetant
    Reporting group description
    		 Participants received fezolinetant 45 milligrams (mg) (one 30 mg tablet and one 15 mg tablet) orally once daily for 24 weeks of treatment.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo matched to fezolinetant tablets orally once daily for 24 weeks of treatment.

    Primary: Mean change in the frequency of moderate to severe VMS from baseline at week 24

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    End point title
    		 Mean change in the frequency of moderate to severe VMS from baseline at week 24
    End point description
    The frequency of moderate to severe VMS was the number of moderate to severe VMS per 24 hours. A daily frequency per week was derived by taking the mean of the data over 7 days. Moderate VMS was defined as sensation of heat with sweating/dampness but was able to continue activity. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. Full Analysis Set (FAS) (consisted of all randomized participants who received at least one dose of study intervention) with available data were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline, week 24
    End point values
    		 Fezolinetant Placebo
    Number of subjects analysed
    176
    164
    Units: VMS per day
        least squares mean (standard error)
    -8.13 ( 0.25 )
    -6.20 ( 0.26 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    340
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -1.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.64
         upper limit
    		 -1.22
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.36
    Notes
    [1] - The Least Square (LS) Means, standard error (SE) and p-values came from a Mixed Model Repeated Measures (MMRM) analysis of covariance model with change from baseline as the dependent variable and treatment group, week and smoking status (current vs former/never) as factors, with baseline weight and baseline value as covariates, treatment group by week and baseline value by week as interaction terms.

    Secondary: Mean change in the severity of moderate to severe VMS from baseline at week 24

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    End point title
    		 Mean change in the severity of moderate to severe VMS from baseline at week 24
    End point description
    Severity of moderate to severe VMS per day was calculated as follows: [(number of moderate Hot Flashes (HFs) × 2) + (number of severe HFs/day × 3)]/number of daily moderate/severe HFs. Moderate VMS was defined as sensation of heat with sweating but able to continue activity. Severe VMS was defined as sensation of intense heat with sweating, causing cessation of activity. Severity was zero for participants that had no moderate or severe VMS. Higher score indicated greater severity. A negative change indicated a reduction/improvement. FAS population with available data was analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, week 24
    End point values
    		 Fezolinetant Placebo
    Number of subjects analysed
    176
    164
    Units: Score on scale
        least squares mean (standard error)
    -1.01 ( 0.06 )
    -0.62 ( 0.06 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    340
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.57
         upper limit
    		 -0.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.09
    Notes
    [2] - The LS Means, SE and p-values came from a MMRM analysis of covariance model with change from baseline as the dependent variable and treatment group, week and smoking status (current vs former/never) as factors, with baseline weight and baseline value as covariates, treatment group by week and baseline value by week as interaction terms.

    Secondary: Mean change in the patient-reported sleep disturbance by the Patient-reported Outcomes Measurement Information System Sleep Disturbance – Short Form 8b (PROMIS SD SF 8b total score) from baseline at week 24

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    End point title
    		 Mean change in the patient-reported sleep disturbance by the Patient-reported Outcomes Measurement Information System Sleep Disturbance – Short Form 8b (PROMIS SD SF 8b total score) from baseline at week 24
    End point description
    The PROMIS SD SF 8b assesses self-reported sleep disturbance over the past 7 days and includes perceptions of restless sleep; satisfaction with sleep; refreshing sleep; difficulties sleeping, getting to sleep or staying asleep; amount of sleep; and sleep quality. Because it assesses the participants experience of sleep disturbance, the measure does not focus on specific sleep-disorder symptoms or ask participants to report objective measures of sleep (e.g., total amount of sleep, time to fall asleep and amount of wakefulness during sleep). Responses to each of the 8 items range from 1 (no disturbed sleep) to 5 (disturbed sleep), and the range of possible summed raw scores is 8 to 40. Higher scores on the PROMIS SD SF 8b indicate more of the disturbed sleep. A negative value indicates a better outcome. FAS population with available data was analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, week 24
    End point values
    		 Fezolinetant Placebo
    Number of subjects analysed
    196
    178
    Units: Score on scale
        least squares mean (standard error)
    -7.0 ( 0.5 )
    -4.5 ( 0.5 )
    Statistical analysis title
    		 Statistical Analysis
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.9
         upper limit
    		 -1.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.7
    Notes
    [3] - The LS Means, SE and p-values came from a MMRM analysis of covariance model with change from baseline as the dependent variable and treatment group, week and smoking status (current vs former/never) as factors, with baseline weight and baseline value as covariates, treatment group by week and baseline value by week as interaction terms.

    Secondary: Mean change in the frequency of moderate to severe VMS from baseline at weeks 1, 4, 8, 12, 16 and 20

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    End point title
    		 Mean change in the frequency of moderate to severe VMS from baseline at weeks 1, 4, 8, 12, 16 and 20
    End point description
    The frequency of moderate to severe VMS was the number of moderate to severe VMS per 24 hours. A daily frequency per week was derived by taking the mean of the data over 7 days. Moderate VMS was defined as sensation of heat with sweating/dampness but was able to continue activity. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. FAS population with available data was analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 1, 4, 8, 12, 16 and 20
    End point values
    		 Fezolinetant Placebo
    Number of subjects analysed
    225
    223
    Units: VMS per day
    least squares mean (standard error)
        Week 1 (n= 225, 223)
    -4.56 ( 0.21 )
    -2.36 ( 0.21 )
        Week 4 (n= 217, 212)
    -6.79 ( 0.23 )
    -4.50 ( 0.24 )
        Week 8 (n= 208, 201)
    -7.41 ( 0.25 )
    -5.44 ( 0.25 )
        Week 12 (n= 203, 185)
    -7.65 ( 0.25 )
    -5.69 ( 0.25 )
        Week 16 (n= 190, 175)
    -7.70 ( 0.26 )
    -5.81 ( 0.26 )
        Week 20 (n= 184, 172)
    -8.07 ( 0.25 )
    -5.90 ( 0.25 )
    Statistical analysis title
    		 Statistical Analysis (Week 1)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.78
         upper limit
    		 -1.61
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3
    Notes
    [4] - The LS Means, SE and p-values came from a MMRM analysis of covariance model with change from baseline as the dependent variable and treatment group, week and smoking status (current vs former/never) as factors, with baseline weight and baseline value as covariates, treatment group by week and baseline value by week as interaction terms.
    Statistical analysis title
    		 Statistical Analysis (Week 20)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -2.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.87
         upper limit
    		 -1.48
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.35
    Notes
    [5] - The LS Means, SE and p-values came from a MMRM analysis of covariance model with change from baseline as the dependent variable and treatment group, week and smoking status (current vs former/never) as factors, with baseline weight and baseline value as covariates, treatment group by week and baseline value by week as interaction terms.
    Statistical analysis title
    		 Statistical Analysis (Week 12)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -1.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.65
         upper limit
    		 -1.26
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.35
    Notes
    [6] - The LS Means, SE and p-values came from a MMRM analysis of covariance model with change from baseline as the dependent variable and treatment group, week and smoking status (current vs former/never) as factors, with baseline weight and baseline value as covariates, treatment group by week and baseline value by week as interaction terms.
    Statistical analysis title
    		 Statistical Analysis (Week 16)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -1.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 -1.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.37
    Notes
    [7] - The LS Means, SE and p-values came from a MMRM analysis of covariance model with change from baseline as the dependent variable and treatment group, week and smoking status (current vs former/never) as factors, with baseline weight and baseline value as covariates, treatment group by week and baseline value by week as interaction terms.
    Statistical analysis title
    		 Statistical Analysis (Week 4)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -2.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.93
         upper limit
    		 -1.63
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.33
    Notes
    [8] - The LS Means, SE and p-values came from a MMRM analysis of covariance model with change from baseline as the dependent variable and treatment group, week and smoking status (current vs former/never) as factors, with baseline weight and baseline value as covariates, treatment group by week and baseline value by week as interaction terms.
    Statistical analysis title
    		 Statistical Analysis (Week 8)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -1.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.66
         upper limit
    		 -1.27
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.35
    Notes
    [9] - The LS Means, SE and p-values came from a MMRM analysis of covariance model with change from baseline as the dependent variable and treatment group, week and smoking status (current vs former/never) as factors, with baseline weight and baseline value as covariates, treatment group by week and baseline value by week as interaction terms.

    Secondary: Mean change in severity of moderate to severe VMS from baseline at weeks 1, 4, 8, 12, 16 and 20

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    End point title
    		 Mean change in severity of moderate to severe VMS from baseline at weeks 1, 4, 8, 12, 16 and 20
    End point description
    Severity of moderate to severe VMS per day was calculated as follows: [(number of moderate HFs × 2) + (number of severe HFs/day × 3)]/number of daily moderate/severe HFs. Moderate VMS was defined as sensation of heat with sweating/dampness but was able to continue activity. Severe VMS was defined as sensation of intense heat with sweating, causing cessation of activity. Severity was zero for participants that had no moderate or severe VMS. Higher score indicated greater severity. A negative change indicated a reduction/improvement. FAS population with available data was analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 1, 4, 8, 12, 16 and 20
    End point values
    		 Fezolinetant Placebo
    Number of subjects analysed
    223
    225
    Units: Score on scale
    least squares mean (standard error)
        Week 1 (n= 223, 225)
    -0.34 ( 0.02 )
    -0.17 ( 0.02 )
        Week 4 (n= 217, 212)
    -0.66 ( 0.04 )
    -0.30 ( 0.04 )
        Week 8 (n= 208, 201)
    -0.83 ( 0.05 )
    -0.52 ( 0.05 )
        Week 12 (n= 203, 185)
    -0.87 ( 0.05 )
    -0.57 ( 0.06 )
        Week 16 (n= 190, 175)
    -0.90 ( 0.06 )
    -0.62 ( 0.06 )
        Week 20 (n= 184, 172)
    -0.98 ( 0.06 )
    -0.62 ( 0.06 )
    Statistical analysis title
    		 Statistiical Analysis (Week 1)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.03
    Notes
    [10] - The LS Means, SE and p-values came from a MMRM analysis of covariance model with change from baseline as the dependent variable and treatment group, week and smoking status (current vs former/never) as factors, with baseline weight and baseline value as covariates, treatment group by week and baseline value by week as interaction terms.
    Statistical analysis title
    		 Statistical Analysis (Week 4)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.47
         upper limit
    		 -0.24
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.06
    Notes
    [11] - The LS Means, SE and p-values came from a MMRM analysis of covariance model with change from baseline as the dependent variable and treatment group, week and smoking status (current vs former/never) as factors, with baseline weight and baseline value as covariates, treatment group by week and baseline value by week as interaction terms.
    Statistical analysis title
    		 Statistical Analysis (Week 8)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.45
         upper limit
    		 -0.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.07
    Notes
    [12] - The LS Means, SE and p-values came from a MMRM analysis of covariance model with change from baseline as the dependent variable and treatment group, week and smoking status (current vs former/never) as factors, with baseline weight and baseline value as covariates, treatment group by week and baseline value by week as interaction terms.
    Statistical analysis title
    		 Statistical Analysis (Week 12)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.45
         upper limit
    		 -0.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.08
    Notes
    [13] - The LS Means, SE and p-values came from a MMRM analysis of covariance model with change from baseline as the dependent variable and treatment group, week and smoking status (current vs former/never) as factors, with baseline weight and baseline value as covariates, treatment group by week and baseline value by week as interaction terms.
    Statistical analysis title
    		 Statistical Analysis (Week 16)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 = 0.001
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.45
         upper limit
    		 -0.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.08
    Notes
    [14] - The LS Means, SE and p-values came from a MMRM analysis of covariance model with change from baseline as the dependent variable and treatment group, week and smoking status (current vs former/never) as factors, with baseline weight and baseline value as covariates, treatment group by week and baseline value by week as interaction terms.
    Statistical analysis title
    		 Statistical Analysis (Week 20)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.53
         upper limit
    		 -0.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.09
    Notes
    [15] - The LS Means, SE and p-values came from a MMRM analysis of covariance model with change from baseline as the dependent variable and treatment group, week and smoking status (current vs former/never) as factors, with baseline weight and baseline value as covariates, treatment group by week and baseline value by week as interaction terms.

    Secondary: Mean percent change in the frequency of moderate to severe VMS from baseline at weeks 1, 4, 8, 12, 16, 20 and 24

    		 Close Top of page
    End point title
    		 Mean percent change in the frequency of moderate to severe VMS from baseline at weeks 1, 4, 8, 12, 16, 20 and 24
    End point description
    The frequency of moderate to severe VMS was the number of moderate to severe VMS per 24 hours. A daily frequency per week was derived by taking the mean of the data over 7 days. Moderate VMS was defined as sensation of heat with sweating/dampness but was able to continue activity. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. FAS population with available data was analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 1, 4, 8, 12, 16, 20 and 24
    End point values
    		 Fezolinetant Placebo
    Number of subjects analysed
    223
    225
    Units: Percent Change
    least squares mean (standard error)
        Week 1 (n= 223, 225)
    -41.19 ( 1.92 )
    -22.56 ( 1.91 )
        Week 4 (n= 217, 212)
    -63.01 ( 2.12 )
    -43.98 ( 2.13 )
        Week 8 (n= 208, 201)
    -69.27 ( 2.23 )
    -53.12 ( 2.25 )
        Week 12 (n= 203, 185)
    -71.18 ( 2.23 )
    -55.27 ( 2.28 )
        Week 16 (n= 190, 175)
    -71.75 ( 2.37 )
    -55.83 ( 2.43 )
        Week 20 (n= 184, 172)
    -75.49 ( 2.25 )
    -56.45 ( 2.32 )
        Week 24 (n= 176, 164)
    -75.66 ( 2.27 )
    -59.12 ( 2.34 )
    Statistical analysis title
    		 Statistical Analysis (Week 1)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -18.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -23.95
         upper limit
    		 -13.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.71
    Notes
    [16] - The LS Means, SE and p-values came from a MMRM analysis of covariance model with change from baseline as the dependent variable and treatment group, week and smoking status (current vs former/never) as factors, with baseline weight and baseline value as covariates, treatment group by week and baseline value by week as interaction terms.
    Statistical analysis title
    		 Statistical Analysis (Week 8)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -16.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.38
         upper limit
    		 -9.92
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.17
    Notes
    [17] - The LS Means, SE and p-values came from a MMRM analysis of covariance model with change from baseline as the dependent variable and treatment group, week and smoking status (current vs former/never) as factors, with baseline weight and baseline value as covariates, treatment group by week and baseline value by week as interaction terms.
    Statistical analysis title
    		 Statistical Analysis (Week 4)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -19.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.95
         upper limit
    		 -13.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.01
    Notes
    [18] - The LS Means, SE and p-values came from a MMRM analysis of covariance model with change from baseline as the dependent variable and treatment group, week and smoking status (current vs former/never) as factors, with baseline weight and baseline value as covariates, treatment group by week and baseline value by week as interaction terms.
    Statistical analysis title
    		 Statistical Analysis (Week 20)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -19.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.4
         upper limit
    		 -12.68
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.23
    Notes
    [19] - The LS Means, SE and p-values came from a MMRM analysis of covariance model with change from baseline as the dependent variable and treatment group, week and smoking status (current vs former/never) as factors, with baseline weight and baseline value as covariates, treatment group by week and baseline value by week as interaction terms.
    Statistical analysis title
    		 Statistical Analysis (Week 16)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -15.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.6
         upper limit
    		 -9.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.39
    Notes
    [20] - The LS Means, SE and p-values came from a MMRM analysis of covariance model with change from baseline as the dependent variable and treatment group, week and smoking status (current vs former/never) as factors, with baseline weight and baseline value as covariates, treatment group by week and baseline value by week as interaction terms.
    Statistical analysis title
    		 Statistical Analysis (Week 24)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -16.55
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.96
         upper limit
    		 -10.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.26
    Notes
    [21] - The LS Means, SE and p-values came from a MMRM analysis of covariance model with change from baseline as the dependent variable and treatment group, week and smoking status (current vs former/never) as factors, with baseline weight and baseline value as covariates, treatment group by week and baseline value by week as interaction terms.
    Statistical analysis title
    		 Statistical Analysis (Week 12)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [22]
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -15.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.18
         upper limit
    		 -9.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.19
    Notes
    [22] - The LS Means, SE and p-values came from a MMRM analysis of covariance model with change from baseline as the dependent variable and treatment group, week and smoking status (current vs former/never) as factors, with baseline weight and baseline value as covariates, treatment group by week and baseline value by week as interaction terms.

    Secondary: Number of participants with percent reduction of ≥ 50% in the frequency of moderate to severe VMS from baseline at weeks 1, 4, 8, 12, 16, 20 and 24

    		 Close Top of page
    End point title
    		 Number of participants with percent reduction of ≥ 50% in the frequency of moderate to severe VMS from baseline at weeks 1, 4, 8, 12, 16, 20 and 24
    End point description
    The frequency of moderate to severe VMS was the number of moderate to severe VMS per 24 hours. A daily frequency per week was derived by taking the mean of the data over 7 days. Moderate VMS was defined as sensation of heat with sweating/dampness but was able to continue activity. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. FAS population.
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 1, 4, 8, 12, 16, 20 and 24
    End point values
    		 Fezolinetant Placebo
    Number of subjects analysed
    226
    226
    Units: Participants
    number (not applicable)
        Week 1
    95
    33
        Week 4
    148
    100
        Week 8
    149
    117
        Week 12
    154
    106
        Week 16
    140
    107
        Week 20
    149
    101
        Week 24
    137
    104
    Statistical analysis title
    		 Statistical Analysis (Week 8)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 = 0.003
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.798
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.231
         upper limit
    		 2.637
    Notes
    [23] - Based on logistic regression with treatment group and smoking status (current vs former/never) as factors and mean frequency of VMS at baseline as a covariate. An odds ratio of > 1 indicated a favorable response in the fezolinetant group.
    Statistical analysis title
    		 Statistical Analysis (Week 12)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [24]
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.421
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.653
         upper limit
    		 3.568
    Notes
    [24] - Based on logistic regression with treatment group and smoking status (current vs former/never) as factors and mean frequency of VMS at baseline as a covariate. An odds ratio of > 1 indicated a favorable response in the fezolinetant group.
    Statistical analysis title
    		 Statistical Analysis (Week 16)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 = 0.002
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.812
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.248
         upper limit
    		 2.642
    Notes
    [25] - Based on logistic regression with treatment group and smoking status (current vs former/never) as factors and mean frequency of VMS at baseline as a covariate. An odds ratio of > 1 indicated a favorable response in the fezolinetant group.
    Statistical analysis title
    		 Statistical Analysis (Week 4)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [26]
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.386
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.636
         upper limit
    		 3.499
    Notes
    [26] - Based on logistic regression with treatment group and smoking status (current vs former/never) as factors and mean frequency of VMS at baseline as a covariate. An odds ratio of > 1 indicated a favorable response in the fezolinetant group.
    Statistical analysis title
    		 Statistical Analysis (Week 20)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.403
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.645
         upper limit
    		 3.53
    Notes
    [27] - Based on logistic regression with treatment group and smoking status (current vs former/never) as factors and mean frequency of VMS at baseline as a covariate. An odds ratio of > 1 indicated a favorable response in the fezolinetant group.
    Statistical analysis title
    		 Statistical Analysis (Week 1)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [28]
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    4.377
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.792
         upper limit
    		 7.005
    Notes
    [28] - Based on logistic regression with treatment group and smoking status (current vs former/never) as factors and mean frequency of VMS at baseline as a covariate. An odds ratio of > 1 indicated a favorable response in the fezolinetant group.
    Statistical analysis title
    		 Statistical Analysis (Week 24)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 = 0.002
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.815
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.249
         upper limit
    		 2.647
    Notes
    [29] - Based on logistic regression with treatment group and smoking status (current vs former/never) as factors and mean frequency of VMS at baseline as a covariate. An odds ratio of > 1 indicated a favorable response in the fezolinetant group.

    Secondary: Number of participants with percent reduction of ≥ 75% in the frequency of moderate to severe VMS from baseline at weeks 1, 4, 8, 12, 16, 20 and 24

    		 Close Top of page
    End point title
    		 Number of participants with percent reduction of ≥ 75% in the frequency of moderate to severe VMS from baseline at weeks 1, 4, 8, 12, 16, 20 and 24
    End point description
    The frequency of moderate to severe VMS was the number of moderate to severe VMS per 24 hours. A daily frequency per week was derived by taking the mean of the data over 7 days. Moderate VMS was defined as sensation of heat with sweating/dampness but was able to continue activity. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. FAS population.
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 1, 4, 8, 12, 16, 20 and 24
    End point values
    		 Fezolinetant Placebo
    Number of subjects analysed
    226
    226
    Units: Participants
    number (not applicable)
        Week 1
    35
    5
        Week 4
    90
    39
        Week 8
    104
    69
        Week 12
    110
    66
        Week 16
    104
    67
        Week 20
    109
    66
        Week 24
    106
    67
    Statistical analysis title
    		 Statistical Analysis (Week 1)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [30]
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    8.361
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.49
         upper limit
    		 24.82
    Notes
    [30] - Based on logistic regression with treatment group and smoking status (current vs former/never) as factors and mean frequency of VMS at baseline as a covariate. An odds ratio of > 1 indicated a favorable response in the fezolinetant group.
    Statistical analysis title
    		 Statistical Analysis (Week 4)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.177
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.065
         upper limit
    		 4.958
    Notes
    [31] - Based on logistic regression with treatment group and smoking status (current vs former/never) as factors and mean frequency of VMS at baseline as a covariate. An odds ratio of > 1 indicated a favorable response in the fezolinetant group.
    Statistical analysis title
    		 Statistical Analysis (Week 8)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [32]
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.936
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.318
         upper limit
    		 2.858
    Notes
    [32] - Based on logistic regression with treatment group and smoking status (current vs former/never) as factors and mean frequency of VMS at baseline as a covariate. An odds ratio of > 1 indicated a favorable response in the fezolinetant group.
    Statistical analysis title
    		 Statistical ANalysis (Week 24)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [33]
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.099
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.427
         upper limit
    		 3.103
    Notes
    [33] - Based on logistic regression with treatment group and smoking status (current vs former/never) as factors and mean frequency of VMS at baseline as a covariate. An odds ratio of > 1 indicated a favorable response in the fezolinetant group.
    Statistical analysis title
    		 Statistical Analysis (Week 16)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [34]
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.373
         upper limit
    		 2.987
    Notes
    [34] - Based on logistic regression with treatment group and smoking status (current vs former/never) as factors and mean frequency of VMS at baseline as a covariate. An odds ratio of > 1 indicated a favorable response in the fezolinetant group.
    Statistical analysis title
    		 Statistical Analysis (Week 20)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [35]
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.283
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.547
         upper limit
    		 3.389
    Notes
    [35] - Based on logistic regression with treatment group and smoking status (current vs former/never) as factors and mean frequency of VMS at baseline as a covariate. An odds ratio of > 1 indicated a favorable response in the fezolinetant group.
    Statistical analysis title
    		 Statistical Analysis (Week 12)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [36]
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.298
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.563
         upper limit
    		 3.4
    Notes
    [36] - Based on logistic regression with treatment group and smoking status (current vs former/never) as factors and mean frequency of VMS at baseline as a covariate. An odds ratio of > 1 indicated a favorable response in the fezolinetant group.

    Secondary: Number of participants with percent reduction at 100% in the frequency of moderate to severe VMS from baseline at weeks 1, 4, 8, 12, 16, 20 and 24

    		 Close Top of page
    End point title
    		 Number of participants with percent reduction at 100% in the frequency of moderate to severe VMS from baseline at weeks 1, 4, 8, 12, 16, 20 and 24
    End point description
    The frequency of moderate to severe VMS was the number of moderate to severe VMS per 24 hours. A daily frequency per week was derived by taking the mean of the data over 7 days. Moderate VMS was defined as sensation of heat with sweating/dampness but was able to continue activity. Severe VMS was defined as sensation of intense heat with sweating, caused disruption of activity. FAS population.
    End point type
    Secondary
    End point timeframe
    Baseline, weeks 1, 4, 8, 12, 16, 20 and 24
    End point values
    		 Fezolinetant Placebo
    Number of subjects analysed
    226
    226
    Units: Participants
    number (not applicable)
        Week 1
    0
    0
        Week 4
    18
    8
        Week 8
    35
    17
        Week 12
    49
    22
        Week 16
    50
    27
        Week 20
    47
    27
        Week 24
    50
    24
    Statistical analysis title
    		 Statistical Analysis (Week 4)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [37]
    P-value
    		 = 0.049
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.365
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.037
         upper limit
    		 5.878
    Notes
    [37] - Based on logistic regression with treatment group and smoking status (current vs former/never) as factors and mean frequency of VMS at baseline as a covariate. An odds ratio of > 1 indicated a favorable response in the fezolinetant group.
    Statistical analysis title
    		 Statistical Analysis (Week 8)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [38]
    P-value
    		 = 0.009
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.257
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.239
         upper limit
    		 4.259
    Notes
    [38] - Based on logistic regression with treatment group and smoking status (current vs former/never) as factors and mean frequency of VMS at baseline as a covariate. An odds ratio of > 1 indicated a favorable response in the fezolinetant group.
    Statistical analysis title
    		 Statistical Analysis (Week 12)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [39]
    P-value
    		 < 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.562
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.506
         upper limit
    		 4.485
    Notes
    [39] - Based on logistic regression with treatment group and smoking status (current vs former/never) as factors and mean frequency of VMS at baseline as a covariate. An odds ratio of > 1 indicated a favorable response in the fezolinetant group.
    Statistical analysis title
    		 Statistical Analysis (Week 16)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [40]
    P-value
    		 = 0.005
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.088
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.262
         upper limit
    		 3.52
    Notes
    [40] - Based on logistic regression with treatment group and smoking status (current vs former/never) as factors and mean frequency of VMS at baseline as a covariate. An odds ratio of > 1 indicated a favorable response in the fezolinetant group.
    Statistical analysis title
    		 Statistical Analysis (Week 20)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [41]
    P-value
    		 = 0.013
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.928
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.159
         upper limit
    		 3.624
    Notes
    [41] - Based on logistic regression with treatment group and smoking status (current vs former/never) as factors and mean frequency of VMS at baseline as a covariate. An odds ratio of > 1 indicated a favorable response in the fezolinetant group.
    Statistical analysis title
    		 Statistical Analysis (Week 24)
    Comparison groups
    Fezolinetant v Placebo
    Number of subjects included in analysis
    452
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [42]
    P-value
    		 = 0.001
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.385
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.422
         upper limit
    		 4.098
    Notes
    [42] - Based on logistic regression with treatment group and smoking status (current vs former/never) as factors and mean frequency of VMS at baseline as a covariate. An odds ratio of > 1 indicated a favorable response in the fezolinetant group.

    Secondary: Number of participants with Treatment Emergent Adverse Events (TEAEs)

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    End point title
    		 Number of participants with Treatment Emergent Adverse Events (TEAEs)
    End point description
    An AE is any untoward medical occurrence in a participant administered a study drug, which does not necessarily have to have a causal relationship with this treatment. An AE can be any unfavorable & unintended sign, symptom, or disease temporally associated with the use of medicinal product (MP) whether considered related to MP. A TEAE was defined as an AE observed after starting administration of study intervention and up to 21 days after the last dose of study intervention. Safety Analysis set (SAF) consisted of all randomized participants who received at least one dose of study intervention,
    End point type
    Secondary
    End point timeframe
    From first dose to week 27
    End point values
    		 Fezolinetant Placebo
    Number of subjects analysed
    226
    226
    Units: Participants
        number (not applicable)
    147
    138
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose to week 27
    Adverse event reporting additional description
    SAF population
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    v25.0
    Reporting groups
    Reporting group title
    Fezolinetant
    Reporting group description
    		 Participants received fezolinetant 45 mg up to 24 weeks of treatment and a safety follow-up visit 3 weeks after the EOT visit.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo matched to fezolinetant up to 24 weeks of treatment and a safety follow-up visit 3 weeks after the end of treatment (EOT) visit.

    Serious adverse events
    		 Fezolinetant Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 226 (4.42%)
    8 / 226 (3.54%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Hernia hiatus repair
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory distress
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychotic disorder
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Spinal column injury
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery dissection
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Sciatica
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental impairment
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Enteritis
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureterolithiasis
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pyelonephritis
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelocystitis
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 226 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 226 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Fezolinetant Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    52 / 226 (23.01%)
    49 / 226 (21.68%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    20 / 226 (8.85%)
    21 / 226 (9.29%)
         occurrences all number
    34
    27
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    13 / 226 (5.75%)
    1 / 226 (0.44%)
         occurrences all number
    15
    1
    Infections and infestations
    COVID-19
         subjects affected / exposed
    30 / 226 (13.27%)
    29 / 226 (12.83%)
         occurrences all number
    30
    29

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Mar 2022
    Revised Synopsis and Section 4.1 to clarify that participants who discontinue IP early will remain in the study and continue to complete the electronic daily VMS diary and electronic patient-reported outcome (ePRO) assessments as scheduled through week 24, and be monitored for AEs, SAEs and concomitant medications through week 27. Revised Figure 1 Study Schema footnote ‘*’ to clarify that AEs, SAEs and concomitant medications will be monitored continuously from informed consent until the last study-related activity at week 27 for all participants, including participants who discontinue IP early. For participants who discontinued IP early, their week 27 visit can be conducted virtually. Intake of caffeinated beverages will be monitored continuously from informed consent until the safety follow-up visit (i.e., 3 weeks from the last dose). Revised Table 1 SOA footnote ‘a’ to clarify that participants who discontinue IP early will be monitored for AEs, SAEs and concomitant medications through week 27. Revised Table 1 SOA footnote ‘r’ to clarify that AEs, SAEs and concomitant medications will be monitored continuously from informed consent until the last study-related activity at week 27 for all participants, including participants who discontinue IP early. For participants who discontinue IP early, their week 27 visit can be conducted virtually. Intake of caffeinated beverages will be monitored continuously from informed consent until the safety follow-up visit (i.e., 3 weeks from the last dose).
    18 Mar 2022
    Revised Section 7.3.1 Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event Information to clarify that all AEs and SAEs will be collected for all participants, including participants who discontinue IP early, from signing of the ICF through week 27 at the time points specified in the SOA. Revised Section 8.1 Discontinuation of Individual Participants from Study Treatment to clarify that participants who discontinue IP early will be monitored for AEs, SAEs and concomitant medications through week 27. Revised Section 8.2 Discontinuation of Individual Participant(s) from Study to clarify that all participants who discontinue study treatment will remain in the study to complete the electronic daily VMS diary and ePRO assessments as scheduled through week 24. Participants who discontinue IP early will be monitored for AEs, SAEs and concomitant medications through week 27. Added bullet point to inclusion criterion #3 for hysterectomy without oophorectomy and who meet the biochemical criterion of menopause (FSH > 40 IU/L).

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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