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    Clinical Trial Results:
    A Phase 3 Efficacy and Safety Study of ALKS 5461 for the Adjunctive Treatment of Major Depressive Disorder (the FORWARD-3 Study)

    Summary
    EudraCT number
    		 2014-000399-25
    Trial protocol
    		 HU   SK   BG  
    Global end of trial date
    23 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jan 2017
    First version publication date
    06 Jan 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ALK5461-206
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02158546
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Alkermes, Inc.
    Sponsor organisation address
    852 Winter Street, Waltham, United States, 02451
    Public contact
    Clinical Developement, Alkermes, Inc, +1 781-609 6012, william.martin@alkermes.com
    Scientific contact
    Clinical Developement, Alkermes, Inc, +1 781-609 6012, william.martin@alkermes.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
    24 Aug 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Dec 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • To evaluate the efficacy of ALKS 5461 for the adjunctive treatment of major depressive disorder (MDD) in adults who have an inadequate response to antidepressant therapy (ADT) • To evaluate the safety and tolerability of ALKS 5461 in adults who have MDD and an inadequate response to ADT
    Protection of trial subjects
    This trial was conducted in compliance with Good Clinical Practice (GCP) guidelines for conducting clinical trials. The informed consent form (ICF), protocol, and amendments were reviewed and approved by the institutional review board (IRB) or independent ethics committee (IEC) for each clinical trial site.
    Background therapy
    		 Subjects were required to take an adequate dose of an antidepressant therapy (ADT), including an SSRI, SNRI, or bupropion, and the dose could not exceed the maximum daily dose identified for these agents during the course of the study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 May 2014
    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
    Bulgaria: 49
    Country: Number of subjects enrolled
    United States: 246
    Worldwide total number of subjects
    295
    EEA total number of subjects
    49
    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)
    271
    From 65 to 84 years
    24
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were diagnosed with major depressive disorder (MDD), and had an inadequate response to 1 or 2 adequate courses of treatment with a commercially available ADT during the current major depressive episode (MDE).

    Pre-assignment
    Screening details
    		 The screening period lasted 4 - 12 weeks, and included an assessment of MDD history.

    Period 1
    Period 1 title
    Double Blind Primary Efficacy Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Randomization and treatment assignment occurred via IxRS. Once a randomization number was assigned, that number could not be used again if, for example, a subject was withdrawn from the study. Randomization codes were prepared by an independent biostatistician who was not otherwise involved in this study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ALKS 5461 2/2
    Arm description
    		 Sublingual tablet, daily administration
    Arm type
    		 Experimental

    Investigational medicinal product name
    ALKS 5461
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    Each tablet contained 2 mg buprenorphine:2 mg samidorphan

    Arm title
    		 Placebo
    Arm description
    		 Placebo tablets, daily administration
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo for ALKS 5461
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    Placebo tablets were prepared using a similar formulation composition without buprenorphine and samidorphan

    Number of subjects in period 1
    		ALKS 5461 2/2 Placebo
    Started
    147
    148
    Completed
    133
    136
    Not completed
    14
    12
         Consent withdrawn by subject
    6
    2
         Physician decision
    -
    1
         Adverse event, non-fatal
    2
    2
         Failure to meet eligibility criteria
    -
    1
         Other
    -
    1
         Lost to follow-up
    5
    4
         Lack of efficacy
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ALKS 5461 2/2
    Reporting group description
    		 Sublingual tablet, daily administration

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablets, daily administration

    Reporting group values
    		 ALKS 5461 2/2 Placebo Total
    Number of subjects
    		 147 148 295
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.4 ( 12.31 ) 48.1 ( 12.51 ) -
    Gender categorical
    Units: Subjects
        Female
    		 88 94 182
        Male
    		 59 54 113

    End points

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    End points reporting groups
    Reporting group title
    ALKS 5461 2/2
    Reporting group description
    		 Sublingual tablet, daily administration

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo tablets, daily administration

    Primary: Change in MADRS total score

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    End point title
    		 Change in MADRS total score
    End point description
    Change from randomization to the end of the efficacy period in Montgomery Asberg Depression Rating Scale (MADRS) total score
    End point type
    Primary
    End point timeframe
    6 weeks
    End point values
    		 ALKS 5461 2/2 Placebo
    Number of subjects analysed
    147
    148
    Units: Points
        least squares mean (standard error)
    -4.8 ( 0.67 )
    -4.6 ( 0.66 )
    Statistical analysis title
    		 Mixed models of repeated measure
    Comparison groups
    ALKS 5461 2/2 v Placebo
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.782
    Method
    		 Mixed models analysis
    Parameter type
    		 Least squares mean difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 1.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.95

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE reporting includes the 6-week double-blind, placebo-controlled period.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects enrolled in Group 1 who received placebo treatment

    Reporting group title
    ALKS 5461 2/2
    Reporting group description
    		 Subjects enrolled in Group 1 who received active study drug

    Serious adverse events
    		 Placebo ALKS 5461 2/2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 147 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 148 (0.68%)
    0 / 147 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    		 Placebo ALKS 5461 2/2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 148 (0.68%)
    13 / 147 (8.84%)
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 148 (0.68%)
    13 / 147 (8.84%)
         occurrences all number
    1
    14

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Mar 2014
    Amendment to the Unmasked Protocol Addendum - clarification in screening procedures for study participants.
    31 Mar 2014
    Protocol Amendment #1 clarified study procedures, improved generalizability of the study population and excluded subjects with a known history of respiratory depression, and optimized the assessment of efficacy and safety.
    07 Oct 2014
    Amendment to Unmasked Protocol Addendum: Modification in eligibility criteria in the screening period.
    20 Nov 2014
    Amendment to Unmasked Protocol Addendum: This amendment reduced the sample size in the trial in order to reflect revised assumptions regarding true treatment effect.
    20 Nov 2014
    Amendment #2 clarified details on study procedures and population, allowed sufficient time for subjects to titrate into the adequate dose range of their ADT, reduced the sample size, limited concomitant medications, and restricted the maximum dose of open-label antidepressants.

    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.
    Pre-specified primary population data are shown. Data from one site were excluded as pre-specified due to data integrity concerns. Other excluded subjects did not receive randomized study drug.
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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
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