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    Clinical Trial Results:
    A double-blind, randomized, placebo-controlled multicenter study to investigate efficacy and safety of elinzanetant for the treatment of vasomotor symptoms over 26 weeks in postmenopausal women

    Summary
    EudraCT number
    		 2020-004855-34
    Trial protocol
    		 DE   NO   PT   SK   PL   CZ   IT  
    Global end of trial date
    10 Oct 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Oct 2024
    First version publication date
    12 Oct 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    21652
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05099159
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser Wilhelm Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, +49 30300139 003, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, +49 30300139 003, clinical-trials-contact@bayer.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
    03 Nov 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Oct 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of elinzanetant for the treatment of Vasomotor symptoms (VMS) associated with menopause
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Oct 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
    United States: 175
    Country: Number of subjects enrolled
    Czechia: 21
    Country: Number of subjects enrolled
    Germany: 43
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Norway: 23
    Country: Number of subjects enrolled
    Poland: 84
    Country: Number of subjects enrolled
    Portugal: 7
    Country: Number of subjects enrolled
    Slovakia: 13
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    Canada: 27
    Worldwide total number of subjects
    400
    EEA total number of subjects
    197
    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)
    397
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study was conducted at 95 study centers in 10 countries worldwide, between 29-Oct-2021 (first subject first visit) and 10-Oct-2023 (last subject last visit).

    Pre-assignment
    Screening details
    		 A total of 1483 subjects were screened, of whom 1083 subjects were screen failures. Most common reason for screen failure was not meeting the eligibility criteria (1044 subjects). 400 of the screened subjects were randomized to treatment and 324 subjects completed the study.

    Period 1
    Period 1 title
    Overall (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
    		 Elinzanetant 120 mg
    Arm description
    		 Subjects received elinzanetant 120 mg orally once daily for 26 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Elinzanetant
    Investigational medicinal product code
    BAY3427080
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Two capsules of 60 mg elinzanetant once daily before going to bed with or without food for 26 weeks.

    Arm title
    		 Placebo - Elinzanetant 120 mg
    Arm description
    		 Subjects received placebo for 12 weeks, followed by elinzanetant 120 mg orally once daily for 14 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Elinzanetant
    Investigational medicinal product code
    BAY3427080
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Two capsules of 60 mg elinzanetant once daily before going to bed with or without food for week 13-26.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Two capsules of Elinzanetant matching placebo once daily before going to bed with or without food for week 1-12.

    Number of subjects in period 1
    		Elinzanetant 120 mg Placebo - Elinzanetant 120 mg
    Started
    200
    200
    Completed
    157
    167
    Not completed
    43
    33
         Subject Decision
    14
    10
         Adverse event, non-fatal
    7
    3
         Non-compliance with study drug
    1
    4
         Did not complete study treatment but completed FU
    13
    12
         Unspecified
    1
    1
         Lost to follow-up
    6
    1
         Lack of efficacy
    1
    1
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Elinzanetant 120 mg
    Reporting group description
    		 Subjects received elinzanetant 120 mg orally once daily for 26 weeks

    Reporting group title
    Placebo - Elinzanetant 120 mg
    Reporting group description
    		 Subjects received placebo for 12 weeks, followed by elinzanetant 120 mg orally once daily for 14 weeks

    Reporting group values
    		 Elinzanetant 120 mg Placebo - Elinzanetant 120 mg Total
    Number of subjects
    		 200 200 400
    Age Categorical
    Units: Subjects
    Age Continuous
    Units: years
         (standard deviation)
    		 54.8 ( 5.0 ) 54.4 ( 4.5 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 200 200 400
        Male
    		 0 0 0
    Race
    Units: Subjects
        White
    		 163 172 335
        Black or African American
    		 35 25 60
        Asian
    		 0 1 1
        American Indian or Alaska Native
    		 1 1 2
        Multiple
    		 0 1 1
        Not reported
    		 1 0 1
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    		 186 175 361
        Hispanic or Latino
    		 13 24 37
        Other
    		 1 1 2
    Mean frequency of moderate to severe hot flash (HF) at baseline
    Subjects’ assessments of HF were recorded electronically using the sponsor developed Hot Flash Daily Diary (HFDD). HFDD items assessed the number of mild, moderate, and severe HF experienced during the day and during the night. Mild HF was defined as a “sensation of heat without sweating”, moderate HF was defined as a “sensation of heat with sweating, but able to continue activity”, and severe HF was defined as a “sensation of heat with sweating, causing cessation (stopping) of activity”. The number of analyzed subjects was 199 for elinzanetant 120 mg and 200 for placebo - elinzanetant 120 mg.
    Units: Hot flashes per day
        arithmetic mean (standard deviation)
    		 14.66 ( 11.08 ) 16.16 ( 11.15 ) -
    Mean severity of moderate to severe HF at baseline
    The HFDD items assessed the number of mild, moderate, and severe HF experienced during the day and during the night. Mild HF are defined as a “sensation of heat without sweating”, moderate HF are defined as a “sensation of heat with sweating, but able to continue activity”, and severe HF are defined as a “sensation of heat with sweating, causing cessation (stopping) of activity”. The number of analyzed subjects was 199 for elinzanetant 120 mg and 200 for placebo - elinzanetant 120 mg.
    Units: Severity scale
        arithmetic mean (standard deviation)
    		 2.53 ( 0.24 ) 2.54 ( 0.24 ) -
    PROMIS SD SF 8b total T-score at baseline
    The PROMIS SD SF 8b included 8 items assessing sleep disturbance over the past 7 days. Items assessed sleep quality, sleep depth and restoration associated with sleep, perceived difficulties with getting to sleep or staying asleep and perceptions of the adequacy of and satisfaction with sleep. A total raw scores (range 8–40), which were converted to total T-scores for analysis of this endpoint (range 28.9–76.5), with higher scores indicating greater severity of sleep disturbance. The number of analyzed subjects was 188 for elinzanetant 120 mg and and 193 for placebo - elinzanetant 120 mg.
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    		 61.7 ( 6.2 ) 60.7 ( 7.2 ) -
    Beck depression inventory (BDI-II) total score at baseline
    The BDI-II consisted of 21 items to assess the severity of depression over the past 2 weeks. Each item was a list of four statements arranged in increasing levels of severity about a particular symptom of depression. Items used a 4-point verbal response scale ranging from 0 (not at all) to 3 (extreme form of each symptom); specific response options were tailored to the aspect of depression being measured in each item.
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    		 6.6 ( 6.5 ) 7.2 ( 6.8 ) -
    Menopause-specific quality of life scale (MENQOL) total score at baseline
    The MENQOL questionnaire was comprised of 29 items assessing the presence of menopausal symptoms and the impact of menopause on health-related quality of life over the past week. The items assessed four domains of symptoms and functioning: VMS, psychosocial functioning, physical functioning, and sexual functioning. Based on the individual responses, item scores, domain scores, and a total MENQOL score were calculated. Each score ranged from 1-8, higher scores indicated greater bother. The number of analyzed subjects was 186 for elinzanetant 120 mg and 189 for placebo - elinzanetant 120 mg.
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    		 4.48 ( 1.14 ) 4.49 ( 1.17 ) -

    End points

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    End points reporting groups
    Reporting group title
    Elinzanetant 120 mg
    Reporting group description
    		 Subjects received elinzanetant 120 mg orally once daily for 26 weeks

    Reporting group title
    Placebo - Elinzanetant 120 mg
    Reporting group description
    		 Subjects received placebo for 12 weeks, followed by elinzanetant 120 mg orally once daily for 14 weeks

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized subjects were included. Subjects in the full analysis set were analyzed according to the randomized intervention (intention-to-treat).

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All subjects who received at least one dose of study intervention were analyzed according to the intervention they received.

    Primary: Mean change in frequency of moderate to severe HF from baseline to Week 4 (assessed by HFDD)

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    End point title
    		 Mean change in frequency of moderate to severe HF from baseline to Week 4 (assessed by HFDD)
    End point description
    Subjects’ assessments of HF were recorded electronically twice daily using the sponsor developed Hot Flash Daily Diary (HFDD). The HFDD was completed in the morning after waking up (morning diary) and each evening at bedtime (evening diary) on the hand-held device. The HFDD items assessed the number of mild, moderate, and severe HF experienced during the day and during the night. Mild HF was defined as a “sensation of heat without sweating”, moderate HF was defined as a “sensation of heat with sweating, but able to continue activity”, and severe HF was defined as a “sensation of heat with sweating, causing cessation (stopping) of activity”. The frequency of moderate to severe HF for each week during the treatment period was calculated using the available data during that particular week. Specifically, for Week 4, Day 22-28 were used (Day 1 corresponds to start of treatment).
    End point type
    Primary
    End point timeframe
    From baseline to Week 4
    End point values
    		 Elinzanetant 120 mg Placebo - Elinzanetant 120 mg
    Number of subjects analysed
    185 [1]
    192 [2]
    Units: Hot Flashes per day
        arithmetic mean (standard deviation)
    -8.58 ( 9.16 )
    -6.07 ( 8.91 )
    Notes
    [1] - FAS
    [2] - FAS
    Statistical analysis title
    		 Elinzanetant 120 mg vs placebo
    Statistical analysis description
    The total number of subjects with observed value for this timepoint, who were considered in the analysis model, was 384. This included subjects who prematurely discontinued study drug, and continued in a post-treatment period who were not considered under “number of subjects included in analysis” given below.
    Comparison groups
    Elinzanetant 120 mg v Placebo - Elinzanetant 120 mg
    Number of subjects included in analysis
    377
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [3]
    Method
    		 Mixed model repeated measures (MMRM)
    Parameter type
    		 Least squares (LS)-means
    Point estimate
    -3.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.4
         upper limit
    		 -1.68
    Notes
    [3] - one-sided

    Primary: Mean change in frequency of moderate to severe HF from baseline to Week 12 (assessed by HFDD)

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    End point title
    		 Mean change in frequency of moderate to severe HF from baseline to Week 12 (assessed by HFDD)
    End point description
    Subjects’ assessments of HF were recorded electronically twice daily using the sponsor developed Hot Flash Daily Diary (HFDD). The HFDD was completed in the morning after waking up (morning diary) and each evening at bedtime (evening diary) on the hand-held device. The HFDD items assessed the number of mild, moderate, and severe HF experienced during the day and during the night. Mild HF was defined as a “sensation of heat without sweating”, moderate HF was defined as a “sensation of heat with sweating, but able to continue activity”, and severe HF was defined as a “sensation of heat with sweating, causing cessation (stopping) of activity”. The frequency of moderate to severe HF for each week during the treatment period was calculated using the available data during that particular week. Specifically, for Week 12, Day 78-84 were used (Day 1 corresponds to start of treatment).
    End point type
    Primary
    End point timeframe
    From baseline to Week 12
    End point values
    		 Elinzanetant 120 mg Placebo - Elinzanetant 120 mg
    Number of subjects analysed
    174 [4]
    180 [5]
    Units: Hot flashes per day
        arithmetic mean (standard deviation)
    -9.96 ( 10.25 )
    -7.24 ( 8.49 )
    Notes
    [4] - FAS
    [5] - FAS
    Statistical analysis title
    		 Elinzanetant 120 mg vs placebo
    Statistical analysis description
    The total number of subjects with observed value for this timepoint, who were considered in the analysis model, was 364. This included subjects who prematurely discontinued study drug, and continued in a post-treatment period who were not considered under “number of subjects included in analysis” given below.
    Comparison groups
    Elinzanetant 120 mg v Placebo - Elinzanetant 120 mg
    Number of subjects included in analysis
    354
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [6]
    Method
    		 MMRM
    Parameter type
    		 LS-means
    Point estimate
    -3.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.6
         upper limit
    		 -1.88
    Notes
    [6] - One-sided

    Secondary: Mean change in severity of moderate to severe HF from baseline to Week 4 (assessed by HFDD)

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    End point title
    		 Mean change in severity of moderate to severe HF from baseline to Week 4 (assessed by HFDD)
    End point description
    In the HFDD, the severity of HFs was categorized as: 1 = mild, 2 = moderate, and 3 = severe; therefore, a decrease in the HF severity score indicates an improvement. The HFDD items assessed the number of mild, moderate, and severe HF experienced during the day and during the night. Mild HF are defined as a “sensation of heat without sweating”, moderate HF are defined as a “sensation of heat with sweating, but able to continue activity”, and severe HF are defined as a “sensation of heat with sweating, causing cessation (stopping) of activity”.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 4
    End point values
    		 Elinzanetant 120 mg Placebo - Elinzanetant 120 mg
    Number of subjects analysed
    185 [7]
    192 [8]
    Units: Severity scale
        arithmetic mean (standard deviation)
    -0.75 ( 0.68 )
    -0.53 ( 0.55 )
    Notes
    [7] - FAS
    [8] - FAS
    Statistical analysis title
    		 Elinzanetant 120 mg vs placebo
    Statistical analysis description
    The total number of subjects with observed value for this timepoint, who were considered in the analysis model, was 384. This included subjects who prematurely discontinued study drug, and continued in a post-treatment period who were not considered under “number of subjects included in analysis” given below.
    Comparison groups
    Elinzanetant 120 mg v Placebo - Elinzanetant 120 mg
    Number of subjects included in analysis
    377
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0003 [9]
    Method
    		 MMRM
    Parameter type
    		 LS-means
    Point estimate
    -0.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.34
         upper limit
    		 -0.09
    Notes
    [9] - One-sided

    Secondary: Mean change in severity of moderate to severe HF from baseline to Week 12 (assessed by HFDD)

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    End point title
    		 Mean change in severity of moderate to severe HF from baseline to Week 12 (assessed by HFDD)
    End point description
    In the HFDD, the severity of HFs was categorized as: 1 = mild, 2 = moderate, and 3 = severe; therefore, a decrease in the HF severity score indicates an improvement. The HFDD items assessed the number of mild, moderate, and severe HF experienced during the day and during the night. Mild HF are defined as a “sensation of heat without sweating”, moderate HF are defined as a “sensation of heat with sweating, but able to continue activity”, and severe HF are defined as a “sensation of heat with sweating, causing cessation (stopping) of activity”.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 12
    End point values
    		 Elinzanetant 120 mg Placebo - Elinzanetant 120 mg
    Number of subjects analysed
    174 [10]
    180 [11]
    Units: Severity scale
        arithmetic mean (standard deviation)
    -0.97 ( 0.78 )
    -0.65 ( 0.67 )
    Notes
    [10] - FAS
    [11] - FAS
    Statistical analysis title
    		 Elinzanetant 120 mg vs placebo
    Statistical analysis description
    The total number of subjects with observed value for this timepoint, who were considered in the analysis model, was 364. This included subjects who prematurely discontinued study drug, and continued in a post-treatment period who were not considered under “number of subjects included in analysis” given below.
    Comparison groups
    Elinzanetant 120 mg v Placebo - Elinzanetant 120 mg
    Number of subjects included in analysis
    354
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [12]
    Method
    		 MMRM
    Parameter type
    		 LS-means
    Point estimate
    -0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.44
         upper limit
    		 -0.14
    Notes
    [12] - One-sided

    Secondary: Mean change in frequency of moderate to severe HF from baseline to Week 1 (assessed by HFDD)

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    End point title
    		 Mean change in frequency of moderate to severe HF from baseline to Week 1 (assessed by HFDD)
    End point description
    Subjects’ assessments of HF were recorded electronically twice daily using the sponsor developed HFDD. The HFDD was completed in the morning after waking up (morning diary) and each evening at bedtime (evening diary) on the hand-held device.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 1
    End point values
    		 Elinzanetant 120 mg Placebo - Elinzanetant 120 mg
    Number of subjects analysed
    198 [13]
    197 [14]
    Units: Hot flashes per day
        arithmetic mean (standard deviation)
    -4.66 ( 6.70 )
    -3.57 ( 6.86 )
    Notes
    [13] - FAS
    [14] - FAS
    Statistical analysis title
    		 Elinzanetant 120 mg vs placebo
    Statistical analysis description
    The total number of subjects with observed value for this timepoint, who were considered in the analysis model, was 395. This included subjects who prematurely discontinued study drug, and continued in a post-treatment period who were not considered under “number of subjects included in analysis” given below.
    Comparison groups
    Elinzanetant 120 mg v Placebo - Elinzanetant 120 mg
    Number of subjects included in analysis
    395
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0013 [15]
    Method
    		 Mixed model repeated measures (MMRM)
    Parameter type
    		 LS-means
    Point estimate
    -1.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.73
         upper limit
    		 -0.58
    Notes
    [15] - One side

    Secondary: Mean change in frequency of moderate to severe HF from baseline over time (assessed by HFDD)

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    End point title
    		 Mean change in frequency of moderate to severe HF from baseline over time (assessed by HFDD)
    End point description
    The frequency of moderate to severe HF for each week during the treatment period was calculated using the available data during that particular week. Specifically, for Week 1 Days 2-8 were used instead of 1-7, because the intake started on Day 1 only before going to bed, for Week 4 Days 22-28 were used and for Week 12 Days 78-84 were used (Day 1 corresponds to start of treatment). These data were aggregated to a mean daily frequency as (total number of moderate to severe HF during that week) / (total number of available days with data during that week). In case data is not available for more than 2 days within a week, the value for that particular week was be set to missing.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 30
    End point values
    		 Elinzanetant 120 mg Placebo - Elinzanetant 120 mg
    Number of subjects analysed
    200
    200
    Units: Hot flashes per day
    arithmetic mean (standard deviation)
        Week 1 (n=198, 197)
    -4.66 ( 6.70 )
    -3.57 ( 6.86 )
        Week 4 (n=185, 192)
    -8.58 ( 9.16 )
    -6.07 ( 8.91 )
        Week 8 (n=178, 181)
    -9.67 ( 10.02 )
    -6.91 ( 9.07 )
        Week 12 (n=174, 180)
    -9.96 ( 10.25 )
    -7.24 ( 8.49 )
        Week 16 (n=166, 175)
    -10.96 ( 11.55 )
    -10.89 ( 9.54 )
        Week 20 (n=162, 169)
    -11.60 ( 11.54 )
    -11.26 ( 9.31 )
        Week 26 (n=108, 120)
    -11.76 ( 11.38 )
    -12.76 ( 12.28 )
        Week 30 (n=132, 134)
    -7.90 ( 11.68 )
    -9.36 ( 11.71 )
    No statistical analyses for this end point

    Secondary: Mean change in patient-reported outcomes measurement information system sleep disturbance short form 8b (PROMIS SD SF 8b) total T-score from baseline to Week 12

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    End point title
    		 Mean change in patient-reported outcomes measurement information system sleep disturbance short form 8b (PROMIS SD SF 8b) total T-score from baseline to Week 12
    End point description
    The PROMIS SD SF 8b included 8 items assessing sleep disturbance over the past 7 days. Items assessed sleep quality, sleep depth and restoration associated with sleep, perceived difficulties with getting to sleep or staying asleep and perceptions of the adequacy of and satisfaction with sleep. Subjects responded to the items on a 5-point scale from not at all, never or very poor to very much, always or very good. Four of the items were scored reversely. A total raw scores (range 8–40), which were converted to total T-scores for analysis of this endpoint (range 28.9–76.5), with higher scores indicating greater severity of sleep disturbance.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 12
    End point values
    		 Elinzanetant 120 mg Placebo - Elinzanetant 120 mg
    Number of subjects analysed
    161 [16]
    172 [17]
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -10.6 ( 7.7 )
    -5.5 ( 6.9 )
    Notes
    [16] - FAS
    [17] - FAS
    Statistical analysis title
    		 Elinzanetant 120 mg vs placebo
    Statistical analysis description
    The total number of subjects with observed value for this timepoint, who were considered in the analysis model, was 361. This included subjects who prematurely discontinued study drug, and continued in a post-treatment period who were not considered under “number of subjects included in analysis” given below.
    Comparison groups
    Elinzanetant 120 mg v Placebo - Elinzanetant 120 mg
    Number of subjects included in analysis
    333
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [18]
    Method
    		 MMRM
    Parameter type
    		 LS-means
    Point estimate
    -4.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.77
         upper limit
    		 -2.86
    Notes
    [18] - One-sided

    Secondary: Mean change in menopause specific quality of life scale (MENQOL) total score from baseline to Week 12

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    End point title
    		 Mean change in menopause specific quality of life scale (MENQOL) total score from baseline to Week 12
    End point description
    The MENQOL questionnaire was comprised of 29 items assessing the presence of menopausal symptoms and the impact of menopause on health-related quality of life over the past week. The items assessed four domains of symptoms and functioning: VMS, psychosocial functioning, physical functioning, and sexual functioning. For each item, the subjects indicated if they had experienced the symptom (yes/no). If subjects selected yes, subjects rated how bothered they were by the symptom using a six-point verbal descriptor scale, with response options ranging from 0 'not at all bothered' to 6 'extremely bothered'. Based on the individual responses, item scores, domain scores, and a total MENQOL score were calculated. The four domain scores were calculated as a mean of converted single item scores (range 1–8), and the mean of the four domain scores yielded the MENQOL total score. Higher scores indicated greater bother.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 12
    End point values
    		 Elinzanetant 120 mg Placebo - Elinzanetant 120 mg
    Number of subjects analysed
    157 [19]
    167 [20]
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -1.34 ( 1.29 )
    -0.97 ( 1.16 )
    Notes
    [19] - FAS
    [20] - FAS
    Statistical analysis title
    		 Elinzanetant 120 mg vs placebo
    Statistical analysis description
    The total number of subjects with observed value for this timepoint, who were considered in the analysis model, was 355. This included subjects who prematurely discontinued study drug, and continued in a post-treatment period who were not considered under “number of subjects included in analysis” given below.
    Comparison groups
    Elinzanetant 120 mg v Placebo - Elinzanetant 120 mg
    Number of subjects included in analysis
    324
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0059 [21]
    Method
    		 MMRM
    Parameter type
    		 LS-means
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.53
         upper limit
    		 -0.07
    Notes
    [21] - One-sided

    Secondary: Mean change in Beck depression inventory (BDI-II) total score from baseline to Week 12

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    End point title
    		 Mean change in Beck depression inventory (BDI-II) total score from baseline to Week 12
    End point description
    The BDI-II consisted of 21 items to assess the severity of depression over the past 2 weeks. Each item was a list of four statements arranged in increasing levels of severity about a particular symptom of depression. Items used a 4-point verbal response scale ranging from 0 (not at all) to 3 (extreme form of each symptom); specific response options were tailored to the aspect of depression being measured in each item. A total score ranging from 0 to 63 was calculated with scores of 0-13 indicating mild minimal range, 14 – 19 indicating mild depression, 20 – 28 indicating moderate and 29 – 63 indicating severe depression (higher score = greater depression).
    End point type
    Secondary
    End point timeframe
    From baseline to Week 12
    End point values
    		 Elinzanetant 120 mg Placebo - Elinzanetant 120 mg
    Number of subjects analysed
    170 [22]
    174 [23]
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -0.2 ( 8.3 )
    0.8 ( 8.6 )
    Notes
    [22] - FAS
    [23] - FAS
    No statistical analyses for this end point

    Secondary: Mean change in BDI-II total score from baseline to Week 26

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    End point title
    		 Mean change in BDI-II total score from baseline to Week 26
    End point description
    The BDI-II consisted of 21 items to assess the severity of depression over the past 2 weeks. Each item was a list of four statements arranged in increasing levels of severity about a particular symptom of depression. Items used a 4-point verbal response scale ranging from 0 (not at all) to 3 (extreme form of each symptom); specific response options were tailored to the aspect of depression being measured in each item. A total score ranging from 0 to 63 was calculated with scores of 0-13 indicating mild minimal range, 14 – 19 indicating mild depression, 20 – 28 indicating moderate and 29 – 63 indicating severe depression (higher score = greater depression).
    End point type
    Secondary
    End point timeframe
    From baseline to Week 26
    End point values
    		 Elinzanetant 120 mg Placebo - Elinzanetant 120 mg
    Number of subjects analysed
    111 [24]
    110 [25]
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -1.0 ( 6.9 )
    -1.1 ( 6.7 )
    Notes
    [24] - FAS
    [25] - FAS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the start of study medication up to 14 days after the last dose of medication, approximately 28 weeks.
    Adverse event reporting additional description
    Adverse event reporting for the deaths (all causes) considers all deaths that occurred at any time during the study before the last contact, approximately 30 weeks.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Elinzanetant 120mg Week 1-12
    Reporting group description
    		 Subjects who received elinzanetant 120 mg during Weeks 1-12. Reported AEs for the exposure period Week 1-12 to elinzanetant.

    Reporting group title
    Placebo Week 1-12
    Reporting group description
    		 Subjects who received placebo during Weeks 1-12. Reported AEs for the exposure period to placebo.

    Reporting group title
    Elinzanetant 120mg Week 1-26
    Reporting group description
    		 Subjects who received elinzanetant 120 mg at any time during the study (including those who switched from placebo to elinzanetant 120 mg at Week 13). Reported AEs for the exposure period to elinzanetant for both treatment groups.

    Reporting group title
    Placebo - Elinzanetant 120mg Week 13-26
    Reporting group description
    		 Subjects who received placebo during Weeks 1-12 and switched to elinzanetant 120 mg after Week 12. Reported AEs for the exposure period to elinzanetant.

    Reporting group title
    Elinzanetant 120mg Week 13-26
    Reporting group description
    		 Subjects who received elinzanetant 120 mg during Week 1-12 and continued with elinzanetant 120 mg after Week 12. Reported AEs for the exposure period Week 13 - 26 to elinzanetant.

    Serious adverse events
    		 Elinzanetant 120mg Week 1-12 Placebo Week 1-12 Elinzanetant 120mg Week 1-26 Placebo - Elinzanetant 120mg Week 13-26 Elinzanetant 120mg Week 13-26
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 201 (0.50%)
    1 / 199 (0.50%)
    5 / 381 (1.31%)
    3 / 180 (1.67%)
    1 / 171 (0.58%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
    1 / 381 (0.26%)
    0 / 180 (0.00%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 199 (0.00%)
    1 / 381 (0.26%)
    1 / 180 (0.56%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Mechanical ileus
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 199 (0.00%)
    1 / 381 (0.26%)
    1 / 180 (0.56%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 199 (0.00%)
    1 / 381 (0.26%)
    0 / 180 (0.00%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Joint range of motion decreased
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 199 (0.00%)
    1 / 381 (0.26%)
    1 / 180 (0.56%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pyelonephritis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
    0 / 381 (0.00%)
    0 / 180 (0.00%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 199 (0.00%)
    1 / 381 (0.26%)
    0 / 180 (0.00%)
    1 / 171 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 199 (0.50%)
    0 / 381 (0.00%)
    0 / 180 (0.00%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device loosening
         subjects affected / exposed
    0 / 201 (0.00%)
    0 / 199 (0.00%)
    1 / 381 (0.26%)
    1 / 180 (0.56%)
    0 / 171 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Elinzanetant 120mg Week 1-12 Placebo Week 1-12 Elinzanetant 120mg Week 1-26 Placebo - Elinzanetant 120mg Week 13-26 Elinzanetant 120mg Week 13-26
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 201 (16.92%)
    25 / 199 (12.56%)
    45 / 381 (11.81%)
    8 / 180 (4.44%)
    5 / 171 (2.92%)
    Investigations
    Depression rating scale score increased
         subjects affected / exposed
    9 / 201 (4.48%)
    17 / 199 (8.54%)
    11 / 381 (2.89%)
    2 / 180 (1.11%)
    0 / 171 (0.00%)
         occurrences all number
    10
    19
    12
    2
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    18 / 201 (8.96%)
    5 / 199 (2.51%)
    24 / 381 (6.30%)
    4 / 180 (2.22%)
    4 / 171 (2.34%)
         occurrences all number
    21
    5
    30
    4
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    11 / 201 (5.47%)
    3 / 199 (1.51%)
    15 / 381 (3.94%)
    3 / 180 (1.67%)
    1 / 171 (0.58%)
         occurrences all number
    14
    3
    18
    3
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Feb 2022
    Changes in protocol amendment 1 consist of three types, (i) address comments from authorities (FDA and Portuguese Health Authority) during the initial CTA review process, (ii) help to clarify certain aspects of the protocol or (iii) minor corrections. In addition, the sleep quality tracking sub-study was removed due to technical difficulties.
    22 Jun 2022
    Changes in protocol amendment 2 consist of three types, (i) address comments from FDA, (ii) help to clarify certain aspects of the protocol or (iii) minor corrections.

    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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