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    Clinical Trial Results:
    A Phase 2, Randomized, Multicenter, Safety, Tolerability, and Dose-Ranging Study of Samidorphan, a Component of ALKS 3831, in Adults with Schizophrenia Treated with Olanzapine

    Summary
    EudraCT number
    		 2013-002193-45
    Trial protocol
    		 CZ   BG  
    Global end of trial date
    09 Mar 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Sep 2016
    First version publication date
    24 Sep 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ALK3831-302
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01903837
    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 7816096000, eva.stroynowski@alkermes.com
    Scientific contact
    Eva Stroynowski, Alkermes Inc., +1 7816096000, 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
    18 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Mar 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Mar 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate 3 doses of samidorphan co-administered with olanzapine (ALKS 3831) in subjects with schizophrenia to: (1) evaluate ALKS 3831 as a treatment of schizophrenia; (2) assess the safety and tolerability of ALKS 3831; (3)characterize the impact of samidorphan component of ALKS 3831 on weight and other metabolic factors.
    Protection of trial subjects
    All eligible subjects were initiated on open-label olanzapine for 1 week. Subjects returned on Day 8 for a 2-night inpatient stay and the start of the 12-week double-blind olanzapine-controlled treatment period. Subjects were discharged from the inpatient unit on Day 10. Subjects who were taking antipsychotic medications were tapered off of their prior antipsychotic medication within 2 weeks after initiation. This cross-taper from prior antipsychotic treatment to olanzapine was conducted under the care and discretion of the investigator and was consistent with current clinical practice. This study used an independent Data Safety Monitoring Board to monitor for tolerability of study drug. The DSMB reviewed safety data 1 week after about 40, 96, and 150 subjects had been randomized.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Jun 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 50
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    United States: 258
    Worldwide total number of subjects
    309
    EEA total number of subjects
    51
    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)
    309
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were enrolled in study sites located in 3 countries: United States, Bulgaria, and the Czech Republic. Subjects completed a 7-day lead-in period before being randomized into the 12-week double-blind treatment period. Baseline data includes subjects who completed the lead-in period and were randomized to include study treatment.

    Pre-assignment
    Screening details
    		 This study included subjects who had a diagnosis of schizophrenia who had not been exposed to olanzapine, clozapine, mesoridazine, chlorpromazine, or thioridazine at any time in the 3 months prior to screening.

    Period 1
    Period 1 title
    Study Part A
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Data analyst, Subject, Carer, Assessor
    Blinding implementation details
    All clinical trial personnel were blinded to treatment assignment until Part A of the study was completed. Randomization was performed centrally through an Interactive Web Response System (IWRS).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Olanzapine plus Placebo
    Arm description
    		 Olanzapine dose (as determined by Investigator) + placebo
    Arm type
    		 Active comparator

    Investigational medicinal product name
    ALKS 3831 Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Olanzapine (as determined by Investigator) + placebo

    Arm title
    		 ALKS 3831 5 mg
    Arm description
    		 olanzapine + 5 mg samidophan
    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
    Daily dose Olanzapine (as determined by Investigator) + 5 mg samidorphan

    Arm title
    		 ALKS 3831 10 mg
    Arm description
    		 olanzapine + 10 mg samidorphan
    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
    Daily dose Olanzapine (as determined by Investigator) + 10 mg samidorphan

    Arm title
    		 ALKS 3831 20 mg
    Arm description
    		 Olanzapine + 20 mg samidorphan
    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
    Daily dose Olanzapine (as determined by Investigator) + 20 mg samidorphan

    Number of subjects in period 1
    		Olanzapine plus Placebo ALKS 3831 5 mg ALKS 3831 10 mg ALKS 3831 20 mg
    Started
    75
    80
    86
    68
    Completed
    56
    52
    58
    55
    Not completed
    19
    28
    28
    13
         Consent withdrawn by subject
    4
    9
    8
    5
         Physician decision
    1
    1
    -
    -
         Adverse event, non-fatal
    3
    6
    9
    6
         Non-compliance with study drug
    1
    4
    4
    -
         Lost to follow-up
    9
    7
    7
    2
         Protocol deviation
    1
    1
    -
    -
    Period 2
    Period 2 title
    Study Part B
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    In Part B all participating subjects received active treatment with samidorphan and olanzapine. The dose level of samidorphan during Part B remained blinded to subjects and study personnel. The sponsor's representatives were unblinded to the samidorphan dose level in Part B but only after Part A data was unblinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Olz+Pbo/ALKS 3831 20 mg
    Arm description
    		 Part A = olanzapine (as determined by Investigator) + placebo Part B = olanzapine (as determined by Investigator) + 20 mg samidorphan
    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
    Daily dose Olanzapine (as determined by Investigator) + 20 mg samidorphan

    Arm title
    		 ALKS 3831 5 mg/ALKS 3831 5 mg
    Arm description
    		 Part A = olanzapine (as determined by Investigator) + 5 mg samidorphan Part B = olanzapine (as determined by Investigator) + 5 mg samidorphan
    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
    Daily dose Olanzapine (as determined by Investigator) + 5 mg samidorphan

    Arm title
    		 ALKS 3831 10 mg/ALKS 3831 10 mg
    Arm description
    		 Part A = olanzapine (as determined by Investigator) + 10 mg samidorphan Part B = olanzapine (as determined by Investigator) + 10 mg samidorphan
    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
    Daily dose Olanzapine (as determined by Investigator) + 10 mg samidorphan

    Arm title
    		 ALKS 3831 20 mg/ALKS 3831 20 mg
    Arm description
    		 Part A = olanzapine (as determined by Investigator) + 20 mg samidorphan Part B = olanzapine (as determined by Investigator) + 20 mg samidorphan
    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
    Daily dose Olanzapine (as determined by Investigator) + 20 mg samidorphan

    Number of subjects in period 2 [1]
    		Olz+Pbo/ALKS 3831 20 mg ALKS 3831 5 mg/ALKS 3831 5 mg ALKS 3831 10 mg/ALKS 3831 10 mg ALKS 3831 20 mg/ALKS 3831 20 mg
    Started
    54
    52
    57
    55
    Completed
    45
    46
    52
    44
    Not completed
    9
    6
    5
    11
         Consent withdrawn by subject
    1
    2
    -
    3
         Physician decision
    1
    -
    -
    2
         Adverse event, non-fatal
    3
    -
    2
    -
         Non-compliance with study drug
    2
    -
    -
    1
         Incarceration
    2
    -
    -
    1
         Lost to follow-up
    -
    3
    3
    4
         Lack of efficacy
    -
    1
    -
    -
    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: 3 subjects discontinued the study after completing Part A, and did not participate in Part B.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Study Part A
    Reporting group description
    		 -

    Reporting group values
    		 Study Part A Total
    Number of subjects
    		 309 309
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 309 309
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 38.4 ( 8.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 81 81
        Male
    		 228 228
    Subject analysis sets

    Subject analysis set title
    Part A FAS 1 - Active
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who were randomized to olanzapine + samidorphan in study Part A, received at least 1 dose of study drug, and had at least 1 postbaseline PANSS assessment

    Subject analysis set title
    Part A FAS 1 - Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who were randomized to receive olanzapine + placebo in study Part A, received at least 1 dose of study drug, and had at least 1 postbaseline PANSS assessment.

    Subject analysis set title
    Part A FAS 2 - active
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who were randomized to olanzapine + samidorphan in study Part A, received at least 1 dose of study drug, had at least 1 postbaseline PANSS assessment, and had weight gain > 0 kg during the 1-week olanzapine lead-in period.

    Subject analysis set title
    Part A FAS 2 - placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who were randomized to olanzapine + placebo in study Part A, received at least 1 dose of study drug, had at least 1 postbaseline PANSS assessment, and had weight gain > 0 kg during the 1-week olanzapine lead-in period.

    Subject analysis sets values
    		 Part A FAS 1 - Active Part A FAS 1 - Placebo Part A FAS 2 - active Part A FAS 2 - placebo
    Number of subjects
    226
    74
    150
    45
    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)
    226
    74
    150
    45
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    38.4 ( 8.27 )
    40.2 ( 8.19 )
    37.5 ( 8.4 )
    39.4 ( 8.47 )
    Gender categorical
    Units: Subjects
        Female
    56
    22
    40
    16
        Male
    170
    52
    110
    29

    End points

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    End points reporting groups
    Reporting group title
    Olanzapine plus Placebo
    Reporting group description
    		 Olanzapine dose (as determined by Investigator) + placebo

    Reporting group title
    ALKS 3831 5 mg
    Reporting group description
    		 olanzapine + 5 mg samidophan

    Reporting group title
    ALKS 3831 10 mg
    Reporting group description
    		 olanzapine + 10 mg samidorphan

    Reporting group title
    ALKS 3831 20 mg
    Reporting group description
    		 Olanzapine + 20 mg samidorphan
    Reporting group title
    Olz+Pbo/ALKS 3831 20 mg
    Reporting group description
    		 Part A = olanzapine (as determined by Investigator) + placebo Part B = olanzapine (as determined by Investigator) + 20 mg samidorphan

    Reporting group title
    ALKS 3831 5 mg/ALKS 3831 5 mg
    Reporting group description
    		 Part A = olanzapine (as determined by Investigator) + 5 mg samidorphan Part B = olanzapine (as determined by Investigator) + 5 mg samidorphan

    Reporting group title
    ALKS 3831 10 mg/ALKS 3831 10 mg
    Reporting group description
    		 Part A = olanzapine (as determined by Investigator) + 10 mg samidorphan Part B = olanzapine (as determined by Investigator) + 10 mg samidorphan

    Reporting group title
    ALKS 3831 20 mg/ALKS 3831 20 mg
    Reporting group description
    		 Part A = olanzapine (as determined by Investigator) + 20 mg samidorphan Part B = olanzapine (as determined by Investigator) + 20 mg samidorphan

    Subject analysis set title
    Part A FAS 1 - Active
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who were randomized to olanzapine + samidorphan in study Part A, received at least 1 dose of study drug, and had at least 1 postbaseline PANSS assessment

    Subject analysis set title
    Part A FAS 1 - Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who were randomized to receive olanzapine + placebo in study Part A, received at least 1 dose of study drug, and had at least 1 postbaseline PANSS assessment.

    Subject analysis set title
    Part A FAS 2 - active
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who were randomized to olanzapine + samidorphan in study Part A, received at least 1 dose of study drug, had at least 1 postbaseline PANSS assessment, and had weight gain > 0 kg during the 1-week olanzapine lead-in period.

    Subject analysis set title
    Part A FAS 2 - placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects who were randomized to olanzapine + placebo in study Part A, received at least 1 dose of study drug, had at least 1 postbaseline PANSS assessment, and had weight gain > 0 kg during the 1-week olanzapine lead-in period.

    Primary: Absolute change in PANSS total score from randomization (Day 8) to the end of Part A

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    End point title
    		 Absolute change in PANSS total score from randomization (Day 8) to the end of Part A
    End point description
    Change in PANSS total score from randomization (Day 8) to Day 92 (study Part A)
    End point type
    Primary
    End point timeframe
    12 weeks
    End point values
    		 Part A FAS 1 - Active Part A FAS 1 - Placebo
    Number of subjects analysed
    226
    74
    Units: Points
        least squares mean (confidence interval 95%)
    -2.2 (-3.2 to -1.3)
    -2.9 (-4.5 to -1.3)
    Statistical analysis title
    		 Mixed Model of Repeated Measure
    Comparison groups
    Part A FAS 1 - Active v Part A FAS 1 - Placebo
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    Method
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 2.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.94
    Notes
    [1] - Per the protocol pre-specified primary analysis, an equivalence test was conducted in which a p value is not applicable.

    Secondary: Percent change in body weight from randomization (Day 8) to the end of Part A

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    End point title
    		 Percent change in body weight from randomization (Day 8) to the end of Part A
    End point description
    Percent change in body weight from randomization (Day 8) to Day 92 (study Part A)
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Part A FAS 1 - Active Part A FAS 1 - Placebo Part A FAS 2 - active Part A FAS 2 - placebo
    Number of subjects analysed
    225
    74
    149
    45
    Units: Percentage points
        least squares mean (confidence interval 95%)
    2.6 (2.1 to 3.1)
    4.1 (3.2 to 5)
    2.6 (1.9 to 3.2)
    5.3 (4.2 to 6.4)
    Statistical analysis title
    		 Percent change in body weight (Part A) FAS 1
    Comparison groups
    Part A FAS 1 - Active v Part A FAS 1 - Placebo
    Number of subjects included in analysis
    299
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006
    Method
    		 Mixed models analysis
    Parameter type
    		 Least square mean
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.5
         upper limit
    		 -0.4
    Statistical analysis title
    		 Percent change in body weight (Part A) FAS 2
    Comparison groups
    Part A FAS 2 - active v Part A FAS 2 - placebo
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Least square mean
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4
         upper limit
    		 -1.4

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Safety assessments are presented for all dosing groups in both Study Parts A and B.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Part A-OLZ+PBO
    Reporting group description
    		 Subjects who were randomized to the 12-week double-blind treatment period and received olanzapine (as directed by Investigator) + placebo

    Reporting group title
    Part A-ALKS 3831 5mg
    Reporting group description
    		 Subjects who participated in the 12-week double-blind treatment period and received ALKS 3831 5 mg

    Reporting group title
    Part A-ALKS 3831 10 mg
    Reporting group description
    		 Subjects who were randomized to the 12-week double-blind treatment period and received ALKS 3831 10 mg

    Reporting group title
    Part A-ALKS 3831 20 mg
    Reporting group description
    		 Subjects who were randomized to the 12-week double-blind treatment period and received ALKS 3831 20 mg

    Reporting group title
    Part B-OLZ+PBO/ALKS 3831 20 mg
    Reporting group description
    		 Subjects who participated in the 12-week active treatment period. These subjects received olanzapine + placebo in Part A and ALKS 3831 20 mg in Part B

    Reporting group title
    Part B-ALKS 3831 5 mg
    Reporting group description
    		 Subjects who participated in the 12-week active treatment period. These subjects received ALKS 3831 5 mg in both Parts A and B.

    Reporting group title
    Part B-ALKS 3831 10 mg
    Reporting group description
    		 Subjects who participated in the 12-week active treatment period. These subjects received ALKS 3831 10 mg in both Parts A and B.

    Reporting group title
    Part B-ALKS 3831 20 mg
    Reporting group description
    		 Subjects who participated in the 12-week active treatment period. These subjects received ALKS 3831 20 mg in both Parts A and B.

    Serious adverse events
    		 Part A-OLZ+PBO Part A-ALKS 3831 5mg Part A-ALKS 3831 10 mg Part A-ALKS 3831 20 mg Part B-OLZ+PBO/ALKS 3831 20 mg Part B-ALKS 3831 5 mg Part B-ALKS 3831 10 mg Part B-ALKS 3831 20 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 75 (2.67%)
    3 / 80 (3.75%)
    4 / 86 (4.65%)
    4 / 68 (5.88%)
    1 / 54 (1.85%)
    1 / 52 (1.92%)
    1 / 57 (1.75%)
    0 / 55 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 80 (0.00%)
    0 / 86 (0.00%)
    0 / 68 (0.00%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Psychiatric disorders
    Schizoprenia
         subjects affected / exposed
    1 / 75 (1.33%)
    2 / 80 (2.50%)
    1 / 86 (1.16%)
    3 / 68 (4.41%)
    1 / 54 (1.85%)
    0 / 52 (0.00%)
    1 / 57 (1.75%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    1 / 1
    1 / 3
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 80 (1.25%)
    0 / 86 (0.00%)
    1 / 68 (1.47%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 80 (0.00%)
    1 / 86 (1.16%)
    0 / 68 (0.00%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 80 (0.00%)
    1 / 86 (1.16%)
    0 / 68 (0.00%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 80 (0.00%)
    1 / 86 (1.16%)
    0 / 68 (0.00%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Subcutaneous abscess
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 80 (0.00%)
    0 / 86 (0.00%)
    0 / 68 (0.00%)
    0 / 54 (0.00%)
    1 / 52 (1.92%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Part A-OLZ+PBO Part A-ALKS 3831 5mg Part A-ALKS 3831 10 mg Part A-ALKS 3831 20 mg Part B-OLZ+PBO/ALKS 3831 20 mg Part B-ALKS 3831 5 mg Part B-ALKS 3831 10 mg Part B-ALKS 3831 20 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 75 (54.67%)
    35 / 80 (43.75%)
    45 / 86 (52.33%)
    43 / 68 (63.24%)
    21 / 54 (38.89%)
    22 / 52 (42.31%)
    19 / 57 (33.33%)
    25 / 55 (45.45%)
    Investigations
    Weight increased
         subjects affected / exposed
    9 / 75 (12.00%)
    8 / 80 (10.00%)
    7 / 86 (8.14%)
    6 / 68 (8.82%)
    3 / 54 (5.56%)
    6 / 52 (11.54%)
    2 / 57 (3.51%)
    3 / 55 (5.45%)
         occurrences all number
    10
    8
    9
    7
    4
    6
    3
    3
    Weight decreased
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 80 (0.00%)
    0 / 86 (0.00%)
    0 / 68 (0.00%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
    0 / 57 (0.00%)
    3 / 55 (5.45%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    3
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    3 / 75 (4.00%)
    10 / 80 (12.50%)
    11 / 86 (12.79%)
    8 / 68 (11.76%)
    2 / 54 (3.70%)
    0 / 52 (0.00%)
    3 / 57 (5.26%)
    4 / 55 (7.27%)
         occurrences all number
    3
    10
    11
    8
    2
    0
    3
    5
    Sedation
         subjects affected / exposed
    3 / 75 (4.00%)
    0 / 80 (0.00%)
    4 / 86 (4.65%)
    8 / 68 (11.76%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    3
    0
    4
    8
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 80 (0.00%)
    3 / 86 (3.49%)
    6 / 68 (8.82%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    1
    0
    3
    7
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    4 / 75 (5.33%)
    3 / 80 (3.75%)
    1 / 86 (1.16%)
    1 / 68 (1.47%)
    1 / 54 (1.85%)
    0 / 52 (0.00%)
    4 / 57 (7.02%)
    1 / 55 (1.82%)
         occurrences all number
    4
    3
    1
    1
    1
    0
    4
    1
    Tremor
         subjects affected / exposed
    4 / 75 (5.33%)
    0 / 80 (0.00%)
    0 / 86 (0.00%)
    0 / 68 (0.00%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    5
    0
    0
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    4 / 75 (5.33%)
    5 / 80 (6.25%)
    4 / 86 (4.65%)
    5 / 68 (7.35%)
    6 / 54 (11.11%)
    1 / 52 (1.92%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    4
    5
    4
    5
    8
    1
    0
    0
    Dry mouth
         subjects affected / exposed
    4 / 75 (5.33%)
    2 / 80 (2.50%)
    5 / 86 (5.81%)
    6 / 68 (8.82%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    4
    2
    5
    6
    0
    0
    0
    0
    Constipation
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 80 (0.00%)
    5 / 86 (5.81%)
    2 / 68 (2.94%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    1
    0
    5
    2
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 80 (0.00%)
    0 / 86 (0.00%)
    0 / 68 (0.00%)
    6 / 54 (11.11%)
    0 / 52 (0.00%)
    1 / 57 (1.75%)
    0 / 55 (0.00%)
         occurrences all number
    0
    0
    0
    0
    6
    0
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 75 (5.33%)
    2 / 80 (2.50%)
    2 / 86 (2.33%)
    1 / 68 (1.47%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    4
    2
    2
    1
    0
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 80 (0.00%)
    0 / 86 (0.00%)
    0 / 68 (0.00%)
    0 / 54 (0.00%)
    3 / 52 (5.77%)
    4 / 57 (7.02%)
    2 / 55 (3.64%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    5
    2
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    6 / 75 (8.00%)
    5 / 80 (6.25%)
    5 / 86 (5.81%)
    6 / 68 (8.82%)
    0 / 54 (0.00%)
    0 / 52 (0.00%)
    0 / 57 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    6
    5
    5
    6
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Jun 2013
    Included CRO Medical Monitor information; clarified study design and instructions for assessments; Modified primary and secondary endpoints, subject inclusion and exclusion criteria, schedule of assessments, timing of assessments with respect to dosing, ICF description, and description of samidorphan drug structure and study drug tablets.
    19 Nov 2013
    Czech Republic only - included information on contraception requirements, breaking of study blind by investigators, and data handling and record keeping procedures.
    10 Dec 2013
    Bulgaria only - modified the eligibility criteria and consent procedures.
    17 Dec 2013
    Czech Republic only - included clarification of unblinding procedures.
    26 Feb 2014
    US and Bulgaria only - modified eligibility criteria, consent procedures, contraception requirements, objectives, endpoints, and statistical methods, sample size and visit windows; clarified end-of-treatment versus early termination procedures and benzodiazepine use; addition of a partial list of Cytochrome P450 34A inhibitors, removal of restrictions on "nonessential" medications; and addition of procedures for capturing adverse events of special interest and determining the relationship between adverse events and study drug.
    13 Jun 2014
    Czech Republic only - included updated Medical Monitor information, clarification of procedures for breaking study blind in an emergency, modification of informant/caregiver criteria under study eligibility criteria, and contraception requirements.

    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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    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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