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    Clinical Trial Results:
    A Phase 3 Study to Determine the Antipsychotic Efficacy and Safety of ALKS 3831 in Adult Subjects with Acute Exacerbation of Schizophrenia

    Summary
    EudraCT number
    		 2015-003373-15
    Trial protocol
    		 SK   HU   BG  
    Global end of trial date
    07 Jun 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Jun 2018
    First version publication date
    10 Jun 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ALK3831-A305
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02634346
    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 781609-7000, Eva.Stroynowski@alkermes.com
    Scientific contact
    Eva Stroynowski, Alkermes, Inc, ++1 781609-7000, 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
    27 Jun 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 May 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the antipsychotic efficacy of ALKS 3831(a fixed-dose combination of olanzapine and samidorphan) in adult subjects with an acute exacerbation of schizophrenia.
    Protection of trial subjects
    Subjects were required to be inpatient for the first 2 weeks of the treatment period (until Day 15). Following the mandatory 2-week inpatient stay, subjects could either continue the study as inpatients for the full 4-week treatment period or be discharged at the end of Week 2 or Week 3 if they met the discharge criteria.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jan 2016
    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: 127
    Country: Number of subjects enrolled
    United States: 154
    Country: Number of subjects enrolled
    Ukraine: 79
    Country: Number of subjects enrolled
    Serbia: 41
    Worldwide total number of subjects
    401
    EEA total number of subjects
    127
    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)
    396
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects met criteria for the DSM-5 diagnosis of schizophrenia, confirmed with the Mini International Neuropsychiatric Interview (MINI).

    Pre-assignment
    Screening details
    		 Subjects were screened up to 10 days prior to randomization.

    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, Monitor, Data analyst, Carer, Subject, Assessor
    Blinding implementation details
    All Alkermes staff, clinical staff, subjects, and caregivers were blinded to treatment assignment until database lock. Randomization was performed centrally through an Interactive Web Response System (IWRS). Codes were prepared by an independent biostatistician who was not otherwise involved in the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ALKS 3831
    Arm description
    		 Olanzapine + samidorphan; administered as a coated bilayer tablet
    Arm type
    		 Experimental

    Investigational medicinal product name
    ALKS 3831
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablets were administered for daily dosing

    Arm title
    		 Olanzapine
    Arm description
    		 Administered as a coated bilayer tablet
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Olanzapine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered for daily dosing; dose was determined by the investigator.

    Arm title
    		 Placebo
    Arm description
    		 Tablets matched to ALKS 3831 and olanzapine
    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
    Administered for daily dosing

    Number of subjects in period 1
    		ALKS 3831 Olanzapine Placebo
    Started
    134
    133
    134
    Completed
    122
    119
    111
    Not completed
    12
    14
    23
         Adverse event, serious fatal
    -
    1
    -
         Consent withdrawn by subject
    8
    9
    8
         Adverse event, non-fatal
    2
    1
    7
         Lost to follow-up
    1
    -
    -
         Lack of efficacy
    1
    2
    8
         Protocol deviation
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ALKS 3831
    Reporting group description
    		 Olanzapine + samidorphan; administered as a coated bilayer tablet

    Reporting group title
    Olanzapine
    Reporting group description
    		 Administered as a coated bilayer tablet

    Reporting group title
    Placebo
    Reporting group description
    		 Tablets matched to ALKS 3831 and olanzapine

    Reporting group values
    		 ALKS 3831 Olanzapine Placebo Total
    Number of subjects
    		 134 133 134 401
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 40.8 ( 12.55 ) 41.5 ( 10.89 ) 41.1 ( 10.59 ) -
    Gender categorical
    Units: Subjects
        Female
    		 49 52 56 157
        Male
    		 85 81 78 244

    End points

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    End points reporting groups
    Reporting group title
    ALKS 3831
    Reporting group description
    		 Olanzapine + samidorphan; administered as a coated bilayer tablet

    Reporting group title
    Olanzapine
    Reporting group description
    		 Administered as a coated bilayer tablet

    Reporting group title
    Placebo
    Reporting group description
    		 Tablets matched to ALKS 3831 and olanzapine

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects that received at least 1 dose of study drug and had at least 1 post-baseline PANSS assessment.

    Primary: Change from baseline in Positive and Negative Syndrome Scale (PANSS) total score at Week 4

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    End point title
    		 Change from baseline in Positive and Negative Syndrome Scale (PANSS) total score at Week 4
    End point description
    The PANSS scale consists of symptom constructs (7 positive, 7 negative, 16 general psychopathology), each to be rated on a 7-point Likert-type scale of severity with 1 being absent to 7 being extreme. Minimum scores (best outcome) equals 30 (total scale); maximum scores (worst outcome) equals 210 (total scale). Change is calculated between the baseline visit and Week 4.
    End point type
    Primary
    End point timeframe
    4 weeks
    End point values
    		 ALKS 3831 Olanzapine Placebo
    Number of subjects analysed
    132
    132
    133
    Units: Units on a scale
        least squares mean (standard error)
    -23.9 ( 1.28 )
    -22.8 ( 1.29 )
    -17.5 ( 1.32 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    ALKS 3831 v Placebo
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least square mean difference
    Point estimate
    -6.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10
         upper limit
    		 -2.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.83
    Notes
    [1] - Mixed model for repeated measures is based on observed data without imputation of missing data.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Olanzapine v Placebo
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.004 [2]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least square mean difference
    Point estimate
    -5.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.9
         upper limit
    		 -1.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.84
    Notes
    [2] - Mixed model for repeated measures is based on observed data without imputation of missing data.

    Secondary: Change from baseline in Clinical Global Impressions-Severity (CGI-S) Score at Week 4

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    End point title
    		 Change from baseline in Clinical Global Impressions-Severity (CGI-S) Score at Week 4
    End point description
    The CGI-S is a 7-point scale that requires the clinician to assess how mentally ill the patient is in a specific point in time. Results indicate participants evaluated at one of the following categories: "1: normal, not at all ill"; "2: borderline mentally ill"; "3: mildly ill"; "4: moderately ill"; "5: markedly ill"; "6: severely ill"; and "7: among the most extremely ill patients". Results indicate a change in CGI-S score from baseline to Week 4 based on the observed data. Change is calculated between the baseline visit and Week 4.
    End point type
    Secondary
    End point timeframe
    4 weeks
    End point values
    		 ALKS 3831 Olanzapine Placebo
    Number of subjects analysed
    132
    132
    133
    Units: Units on a scale
        least squares mean (standard error)
    -1.21 ( 0.082 )
    -1.27 ( 0.083 )
    -0.84 ( 0.085 )
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    ALKS 3831 v Placebo
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002 [3]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least square mean difference
    Point estimate
    -0.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.61
         upper limit
    		 -0.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.118
    Notes
    [3] - Mixed model for repeated measures is based on observed data without imputation of missing data.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Olanzapine v Placebo
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [4]
    Method
    		 Mixed models analysis
    Parameter type
    		 Least square mean difference
    Point estimate
    -0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.67
         upper limit
    		 -0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.118
    Notes
    [4] - Mixed model for repeated measures is based on observed data without imputation of missing data.

    Secondary: Incidence of Adverse Events

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    End point title
    		 Incidence of Adverse Events
    End point description
    End point type
    Secondary
    End point timeframe
    Approximately 4 weeks
    End point values
    		 ALKS 3831 Olanzapine Placebo
    Number of subjects analysed
    134
    133
    134
    Units: Participants
    73
    73
    60
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment emergent adverse events (TEAEs) are presented for the double-blind treatment period (4 weeks).
    Adverse event reporting additional description
    The safety population includes all subjects who received at least 1 dose of study drug.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    ALKS 3831
    Reporting group description
    		 Subjects who received at least 1 dose of ALKS 3831.

    Reporting group title
    Olanzapine
    Reporting group description
    		 Subjects who received at least 1 dose of olanzapine.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects who received at least 1 dose of placebo.

    Serious adverse events
    		 ALKS 3831 Olanzapine Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 134 (0.75%)
    1 / 133 (0.75%)
    0 / 134 (0.00%)
         number of deaths (all causes)
    0
    1
    0
         number of deaths resulting from adverse events
    0
    1
    0
    Injury, poisoning and procedural complications
    Toxicity to various agents
         subjects affected / exposed
    0 / 134 (0.00%)
    1 / 133 (0.75%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Psychiatric disorders
    Catatonia
         subjects affected / exposed
    1 / 134 (0.75%)
    0 / 133 (0.00%)
    0 / 134 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ALKS 3831 Olanzapine Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 134 (37.31%)
    45 / 133 (33.83%)
    24 / 134 (17.91%)
    Investigations
    Weight increased
         subjects affected / exposed
    25 / 134 (18.66%)
    19 / 133 (14.29%)
    4 / 134 (2.99%)
         occurrences all number
    25
    19
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 134 (5.97%)
    7 / 133 (5.26%)
    4 / 134 (2.99%)
         occurrences all number
    8
    9
    7
    Somnolence
         subjects affected / exposed
    12 / 134 (8.96%)
    13 / 133 (9.77%)
    3 / 134 (2.24%)
         occurrences all number
    12
    13
    3
    Gastrointestinal disorders
    Dry mouth
         subjects affected / exposed
    10 / 134 (7.46%)
    7 / 133 (5.26%)
    1 / 134 (0.75%)
         occurrences all number
    10
    8
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    8 / 134 (5.97%)
    7 / 133 (5.26%)
    8 / 134 (5.97%)
         occurrences all number
    8
    7
    12
    Schizophrenia
         subjects affected / exposed
    1 / 134 (0.75%)
    2 / 133 (1.50%)
    8 / 134 (5.97%)
         occurrences all number
    1
    2
    8

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Sep 2016
    Protocol Amendment #1 adjusted key secondary endpoint language, and added assessments.

    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 dose of olanzapine was not fixed and could be titrated during the first 2 weeks of the study.
    For support, Contact us.
    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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