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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-5 Study)

    Summary
    EudraCT number
    		 2014-000379-14
    Trial protocol
    		 DE   PL  
    Global end of trial date
    27 Sep 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Oct 2017
    First version publication date
    27 Oct 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ALK5461-207
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02218008
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Alkermes, Inc.
    Sponsor organisation address
    852 Winter Street, Waltham, United States, 02451
    Public contact
    Eva Stroynowski, Alkermes, Inc, +1 781-609-7000, eva.stroynowski@alkermes.com
    Scientific contact
    Eva Stroynowski, Alkermes, Inc, +1 781-609-7000, eva.stroynowski@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
    19 Sep 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Sep 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Sep 2016
    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 This study was a 2-stage sequential parallel comparison design (SPCD) study design. At the end of Stage 1 subjects receiving placebo were categorized as either placebo responders or placebo non-responders according to their MADRS-10 score. Subjects categorized as placebo non-responders were re-randomized in a 1:1:1 ratio to ALKS 5461 1/1, ALKS 5461 2/2, or placebo for Stage 2. Subjects categorized as placebo responders were not re-randomized and remained on placebo for Stage 2.
    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
    24 Jun 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
    Germany: 65
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    United States: 335
    Worldwide total number of subjects
    407
    EEA total number of subjects
    65
    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)
    383
    From 65 to 84 years
    24
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    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). All subjects were taking a dose of ADT for the duration of the study.

    Pre-assignment
    Screening details
    		 The screening period lasted 4-12 weeks and included an assessment of MDD history. One subject was randomized to the placebo group but never received study drug.

    Period 1
    Period 1 title
    Stage 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo S1
    Arm description
    		 Subjects randomized to placebo in Stage 1
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    Sublingual tablet, taken once daily (in addition to open-label treatment with a commercially available antidepressant)

    Arm title
    		 ALKS 5461 1/1 S1
    Arm description
    		 Subjects randomized to ALKS 5461 1/1 in Stage 1
    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
    1 mg buprenorphine:1 mg samidorphan given as sublingual tablet, taken once daily (in addition to open-label treatment with a commercially available antidepressant)

    Arm title
    		 ALKS 5461 2/2 S1
    Arm description
    		 Subjects randomized to ALKS 5461 2/2 in Stage 1
    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
    2 mg buprenorphine:2 mg samidorphan, taken once daily (in addition to open-label treatment with a commercially available antidepressant)

    Number of subjects in period 1
    		Placebo S1 ALKS 5461 1/1 S1 ALKS 5461 2/2 S1
    Started
    281
    63
    63
    Completed
    258
    56
    48
    Not completed
    23
    7
    15
         Consent withdrawn by subject
    6
    1
    1
         Non-compliance; drug use
    1
    -
    -
         Failure to meet eligibility criteria
    2
    -
    -
         Adverse event, non-fatal
    6
    5
    11
         Pregnancy
    -
    -
    1
         Non-compliance with study drug
    2
    1
    -
         Lost to follow-up
    3
    -
    1
         Lack of efficacy
    3
    -
    -
         Protocol deviation
    -
    -
    1
    Period 2
    Period 2 title
    Stage 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo S2
    Arm description
    		 Subjects randomized to placebo in Stage 2
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    Sublingual tablet, taken once daily (in addition to open-label treatment with a commercially available antidepressant)

    Arm title
    		 ALKS 5461 1/1 S2
    Arm description
    		 Subjects randomized to ALKS 5461 1/1 in Stage 2
    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
    1 mg buprenorphine:1 mg samidorphan given as sublingual tablet, taken once daily (in addition to open-label treatment with a commercially available antidepressant)

    Arm title
    		 ALKS 5461 2/2 S2
    Arm description
    		 Subjects randomized to ALKS 5461 2/2 in Stage 2
    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
    2 mg buprenorphine:2 mg samidorphan, taken once daily (in addition to open-label treatment with a commercially available antidepressant)

    Number of subjects in period 2 [1]
    		Placebo S2 ALKS 5461 1/1 S2 ALKS 5461 2/2 S2
    Started
    62
    62
    63
    Completed
    58
    58
    57
    Not completed
    4
    4
    6
         Consent withdrawn by subject
    1
    1
    -
         Adverse event, non-fatal
    2
    3
    3
         Failure to meet eligibility criteria
    1
    -
    -
         Lost to follow-up
    -
    -
    1
         Lack of efficacy
    -
    -
    2
    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: Subjects randomized to Stage 2 are those who received placebo in Stage 1 and met placebo non-responder criteria.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo S1
    Reporting group description
    		 Subjects randomized to placebo in Stage 1

    Reporting group title
    ALKS 5461 1/1 S1
    Reporting group description
    		 Subjects randomized to ALKS 5461 1/1 in Stage 1

    Reporting group title
    ALKS 5461 2/2 S1
    Reporting group description
    		 Subjects randomized to ALKS 5461 2/2 in Stage 1

    Reporting group values
    		 Placebo S1 ALKS 5461 1/1 S1 ALKS 5461 2/2 S1 Total
    Number of subjects
    		 281 63 63 407
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    		 47 (18 to 68) 47 (19 to 66) 43 (18 to 69) -
    Gender categorical
    Units: Subjects
        Female
    		 193 42 42 277
        Male
    		 88 21 21 130

    End points

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    End points reporting groups
    Reporting group title
    Placebo S1
    Reporting group description
    		 Subjects randomized to placebo in Stage 1

    Reporting group title
    ALKS 5461 1/1 S1
    Reporting group description
    		 Subjects randomized to ALKS 5461 1/1 in Stage 1

    Reporting group title
    ALKS 5461 2/2 S1
    Reporting group description
    		 Subjects randomized to ALKS 5461 2/2 in Stage 1
    Reporting group title
    Placebo S2
    Reporting group description
    		 Subjects randomized to placebo in Stage 2

    Reporting group title
    ALKS 5461 1/1 S2
    Reporting group description
    		 Subjects randomized to ALKS 5461 1/1 in Stage 2

    Reporting group title
    ALKS 5461 2/2 S2
    Reporting group description
    		 Subjects randomized to ALKS 5461 2/2 in Stage 2

    Primary: Change in Montgomery Asberg Depression Rating Scale (MADRS)-6 score using average of changes from baseline to Week 3 through the end of treatment period (Week 5 for Stage 1, Week 6 for Stage 2)

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    End point title
    		 Change in Montgomery Asberg Depression Rating Scale (MADRS)-6 score using average of changes from baseline to Week 3 through the end of treatment period (Week 5 for Stage 1, Week 6 for Stage 2)
    End point description
    MADRS-6 comprises the following 6 items from the MADRS scale: Apparent Sadness, Reported Sadness, Inner Tension, Lassitude, Inability to Feel, and Pessimistic Thoughts. Scores range from 0 (no apparent symptoms) to 36 (most severe symptoms). The primary hypotheses were evaluated using a six-step, fixed sequence approach to adjust for multiple comparisons. Using this method, hypothesis testing (using alpha=0.05) continued through the sequence until statistical significance was not achieved. Steps 1 through 3 included testing the ALKS 5461 2/2 dose vs placebo for the 3 primary endpoints; steps 4-6 repeated the primary endpoint testing for the ALKS 5461 1/1 dose.
    End point type
    Primary
    End point timeframe
    5-6 Weeks (5 weeks for Stage 1 and 6 weeks for Stage 2, combined together for the overall estimate of treatment effect)
    End point values
    		 Placebo S1 ALKS 5461 1/1 S1 ALKS 5461 2/2 S1 Placebo S2 ALKS 5461 1/1 S2 ALKS 5461 2/2 S2
    Number of subjects analysed
    273
    62
    63
    60
    62
    63
    Units: Units on a scale
        least squares mean (standard error)
    -5.6 ( 0.34 )
    -6 ( 0.74 )
    -6.8 ( 0.75 )
    -1.5 ( 0.65 )
    -2.2 ( 0.67 )
    -3.2 ( 0.67 )
    Statistical analysis title
    		 Weighted Analysis: ALKS 5461 2/2 vs Placebo
    Statistical analysis description
    ALKS 5461 was compared to placebo within each of the 2 stages (i.e., ALKS 5461 2/2 S1 vs Placebo S1; and ALKS 5461 2/2 S2 vs Placebo S2)
    Comparison groups
    Placebo S1 v ALKS 5461 2/2 S1 v Placebo S2 v ALKS 5461 2/2 S2
    Number of subjects included in analysis
    459
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.018 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.7
         upper limit
    		 -0.3
    Notes
    [1] - Subjects who received placebo in Stage 1 and met placebo non-responder criteria were analyzed in both Stage 1 and Stage 2 for the weighted combined stage analysis.
    [2] - ALKS 5461 was compared to placebo within each of the 2 stages, and resulting treatment effects from each stage were combined for a single hypothesis test using equal weights of 0.5 for both stages.

    Primary: Change in Montgomery Asberg Depression Rating Scale (MADRS)-10 score using average of changes from baseline to Week 3 through the end of treatment period (Week 5 for Stage 1, Week 6 for Stage 2)

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    End point title
    		 Change in Montgomery Asberg Depression Rating Scale (MADRS)-10 score using average of changes from baseline to Week 3 through the end of treatment period (Week 5 for Stage 1, Week 6 for Stage 2)
    End point description
    MADRS-10 comprises 10 questions geared to assess depression in patients in the following aspects: Apparent Sadness, Reported Sadness, Inner Tension, Reduced Sleep, Reduced Appetite, Concentration Difficulties, Lassitude, Inability to Feel, Pessimistic Thoughts, and Suicidal Thoughts. Scores range from 0 (no apparent symptoms) to 60 (most severe symptoms). The primary hypotheses were evaluated using a six-step, fixed sequence approach to adjust for multiple comparisons. Using this method, hypothesis testing (using alpha=0.05) continued through the sequence until statistical significance was not achieved. Steps 1 through 3 included testing the ALKS 5461 2/2 dose vs placebo for the 3 primary endpoints; steps 4-6 repeated the primary endpoint testing for the ALKS 5461 1/1 dose.
    End point type
    Primary
    End point timeframe
    5-6 Weeks (5 weeks for Stage 1 and 6 weeks for Stage 2, combined together for the overall estimate of treatment effect)
    End point values
    		 Placebo S1 ALKS 5461 1/1 S1 ALKS 5461 2/2 S1 Placebo S2 ALKS 5461 1/1 S2 ALKS 5461 2/2 S2
    Number of subjects analysed
    273
    62
    63
    60
    62
    63
    Units: Units on a scale
        least squares mean (standard error)
    -8.1 ( 0.48 )
    -8.8 ( 1.05 )
    -10.3 ( 1.06 )
    -2.1 ( 0.88 )
    -3.2 ( 0.91 )
    -3.7 ( 0.9 )
    Statistical analysis title
    		 Weighted Analysis: ALKS 5461 2/2 vs Placebo
    Statistical analysis description
    ALKS 5461 is compared to placebo within each of the 2 stages (i.e., ALKS 5461 2/2 S1 vs Placebo S1; and ALKS 5461 2/2 S2 vs Placebo S2).
    Comparison groups
    Placebo S1 v ALKS 5461 2/2 S1 v Placebo S2 v ALKS 5461 2/2 S2
    Number of subjects included in analysis
    459
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.026 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.6
         upper limit
    		 -0.2
    Notes
    [3] - Subjects who received placebo in Stage 1 and met placebo non-responder criteria were analyzed in both Stage 1 and Stage 2 for the weighted combined stage analysis.
    [4] - ALKS 5461 is compared to placebo within each of the 2 stages, and resulting treatment effects from each stage are combined for a single hypothesis test using equal weights of 0.5 for both stages.

    Primary: Change from baseline to end of treatment in the MADRS-10

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    End point title
    		 Change from baseline to end of treatment in the MADRS-10
    End point description
    Change from baseline to the End of Treatment in MADRS-10 The primary hypotheses were evaluated using a six-step, fixed sequence approach to adjust for multiple comparisons. Using this method, hypothesis testing (using alpha=0.05) continued through the sequence until statistical significance was not achieved. Steps 1 through 3 included testing the ALKS 5461 2/2 dose vs placebo for the 3 primary endpoints; steps 4-6 repeated the primary endpoint testing for the ALKS 5461 1/1 dose.
    End point type
    Primary
    End point timeframe
    5-6 Weeks (5 weeks for Stage 1 and 6 weeks for Stage 2, combined together for the overall estimate of treatment effect)
    End point values
    		 Placebo S1 ALKS 5461 1/1 S1 ALKS 5461 2/2 S1 Placebo S2 ALKS 5461 1/1 S2 ALKS 5461 2/2 S2
    Number of subjects analysed
    273
    62
    63
    60
    62
    63
    Units: Units on a scale
        least squares mean (standard error)
    -9.2 ( 0.55 )
    -10.3 ( 1.19 )
    -10.8 ( 1.22 )
    -1.9 ( 0.96 )
    -3.4 ( 0.98 )
    -3.6 ( 0.98 )
    Statistical analysis title
    		 Weighted Analysis: ALKS 5461 2/2 vs Placebo
    Statistical analysis description
    ALKS 5461 is compared to placebo within each of the 2 stages (i.e., ALKS 5461 2/2 S1 vs Placebo S1; and ALKS 5461 2/2 S2 vs Placebo S2).
    Comparison groups
    Placebo S1 v ALKS 5461 2/2 S1 v Placebo S2 v ALKS 5461 2/2 S2
    Number of subjects included in analysis
    459
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.076 [6]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Squares Mean Difference
    Point estimate
    -1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.6
         upper limit
    		 0.2
    Notes
    [5] - Subjects who received placebo in Stage 1 and met placebo non-responder criteria were analyzed in both Stage 1 and Stage 2 for the weighted combined stage analysis.
    [6] - ALKS 5461 is compared to placebo within each of the 2 stages, and resulting treatment effects from each stage are combined for a single hypothesis test using equal weights of 0.5 for both stages.

    Secondary: Incidence of Adverse Events (AEs)

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    End point title
    		 Incidence of Adverse Events (AEs)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 13 weeks
    End point values
    		 Placebo S1 ALKS 5461 1/1 S1 ALKS 5461 2/2 S1 Placebo S2 ALKS 5461 1/1 S2 ALKS 5461 2/2 S2
    Number of subjects analysed
    280
    63
    63
    62
    62
    63
    Units: Count of participants
    151
    37
    42
    25
    29
    25
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    13 weeks - including treatment period and follow-up period
    Adverse event reporting additional description
    Treatment emergent adverse events are those that occur on or after the baseline during the relevant safety period. AEs with the greatest severity before the baseline of the respective safety period will be used as the benchmark for comparison with the AEs occurring during the respective safety period.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Placebo S1
    Reporting group description
    		 Subjects randomized to placebo in Stage 1

    Reporting group title
    ALKS 5461 1/1 S1
    Reporting group description
    		 Subjects randomized to ALKS 5461 1/1 in Stage 1

    Reporting group title
    ALKS 5461 2/2 S1
    Reporting group description
    		 Subjects randomized to ALKS 5461 2/2 in Stage 1

    Reporting group title
    Placebo S2
    Reporting group description
    		 Subjects randomized to placebo in Stage 2

    Reporting group title
    ALKS 5461 1/1 S2
    Reporting group description
    		 Subjects randomized to ALKS 5461 1/1 in Stage 2

    Reporting group title
    ALKS 5461 2/2 S2
    Reporting group description
    		 Subjects randomized to ALKS 5461 2/2 in Stage 2

    Serious adverse events
    		 Placebo S1 ALKS 5461 1/1 S1 ALKS 5461 2/2 S1 Placebo S2 ALKS 5461 1/1 S2 ALKS 5461 2/2 S2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 63 (0.00%)
    2 / 63 (3.17%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Muscle strain
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 63 (0.00%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (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
    Wrist fracture
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 63 (0.00%)
    1 / 63 (1.59%)
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (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
    Abdominal pain
         subjects affected / exposed
    1 / 280 (0.36%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (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
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    0 / 280 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    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
    		 Placebo S1 ALKS 5461 1/1 S1 ALKS 5461 2/2 S1 Placebo S2 ALKS 5461 1/1 S2 ALKS 5461 2/2 S2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    72 / 280 (25.71%)
    25 / 63 (39.68%)
    28 / 63 (44.44%)
    11 / 62 (17.74%)
    6 / 62 (9.68%)
    10 / 63 (15.87%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    12 / 280 (4.29%)
    6 / 63 (9.52%)
    7 / 63 (11.11%)
    1 / 62 (1.61%)
    1 / 62 (1.61%)
    2 / 63 (3.17%)
         occurrences all number
    13
    6
    7
    1
    1
    2
    Headache
         subjects affected / exposed
    22 / 280 (7.86%)
    4 / 63 (6.35%)
    5 / 63 (7.94%)
    4 / 62 (6.45%)
    0 / 62 (0.00%)
    2 / 63 (3.17%)
         occurrences all number
    23
    5
    5
    6
    0
    2
    Somnolence
         subjects affected / exposed
    12 / 280 (4.29%)
    4 / 63 (6.35%)
    3 / 63 (4.76%)
    0 / 62 (0.00%)
    0 / 62 (0.00%)
    0 / 63 (0.00%)
         occurrences all number
    12
    4
    3
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 280 (0.36%)
    5 / 63 (7.94%)
    7 / 63 (11.11%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    1
    5
    8
    1
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    20 / 280 (7.14%)
    9 / 63 (14.29%)
    17 / 63 (26.98%)
    1 / 62 (1.61%)
    2 / 62 (3.23%)
    5 / 63 (7.94%)
         occurrences all number
    21
    11
    20
    1
    2
    5
    Vomiting
         subjects affected / exposed
    7 / 280 (2.50%)
    3 / 63 (4.76%)
    6 / 63 (9.52%)
    1 / 62 (1.61%)
    0 / 62 (0.00%)
    1 / 63 (1.59%)
         occurrences all number
    8
    3
    6
    1
    0
    2
    Constipation
         subjects affected / exposed
    9 / 280 (3.21%)
    9 / 63 (14.29%)
    5 / 63 (7.94%)
    0 / 62 (0.00%)
    2 / 62 (3.23%)
    4 / 63 (6.35%)
         occurrences all number
    10
    10
    5
    0
    2
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 280 (2.86%)
    1 / 63 (1.59%)
    3 / 63 (4.76%)
    4 / 62 (6.45%)
    2 / 62 (3.23%)
    1 / 63 (1.59%)
         occurrences all number
    8
    1
    3
    4
    2
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Apr 2014
    Protocol Amendment #1 - updated contraception and eligibility requirements, updated procedures.
    01 Apr 2014
    Amendment to the Unmasked Protocol Addendum - clarified definitions and entry requirements.
    07 Oct 2014
    Amendment to the Unmasked Protocol Addendum - added flexibility in eligibility requirements.
    13 Nov 2014
    Protocol Amendment #2 - updated definitions for antidepressant therapy (ADT) and updated eligibility requirements.
    13 Nov 2014
    Amendment to the Unmasked Protocol Addendum - reduced the number of randomized subjects.
    15 Sep 2016
    Protocol Amendment #3 - changed the initially planned primary endpoints.
    15 Sep 2016
    Amendment to the Unmasked Protocol Addendum - changed the initially planned primary endpoints.

    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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