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    Clinical Trial Results:
    A Double-Blind, Randomized, Parallel-Group Study with Quetiapine Extended Release as Comparator 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

    Summary
    EudraCT number
    		 2020-000341-14
    Trial protocol
    		 CZ   GB   LT   LV   BE   BG   PL   SK  
    Global end of trial date
    03 Oct 2023

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

    Trial information

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    Trial identification
    Sponsor protocol code
    42847922MDD3005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04513912
    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
    03 Oct 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Oct 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study was to assess the efficacy of seltorexant compared with quetiapine extended-release (XR) as adjunctive therapy to an antidepressant drug in treatment response in subjects with major depressive disorder with insomnia symptoms (MDDIS), who have had an inadequate response to current antidepressant therapy with a serotonin-norepinephrine reuptake inhibitor or selective serotonin reuptake inhibitor (SSRI/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
    		 -
    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
    Argentina: 88
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Bulgaria: 95
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Czechia: 33
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Lithuania: 15
    Country: Number of subjects enrolled
    Latvia: 18
    Country: Number of subjects enrolled
    Malaysia: 22
    Country: Number of subjects enrolled
    Poland: 32
    Country: Number of subjects enrolled
    Russian Federation: 33
    Country: Number of subjects enrolled
    Serbia: 111
    Country: Number of subjects enrolled
    Slovakia: 57
    Country: Number of subjects enrolled
    Ukraine: 23
    Country: Number of subjects enrolled
    United States: 223
    Worldwide total number of subjects
    756
    EEA total number of subjects
    253
    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)
    686
    From 65 to 84 years
    70
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 757 subjects were randomised in this study, out of which 756 were treated with either seltorexant 20 milligrams (mg) tablet once daily (OD) or quetiapine XR 50 mg or 150 mg or 300 mg tablet. One subject randomised to seltorexant 20 mg treatment group did not receive treatment as enrollment criteria was not met.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm 1: Quetiapine extended release (XR)
    Arm description
    		 Adult subjects received 1 capsule daily during the first week and 2 capsules daily from the second week onwards. For the first 2 days (Day 1 to 2), adult subjects received one over-encapsulated tablet of quetiapine XR 50 milligrams (mg) daily at bedtime, followed by 1 over-encapsulated tablet of 150 mg tablet daily (lower dose) from Day 3 to 7. Elderly subjects on quetiapine XR started treatment with one over-encapsulated 50 mg tablet daily at bedtime from Day 1 to 3 and took a second over-encapsulated 50 mg tablet from Day 4-7 according to the local prescribing label and investigator’s judgement. From the second week, subjects on the quetiapine XR lower dose received 1 over-encapsulated tablet of quetiapine XR 150 mg and 1 capsule of placebo daily at bedtime. Subjects on the quetiapine XR higher dose received two over encapsulated tablets of 150 mg quetiapine XR daily at bedtime from Day 14 onwards till Day 182.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Quetiapine XR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received over encapsulated tablets of either quetiapine 50 mg, or 150 mg or 300 mg once daily dose at bedtime from Day 1 to Day 182.

    Arm title
    		 Arm 2: Seltorexant
    Arm description
    		 Adult subjects received 1 capsule daily during the first week and 2 capsules daily from the second week onwards. For first week (from Day 1 to 7), adult subjects received one over encapsulated tablet of seltorexant 20 mg daily at bedtime. During the second week adult subjects received 2 capsules (1 over encapsulated tablet of seltorexant 20 mg and placebo) at bedtime from Day 8 to 182. Elderly patients on seltorexant will start with 1 over-encapsulated tablet of 20 mg on Day 1 and a second capsule of placebo to match the blinded dose titration schedule of quetiapine XR from Day 4 till Day 182. Matching placebo dosing for elderly subjects were flexible for Days 4 to 7 alone.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Seltorexant 20 mg
    Investigational medicinal product code
    JNJ-42847922
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received over encapsulated tablets of seltorexant 20 mg once daily dose at bedtime from Day 1 to Day 182.

    Number of subjects in period 1
    		Arm 1: Quetiapine extended release (XR) Arm 2: Seltorexant
    Started
    390
    366
    Completed
    304
    300
    Not completed
    86
    66
         Adverse event, non-fatal
    16
    9
         Unspecified
    13
    16
         Lost to follow-up
    8
    10
         Withdrawal by subject
    49
    31

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm 1: Quetiapine extended release (XR)
    Reporting group description
    		 Adult subjects received 1 capsule daily during the first week and 2 capsules daily from the second week onwards. For the first 2 days (Day 1 to 2), adult subjects received one over-encapsulated tablet of quetiapine XR 50 milligrams (mg) daily at bedtime, followed by 1 over-encapsulated tablet of 150 mg tablet daily (lower dose) from Day 3 to 7. Elderly subjects on quetiapine XR started treatment with one over-encapsulated 50 mg tablet daily at bedtime from Day 1 to 3 and took a second over-encapsulated 50 mg tablet from Day 4-7 according to the local prescribing label and investigator’s judgement. From the second week, subjects on the quetiapine XR lower dose received 1 over-encapsulated tablet of quetiapine XR 150 mg and 1 capsule of placebo daily at bedtime. Subjects on the quetiapine XR higher dose received two over encapsulated tablets of 150 mg quetiapine XR daily at bedtime from Day 14 onwards till Day 182.

    Reporting group title
    Arm 2: Seltorexant
    Reporting group description
    		 Adult subjects received 1 capsule daily during the first week and 2 capsules daily from the second week onwards. For first week (from Day 1 to 7), adult subjects received one over encapsulated tablet of seltorexant 20 mg daily at bedtime. During the second week adult subjects received 2 capsules (1 over encapsulated tablet of seltorexant 20 mg and placebo) at bedtime from Day 8 to 182. Elderly patients on seltorexant will start with 1 over-encapsulated tablet of 20 mg on Day 1 and a second capsule of placebo to match the blinded dose titration schedule of quetiapine XR from Day 4 till Day 182. Matching placebo dosing for elderly subjects were flexible for Days 4 to 7 alone.

    Reporting group values
    		 Arm 1: Quetiapine extended release (XR) Arm 2: Seltorexant Total
    Number of subjects
    		 390 366 756
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 349 337 686
        From 65 to 84 years
    		 41 29 70
        85 years and over
    		 0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.9 ( 13.64 ) 47.8 ( 13.15 ) -
    Title for Gender
    Units: subjects
        Female
    		 277 281 558
        Male
    		 113 85 198

    End points

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    End points reporting groups
    Reporting group title
    Arm 1: Quetiapine extended release (XR)
    Reporting group description
    		 Adult subjects received 1 capsule daily during the first week and 2 capsules daily from the second week onwards. For the first 2 days (Day 1 to 2), adult subjects received one over-encapsulated tablet of quetiapine XR 50 milligrams (mg) daily at bedtime, followed by 1 over-encapsulated tablet of 150 mg tablet daily (lower dose) from Day 3 to 7. Elderly subjects on quetiapine XR started treatment with one over-encapsulated 50 mg tablet daily at bedtime from Day 1 to 3 and took a second over-encapsulated 50 mg tablet from Day 4-7 according to the local prescribing label and investigator’s judgement. From the second week, subjects on the quetiapine XR lower dose received 1 over-encapsulated tablet of quetiapine XR 150 mg and 1 capsule of placebo daily at bedtime. Subjects on the quetiapine XR higher dose received two over encapsulated tablets of 150 mg quetiapine XR daily at bedtime from Day 14 onwards till Day 182.

    Reporting group title
    Arm 2: Seltorexant
    Reporting group description
    		 Adult subjects received 1 capsule daily during the first week and 2 capsules daily from the second week onwards. For first week (from Day 1 to 7), adult subjects received one over encapsulated tablet of seltorexant 20 mg daily at bedtime. During the second week adult subjects received 2 capsules (1 over encapsulated tablet of seltorexant 20 mg and placebo) at bedtime from Day 8 to 182. Elderly patients on seltorexant will start with 1 over-encapsulated tablet of 20 mg on Day 1 and a second capsule of placebo to match the blinded dose titration schedule of quetiapine XR from Day 4 till Day 182. Matching placebo dosing for elderly subjects were flexible for Days 4 to 7 alone.

    Primary: Percentage of Subjects with Response (Greater than or Equal to [>=] 50 Percent [%] Improvement from Baseline in Montgomery-Asberg Depression Rating Scale [MADRS] Total Score) at Week 26

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    End point title
    		 Percentage of Subjects with Response (Greater than or Equal to [>=] 50 Percent [%] Improvement from Baseline in Montgomery-Asberg Depression Rating Scale [MADRS] Total Score) at Week 26
    End point description
    The 10-item clinician-administered MADRS scale score was designed to measure depression severity and to detect changes due to antidepressant treatment using the 10 items followed: apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, & suicidal thoughts. Each item scored from 0 (no item/normal) to 6 (severe/continuous presence of symptoms), & sum of scores of individual questions at a given time point ranged from 0 to 60. Higher scores indicated more severe condition. Responders were defined as subjects with >=50% improvement in MADRS total score from baseline & those with missing values were imputed as non-responders. Full analysis set 2 without Ukraine subjects involved in conflict (FAS2CON) included all randomised subjects who received at least 1 dose of study drug but excluded Ukraine subjects who were ongoing in double-blind phase at time of Ukraine-Russian war in 2022.
    End point type
    Primary
    End point timeframe
    From baseline (Day 1) up to Week 26
    End point values
    		 Arm 1: Quetiapine extended release (XR) Arm 2: Seltorexant
    Number of subjects analysed
    382
    361
    Units: percentage of subjects
        number (not applicable)
    53.7
    57.9
    Statistical analysis title
    		 Seltorexant vs Quetiapine XR
    Comparison groups
    Arm 1: Quetiapine extended release (XR) v Arm 2: Seltorexant
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Percentage difference
    Point estimate
    4.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.9
         upper limit
    		 11.4

    Secondary: Change from Baseline in Body Weight (in Kilograms) up to Week 26

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    End point title
    		 Change from Baseline in Body Weight (in Kilograms) up to Week 26
    End point description
    Change from baseline in body weight (in kilograms) up to Week 26 were reported. The full analysis set 2 (FAS2) included all randomised subjects who received at least 1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    From baseline (Day 1) up to Week 26
    End point values
    		 Arm 1: Quetiapine extended release (XR) Arm 2: Seltorexant
    Number of subjects analysed
    390
    366
    Units: Kilograms (Kg)
        arithmetic mean (standard deviation)
    2.0 ( 3.81 )
    0.5 ( 2.96 )
    Statistical analysis title
    		 Seltorexant vs Quetiapine XR
    Comparison groups
    Arm 1: Quetiapine extended release (XR) v Arm 2: Seltorexant
    Number of subjects included in analysis
    756
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of Least Square (LS) Means
    Point estimate
    -1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.93
         upper limit
    		 -0.93
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.25

    Secondary: Time to Study Drug Discontinuation for Potentially Treatment Related Reasons

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    End point title
    		 Time to Study Drug Discontinuation for Potentially Treatment Related Reasons
    End point description
    Time to study drug discontinuation for potentially treatment related reasons were reported. Time to discontinuation of study drug: the number of days from first dose up to last dose of study drug. Potentially treatment related reasons were all study drug discontinuations excluding potentially non-treatment related discontinuations (for example, loss of insurance for antidepressant therapy, movement/travel out of area, change of work-schedule being unable to accommodate visit schedule, family circumstances). Subjects who complete double-blind treatment were not considered as discontinued. Discontinuations due to AE or lack of efficacy or product quality complaints were considered potentially treatment related. FAS2 analysis set were analysed. Here, "99999" signifies that data were not estimable due to low number of subjects with events. Here "N" (Number of subjects analysed) signifies the number of subjects that were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From baseline (Day 1) up to Week 26
    End point values
    		 Arm 1: Quetiapine extended release (XR) Arm 2: Seltorexant
    Number of subjects analysed
    68
    44
    Units: days
        median (full range (min-max))
    206 (-99999 to 99999)
    99999 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 26 in MADRS Total Score

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    End point title
    		 Change from Baseline to Week 26 in MADRS Total Score
    End point description
    Change from baseline to Week 26 in MADRS total score were reported. The MADRS scale score was a 10-item clinician-administered scale designed to measure depression severity and to detect changes due to antidepressant treatment using the 10 items followed: apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. Each item scored from 0 (no item or normal) to 6 (severe or continuous presence of symptoms), and the sum of scores of individual question items at a given time point ranged from 0 to 60. Higher scores indicated more severe condition. FAS2 analysis set included all randomised subjects who received at least 1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    From baseline (Day 1) up to Week 26
    End point values
    		 Arm 1: Quetiapine extended release (XR) Arm 2: Seltorexant
    Number of subjects analysed
    390
    366
    Units: score on a scale
        arithmetic mean (standard deviation)
    -22.5 ( 9.42 )
    -22.8 ( 10.08 )
    Statistical analysis title
    		 Seltorexant Vs Quetiapine XR
    Comparison groups
    Arm 1: Quetiapine extended release (XR) v Arm 2: Seltorexant
    Number of subjects included in analysis
    756
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of LS Means
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.66
         upper limit
    		 1.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.77

    Secondary: Change from Baseline to Week 26 in MADRS-6 Total Score

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    End point title
    		 Change from Baseline to Week 26 in MADRS-6 Total Score
    End point description
    Change from baseline to Week 26 in MADRS-6 total score were reported. The MADRS-6 scale was a subset of the MADRS-10 scale, the clinician-administered questionnaire used to measure the core symptoms of depression severity and to detect changes due to antidepressant intervention using the 7 core symptoms from the MADRS-10 scale as followed: Apparent Sadness, Reported Sadness, Inner Tension, Lassitude, Inability to Feel, and Pessimistic Thoughts. MADRS-6 scale was the sum of the scores from individual question items at a given time point and ranged from 0 (no apparent symptoms) to 36 (most severe symptoms). Higher scores represent a more severe condition. FAS2 analysis set included all randomised subjects who received at least 1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    From baseline (Day 1) up to Week 26
    End point values
    		 Arm 1: Quetiapine extended release (XR) Arm 2: Seltorexant
    Number of subjects analysed
    390
    366
    Units: score on a scale
        arithmetic mean (standard deviation)
    -14.4 ( 6.56 )
    -14.7 ( 6.81 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 26 in the MADRS Without Sleep Item (MADRS-WOSI) Total Score

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    End point title
    		 Change from Baseline to Week 26 in the MADRS Without Sleep Item (MADRS-WOSI) Total Score
    End point description
    Change from baseline to Week 26 in MADRS-WOSI were reported. MADRS-WOSI was defined as full MADRS total score without sleep item. The MADRS was a 10-item clinician-administered scale designed to measure depression severity and to detect changes due to antidepressant treatment using items on a scale scored from 0 (no item or normal) to 6 (severe or continuous presence of symptoms), & higher scores indicated greater symptom severity. MADRS-WOSI included 9 items (apparent sadness, reported sadness, inner tension, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, & suicidal thoughts) of 10 MADRS total score items, excluding "reduced sleep" item. The total score ranged from 0 to 54. Higher scores indicated a more severe condition. FAS2 analysis set included all randomised subjects who received at least 1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    From baseline (Day 1) up to Week 26
    End point values
    		 Arm 1: Quetiapine extended release (XR) Arm 2: Seltorexant
    Number of subjects analysed
    390
    366
    Units: score on a scale
        arithmetic mean (standard deviation)
    -19.3 ( 8.55 )
    -19.6 ( 9.18 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 26 in Patient Health Questionnaire, 9-Item (PHQ-9) Scale Total Score

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    End point title
    		 Change from Baseline to Week 26 in Patient Health Questionnaire, 9-Item (PHQ-9) Scale Total Score
    End point description
    Change from baseline to Week 26 in PHQ-9 scale total score were reported. The PHQ-9 scale was a 9-item, patient-reported outcome measure used to assess depressive symptoms. PHQ-9 scale scored 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 on the 4-point score scale ranged from 0 to 4 with 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 achieve the total score (ranged from 0 to 27), where the higher score indicated greater severity of depressive symptoms. FAS2 analysis set included all randomised subjects who received at least 1 dose of study intervention.
    End point type
    Secondary
    End point timeframe
    From baseline (Day 1) up to Week 26
    End point values
    		 Arm 1: Quetiapine extended release (XR) Arm 2: Seltorexant
    Number of subjects analysed
    390
    366
    Units: score on a scale
        arithmetic mean (standard deviation)
    -12.4 ( 5.94 )
    -12.0 ( 6.34 )
    Statistical analysis title
    		 Seltorexant vs Quetiapine XR
    Comparison groups
    Arm 1: Quetiapine extended release (XR) v Arm 2: Seltorexant
    Number of subjects included in analysis
    756
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Difference of LS means
    Point estimate
    0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.62
         upper limit
    		 1.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.47

    Secondary: Percentage of Subjects with Remission (MADRS Total Score less than or equal to (<=) 12) at Week 26

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    End point title
    		 Percentage of Subjects with Remission (MADRS Total Score less than or equal to (<=) 12) at Week 26
    End point description
    The MADRS scale score was a 10-item clinician-administered scale designed to measure depression severity and to detect changes due to antidepressant treatment using 10 items followed: apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. Each item scored from 0 (no item or normal) to 6 (severe or continuous presence of symptoms), and sum of scores of individual question items at a given time point ranged from 0 to 60. Higher scores indicated more severe condition. A subject was considered a remitter at time if MADRS total score <=12 at that time. Subjects who did not meet criterion were non-remitters. Subjects with missing values at a given time point were imputed as non-remitters. FAS2CON analysis set was analysed. Here "N" (Number of subjects analysed) signifies the number of subjects that were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    At Week 26
    End point values
    		 Arm 1: Quetiapine extended release (XR) Arm 2: Seltorexant
    Number of subjects analysed
    382
    361
    Units: percentage of subjects
        number (not applicable)
    44.2
    47.6
    Statistical analysis title
    		 Seltorexant vs Quetiapine XR
    Comparison groups
    Arm 1: Quetiapine extended release (XR) v Arm 2: Seltorexant
    Number of subjects included in analysis
    743
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Percentage difference
    Point estimate
    3.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.8
         upper limit
    		 10.6

    Secondary: Percentage of Subjects with a >=50 Percent Improvement in MADRS Total Score and a MADRS Total Score <=18 at Week 26

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    End point title
    		 Percentage of Subjects with a >=50 Percent Improvement in MADRS Total Score and a MADRS Total Score <=18 at Week 26
    End point description
    Percentage of subjects with a >=50% improvement in MADRS total score & MADRS total score <=18 at Week 26 were reported. The 10-item clinician-administered MADRS score measured depression severity & changes by antidepressant treatment from 10 items followed: apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, & suicidal thoughts. Scale scored from 0 (no item/normal) to 6 (severe/continuous presence of symptoms),& summed scores of each item at a given time point ranged from 0 to 60. Higher scores indicated more severe condition. A >=50% improvement from baseline in MADRS total score & MADRS total score <=18 at assessed time point indicated a responder with mild symptoms & those did not meet both criteria were considered non-responders. FAS2CON analysis set was analysed. Here "N" (Number of subjects analysed) signifies number of subjects that were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    At Week 26
    End point values
    		 Arm 1: Quetiapine extended release (XR) Arm 2: Seltorexant
    Number of subjects analysed
    382
    361
    Units: percentage of subjects
        number (not applicable)
    52.4
    57.6
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Body Weight Increase >=7% from Baseline at Week 26

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    End point title
    		 Percentage of Subjects with Body Weight Increase >=7% from Baseline at Week 26
    End point description
    Percentage of subjects with body weight increase >=7% from baseline was reported. FAS2 analysis set included all randomised subjects who received at least 1 dose of study intervention. Here "N" (Number of subjects analysed) signifies the number of subjects that were evaluable for this endpoint and "n"(number of subjects analysed) signifies number of subjects analysed at specified timepoints.
    End point type
    Secondary
    End point timeframe
    From baseline (Day 1) up to Week 26
    End point values
    		 Arm 1: Quetiapine extended release (XR) Arm 2: Seltorexant
    Number of subjects analysed
    274
    279
    Units: percentage of subjects
        number (not applicable)
    18.6
    4.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline (Day 1) up to Week 28 (Day 196)
    Adverse event reporting additional description
    Safety analysis set included all randomised subjects who received at least 1 dose of study intervention.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Arm 2: Seltorexant
    Reporting group description
    		 Adult subjects received 1 capsule daily during the first week and 2 capsules daily from the second week onwards. For first week (from Day 1 to 7), adult subjects received one over encapsulated tablet of seltorexant 20 mg daily at bedtime. During the second week adult subjects received 2 capsules (1 over encapsulated tablet of seltorexant 20 mg and placebo) at bedtime from Day 8 to 182. Elderly patients on seltorexant will start with 1 over-encapsulated tablet of 20 mg on Day 1 and a second capsule of placebo to match the blinded dose titration schedule of quetiapine XR from Day 4 till Day 182. Matching placebo dosing for elderly subjects were flexible for Days 4 to 7 alone.

    Reporting group title
    Arm 1: Quetiapine extended release (XR)
    Reporting group description
    		 Adult subjects received 1 capsule daily during the first week and 2 capsules daily from the second week onwards. For the first 2 days (Day 1 to 2), adult subjects received one over-encapsulated tablet of quetiapine XR 50 milligrams (mg) daily at bedtime, followed by 1 over-encapsulated tablet of 150 mg tablet daily (lower dose) from Day 3 to 7. Elderly subjects on quetiapine XR started treatment with one over-encapsulated 50 mg tablet daily at bedtime from Day 1 to 3 and took a second over-encapsulated 50 mg tablet from Day 4-7 according to the local prescribing label and investigator’s judgement. From the second week, subjects on the quetiapine XR lower dose received 1 over-encapsulated tablet of quetiapine XR 150 mg and 1 capsule of placebo daily at bedtime. Subjects on the quetiapine XR higher dose received two over encapsulated tablets of 150 mg quetiapine XR daily at bedtime from Day 14 onwards till Day 182.

    Serious adverse events
    		 Arm 2: Seltorexant Arm 1: Quetiapine extended release (XR)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 366 (1.37%)
    6 / 390 (1.54%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Burns Second Degree
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Sciatica
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Haemorrhoidal Haemorrhage
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cervical Dysplasia
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Drug-Induced Liver Injury
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral Disc Disorder
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Burn Infection
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 390 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Covid-19
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 390 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm 2: Seltorexant Arm 1: Quetiapine extended release (XR)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    99 / 366 (27.05%)
    200 / 390 (51.28%)
    Investigations
    Weight Increased
         subjects affected / exposed
    20 / 366 (5.46%)
    54 / 390 (13.85%)
         occurrences all number
    20
    54
    Nervous system disorders
    Headache
         subjects affected / exposed
    42 / 366 (11.48%)
    43 / 390 (11.03%)
         occurrences all number
    56
    53
    Somnolence
         subjects affected / exposed
    23 / 366 (6.28%)
    94 / 390 (24.10%)
         occurrences all number
    30
    120
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    13 / 366 (3.55%)
    23 / 390 (5.90%)
         occurrences all number
    13
    29
    Gastrointestinal disorders
    Dry Mouth
         subjects affected / exposed
    10 / 366 (2.73%)
    38 / 390 (9.74%)
         occurrences all number
    10
    39
    Nausea
         subjects affected / exposed
    11 / 366 (3.01%)
    20 / 390 (5.13%)
         occurrences all number
    11
    20

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Jun 2020
    The first amendment addressed health authority feedback concerning neurologic examinations, restrictions on driving, operating machinery or engaging in hazardous activity, European Union (EU)-specific statistical analyses, and concomitant therapy following study drug stoppage, study discontinuation for subjects. No subjects had been enrolled in the study at that point.
    09 Jul 2020
    The second amendment addressed health authority feedback concerning for 26-week response rate estimates for the seltorexant and quetiapine group sample size estimates and analysis sets to be used for the primary and sensitivity analyses. No subjects had been enrolled in the study at that point.
    13 Jan 2021
    The third amendment incorporated recommendations and suggestions from world-wide health authorities and ethics committees, as well as changes made to the 2020-000337-40 and 2020-000338-16 study protocols. The estimand definitions and corresponding analyses for the key secondary endpoint (weight change) were clarified. 5 subjects had been enrolled in the study at that point.
    25 Jun 2021
    The purpose of the fourth amendment was to modify eligibility criteria, based on early enrollment experiences.
    15 Sep 2022
    The purpose of the fifth amendment was to remove the interim analysis from this protocol along with amendment in the schedule of activities to clarify how the consensus sleep diary (CSD) would be collected and to mention how to perform additional follow-up for early withdrawal of study drug and correction of typographical errors.

    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.
    The primary & endpoints related to response and remission analysis were based on FAS1CON & FAS2CON sets that excluded 13 ongoing Ukraine subjects at time of Ukraine-Russian war 2022, with which subjects did not complete DB phase or provide results.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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