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    Clinical Trial Results:
    A Multicenter, Double-Blind, Randomized, Parallel-Group, Placebo-Controlled, Study to Evaluate the Efficacy and Safety of Seltorexant 20 mg as Adjunctive Therapy to Antidepressants in Adult and Elderly Patients with Major Depressive Disorder with Insomnia Symptoms Who Have Responded Inadequately to Antidepressant Therapy and an Open-labeled Long-term Safety Extension Treatment with Seltorexant.

    Summary
    EudraCT number
    		 2020-000337-40
    Trial protocol
    		 CZ   BG  
    Global end of trial date
    30 Apr 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 May 2025
    First version publication date
    16 May 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CR108804
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04533529
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    920 Route 202 South, Raritan, New Jersey, United States, 08869
    Public contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.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
    30 Apr 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Apr 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this trial was to assess the efficacy of seltorexant 20 milligrams compared with placebo as adjunctive therapy to an antidepressant in improving depressive symptoms in subjects with major depressive disorder with insomnia symptoms (MDDIS) who had an inadequate response to current antidepressant therapy with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI).
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements.
    Background therapy
    		 Selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI)
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Sep 2020
    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
    Bulgaria: 77
    Country: Number of subjects enrolled
    Czechia: 78
    Country: Number of subjects enrolled
    Spain: 26
    Country: Number of subjects enrolled
    Sweden: 70
    Country: Number of subjects enrolled
    Brazil: 89
    Country: Number of subjects enrolled
    Colombia: 41
    Country: Number of subjects enrolled
    Mexico: 30
    Country: Number of subjects enrolled
    Russian Federation: 21
    Country: Number of subjects enrolled
    South Africa: 18
    Country: Number of subjects enrolled
    Taiwan: 19
    Country: Number of subjects enrolled
    United States: 117
    Worldwide total number of subjects
    586
    EEA total number of subjects
    251
    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)
    535
    From 65 to 84 years
    51
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 588 subjects were enrolled and randomised, 586 were treated with either seltorexant or matching placebo (2 randomised subjects didn't meet enrollment criteria and were withdrawn before treatment).

    Pre-assignment
    Screening details
    		 Out of 586 treated subjects, 540 completed the double-blind (DB) phase, 522 entered the open-label (OL) phase, and 360 completed OL phase.

    Period 1
    Period 1 title
    DB Treatment phase (Day 1 to Day 43)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Double -blind Phase (DB): Placebo
    Arm description
    		 During DB phase, subjects with major depressive disorder (MDD) with or without insomnia symptoms (IS) who had an inadequate response to an ongoing antidepressant therapy with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) were randomised to receive placebo (matching to seltorexant) once daily from Day 1 to Day 42 as an adjunctive therapy to SSRI/SNRI antidepressant therapy.
    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
    Subjects received placebo matching to seltorexant tablet orally once daily from Day 1 to Day 42.

    Arm title
    		 DB: Seltorexant 20 mg
    Arm description
    		 During DB phase, subjects with MDD with or without IS who had an inadequate response to an ongoing antidepressant therapy with a SSRI or SNRI were randomised to receive seltorexant 20 milligrams (mg) tablet orally once daily from Day 1 to Day 42 as an adjunctive therapy to SSRI/SNRI antidepressant therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Seltorexant
    Investigational medicinal product code
    JNJ-42847922
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received seltorexant 20 mg tablet orally once daily from Day 1 to Day 42.

    Number of subjects in period 1
    		Double -blind Phase (DB): Placebo DB: Seltorexant 20 mg
    Started
    303
    283
    Completed
    277
    263
    Not completed
    26
    20
         Consent withdrawn by subject
    11
    6
         Physician decision
    -
    2
         Adverse event, non-fatal
    5
    5
         Initiated prohibited medication
    1
    -
         Non-Compliance with primary antidepressant
    2
    -
         Pregnancy
    -
    1
         Non-Compliance with study drug
    3
    3
         Lost to follow-up
    2
    1
         Protocol deviation
    1
    2
         Lack of efficacy
    1
    -
    Period 2
    Period 2 title
    OL Treatment Phase (Day 43 to 1 year)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 OL Treatment Phase: Seltorexant 20 mg
    Arm description
    		 Subjects who received placebo or seltorexant 20 mg tablet in the DB treatment phase entered OL phase and received seltorexant 20 mg tablet orally, once daily from Day 43 up to 1 year as an adjunctive therapy to ongoing SSRI/SNRI antidepressant therapy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Seltorexant
    Investigational medicinal product code
    JNJ-42847922
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received seltorexant 20 mg tablet orally, once daily from Day 43 up to 1 year.

    Number of subjects in period 2 [1]
    		OL Treatment Phase: Seltorexant 20 mg
    Started
    522
    Completed
    360
    Not completed
    162
         Adverse event, serious fatal
    1
         Consent withdrawn by subject
    64
         Physician decision
    1
         Adverse event, non-fatal
    33
         Initiated prohibited medication
    6
         Non-Compliance with primary antidepressant
    3
         Site terminated by sponsor
    3
         Non-Compliance with study drug
    11
         Unspecified
    2
         Lost to follow-up
    13
         Lack of efficacy
    22
         Protocol deviation
    3
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Only reported subjects were eligible to include in the current period.
    Period 3
    Period 3 title
    DB FU (Day 44 to Day 57)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DB Follow-up (FU) Phase: Placebo
    Arm description
    		 After completion or discontinuation from the DB treatment, subjects who did not enter the OL phase entered DB follow up phase and were followed up for safety up to 14 days from Day 43 up to Day 57.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 DB FU Phase: Seltorexant 20 mg
    Arm description
    		 After completion or discontinuation from the DB treatment, subjects who did not enter the OL phase entered DB follow up phase and were followed up for safety up to 14 days from Day 43 up to Day 57.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3 [2]
    		DB Follow-up (FU) Phase: Placebo DB FU Phase: Seltorexant 20 mg
    Started
    22
    22
    Completed
    18
    15
    Not completed
    4
    7
         Consent withdrawn by subject
    2
    4
         Adverse event, non-fatal
    -
    2
         Unspecified
    1
    1
         Lost to follow-up
    1
    -
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Only reported subjects were eligible to include in the current period.
    Period 4
    Period 4 title
    OL FU (1 year to 1 year, 2 weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 OL FU Phase: Seltorexant 20 mg
    Arm description
    		 After completion of OL treatment phase, subjects were followed up for safety up to 7 to14 days from 1 year up to 1 year 2 weeks.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 4
    		OL FU Phase: Seltorexant 20 mg
    Started
    453
    Completed
    425
    Not completed
    28
         Consent withdrawn by subject
    16
         Adverse event, non-fatal
    4
         Site terminated by sponsor
    1
         Unspecified
    2
         Lost to follow-up
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Double -blind Phase (DB): Placebo
    Reporting group description
    		 During DB phase, subjects with major depressive disorder (MDD) with or without insomnia symptoms (IS) who had an inadequate response to an ongoing antidepressant therapy with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) were randomised to receive placebo (matching to seltorexant) once daily from Day 1 to Day 42 as an adjunctive therapy to SSRI/SNRI antidepressant therapy.

    Reporting group title
    DB: Seltorexant 20 mg
    Reporting group description
    		 During DB phase, subjects with MDD with or without IS who had an inadequate response to an ongoing antidepressant therapy with a SSRI or SNRI were randomised to receive seltorexant 20 milligrams (mg) tablet orally once daily from Day 1 to Day 42 as an adjunctive therapy to SSRI/SNRI antidepressant therapy.

    Reporting group values
    		 Double -blind Phase (DB): Placebo DB: Seltorexant 20 mg Total
    Number of subjects
    		 303 283
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 45.9 ( 14.28 ) 44.3 ( 13.99 ) -
    Gender categorical
    Units: Subjects
        Male
    		 71 66 137
        Female
    		 232 217 449

    End points

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    End points reporting groups
    Reporting group title
    Double -blind Phase (DB): Placebo
    Reporting group description
    		 During DB phase, subjects with major depressive disorder (MDD) with or without insomnia symptoms (IS) who had an inadequate response to an ongoing antidepressant therapy with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) were randomised to receive placebo (matching to seltorexant) once daily from Day 1 to Day 42 as an adjunctive therapy to SSRI/SNRI antidepressant therapy.

    Reporting group title
    DB: Seltorexant 20 mg
    Reporting group description
    		 During DB phase, subjects with MDD with or without IS who had an inadequate response to an ongoing antidepressant therapy with a SSRI or SNRI were randomised to receive seltorexant 20 milligrams (mg) tablet orally once daily from Day 1 to Day 42 as an adjunctive therapy to SSRI/SNRI antidepressant therapy.
    Reporting group title
    OL Treatment Phase: Seltorexant 20 mg
    Reporting group description
    		 Subjects who received placebo or seltorexant 20 mg tablet in the DB treatment phase entered OL phase and received seltorexant 20 mg tablet orally, once daily from Day 43 up to 1 year as an adjunctive therapy to ongoing SSRI/SNRI antidepressant therapy.
    Reporting group title
    DB Follow-up (FU) Phase: Placebo
    Reporting group description
    		 After completion or discontinuation from the DB treatment, subjects who did not enter the OL phase entered DB follow up phase and were followed up for safety up to 14 days from Day 43 up to Day 57.

    Reporting group title
    DB FU Phase: Seltorexant 20 mg
    Reporting group description
    		 After completion or discontinuation from the DB treatment, subjects who did not enter the OL phase entered DB follow up phase and were followed up for safety up to 14 days from Day 43 up to Day 57.
    Reporting group title
    OL FU Phase: Seltorexant 20 mg
    Reporting group description
    		 After completion of OL treatment phase, subjects were followed up for safety up to 7 to14 days from 1 year up to 1 year 2 weeks.

    Primary: Double-blind (DB) Phase: Change From Baseline to Day 43 in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score : Estimand 2

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    End point title
    		 Double-blind (DB) Phase: Change From Baseline to Day 43 in Montgomery-Asberg Depression Rating Scale (MADRS) Total Score : Estimand 2
    End point description
    MADRS, clinician-rated scale designed to measure depression severity and detected changes due to antidepressant intervention. Scale consisted of 10 items, each of which was scored from 0 (not present or normal) to 6 (severe or continuous presence of symptoms). MADRS evaluated reported sadness, apparent sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic and suicidal thoughts. MADRS total score was sum of scores from individual question items, which ranged from 0-60. Higher scores represented a more severe condition. Negative changes in MADRS total score indicated improvement. Full analysis set 2 (FAS2) included all randomised subjects with major depressive disorder with insomnia symptoms (MDDIS) per interactive web response system (IWRS) who received at least 1 dose of study intervention in DB phase. Here, 'N' (overall number of subjects analysed) signifies subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    DB: Baseline (Day 1), Day 43
    End point values
    		 Double -blind Phase (DB): Placebo DB: Seltorexant 20 mg
    Number of subjects analysed
    207
    201
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -10.2 ( 10.20 )
    -12.9 ( 9.53 )
    Statistical analysis title
    		 Statistical Analysis set -1
    Comparison groups
    DB: Seltorexant 20 mg v Double -blind Phase (DB): Placebo
    Number of subjects included in analysis
    408
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.007
    Method
    		 mixed model repeated measures (MMRM)
    Parameter type
    		 Least square (LS) difference
    Point estimate
    -2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.35
         upper limit
    		 -0.68
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.94

    Primary: Open Label (OL) Treatment Phase: Number of Subjects with Treatment Emergent Adverse Events (TEAEs)

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    End point title
    		 Open Label (OL) Treatment Phase: Number of Subjects with Treatment Emergent Adverse Events (TEAEs) [1]
    End point description
    An AE was defined as any untoward medical occurrence in a clinical investigation subject administered a medicinal (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the study drug. Treatment emergent AEs was defined as any AE occurred at or after the initial administration of study intervention through the day of last dose plus 2 days. The safety (OL) analysis set included all randomised subjects who received at least 1 dose of study intervention in the OL phase.
    End point type
    Primary
    End point timeframe
    From start of the treatment in OL phase (Day 1 [Day 43 from study baseline]) up to 2 days after last dose (up to 52 weeks of the OL phase)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    		 OL Treatment Phase: Seltorexant 20 mg
    Number of subjects analysed
    522
    Units: Subjects
    330
    No statistical analyses for this end point

    Primary: OL Treatment Phase: Number of Subjects with Treatment-emergent Adverse Events of Special Interest (AESI)

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    End point title
    		 OL Treatment Phase: Number of Subjects with Treatment-emergent Adverse Events of Special Interest (AESI) [2]
    End point description
    The AEs considered to be of special interest: cataplexy, sleep paralysis, complex, sleep-related behaviors/parasomnias such as confusional arousals, somnambulism, sleep terrors, bruxism, sleep sex, sleep-related eating disorder, and catathrenia, fall, motor vehicle accident. Treatment emergent AEs was defined as any AE occurred at or after the initial administration of study intervention through the day of last dose plus 2 days. The safety (OL) analysis set included all randomised subjects who received at least 1 dose of study intervention in the OL phase.
    End point type
    Primary
    End point timeframe
    From start of the treatment in OL phase (Day 1 [Day 43 from study baseline]) up to 2 days after last dose (up to 52 weeks of the OL phase)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    		 OL Treatment Phase: Seltorexant 20 mg
    Number of subjects analysed
    522
    Units: Subjects
    18
    No statistical analyses for this end point

    Primary: OL Treatment Phase: Change From Baseline in Vital Signs: Blood Pressure

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    End point title
    		 OL Treatment Phase: Change From Baseline in Vital Signs: Blood Pressure [3]
    End point description
    Change from baseline in vital signs of systolic/diastolic blood pressure (SBP/DBP) were reported. The safety (OL) analysis set included all randomised subjects who received at least 1 dose of study intervention in the OL phase. Here, 'N' (overall number of subjects analysed) signifies subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    OL Baseline (Day 1 [Day 43 from study baseline]) and OL Week 52
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    		 OL Treatment Phase: Seltorexant 20 mg
    Number of subjects analysed
    359
    Units: millimetre of mercury (mmHg)
    arithmetic mean (standard deviation)
        DBP: Week 52
    0.5 ( 8.30 )
        SBP: Week 52
    0.0 ( 10.85 )
    No statistical analyses for this end point

    Primary: OL Treatment Phase: Change From Baseline in Vital Signs: Pulse Rate

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    End point title
    		 OL Treatment Phase: Change From Baseline in Vital Signs: Pulse Rate [4]
    End point description
    Change from baseline in vital signs of pulse rate were reported. The safety (OL) analysis set included all randomised subjects who received at least 1 dose of study intervention in the OL phase. Here, 'N' (overall number of subjects analysed) signifies subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    OL Baseline (Day 1 [Day 43 from study baseline]) and OL Week 52
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    		 OL Treatment Phase: Seltorexant 20 mg
    Number of subjects analysed
    359
    Units: Beats per minute
        arithmetic mean (standard deviation)
    0.3 ( 8.81 )
    No statistical analyses for this end point

    Primary: OL Treatment Phase: Change From Baseline in Vital Signs: Body Mass Index (BMI)

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    End point title
    		 OL Treatment Phase: Change From Baseline in Vital Signs: Body Mass Index (BMI) [5]
    End point description
    Change from baseline in vital signs of BMI were reported. The safety (OL) analysis set included all randomised subjects who received at least 1 dose of study intervention in the OL phase. Here, 'N' (overall number of subjects analysed) signifies subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    OL Baseline (Day 1 [Day 43 from study baseline]) and OL Week 52
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    		 OL Treatment Phase: Seltorexant 20 mg
    Number of subjects analysed
    365
    Units: Kilograms per square meter (kg/m^2)
        arithmetic mean (standard deviation)
    0.55 ( 1.634 )
    No statistical analyses for this end point

    Primary: OL Treatment Phase: Change From Baseline in Vital Signs: Waist Circumference

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    End point title
    		 OL Treatment Phase: Change From Baseline in Vital Signs: Waist Circumference [6]
    End point description
    Change from baseline in vital signs of waist circumference were reported. The safety (OL) analysis set included all randomised subjects who received at least 1 dose of study intervention in the OL phase. Here, 'N' (overall number of subjects analysed) signifies subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    OL Baseline (Day 1 [Day 43 from study baseline]) and OL Week 52
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    		 OL Treatment Phase: Seltorexant 20 mg
    Number of subjects analysed
    362
    Units: Centimeters
        arithmetic mean (standard deviation)
    0.6 ( 5.94 )
    No statistical analyses for this end point

    Primary: OL Treatment Phase: Change From Baseline in Vital Signs: Weight

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    End point title
    		 OL Treatment Phase: Change From Baseline in Vital Signs: Weight [7]
    End point description
    Change from baseline in vital signs of weight were reported. The safety (OL) analysis set included all randomised subjects who received at least 1 dose of study intervention in the OL phase. Here, 'N' (overall number of subjects analysed) signifies subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    OL Baseline (Day 1 [Day 43 from study baseline]) and OL Week 52
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    		 OL Treatment Phase: Seltorexant 20 mg
    Number of subjects analysed
    365
    Units: Kilograms
        arithmetic mean (standard deviation)
    1.54 ( 4.442 )
    No statistical analyses for this end point

    Primary: OL Treatment Phase: Change From Baseline in Vital Signs: Temperature

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    End point title
    		 OL Treatment Phase: Change From Baseline in Vital Signs: Temperature [8]
    End point description
    Change from baseline in vital signs of temperature were reported. The safety (OL) analysis set included all randomised subjects who received at least 1 dose of study intervention in the OL phase. Here, 'N' (overall number of subjects analysed) signifies subjects who were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    OL Baseline (Day 1 [Day 43 from study baseline]) and OL Week 52
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    		 OL Treatment Phase: Seltorexant 20 mg
    Number of subjects analysed
    359
    Units: Centigrade
        arithmetic mean (standard deviation)
    -0.01 ( 0.306 )
    No statistical analyses for this end point

    Primary: OL Treatment Phase: Number of Subjects with New Suicidal Ideation and Behavior Using the Columbia Suicide Severity Rating Scale (C-SSRS)

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    End point title
    		 OL Treatment Phase: Number of Subjects with New Suicidal Ideation and Behavior Using the Columbia Suicide Severity Rating Scale (C-SSRS) [9]
    End point description
    C-SSRS is a clinician-rated instrument that reports severity and frequency of suicide-related ideation and behaviors. Suicidal ideation was classified on a 5-item scale: 1 (wish to be dead), 2 (non-specific active suicidal thoughts), 3 (suicidal ideation without plan and intent), 4 (suicidal ideation intent to act without plan), and 5 (suicidal ideation with plan and intent), Suicidal behavior is classified on a 5-item scale: 6 (preparatory acts or behavior), 7 (aborted attempt), 8 (interrupted attempt), 9 (actual attempt), and 10 (suicide). Minimum total score 0, maximum total score 10; higher total scores indicate more suicidal ideation and/or suicidal behavior. If no events qualify for scores of 1 to 10, score of 0 was assigned (0= "no event that can be assessed on the basis of C-SSRS"). The safety (OL) analysis set included all randomised subjects who received at least 1 dose of study intervention in the OL phase. Higher scores indicated greater severity.
    End point type
    Primary
    End point timeframe
    From DB Baseline up to week 52 of OL phase
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    		 OL Treatment Phase: Seltorexant 20 mg
    Number of subjects analysed
    522
    Units: Subjects
        Suicidal ideation
    87
        Suicidal behavior
    7
    No statistical analyses for this end point

    Primary: OL Treatment Phase: Physician Withdrawal Checklist (PWC-20) Total Scores

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    End point title
    		 OL Treatment Phase: Physician Withdrawal Checklist (PWC-20) Total Scores [10]
    End point description
    Potential withdrawal effects were assessed by the clinician using the PWC-20. The PWC-20 was a reliable and sensitive instrument for the assessment of discontinuation symptoms. The assessment has 20 items evaluated to detect withdrawal symptoms. Symptoms are rated on a scale of 0-3. Symptoms rated on a scale of 0 =not present, 1=mild, 2 =moderate, and 3 =severe. The total PWC-20 score was the sum of 20 item scores and ranged between 0 and 60. The higher score indicates more frequent/severe symptoms. Follow-up analysis set included all randomised subjects who entered the follow-up phase after OL. Here, “N” (overall number of subjects analysed): subjects who were evaluable and “n” (number analysed): number of subjects evaluable for each arm at specified time points.
    End point type
    Primary
    End point timeframe
    End of OL (Week 52 of OL phase), follow-up 1 (1 day after end of OL phase), and follow-up 2 (2 weeks after end of OL phase)
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    		 OL FU Phase: Seltorexant 20 mg
    Number of subjects analysed
    443
    Units: Units on a scale
    arithmetic mean (standard deviation)
        End of OL (Week 59) (n=443)
    7.6 ( 8.37 )
        followup 1 (n=435)
    5.8 ( 7.34 )
        followup 2 (n=401)
    6.7 ( 7.42 )
    No statistical analyses for this end point

    Primary: OL Treatment Phase: Number of Subjects with Clinical Laboratory Abnormalities

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    End point title
    		 OL Treatment Phase: Number of Subjects with Clinical Laboratory Abnormalities [11]
    End point description
    Laboratory parameters: hematology (platelet count, red blood cell [RBC] count, hemoglobin, hematocrit, neutrophils (Segmented/Leukocytes), lymphocytes, monocytes, eosinophils/leukocytes [Eos/Leu], basophils, Reticulocytes/ Erythrocytes [Reti/Ery]); chemistry (sodium, potassium, chloride, bicarbonate, creatinine, glucose, aspartate transaminase [AST], alanine transaminase [ALT], gamma-glutamyl transferase [GGT], alkaline phosphatase, total, bilirubin, phosphate, albumin, total protein, total cholesterol); urine (specific gravity, pH, glucose, blood, bilirubin, urobilinogen, RBC). Clinically significant abnormalities (low/high) were determined at the investigator's discretion. Only those categories in which at least one subject had data were reported in this endpoint. The safety (OL) analysis set included all randomised subjects who received at least 1 dose of study intervention in the OL phase. Here, n (number analysed) signifies number of subjects evaluable for specified categories.
    End point type
    Primary
    End point timeframe
    From OL Baseline (Day 1 [Day 43 from study baseline]) to Week 52 of OL phase
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    		 OL Treatment Phase: Seltorexant 20 mg
    Number of subjects analysed
    522
    Units: Subjects
        ALT High (n=516)
    3
        AST High (n=519)
    1
        Bicarbonate Low (n=507)
    1
        Chloride Low (n=520)
    1
        Cholesterol High (n=520)
    18
        Creatine Kinase High (n=519)
    10
        GGT High (n=516)
    1
        Glucose High (n=518)
    1
        HDL Cholesterol low (n=520)
    43
        Hemoglobin A1C/ Hemoglobin High (n=518)
    5
        LDL Cholesterol Low (n=520)
    85
        LDL Cholesterol High (n=520)
    90
        Phosphate low (n=520)
    8
        Potassium Low (n=517)
    2
        Potassium High (n=517)
    3
        Triglycerides High (n=520)
    1
        Eos/Leu High (n=518)
    5
        Erythrocytes High(n=516)
    5
        Hematocrit High (n=514)
    8
        Leukocytes Low (n=516)
    1
        Leukocytes High (n=516)
    4
        Lymphocytes/Leukocytes High (n=518)
    2
        Lymphocytes/Leukocytes Low (n=518)
    6
        Neutrophils low (n=518)
    5
        Neutrophils High (n=518)
    1
        Platelets Low (n=516)
    1
        Platelets High (n=516)
    2
        Reti/Ery Low (n=518)
    6
        Reti/Ery High (n=518)
    136
        Specific Gravity High (n=522)
    47
        Urine pH High (n=522)
    56
    No statistical analyses for this end point

    Primary: OL Treatment Phase: Number of Subjects with Electrocardiogram (ECG) Abnormalities

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    End point title
    		 OL Treatment Phase: Number of Subjects with Electrocardiogram (ECG) Abnormalities [12]
    End point description
    The ECG parameters that were analysed are heart rate, PR interval, QRS interval, QT interval, and corrected QT (QTc) interval using the following correction methods: Bazetts formula (QTcB), Fridericias formula (QTcF). The safety (OL) analysis set included all randomised subjects who received at least 1 dose of study intervention in the OL phase. Only those categories in which at least one subject had data were reported in this endpoint. Here, n (number analysed) signifies number of subjects evaluable for specified time points. Here B: denotes baseline.
    End point type
    Primary
    End point timeframe
    OL Baseline (Day 1 [Day 43 from study baseline]) and OL Week 52
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    		 OL Treatment Phase: Seltorexant 20 mg
    Number of subjects analysed
    522
    Units: Subjects
        B: ECG Mean Heart Rate <=50 (n=522)
    11
        B: ECG Mean Heart Rate >=100 (n=522)
    4
        B: PR Interval <=120 (n=522)
    10
        B: PR Interval >=200 (n=522)
    6
        B: RR Interval <=600 (n=522)
    4
        B: RR Interval >=1200 (n=522)
    10
        B: QRS Duration >=120 (n=522)
    3
        B: QT Interval >= 500 (n=522)
    1
        W52: ECG Mean Heart Rate <=50 (n=358)
    3
        W52:ECG Mean Heart Rate >=100 (n=358)
    4
        W52:PR Interval <=120 (n=358)
    6
        W52: PR Interval >=200 (n=358)
    5
        W52: RR Interval <=600 (n=358)
    4
        W52: RR Interval >=1200 (n=358)
    3
        W52: QRS Duration >=120 (n=358)
    4
    No statistical analyses for this end point

    Primary: OL Treatment Phase: Number of Subjects With Sexual Dysfunction as Determined by Arizona Sexual Experiences Scale (ASEX) Score

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    End point title
    		 OL Treatment Phase: Number of Subjects With Sexual Dysfunction as Determined by Arizona Sexual Experiences Scale (ASEX) Score [13]
    End point description
    ASEX is a five-item rating scale that quantifies sex drive, arousal, vaginal lubrication/penile erection, ability to reach orgasm, and satisfaction from orgasm. Each of the 5 items is rated on a 6-point Likert scale, ranging from 1 to 6. The 5 items are summed to create a total score, ranging from 5 to 30, with the higher scores indicating more sexual dysfunction. Sexual dysfunction is defined as an ASEX total score of 19 or greater, or a score of 5 or greater on any item, or a score of 4 or greater on any 3 items. The safety (OL) analysis set included all randomised subjects who received at least 1 dose of study intervention in the OL phase. . Here, “N” (overall number of subjects analysed): subjects who were evaluable and “n” (number analysed): number of subjects evaluable for each arm at specified time points.
    End point type
    Primary
    End point timeframe
    OL Baseline (Day 1 [Day 43 from study baseline]) and OL Week 52
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    		 OL Treatment Phase: Seltorexant 20 mg
    Number of subjects analysed
    512
    Units: Subjects
        Baseline (OL) (n=512)
    391
        Week 52 (n=365)
    235
    No statistical analyses for this end point

    Secondary: DB Phase: Change from Baseline to Day 43 in the MADRS Without Sleep Item (MADRS-WOSI) Total Score- Estimand 2

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    End point title
    		 DB Phase: Change from Baseline to Day 43 in the MADRS Without Sleep Item (MADRS-WOSI) Total Score- Estimand 2
    End point description
    The MADRS was a clinician-rated scale designed to measure depression severity and detected changes due to antidepressant treatment. MADRS-WOSI was defined as the full MADRS without the sleep item. The MADRS-WOSI scale consisted of 9 items, each of which was scored from 0 (item not present or normal) to 6 (severe or continuous presence of symptoms). MADRS-WOSI total score was the sum of scores from individual question items, which ranged from 0 to 54, higher scores represented a more severe condition. The MADRS-WOSI evaluated apparent sadness, reported sadness, inner tension, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. Negative change in MADRS total score indicated improvement. FAS2 included all randomised subjects with MDDIS per IWRS who received at least 1 dose of study intervention in DB phase. Here, N (number of subjects analysed) signifies subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    DB: Baseline (Day 1), Day 43
    End point values
    		 Double -blind Phase (DB): Placebo DB: Seltorexant 20 mg
    Number of subjects analysed
    207
    201
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -9.2 ( 9.31 )
    -11.3 ( 8.68 )
    Statistical analysis title
    		 Statistical Analysis set -2
    Statistical analysis description
    In accordance with protocol predefined testing sequence, statistical significance of the primary endpoint and first key secondary endpoint was required before testing the secondary endpoint (MADRS-WOSI) and thus, a formal statistical testing was performed.
    Comparison groups
    DB: Seltorexant 20 mg v Double -blind Phase (DB): Placebo
    Number of subjects included in analysis
    408
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.024
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.61
         upper limit
    		 -0.26
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.85

    Secondary: DB Phase: Change from Baseline to Day 43 in Sleep Disturbance Using the Patient Reported Outcome Measurement Information System-Sleep Disturbance (PROMIS-SD) Short Form (8a) T-score: Estimand 2

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    End point title
    		 DB Phase: Change from Baseline to Day 43 in Sleep Disturbance Using the Patient Reported Outcome Measurement Information System-Sleep Disturbance (PROMIS-SD) Short Form (8a) T-score: Estimand 2
    End point description
    PROMIS-SD Short Form 8a: static 8-item questionnaire, assessed self-perceptions of sleep initiation (2 items), quality of sleep (3 items), early morning feelings (2 items), worrying about sleep (1 item). Each question, 5 options ranged 1 to 5. Direction of responses was not same, sometimes “not at all” =more sleep disturbance; “not at all” =less sleep disturbance. Total raw score for short form with all questions answered was sum of values of response to each question, total score ranged 8 - 40. Lower scores=less sleep disturbance. Total raw score converted into T-score. T-score rescaled the raw score into standardized score with mean-50; SD-10. Negative changes in scores=improvement. Higher values represent more severe sleep disturbance. FAS2 included all randomised subjects with MDDIS per IWRS who received at least 1 dose of study intervention in DB phase. N (number of subjects analysed) signifies subjects evaluable.
    End point type
    Secondary
    End point timeframe
    DB: Baseline (Day 1), Day 43
    End point values
    		 Double -blind Phase (DB): Placebo DB: Seltorexant 20 mg
    Number of subjects analysed
    207
    201
    Units: T-score
        arithmetic mean (standard deviation)
    -7.1 ( 10.44 )
    -10.9 ( 9.10 )
    Statistical analysis title
    		 Statistical analysis set -3
    Statistical analysis description
    In accordance with protocol predefined testing sequence, statistical significance of the primary endpoint was required before testing the secondary endpoint (PROMIS-SD; Short Form 8a) and thus, a formal statistical testing was performed.
    Comparison groups
    DB: Seltorexant 20 mg v Double -blind Phase (DB): Placebo
    Number of subjects included in analysis
    408
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 MMRM
    Parameter type
    		 LS mean difference
    Point estimate
    -3.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.25
         upper limit
    		 -1.85
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.87

    Secondary: DB Phase: Change from Baseline to Day 43 in the MADRS-6 Total Score

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    End point title
    		 DB Phase: Change from Baseline to Day 43 in the MADRS-6 Total Score
    End point description
    The 6-item MADRS was a clinician-administered scale designed to measure the core symptoms of depression severity and detected changes due to antidepressant intervention. It is a subset of MADRS (10-item). The MADRS-6 subscale score was the sum of scores for the following MADRS items: apparent sadness, reported sadness, inner tension, lassitude, inability to feel, and pessimistic thoughts. Each item is scored from 0 (item not present or normal) to 6 (most severe or continuous presence of symptoms); the overall score ranges from 0 to 36, higher scores represented a more severe condition. Negative change in score indicates improvement. FAS2 included all randomised subjects with MDDIS per IWRS who received at least 1 dose of study intervention in DB phase. Here, N (number of subjects analysed) signifies subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    DB: Baseline (Day 1), Day 43
    End point values
    		 Double -blind Phase (DB): Placebo DB: Seltorexant 20 mg
    Number of subjects analysed
    207
    201
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -6.9 ( 7.02 )
    -8.4 ( 6.73 )
    No statistical analyses for this end point

    Secondary: DB Phase: Percentage of Subjects with Response on Depressive Symptoms Scale Based on MADRS at Day 43

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    End point title
    		 DB Phase: Percentage of Subjects with Response on Depressive Symptoms Scale Based on MADRS at Day 43
    End point description
    Responders, defined as subjects with a >=50 percent (%) improvement in the MADRS total score from baseline to a given timepoint. The MADRS was a clinician-rated scale designed to measure depression severity and detected changes due to antidepressant treatment. Scale consisted of 10 items, each of which was scored from 0 (item not present or normal) to 6 (severe or continuous presence of symptoms). MADRS total score was sum of scores from individual question items, which ranged from 0 to 60, higher scores represented a more severe condition. The MADRS evaluated apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, suicidal thoughts. Negative change in MADRS total score indicated improvement. FAS2 included all randomised subjects with MDDIS per IWRS who received at least 1 dose of study intervention in DB phase.
    End point type
    Secondary
    End point timeframe
    At Day 43
    End point values
    		 Double -blind Phase (DB): Placebo DB: Seltorexant 20 mg
    Number of subjects analysed
    223
    213
    Units: Percentage of subjects
        number (not applicable)
    22.9
    36.2
    No statistical analyses for this end point

    Secondary: DB Phase: Change From Baseline to Day 43 in Patient Health Questionnaire 9-item (PHQ-9) Total Score

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    End point title
    		 DB Phase: Change From Baseline to Day 43 in Patient Health Questionnaire 9-item (PHQ-9) Total Score
    End point description
    The PHQ-9 was a 9-item, subject reported endpoint to assess depressive symptoms. The scale scores each of the 9 symptom domains of the diagnostic and statistical manual of mental disorders-5th edition (DSM-5) major depressive disorder (MDD) criteria. Each item was rated on a 4 points scale (0=not at all, 1=several days, 2=more than half the days, and 3=nearly every day). The subject’s item responses were summed to provide a total score (range of 0 to 27), with higher scores indicating greater severity of depressive symptoms. The severity of the PHQ-9 is categorized as follows: none-minimal (0-4), mild (5-9), moderate (10-14), moderately Severe (15-19) and severe (20-27). Negative changes in PHQ-9 total score indicated improvement. FAS2 included all randomised subjects with MDDIS per IWRS who received at least 1 dose of study intervention in DB phase. Here, N (number of subjects analysed) signifies subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    DB: Baseline (Day 1), Day 43
    End point values
    		 Double -blind Phase (DB): Placebo DB: Seltorexant 20 mg
    Number of subjects analysed
    207
    201
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -5.5 ( 6.63 )
    -7.6 ( 5.98 )
    No statistical analyses for this end point

    Secondary: OL Treatment Phase: Change From Baseline Over Time in MADRS Total Score

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    End point title
    		 OL Treatment Phase: Change From Baseline Over Time in MADRS Total Score
    End point description
    MADRS was a clinician-administered scale designed to measure depression severity and detected changes due to antidepressant treatment. The MADRS evaluates the following 10 items: apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. Each item is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), total score was sum of scores from individual question items, which ranged from 0-60. Higher scores represented a more severe condition. Negative change in MADRS total score indicated improvement. FAS2 (OL) included all FAS2 subjects who received at least 1 dose of study intervention in the OL phase. Here, N (number of subjects analysed) signifies subjects evaluable for this endpoint and n (number analysed) signifies number of subjects evaluable for specified time points.
    End point type
    Secondary
    End point timeframe
    OL Baseline (Day 1 [Day 43 from study baseline]), OL Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
    End point values
    		 OL Treatment Phase: Seltorexant 20 mg
    Number of subjects analysed
    381
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 4 (n=381)
    -5.0 ( 8.27 )
        Week 8 (n=366)
    -6.2 ( 9.53 )
        Week 12 (n=345)
    -6.8 ( 9.88 )
        Week 16 (n=339)
    -7.7 ( 10.41 )
        Week 20 (n=327)
    -8.6 ( 10.53 )
        Week 24 (n=311)
    -8.0 ( 10.93 )
        Week 28 (n=296)
    -8.8 ( 11.03 )
        Week 32 (n=291)
    -9.5 ( 11.20 )
        Week 36 (n=289)
    -9.3 ( 11.32 )
        Week 40 (n=280)
    -10.2 ( 11.45 )
        Week 44 (n=274)
    -11.0 ( 10.93 )
        Week 48 (n=274)
    -11.2 ( 10.62 )
        Week 52 (n=273)
    -11.4 ( 10.43 )
    No statistical analyses for this end point

    Secondary: OL Treatment Phase: Change From Baseline Over Time in the Clinical Global Impression-Severity (CGI S) Score

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    End point title
    		 OL Treatment Phase: Change From Baseline Over Time in the Clinical Global Impression-Severity (CGI S) Score
    End point description
    The CGI-S (depression) provided an overall clinician-determined summary measure of severity of the subject's illness that considers all available information, included knowledge of subject’s history, psychosocial circumstances, symptoms, behavior, impact of symptoms on subject’s ability to function. CGI-S evaluated severity of psychopathology on a scale of 1 to 7. The CGI-S was 7-point global assessment scale that measures clinician's impression of severity of illness, rating: 1=normal (not at all ill), 2=borderline ill, 3=mildly ill, 4=moderately ill, 5=markedly ill, 6=severely ill, 7=among the most extremely ill subjects, with higher scores indicate worsening. Negative changes in CGI-S score indicate improvement. FAS2 (OL) included all FAS2 subjects who received at least 1 dose of study intervention in the OL phase. Here, N (number of subjects analysed) signifies subjects evaluable, n signifies number of subjects evaluable for specified time points.
    End point type
    Secondary
    End point timeframe
    OL Baseline (Day 1 [Day 43 from study baseline]), OL Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
    End point values
    		 OL Treatment Phase: Seltorexant 20 mg
    Number of subjects analysed
    381
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 4 (n=381)
    -0.6 ( 0.99 )
        Week 8 (n=366)
    -0.8 ( 1.12 )
        Week 12 (n=345)
    -0.8 ( 1.21 )
        Week 16 (n=339)
    -1.0 ( 1.34 )
        Week 20 (n=327)
    -1.0 ( 1.35 )
        Week 24 (n=311)
    -1.1 ( 1.39 )
        Week 28 (n=296)
    -1.1 ( 1.40 )
        Week 32 (n=291)
    -1.3 ( 1.35 )
        Week 36 (n=289)
    -1.2 ( 1.47 )
        Week 40 (n=280)
    -1.3 ( 1.45 )
        Week 44 (n=274)
    -1.5 ( 1.42 )
        Week 48 (n=274)
    -1.5 ( 1.39 )
        Week 52 (n=273)
    -1.6 ( 1.37 )
    No statistical analyses for this end point

    Secondary: OL Treatment Phase: Change from Baseline Over Time in the MADRS-WOSI Total Score

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    End point title
    		 OL Treatment Phase: Change from Baseline Over Time in the MADRS-WOSI Total Score
    End point description
    MADRS was a clinician-administered scale designed to measure depression severity and detected changes due to antidepressant treatment. The MADRS evaluates the following 10 items: apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. Each item is scored from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), total score was sum of scores from individual question items, which ranged from 0-60. Higher scores represented a more severe condition. Negative change in MADRS total score indicated improvement. FAS2 (OL) included all FAS2 subjects who received at least 1 dose of study intervention in the OL phase. Here, N (number of subjects analysed) signifies subjects evaluable for this endpoint and n (number analysed) signifies number of subjects evaluable for specified time points.
    End point type
    Secondary
    End point timeframe
    OL Baseline (Day 1 [Day 43 from study baseline]), OL Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
    End point values
    		 OL Treatment Phase: Seltorexant 20 mg
    Number of subjects analysed
    381
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 4 (n=381)
    -4.2 ( 7.47 )
        Week 8 (n=366)
    -5.3 ( 8.56 )
        Week 12 (n=345)
    -5.9 ( 8.91 )
        Week 16 (n= 339)
    -6.7 ( 9.41 )
        Week 20 (n=327)
    -7.5 ( 9.50 )
        Week 24 (n= 311)
    -7.0 ( 9.95 )
        Week 28 (n=296)
    -7.7 ( 10.03 )
        Week 32 (n= 291)
    -8.3 ( 10.25 )
        Week 36 (n=289)
    -8.1 ( 10.19 )
        Week 40 (n=280)
    -8.8 ( 10.44 )
        Week 44 (n= 274)
    -9.6 ( 9.87 )
        Week 48 (n= 274)
    -9.9 ( 9.62 )
        Week 52 (n= 273)
    -9.8 ( 9.34 )
    No statistical analyses for this end point

    Secondary: OL Treatment Phase: Change From Baseline Over Time in Sleep Disturbance Using the PROMIS SD Short Form 8a T-score

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    End point title
    		 OL Treatment Phase: Change From Baseline Over Time in Sleep Disturbance Using the PROMIS SD Short Form 8a T-score
    End point description
    PROMIS-SD Short Form 8a: static 8-item questionnaire, assessed self-perceptions of sleep initiation (2 items), quality of sleep (3 items), early morning feelings (2 items), worrying about sleep (1item). Each question, 5 options ranged 1- 5. Direction of responses was not same, sometimes “not at all” =more sleep disturbance; “not at all” =less sleep disturbance. Total raw score for short form with all questions answered was sum of values of response to each question, total score ranged 8 - 40. Lower scores=less sleep disturbance. Total raw score converted into T-score. T-score rescaled raw score into standardized score with mean-50; SD-10. Negative changes in scores=improvement. Higher values represent more severe sleep disturbance. FAS2 (OL) included all FAS2 subjects who received at least 1 dose of study intervention in OL phase. Here, N (number of subjects analysed) signifies subjects evaluable, n (number analysed) signifies number of subjects evaluable for specified time points.
    End point type
    Secondary
    End point timeframe
    OL Baseline (Day 1 [Day 43 from study baseline]), OL Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52
    End point values
    		 OL Treatment Phase: Seltorexant 20 mg
    Number of subjects analysed
    380
    Units: T-score
    arithmetic mean (standard deviation)
        Week 4 (n=380)
    -4.9 ( 8.57 )
        Week 8 (n=366)
    -5.3 ( 9.21 )
        Week 12 (n=344)
    -6.3 ( 9.48 )
        Week 16 (n=339)
    -6.4 ( 10.24 )
        Week 20 (n=326)
    -6.8 ( 10.29 )
        Week 24 (n=311)
    -6.7 ( 9.99 )
        Week 28 (n=296)
    -7.1 ( 10.09 )
        Week 32 (n=291)
    -7.2 ( 10.32 )
        Week 36 (n= 289)
    -7.6 ( 10.66 )
        Week 40 (n=280)
    -8.2 ( 10.46 )
        Week 44 (n=274)
    -9.1 ( 10.56 )
        Week 48 (n=274)
    -8.6 ( 10.42 )
        Week 52 (n=273)
    -9.6 ( 10.44 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs/other AEs: DB: Day (D) 1 to 2 days after last dose (D44); DB FU: D44 to D57; OL: D1 [D43 study BL] to 2 days after last dose (Week [W] 52); OL FU: W 52 to 2 Weeks after end of OL phase (W61); Death: DB: D1 to D43, OL: D43 to 1 year 2 weeks
    Adverse event reporting additional description
    DB phase: The safety analysis included all randomised subjects who received at least 1 dose of study intervention in the DB phase. OL Phase: The safety analysis included all randomised subjects who received at least 1 dose of study intervention in the OL phase.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Double -blind Phase (DB): Placebo
    Reporting group description
    		 During DB phase, subjects with major depressive disorder (MDD) with or without insomnia symptoms (IS) who had an inadequate response to an ongoing antidepressant therapy with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) were randomised to receive placebo (matching to seltorexant) once daily from Day 1 to Day 42 as an adjunctive therapy to SSRI/SNRI antidepressant therapy.

    Reporting group title
    DB: Seltorexant 20 mg
    Reporting group description
    		 During DB phase, subjects with MDD with or without IS who had an inadequate response to an ongoingantidepressant therapy with a SSRI or SNRI were randomised to receive seltorexant 20 milligrams (mg) tabletorally once daily from Day 1 to Day 42 as an adjunctive therapy to SSRI/SNRI antidepressant therapy.

    Reporting group title
    OL Treatment Phase: Seltorexant 20 mg
    Reporting group description
    		 Subjects who received placebo or seltorexant 20 mg tablet in the DB treatment phase entered OL phase andreceived seltorexant 20 mg tablet orally, once daily from Day 43 up to 1 year as an adjunctive therapy to ongoing SSRI/SNRI antidepressant therapy.

    Reporting group title
    DB Follow-up (FU) Phase: Placebo
    Reporting group description
    		 After completion or discontinuation from the DB treatment, subjects who did not enter the OL phase entered DB follow up phase and were followed up for safety up to 14 days from Day 43 up to Day 57.

    Reporting group title
    DB FU Phase: Seltorexant 20 mg
    Reporting group description
    		 After completion or discontinuation from the DB treatment, subjects who did not enter the OL phase entered DB follow up phase and were followed up for safety up to 14 days from Day 43 up to Day 57.

    Reporting group title
    OL FU Phase: Seltorexant 20 mg
    Reporting group description
    		 After completion of OL treatment phase, subjects were followed up for safety up to 7 to14 days from 1 year up to 1 year 2 weeks.

    Serious adverse events
    		 Double -blind Phase (DB): Placebo DB: Seltorexant 20 mg OL Treatment Phase: Seltorexant 20 mg DB Follow-up (FU) Phase: Placebo DB FU Phase: Seltorexant 20 mg OL FU Phase: Seltorexant 20 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 303 (0.33%)
    1 / 283 (0.35%)
    29 / 522 (5.56%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         number of deaths (all causes)
    0
    0
    1
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neurogenic Tumour
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    1 / 522 (0.19%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Parathyroid Tumour Benign
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    1 / 522 (0.19%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    1 / 522 (0.19%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    1 / 522 (0.19%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    General disorders and administration site conditions
    Chest Pain
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    1 / 522 (0.19%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    1 / 522 (0.19%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    2 / 522 (0.38%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal Ideation
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    2 / 522 (0.38%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    7 / 522 (1.34%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 7
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Transaminases Increased
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    1 / 522 (0.19%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Weight Increased
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    1 / 522 (0.19%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    1 / 522 (0.19%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Fall
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 283 (0.00%)
    0 / 522 (0.00%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin Laceration
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    1 / 522 (0.19%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Spinal Compression Fracture
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 283 (0.00%)
    0 / 522 (0.00%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    1 / 522 (0.19%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    1 / 522 (0.19%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Cerebral Infarction
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    1 / 522 (0.19%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    1 / 522 (0.19%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    1 / 522 (0.19%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    1 / 522 (0.19%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Blood and lymphatic system disorders
    Iron Deficiency Anaemia
         subjects affected / exposed
    0 / 303 (0.00%)
    1 / 283 (0.35%)
    0 / 522 (0.00%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Optic Nerve Sheath Haemorrhage
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    1 / 522 (0.19%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Gastrointestinal disorders
    Lower Gastrointestinal Haemorrhage
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    1 / 522 (0.19%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral Disc Protrusion
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    1 / 522 (0.19%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Spinal Stenosis
         subjects affected / exposed
    1 / 303 (0.33%)
    0 / 283 (0.00%)
    0 / 522 (0.00%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator Cuff Syndrome
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    1 / 522 (0.19%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    1 / 522 (0.19%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Pneumonia Aspiration
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    1 / 522 (0.19%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    1 / 522 (0.19%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Septic Shock
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    1 / 522 (0.19%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    1 / 522 (0.19%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Vestibular Neuronitis
         subjects affected / exposed
    0 / 303 (0.00%)
    0 / 283 (0.00%)
    1 / 522 (0.19%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    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
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Double -blind Phase (DB): Placebo DB: Seltorexant 20 mg OL Treatment Phase: Seltorexant 20 mg DB Follow-up (FU) Phase: Placebo DB FU Phase: Seltorexant 20 mg OL FU Phase: Seltorexant 20 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 303 (11.55%)
    41 / 283 (14.49%)
    162 / 522 (31.03%)
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    10 / 453 (2.21%)
    Investigations
    Weight Increased
         subjects affected / exposed
    4 / 303 (1.32%)
    5 / 283 (1.77%)
    34 / 522 (6.51%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    0 / 453 (0.00%)
         occurrences all number
    4
    5
    34
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    27 / 303 (8.91%)
    25 / 283 (8.83%)
    62 / 522 (11.88%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    6 / 453 (1.32%)
         occurrences all number
    33
    38
    117
    0
    0
    6
    Infections and infestations
    Covid-19
         subjects affected / exposed
    5 / 303 (1.65%)
    9 / 283 (3.18%)
    46 / 522 (8.81%)
    1 / 22 (4.55%)
    0 / 22 (0.00%)
    3 / 453 (0.66%)
         occurrences all number
    5
    10
    47
    1
    0
    3
    Nasopharyngitis
         subjects affected / exposed
    4 / 303 (1.32%)
    4 / 283 (1.41%)
    44 / 522 (8.43%)
    0 / 22 (0.00%)
    0 / 22 (0.00%)
    1 / 453 (0.22%)
         occurrences all number
    4
    4
    56
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Oct 2020
    The purpose of this amendment was to address health authority feedback in regards to the assumption of treatment difference and increase in sample size determination, the addition of the Montgomery-Asberg Depression Rating Scale without Sleep Item (MADRS-WOSI) as a key secondary endpoint, European Union (EU)-specific statistical analyses, use of approved selective serotonin reuptake inhibitor (SSRI)/ serotonin-norepinephrine reuptake inhibitor (SNRI) as a background antidepressant in the participating country, language of restrictions on driving and alcohol use, disallowed concomitant medications, addition of brief neurological examinations, and adjustment of concomitant therapy following study drug stoppage, and study discontinuation for subjects.
    25 Jun 2021
    The purpose of this amendment was to clarify and modify eligibility criteria based on early enrolment experiences and made the following changes at screening: lower the initial screening assessment of the Hamilton Depression Rating Scale (HDRS), 17 items total score from 22 to 20 and greater than or equal to (>=)18 at end of screening; increase the maximum duration of stable antidepressant therapy from 12 months to 18 months; increase the length of the current depressive episode to less than or equal to (<=)24 months (<=18 months); revise the upper limit of body mass index (BMI) eligibility range to kilogram per square meter (kg/m2) 40 kg/m2 (from 37 kg/m2); extend the screening period for up to 2 weeks if approved by the medical monitor and clarify use of concomitant medications in the OL phase. This amendment also included changes to laboratory tests to remove evaluation of prothrombin time (PT) and clarify follicle stimulating hormone (FSH) testing; added text to specify that locally approved (including under emergency use authorization Coronavirus disease 2019 (COVID-19) vaccination may be used during the trial with the recommendation that vaccination occurs at least 5 days prior to the start of dosing, or once randomized, at least 5 days prior to the next scheduled visit.

    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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