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    Clinical Trial Results:
    A Phase IIa, Multicenter, Randomized, Placebo-Controlled Clinical Trial to Evaluate the Safety and Efficacy of MK-6096 for Treatment Augmentation in Patients with Major Depressive Disorder

    Summary
    EudraCT number
    		 2011-005200-15
    Trial protocol
    		 DE   FI   SE   NO  
    Global end of trial date
    03 Sep 2013

    Results information
    Results version number
    		 v3(current)
    This version publication date
    14 Dec 2017
    First version publication date
    21 Jan 2015
    Other versions
    		 v1 , v2
    Version creation reason
    • New data added to full data set
    The record has been updated to present final data following trial completion.

    Trial information

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    Trial identification
    Sponsor protocol code
    6096-022
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01554176
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.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 Sep 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Sep 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the safety and efficacy of filorexant (MK-6096) versus placebo as adjunctive treatment for major depressive disorder (MDD), in participants who are partial responders to antidepressant monotherapy with one of identified selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs), or bupropion. The primary hypothesis of the study is that filorexant is superior to placebo as augmentation therapy with respect to change from baseline to Week 6 in the Montgomery Asberg Depression Rating Scale (MADRS) total score. Participants were randomized to receive filorexant or placebo for a 6-week treatment period. After completion of the treatment period, participants entered a 2-week run-out period. For the run-out period, participants receiving placebo in treatment period continued to receive placebo and participants receiving filorexant in treatment period were randomized to receive either filorexant or placebo.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 Participants will continue to take their pretrial antidepressant medication as prescribed throughout the trial.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 May 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Norway: 3
    Country: Number of subjects enrolled
    Sweden: 6
    Country: Number of subjects enrolled
    Finland: 15
    Country: Number of subjects enrolled
    France: 19
    Country: Number of subjects enrolled
    Germany: 34
    Country: Number of subjects enrolled
    United States: 52
    Worldwide total number of subjects
    129
    EEA total number of subjects
    77
    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)
    129
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 One participant in the Filorexant 10 mg (Treatment Phase) arm did not receive study drug and was discontinued from the study; the reason given for discontinuation was "non-compliance with study drug".

    Pre-assignment
    Screening details
    		 During the 1-2 week screening period participants will be evaluated to determine if they meet study entry criteria. The screening period will serve as a wash-out period for participants taking prohibited medications.

    Period 1
    Period 1 title
    Treatment Phase
    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
    		 Filorexant 10 mg (Treatment Phase)
    Arm description
    		 Treatment Phase: Participants in this group were administered filorexant 10 mg once daily at bedtime for 6 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    filorexant
    Investigational medicinal product code
    Other name
    MK-6096
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Filorexant, one 10 mg tablet, orally, once daily at bedtime

    Arm title
    		 Placebo (Treatment Phase)
    Arm description
    		 Treatment Phase: Participants in this group were administered placebo once daily at bedtime for 6 weeks.
    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
    Placebo, one tablet, orally, once daily at bedtime

    Number of subjects in period 1
    		Filorexant 10 mg (Treatment Phase) Placebo (Treatment Phase)
    Started
    65
    64
    Treated
    64
    64
    Completed
    57
    59
    Not completed
    8
    5
         Physician decision
    1
    1
         Consent withdrawn by subject
    1
    -
         Adverse event, non-fatal
    1
    1
         Lost to follow-up
    3
    -
         Not treated: Non-compliance with study drug
    1
    -
         Protocol deviation
    1
    2
         Lack of efficacy
    -
    1
    Period 2
    Period 2 title
    Run-out Phase
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Filorexant 10 mg/Filorexant 10 mg (Run-out Phase)
    Arm description
    		 Run-out Phase: Following completion of the 6-week treatment phase, participants in this group were administered filorexant 10 mg once daily at bedtime for 2 weeks. Participants in this group had received filorexant 10 mg once daily during the treatment phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    filorexant
    Investigational medicinal product code
    Other name
    MK-6096
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Filorexant, one 10 mg tablet, orally, once daily at bedtime

    Arm title
    		 Filorexant 10 mg/Placebo (Run-out Phase)
    Arm description
    		 Run-out Phase: Following completion of the 6-week treatment phase, participants in this group were administered placebo once daily at bedtime for 2 weeks. Participants in this group had received filorexant 10 mg once daily during the treatment phase.
    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
    Placebo, one tablet, orally, once daily at bedtime

    Arm title
    		 Placebo/Placebo (Run-out Phase)
    Arm description
    		 Run-out Phase: Following completion of the 6-week Treatment Phase, participants in this group were administered placebo once daily at bedtime for 2 weeks. Participants in this group had received placebo once daily during the Treatment Phase.
    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
    Placebo, one tablet, orally, once daily at bedtime

    Number of subjects in period 2
    		Filorexant 10 mg/Filorexant 10 mg (Run-out Phase) Filorexant 10 mg/Placebo (Run-out Phase) Placebo/Placebo (Run-out Phase)
    Started
    29
    28
    59
    Completed
    29
    27
    59
    Not completed
    0
    1
    0
         Protocol deviation
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Filorexant 10 mg (Treatment Phase)
    Reporting group description
    		 Treatment Phase: Participants in this group were administered filorexant 10 mg once daily at bedtime for 6 weeks.

    Reporting group title
    Placebo (Treatment Phase)
    Reporting group description
    		 Treatment Phase: Participants in this group were administered placebo once daily at bedtime for 6 weeks.

    Reporting group values
    		 Filorexant 10 mg (Treatment Phase) Placebo (Treatment Phase) Total
    Number of subjects
    		 65 64 129
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 65 64 129
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.8 ± 12.4 50 ± 10.3 -
    Gender categorical
    Units: Subjects
        Female
    		 40 42 82
        Male
    		 25 22 47

    End points

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    End points reporting groups
    Reporting group title
    Filorexant 10 mg (Treatment Phase)
    Reporting group description
    		 Treatment Phase: Participants in this group were administered filorexant 10 mg once daily at bedtime for 6 weeks.

    Reporting group title
    Placebo (Treatment Phase)
    Reporting group description
    		 Treatment Phase: Participants in this group were administered placebo once daily at bedtime for 6 weeks.
    Reporting group title
    Filorexant 10 mg/Filorexant 10 mg (Run-out Phase)
    Reporting group description
    		 Run-out Phase: Following completion of the 6-week treatment phase, participants in this group were administered filorexant 10 mg once daily at bedtime for 2 weeks. Participants in this group had received filorexant 10 mg once daily during the treatment phase.

    Reporting group title
    Filorexant 10 mg/Placebo (Run-out Phase)
    Reporting group description
    		 Run-out Phase: Following completion of the 6-week treatment phase, participants in this group were administered placebo once daily at bedtime for 2 weeks. Participants in this group had received filorexant 10 mg once daily during the treatment phase.

    Reporting group title
    Placebo/Placebo (Run-out Phase)
    Reporting group description
    		 Run-out Phase: Following completion of the 6-week Treatment Phase, participants in this group were administered placebo once daily at bedtime for 2 weeks. Participants in this group had received placebo once daily during the Treatment Phase.

    Primary: Change from Baseline to Week 6 in MADRS Total Score

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    End point title
    		 Change from Baseline to Week 6 in MADRS Total Score
    End point description
    The MADRS is a 10-item clinician-rated instrument for evaluating severity of symptoms of depression. Each item is rated on a scale from 0 to 6, with total scores ranging from 0-60; higher scores correspond to greater symptom severity. The reported measure is the mean change from baseline to Week 6 of the Treatment Phase; improvement in symptoms is represented by negative values.
    End point type
    Primary
    End point timeframe
    Baseline and Week 6
    End point values
    		 Filorexant 10 mg (Treatment Phase) Placebo (Treatment Phase)
    Number of subjects analysed
    58 [1]
    61 [2]
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline
    30.3 ± 4.6
    31 ± 4.3
        Change at Week 6
    -11 ± 9.5
    -10.3 ± 8.2
    Notes
    [1] - Includes participants who took ≥1 dose of study drug and had baseline and Week 6 value
    [2] - Includes participants who took ≥1 dose of study drug and had baseline and Week 6 value
    Statistical analysis title
    		 Change from Baseline in MADRS Total Score - Week 6
    Statistical analysis description
    Number of participants included for calculation of mean ± SD baseline and mean ± SD change from baseline MADRS Total Score is 119. Constrained longitudinal data analysis (cLDA) model uses efficacy Full Analysis Set (FAS) population (number of participants: filorexant 10 mg – 64, placebo – 64; total number of participants in cLDA analysis – 128). FAS includes participants who took ≥1 dose of study drug and had ≥1 evaluable efficacy measurement, including those who had only a baseline measurement.
    Comparison groups
    Filorexant 10 mg (Treatment Phase) v Placebo (Treatment Phase)
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.679 [3]
    Method
    		 Constrained longitudinal data analysis
    Parameter type
    		 Difference in least squares means
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.8
         upper limit
    		 2.5
    Notes
    [3] - cLDA model included terms for treatment, time, the interaction of time by treatment, severity of disease (Hamilton Depression Rating Scale, 17-items [HAM-D17] ≤20, >20) and insomnia severity index (ISI ≤14, >14).

    Primary: Number of Participants With an Adverse Event (AE) During Treatment Phase

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    End point title
    		 Number of Participants With an Adverse Event (AE) During Treatment Phase
    End point description
    An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with study drug administration, is also an AE. Participants with one or more AEs during the treatment phase (up to study Week 6) are counted once in this summary.
    End point type
    Primary
    End point timeframe
    Up to Week 6
    End point values
    		 Filorexant 10 mg (Treatment Phase) Placebo (Treatment Phase)
    Number of subjects analysed
    64 [4]
    64 [5]
    Units: Participants
    27
    17
    Notes
    [4] - Includes participants who took ≥1 dose of study drug
    [5] - Includes participants who took ≥1 dose of study drug
    Statistical analysis title
    		 Participants with AEs During Treatment Phase
    Statistical analysis description
    Estimated parameter is between-group difference in percentage of participants with an AE = percentage (filorexant 10 mg) − percentage (placebo)
    Comparison groups
    Filorexant 10 mg (Treatment Phase) v Placebo (Treatment Phase)
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in percentage incidence
    Point estimate
    15.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 31.4
    Notes
    [6] - Between-group comparison of AE incidence rate

    Primary: Number of Participants Who Discontinued Study Drug Due to an AE During Treatment Phase

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    End point title
    		 Number of Participants Who Discontinued Study Drug Due to an AE During Treatment Phase
    End point description
    An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with study drug administration, is also an AE. Participants who discontinued study drug treatment due to an AE during the treatment phase (up to study Week 6) are counted once in this summary.
    End point type
    Primary
    End point timeframe
    Up to Week 6
    End point values
    		 Filorexant 10 mg (Treatment Phase) Placebo (Treatment Phase)
    Number of subjects analysed
    64 [7]
    64 [8]
    Units: participants
    1
    1
    Notes
    [7] - Includes participants who received ≥1 dose of study drug
    [8] - Includes participants who received ≥1 dose of study drug
    Statistical analysis title
    		 Drug Discontinuation Due to AE (Treatment Phase)
    Statistical analysis description
    Estimated parameter is between-group difference in percentage of participants discontinued from study drug due to an AE = percentage (filorexant 10 mg) − percentage (placebo)
    Comparison groups
    Filorexant 10 mg (Treatment Phase) v Placebo (Treatment Phase)
    Number of subjects included in analysis
    128
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    Method
    		 Miettinen & Nurminen
    Parameter type
    		 Difference in percentage incidence
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7
         upper limit
    		 7
    Notes
    [9] - Between-group comparison of incidence rate of drug discontinuation due to AE

    Primary: Number of Participants With an AE During Run-out Phase

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    End point title
    		 Number of Participants With an AE During Run-out Phase [10]
    End point description
    An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with study drug administration, is also an AE. Participants with one or more AEs during the 2-week run-out phase and/or during the 2-week follow up after the last dose of study drug, are counted once in this summary.
    End point type
    Primary
    End point timeframe
    From first run-out dose (following Week 6 visit) up to 14 days after last dose of study drug (approximately 4 weeks)
    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: No statistical analyses were planned for this endpoint.
    End point values
    		 Filorexant 10 mg/Filorexant 10 mg (Run-out Phase) Filorexant 10 mg/Placebo (Run-out Phase) Placebo/Placebo (Run-out Phase)
    Number of subjects analysed
    29 [11]
    28 [12]
    59 [13]
    Units: participants
    6
    3
    9
    Notes
    [11] - Includes participants who took ≥1 dose of study drug in run-out phase
    [12] - Includes participants who took ≥1 dose of study drug in run-out phase
    [13] - Includes participants who took ≥1 dose of study drug in run-out phase
    No statistical analyses for this end point

    Primary: Number of Participants Who Discontinued Study Drug Due to an AE During Run-out Phase

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    End point title
    		 Number of Participants Who Discontinued Study Drug Due to an AE During Run-out Phase [14]
    End point description
    An AE is any unfavorable and unintended change in the structure, function or chemistry of the body temporally associated with study drug administration, whether or not considered related to the study drug. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with study drug administration, is also an AE. Participants who discontinued study drug treatment due to an AE during the 2-week run-out phase are counted once in this summary.
    End point type
    Primary
    End point timeframe
    From first run-out dose (following Week 6 visit) up to Week 8 (2 weeks)
    Notes
    [14] - 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: No statistical analyses were planned for this endpoint.
    End point values
    		 Filorexant 10 mg/Filorexant 10 mg (Run-out Phase) Filorexant 10 mg/Placebo (Run-out Phase) Placebo/Placebo (Run-out Phase)
    Number of subjects analysed
    29 [15]
    28 [16]
    59 [17]
    Units: participants
    0
    0
    0
    Notes
    [15] - Includes participants who took ≥1 dose of study drug in run-out phase
    [16] - Includes participants who took ≥1 dose of study drug in run-out phase
    [17] - Includes participants who took ≥1 dose of study drug in run-out phase
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 6 in MADRS Total Score Excluding the Sleep Item

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    End point title
    		 Change from Baseline to Week 6 in MADRS Total Score Excluding the Sleep Item
    End point description
    The MADRS is a 10-item clinician-rated instrument for evaluating severity of symptoms of depression. Each item is rated on a scale from 0 to 6, with higher scores indicating greater symptom severity. The total score ranged from 0 to 54, with higher scores corresponding to greater symptom severity. This measure considered 9 of the 10 MADRS items: apparent sadness, reported sadness, inner tension, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. It excluded "reduced sleep." The reported measure is the mean change from baseline to Week 6 of the Treatment Phase; improvement in symptoms is represented by negative values.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 6
    End point values
    		 Filorexant 10 mg (Treatment Phase) Placebo (Treatment Phase)
    Number of subjects analysed
    58 [18]
    61 [19]
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline
    26.5 ± 4.1
    27.2 ± 4.1
        Change at Week 6
    -9.5 ± 8.5
    -9.1 ± 7.4
    Notes
    [18] - Includes participants who took ≥1 dose of study drug and had baseline and Week 6 value
    [19] - Includes participants who took ≥1 dose of study drug and had baseline and Week 6 value
    Statistical analysis title
    		 Change at Week 6; MADRS Score minus Sleep Item
    Statistical analysis description
    For the calculation of mean ± SD for baseline and change at 6 weeks in MADRS Score excluding the sleep item, the number of participants included is 119. The cLDA model uses efficacy Full Analysis Set (FAS) population (number of participants: filorexant 10 mg – 64, placebo – 64; total number of participants in cLDA analysis – 128). FAS includes participants who took ≥1 dose of study drug and had ≥1 evaluable efficacy measurement, including those who had only a baseline measurement.
    Comparison groups
    Filorexant 10 mg (Treatment Phase) v Placebo (Treatment Phase)
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 = 0.82 [21]
    Method
    		 Constrained longitudinal data analysis
    Parameter type
    		 Difference in least squares means
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.2
         upper limit
    		 2.5
    Notes
    [20] - Pairwise Comparison: Filorexant 10 mg vs. Placebo
    [21] - cLDA model included terms for treatment, time, the interaction of time by treatment, severity of disease (Hamilton Depression Rating Scale, 17-items [HAM-D17] ≤20, >20) and insomnia severity index (ISI ≤14, >14).

    Secondary: Change from Baseline to Week 6 in the Hamilton Depression Rating Scale, 17-item Version (HAM-D17) Bech Subscale Score

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    End point title
    		 Change from Baseline to Week 6 in the Hamilton Depression Rating Scale, 17-item Version (HAM-D17) Bech Subscale Score
    End point description
    The HAM-D, an instrument for evaluating severity of symptoms of depression, was completed by the participant. The instrument used in this study was the 17-item version (HAM-D17). The Bech subscale of the HAM-D17 is composed of 6 identified items out of the 17 items rated. Each item is rated on either a 3-point scale (0 to 2) or a 5-point scale (0 to 4). Total score ranged from 0 to 22, with a higher score indicating greater symptom severity. The following symptoms were rated on a 5-point scale (0-4): depressed mood, low self-esteem (guilt), work and interests, psychomotor retardation, and anxiety (psychic). The following symptom was rated on a 3-point scale (0-2): somatic symptoms (general). The reported measure is the change from baseline to Week 6 of the Treatment Phase; improvement in symptoms is represented by negative values.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 6
    End point values
    		 Filorexant 10 mg (Treatment Phase) Placebo (Treatment Phase)
    Number of subjects analysed
    56 [22]
    61 [23]
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline
    13.1 ± 2.4
    13.0 ± 2.1
        Change at Week 6
    -4.7 ± 4.8
    -4.2 ± 4.0
    Notes
    [22] - Includes participants who took ≥1 dose of study drug and had baseline and Week 6 value
    [23] - Includes participants who took ≥1 dose of study drug and had baseline and Week 6 value
    Statistical analysis title
    		 Change at Week 6; HAM-D17 Bech Subscale Score
    Statistical analysis description
    For the calculation of mean ± SD for baseline and change at 6 weeks in HAM-D17 Bech Subscale Score, the number of participants included is 117. The cLDA model uses efficacy Full Analysis Set (FAS) population (number of participants: filorexant 10 mg – 64, placebo – 64; total number of participants in cLDA analysis – 128). FAS includes participants who took ≥1 dose of study drug and had ≥1 evaluable efficacy measurement, including those who had only a baseline measurement.
    Comparison groups
    Filorexant 10 mg (Treatment Phase) v Placebo (Treatment Phase)
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [24]
    P-value
    		 = 0.701 [25]
    Method
    		 Constrained longitudinal data analysis
    Parameter type
    		 Difference in least squares means
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9
         upper limit
    		 1.3
    Notes
    [24] - Pairwise Comparison: Filorexant 10 mg vs. Placebo
    [25] - cLDA model included terms for treatment, time, the interaction of time by treatment, severity of disease (Hamilton Depression Rating Scale, 17-items [HAM-D17] ≤20, >20) and insomnia severity index (ISI ≤14, >14).

    Secondary: Percentage of Participants with HAM-D17 Remission (HAM-D17 Total Score ≤7) at Week 6

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    End point title
    		 Percentage of Participants with HAM-D17 Remission (HAM-D17 Total Score ≤7) at Week 6
    End point description
    The HAM-D, an instrument for evaluating severity of symptoms of depression, was completed by the participant. The instrument used in this study was the 17-item version (HAM-D17). Each item is rated on either a 3-point scale (0 to 2) or a 5-point scale (0 to 4), with higher scores indicating greater symptom severity. Total score ranged from 0 to 54. The following symptoms were rated on a 5-point scale (0-4): depressed mood, low self-esteem (guilt), suicidal thoughts, work and interests, psychomotor retardation, psychomotor agitation, anxiety (psychic), anxiety (somatic), and hypochondriasis (somatization). The following symptoms were rated on a 3-point scale (0-2): insomnia (initial), insomnia (middle), insomnia (late), gastrointestinal symptoms (appetite), somatic symptoms (general), sexual disturbances, insight, and weight loss. A participant with HAM-D17 total score ≤7 at Week 6 of the Treatment Phase was defined to have achieved HAM-D17 remission.
    End point type
    Secondary
    End point timeframe
    Week 6
    End point values
    		 Filorexant 10 mg (Treatment Phase) Placebo (Treatment Phase)
    Number of subjects analysed
    56 [26]
    61 [27]
    Units: percentage of participants
        number (not applicable)
    21.4
    9.8
    Notes
    [26] - Includes participants who took ≥1 dose of study drug and had baseline and Week 6 value
    [27] - Includes participants who took ≥1 dose of study drug and had baseline and Week 6 value
    Statistical analysis title
    		 Odds Ratio for HAM-D17 Remission at Week 6
    Statistical analysis description
    The odds ratio for HAM-D17 Remission at Week 6 was calculated from a generalized linear mixed effects model utilizing the efficacy Full Analysis Set (FAS) population (number of participants: filorexant 10 mg – 64, placebo – 64; total number of participants in analysis – 128). FAS includes participants who took ≥1 dose of study drug and had ≥1 evaluable efficacy measurement, including those who had only a baseline measurement.
    Comparison groups
    Filorexant 10 mg (Treatment Phase) v Placebo (Treatment Phase)
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [28]
    P-value
    		 = 0.0965 [29]
    Method
    		 Generalized Linear Mixed Effects Model
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 7.3
    Notes
    [28] - Pairwise Comparison: Filorexant 10 mg vs. Placebo
    [29] - Generalized linear mixed effects model included terms for treatment, time, and treatment-by-time interaction.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    [Treatment Phase]: Up to Week 6. [Run-out Phase]: From first run-out dose (following Week 6 visit) up to 14 days after last dose of study drug (approximately 4 weeks)
    Adverse event reporting additional description
    All Participants as Treated (APaT): Population includes participants who took ≥1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Filorexant 10 mg (Treatment Phase)
    Reporting group description
    		 Treatment Phase: Participants in this group were administered filorexant 10 mg once daily at bedtime for 6 weeks.

    Reporting group title
    Placebo (Treatment Phase)
    Reporting group description
    		 Treatment Phase: Participants in this group were administered placebo once daily at bedtime for 6 weeks.

    Reporting group title
    Filorexant 10 mg/Filorexant 10 mg (Run-out Phase)
    Reporting group description
    		 Run-out Phase: Following completion of the 6-week treatment phase, participants in this group were administered filorexant 10 mg once daily at bedtime for 2 weeks. Participants in this group had received filorexant 10 mg once daily during the treatment phase.

    Reporting group title
    Filorexant 10 mg/Placebo (Run-out Phase)
    Reporting group description
    		 Run-out Phase: Following completion of the 6-week treatment phase, participants in this group were administered placebo once daily at bedtime for 2 weeks. Participants in this group had received filorexant 10 mg once daily during the treatment phase.

    Reporting group title
    Placebo/Placebo (Run-out Phase)
    Reporting group description
    		 Run-out Phase: Following completion of the 6-week treatment phase, participants in this group were administered placebo once daily at bedtime for 2 weeks. Participants in this group had received placebo once daily during the treatment phase.

    Serious adverse events
    		 Filorexant 10 mg (Treatment Phase) Placebo (Treatment Phase) Filorexant 10 mg/Filorexant 10 mg (Run-out Phase) Filorexant 10 mg/Placebo (Run-out Phase) Placebo/Placebo (Run-out Phase)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 59 (1.69%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Nervous system disorders
    Presyncope
         subjects affected / exposed
    0 / 64 (0.00%)
    0 / 64 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    1 / 64 (1.56%)
    0 / 64 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Filorexant 10 mg (Treatment Phase) Placebo (Treatment Phase) Filorexant 10 mg/Filorexant 10 mg (Run-out Phase) Filorexant 10 mg/Placebo (Run-out Phase) Placebo/Placebo (Run-out Phase)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 64 (20.31%)
    7 / 64 (10.94%)
    3 / 29 (10.34%)
    1 / 28 (3.57%)
    1 / 59 (1.69%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 64 (0.00%)
    4 / 64 (6.25%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    0
    4
    0
    0
    0
    Headache
         subjects affected / exposed
    4 / 64 (6.25%)
    5 / 64 (7.81%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    5
    6
    0
    0
    0
    Somnolence
         subjects affected / exposed
    5 / 64 (7.81%)
    0 / 64 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 59 (0.00%)
         occurrences all number
    5
    0
    0
    0
    0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    5 / 64 (7.81%)
    1 / 64 (1.56%)
    3 / 29 (10.34%)
    1 / 28 (3.57%)
    1 / 59 (1.69%)
         occurrences all number
    5
    1
    3
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jun 2012
    Amendment 02: Primary reason for amendment was to incorporate revisions to eligibility criteria and timing of HAM-D assessment at screening.
    14 Dec 2012
    Amendment 03: Primary reason for amendment was to incorporate revisions to eligibility criteria, which were intended to address issue of slow rate of enrollment of participants in the study.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    25 Jun 2013
    Study recruitment was terminated early due to slow rate of participant enrollment; overall study enrollment planned in protocol was not achieved.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Study recruitment was terminated early due to slow rate of participant enrollment.
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