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    Clinical Trial Results:
    A Phase 3b, Multicenter, Double-Blind, Fixed-Dose, Parallel-Group, Three Week Placebo Controlled Trial Evaluating the Safety and Efficacy of Asenapine in Subjects With Bipolar 1 Disorder Experiencing an Acute Manic or Mixed Episode (Protocol P05691 [Formerly 041044])

    Summary
    EudraCT number
    2010-018409-13
    Trial protocol
    BG  
    Global end of trial date
    28 May 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Mar 2016
    First version publication date
    10 Apr 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    P05691
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00764478
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Merck: MK-8274-003
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 May 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 May 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This trial will study the efficacy and safety of a fixed dose of asenapine in participants diagnosed with Bipolar 1 Disorder. Participants who qualify for the study will be randomly assigned to receive a fixed dose of asenapine (either 5 mg or 10 mg twice daily [BID]) or placebo (BID) for 3 weeks. Throughout the trial, observations will be made on each participant at various times to assess the safety and effectiveness of the study treatment. The primary hypothesis is that there is at least one dose of asenapine that is superior to placebo in the change from baseline in manic symptoms (as measured by Young Mania Rating Scale [YMRS]) at Day 21 of the trial.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    06 Apr 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Ukraine: 16
    Country: Number of subjects enrolled
    United States: 271
    Country: Number of subjects enrolled
    Bulgaria: 46
    Country: Number of subjects enrolled
    Croatia: 3
    Country: Number of subjects enrolled
    Romania: 10
    Country: Number of subjects enrolled
    Russian Federation: 21
    Worldwide total number of subjects
    367
    EEA total number of subjects
    59
    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)
    360
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Participants were 18 years of age with a current diagnosis of bipolar I disorder, with current manic or mixed episode, and who must have discontinued use of all prohibited psychotropic medication.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Asenapine 5 mg BID
    Arm description
    Participants were administered one asenapine 5 mg tablet, sublingually twice daily (BID) for 21 days.
    Arm type
    Experimental

    Investigational medicinal product name
    Asenapine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    Asenapine tablet, 5 mg sublingually, BID for 21 days

    Arm title
    Asenapine 10 mg BID
    Arm description
    Participants were administered one asenapine 10 mg tablet, sublingually BID for 21 days.
    Arm type
    Experimental

    Investigational medicinal product name
    Asenapine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    Asenapine tablet, 10 mg sublingually BID for 21 days.

    Arm title
    Placebo
    Arm description
    Participants were administered one asenapine-matched placebo tablet sublingually BID for 21 days.
    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
    Placebo sublingual tablet, administered BID for 21 days.

    Number of subjects in period 1
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo
    Started
    122
    119
    126
    Completed
    107
    97
    118
    Not completed
    15
    22
    8
         Protocol deviation
    -
    1
    1
         Adverse event, non-fatal
    1
    1
    1
         Consent withdrawn by subject
    7
    12
    1
         Lost to follow-up
    7
    8
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Asenapine 5 mg BID
    Reporting group description
    Participants were administered one asenapine 5 mg tablet, sublingually twice daily (BID) for 21 days.

    Reporting group title
    Asenapine 10 mg BID
    Reporting group description
    Participants were administered one asenapine 10 mg tablet, sublingually BID for 21 days.

    Reporting group title
    Placebo
    Reporting group description
    Participants were administered one asenapine-matched placebo tablet sublingually BID for 21 days.

    Reporting group values
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo Total
    Number of subjects
    122 119 126 367
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    44.3 ± 10.82 42.5 ± 11.06 44.6 ± 11.54 -
    Gender categorical
    Units: Subjects
        Female
    65 64 72 201
        Male
    57 55 54 166

    End points

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    End points reporting groups
    Reporting group title
    Asenapine 5 mg BID
    Reporting group description
    Participants were administered one asenapine 5 mg tablet, sublingually twice daily (BID) for 21 days.

    Reporting group title
    Asenapine 10 mg BID
    Reporting group description
    Participants were administered one asenapine 10 mg tablet, sublingually BID for 21 days.

    Reporting group title
    Placebo
    Reporting group description
    Participants were administered one asenapine-matched placebo tablet sublingually BID for 21 days.

    Primary: Change from baseline in Young Mania Rating Scale (Y-MRS) total score at Day 21

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    End point title
    Change from baseline in Young Mania Rating Scale (Y-MRS) total score at Day 21
    End point description
    Y-MRS consists of responses to the following 11 items: elevated mood, increased motor activity energy, sexual interest, sleep, language-thought disorder, appearance, insight, irritability, speech - rate and amount, content and disruptive-agressive behavior. The scores from the 11 items are summed to give a total score ranging from 0 to 60, with a higher score indicating greater severity of symptoms. Results reported for all randomized participants who received at least one dose of trial medication and had at least one baseline and post-baseline measurement. The analysis is based on a mixed model repeated measures (MMRM) model. An improvement in symptoms is represented by change from baseline values that are negative.
    End point type
    Primary
    End point timeframe
    Baseline and Day 21
    End point values
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo
    Number of subjects analysed
    120
    113
    126
    Units: Score on a scale
        least squares mean (standard error)
    -14.4 ± 1.02
    -14.9 ± 1.04
    -10.9 ± 0.99
    Statistical analysis title
    Y-MRS total at Day 21: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0136 [1]
    Method
    MMRM
    Parameter type
    Least Square (LS) means difference
    Point estimate
    -3.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.3
         upper limit
    -0.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.41
    Notes
    [1] - Adjusted p-value from graphical approach to control Type 1 error rate among primary and secondary hypotheses
    Statistical analysis title
    Y-MRS total at day 21: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.01 [2]
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.9
         upper limit
    -1.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.43
    Notes
    [2] - Adjusted p-value from graphical approach to control Type 1 error rate among primary and secondary hypotheses

    Secondary: Change from baseline in Clinical Global Impression – Bipolar Mania – Severity of Illness (CGI-BP-S) overall score at Day 21

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    End point title
    Change from baseline in Clinical Global Impression – Bipolar Mania – Severity of Illness (CGI-BP-S) overall score at Day 21
    End point description
    The CGI-BP-S is a score that measures the severity of overall bipolar illness. The score ranges on a scale from 1 to 7, where 1 is normal, and 7 is very severely ill. Results reported for all randomized participants who received at least one dose of trial medication and had at least one baseline and post-baseline measurement. One participant from the Placebo BID arm missed a baseline measurement. The analysis is based on a MMRM model. An improvement in symptoms is represented by change from baseline values that are negative.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 21
    End point values
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo
    Number of subjects analysed
    120
    113
    125
    Units: Score on a scale
        least squares mean (standard error)
    -1.6 ± 0.12
    -1.7 ± 0.12
    -1.1 ± 0.11
    Statistical analysis title
    CGI-BP-S at Day 21: 5 mg Asenapine - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.01 [3]
    Method
    MMRM
    Parameter type
    LS mean difference
    Point estimate
    -0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.8
         upper limit
    -0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16
    Notes
    [3] - Adjusted p-value from Hochberg's method for testing two secondary efficacy hypotheses
    Statistical analysis title
    CGI-BP-S at Day 21: 10 mg Asenapine - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0052 [4]
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.9
         upper limit
    -0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16
    Notes
    [4] - Adjusted p-value from Hochberg's method for testing two secondary efficacy hypotheses

    Secondary: Percentage of participants who are Y-MRS responders at Day 21

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    End point title
    Percentage of participants who are Y-MRS responders at Day 21
    End point description
    Y-MRS consists of responses to the following 11 items: elevated mood, increased motor activity energy, sexual interest, sleep, language-thought disorder, appearance, insight, irritability, speech - rate and amount, content and disruptive-agressive behavior. The scores from the 11 items are summed to give a total score ranging from 0 to 60, with a higher score indicating greater severity of symptoms. Results reported for all randomized participants who received at least one dose of trial medication and had at least one baseline and post-baseline measurement. Missing data were imputed by Last Observation Carried Forward (LOCF). Y-MRS responders are defined as having a >= 50% decrease from baseline in Y-MRS total score.
    End point type
    Secondary
    End point timeframe
    Day 21
    End point values
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo
    Number of subjects analysed
    120
    113
    126
    Units: Percentage of participants
        number (not applicable)
    45
    46.9
    39.7
    Statistical analysis title
    Y-MRS responders Day 21: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5352 [5]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [5] - Overall adjusted p-value from Hochberg's method for testing two secondary efficacy hypotheses
    Statistical analysis title
    Y-MRS responders Day 21: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4274 [6]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [6] - Overall adjusted p-value from Hochberg's method for testing two secondary efficacy hypotheses

    Secondary: Change from baseline in Y-MRS total score at Day 2, Day 4, Day 7 and Day 14

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    End point title
    Change from baseline in Y-MRS total score at Day 2, Day 4, Day 7 and Day 14
    End point description
    Y-MRS consists of responses to the following 11 items: elevated mood, increased motor activity energy, sexual interest, sleep, language-thought disorder, appearance, insight, irritability, speech - rate and amount, content and disruptive-agressive behavior. The scores from the 11 items are summed to give a total score ranging from 0 to 60, with a higher score indicating greater severity of symptoms. Results reported for all randomized participants who received at least one dose of trial medication and had at least one baseline and post-baseline measurement. The analysis is based on a MMRM model. An improvement in symptoms is represented by change from baseline values that are negative
    End point type
    Secondary
    End point timeframe
    Baseline and Day 2, Day 4, Day 7 and Day 14
    End point values
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo
    Number of subjects analysed
    120
    113
    126
    Units: Score on a scale
    least squares mean (standard error)
        Day 2
    -5.6 ± 0.57
    -5.8 ± 0.59
    -2.9 ± 0.56
        Day 4
    -8.6 ± 0.67
    -8.6 ± 0.68
    -4.9 ± 0.64
        Day 7
    -10 ± 0.81
    -10.7 ± 0.83
    -6.6 ± 0.79
        Day 14
    -11.1 ± 0.98
    -12.5 ± 1
    -9.4 ± 0.95
    Statistical analysis title
    Y-MRS total at Day 2: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0007
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -2.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.2
         upper limit
    -1.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.78
    Statistical analysis title
    Y-MRS total at Day 2: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -2.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.4
         upper limit
    -1.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.79
    Statistical analysis title
    Y-MRS total at Day 4: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -3.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.4
         upper limit
    -1.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.91
    Statistical analysis title
    Y-MRS total at Day 4: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -3.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.5
         upper limit
    -1.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.92
    Statistical analysis title
    Y-MRS total at Day 7: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0021
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -3.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.7
         upper limit
    -1.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.12
    Statistical analysis title
    Y-MRS total at Day 7: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -4.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.4
         upper limit
    -2
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.13
    Statistical analysis title
    Y-MRS total at Day 14: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1907
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -1.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.4
         upper limit
    0.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.35
    Statistical analysis title
    Y-MRS total at Day 14: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0238
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -3.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.8
         upper limit
    -0.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.37

    Secondary: Percentage of participants who are Y-MRS responders at Day 2, Day 4, Day 7, Day 14

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    End point title
    Percentage of participants who are Y-MRS responders at Day 2, Day 4, Day 7, Day 14
    End point description
    Y-MRS consists of responses to the following 11 items: elevated mood, increased motor activity energy, sexual interest, sleep, language-thought disorder, appearance, insight, irritability, speech - rate and amount, content and disruptive-agressive behavior. The scores from the 11 items are summed to give a total score ranging from 0 to 60, with a higher score indicating greater severity of symptoms. Results reported for all randomized participants who received at least one dose of trial medication and had at least one baseline and post-baseline measurement, and had evaluable post-baseline measurement at timepoint. Missing data were imputed by LOCF. Y-MRS responders are defined as having a >= 50% decrease from baseline in Y-MRS total score.
    End point type
    Secondary
    End point timeframe
    Day 2, Day 4, Day 7, Day 14
    End point values
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo
    Number of subjects analysed
    120
    113
    126
    Units: Percentage of participants
    number (not applicable)
        Day 2 (n=117,111,123)
    12
    14.4
    8.9
        Day 4 (n=120,113,126)
    21.7
    23
    8.7
        Day 7 (n=120,113,126)
    31.7
    28.3
    19.8
        Day 14 (n=120,113,126)
    36.7
    40.7
    33.3
    Statistical analysis title
    Y-MRS Responders Day 2: Asenapine 5 mg - Placebo
    Statistical analysis description
    Number of participants analyzed = 240
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2922
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    Y-MRS Responders Day 2: Asenapine 10 mg - Placebo
    Statistical analysis description
    Number of participants analyzed = 234
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1001
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    Y-MRS Responders Day 4: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0011
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    Y-MRS Responders Day 4: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0011
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    Y-MRS Responders Day 7: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0194
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    Y-MRS responders Day 7: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0841
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    Y-MRS responders Day 14: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4858
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    Y-MRS responders Day 14: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2496
    Method
    Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Percentage of participants who are Y-MRS remitters at Day 21

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    End point title
    Percentage of participants who are Y-MRS remitters at Day 21
    End point description
    Y-MRS consists of responses to the following 11 items: elevated mood, increased motor activity energy, sexual interest, sleep, language-thought disorder, appearance, insight, irritability, speech - rate and amount, content and disruptive-agressive behavior. The 11 items are summed to give a total score ranging from 0 to 60, with a higher score indicating greater severity of symptoms. Results reported for all randomized participants who received at least one dose of trial medication and had at least one post-baseline measurement. Missing data were imputed by LOCF. Y-MRS remitters are defined as having a Y-MRS total score of 12 or lower.
    End point type
    Secondary
    End point timeframe
    Day 21
    End point values
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo
    Number of subjects analysed
    120
    113
    126
    Units: Percentage of participants
        number (not applicable)
    34.2
    38.1
    30.2
    Statistical analysis title
    Y-MRS remitters Day 21: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2912
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    Y-MRS remitters Day 21: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1151
    Method
    Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Percentage of participants who are Y-MRS remitters at Day 2, Day 4, Day 7, Day 14, Day 21

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    End point title
    Percentage of participants who are Y-MRS remitters at Day 2, Day 4, Day 7, Day 14, Day 21
    End point description
    Y-MRS consists of responses to the following 11 items: elevated mood, increased motor activity energy, sexual interest, sleep, language-thought disorder, appearance, insight, irritability, speech - rate and amount, content and disruptive-agressive behavior. The scores from the 11 items are summed to give a total score ranging from 0 to 60, with a higher score indicating greater severity of symptoms. Results reported for all randomized participants who received at least one dose of trial medication and had at least one post-baseline measurement, and had evaluable post-baseline measurement at timepoint. The analysis is based on a generalized linear mixed model (GLMM). Y-MRS remitters are defined as having a Y-MRS total score of 12 or lower.
    End point type
    Secondary
    End point timeframe
    Day 2, Day 4, Day 7, Day 14, Day 21
    End point values
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo
    Number of subjects analysed
    120
    113
    126
    Units: Percentage of participants
    number (not applicable)
        Day 2 (n=117,111, 123)
    8.5
    11.7
    5.7
        Day 4 (n= 104, 106,118)
    17.3
    15.1
    10.2
        Day 7 (n= 104, 101,110)
    26.9
    24.8
    17.3
        Day 14 (n= 96, 91,102)
    28.1
    27.5
    24.5
        Day 21 (n= 86, 83,93)
    40.7
    43.4
    34.4
    No statistical analyses for this end point

    Secondary: Change from baseline in Montgomery Asberg Depression Rating Scale (MADRS) total score

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    End point title
    Change from baseline in Montgomery Asberg Depression Rating Scale (MADRS) total score
    End point description
    The MADRS measures depression and consists of 10 items, each rated on a scale from 0 to 6. The MADRS total score sums the scores from the 10 items, ranging from 0 to 60, with a higher numeric rating implying a greater degree of symptom severity. Results reported for all randomized participants who received at least one dose of trial medication and had at least one baseline and post-baseline measurement, and had evaluable post-baseline measurement at timepoint. Missing data were imputed by LOCF. An improvement in symptoms is represented by change from baseline values that are negative.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 7 and Day 21
    End point values
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo
    Number of subjects analysed
    115
    110
    123
    Units: Score on a scale
    least squares mean (standard error)
        Day 7 (n=112,106, 117)
    -4.3 ± 0.47
    -4.2 ± 0.48
    -2.3 ± 0.46
        Day 21 (n =115, 110,123)
    -4.6 ± 0.61
    -5.1 ± 0.63
    -2.5 ± 0.6
    Statistical analysis title
    MADRS Total Day 7: Asenapine 5 mg - Placebo
    Statistical analysis description
    Number of participants analyzed = 229
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0019
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    MADRS Total Day 7: Asenapine 10 mg - Placebo
    Statistical analysis description
    Number of participants analyzed = 223
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0045
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    MADRS Total Day 21: Asenapine 5 mg - Placebo
    Statistical analysis description
    Number of participants analyzed = 238
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0112
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    MADRS Total Day 21: Asenapine 10 mg - Placebo
    Statistical analysis description
    Number of participants analyzed = 233
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0021
    Method
    ANCOVA
    Confidence interval

    Secondary: Change from baseline in CGI-BP-S overall score at Day 2, Day 4, Day 7, Day 14

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    End point title
    Change from baseline in CGI-BP-S overall score at Day 2, Day 4, Day 7, Day 14
    End point description
    The CGI-BP-S is a score that measures the severity of overall bipolar illness. The score ranges on a scale from 1 to 7, where 1 is normal, and 7 is very severely ill. Results reported for all randomized participants who received at least one dose of trial medication and had at least one baseline and post-baseline measurement. One participant from the Placebo BID arm missed a baseline measurement. The analysis is based on a MMRM model. An improvement in symptoms is represented by change from baseline values that are negative.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 2, Day 4, Day 7, Day 14
    End point values
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo
    Number of subjects analysed
    120
    113
    125
    Units: Score on a scale
    least squares mean (standard error)
        Day 2
    -0.5 ± 0.05
    -0.4 ± 0.06
    -0.2 ± 0.05
        Day 4
    -0.8 ± 0.07
    -0.7 ± 0.07
    -0.4 ± 0.07
        Day 7
    -1 ± 0.09
    -1.1 ± 0.09
    -0.7 ± 0.09
        Day 14
    -1.3 ± 0.1
    -1.3 ± 0.11
    -1 ± 0.1
    Statistical analysis title
    CGI-BP-S Overall Day 2: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.07
    Statistical analysis title
    CGI-BP-S Overall Day 2: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0076
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.07
    Statistical analysis title
    CGI-BP-S Overall Day 4: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0004
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    -0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1
    Statistical analysis title
    CGI-BP-S Overall Day 4: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.004
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.5
         upper limit
    -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1
    Statistical analysis title
    CGI-BP-S Overall Day 7: Asenapine 5 mg - Placebo
    Comparison groups
    Placebo v Asenapine 5 mg BID
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0061
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.12
    Statistical analysis title
    CGI-BP-S Overall Day 7: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0031
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.13
    Statistical analysis title
    CGI-BP-S Overall Day 14: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1086
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.5
         upper limit
    0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.14
    Statistical analysis title
    CGI-BP-S Overall Day 14: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0376
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    0
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.15

    Secondary: Change from baseline in CGI-BP-S mania score

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    End point title
    Change from baseline in CGI-BP-S mania score
    End point description
    The CGI-BP-S mania is a score that assesses the severity of the mania component of bipolar illness. The score ranges on a scale from 1 to 7, where 1 is normal, and 7 is very severely ill. Results reported for all randomized participants who received at least one dose of trial medication and had at least one baseline and post-baseline measurement, and had evaluable post-baseline measurement at timepoint. Missing data were imputed by LOCF. An improvement in symptoms is represented by change from baseline values that are negative.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 2, Day 4, Day 7, Day 14, and Day 21
    End point values
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo
    Number of subjects analysed
    120
    113
    125
    Units: Score on a scale
    least squares mean (standard error)
        Day 2 (n=118,111,122)
    -0.4 ± 0.06
    -0.4 ± 0.06
    -0.1 ± 0.06
        Day 4 (n=120,113,125)
    -0.7 ± 0.07
    -0.7 ± 0.08
    -0.3 ± 0.07
        Day 7 (n=120,113,125)
    -0.9 ± 0.09
    -1 ± 0.09
    -0.7 ± 0.09
        Day 14 (n=120,113,125)
    -1.2 ± 0.1
    -1.3 ± 0.11
    -1 ± 0.1
        Day 21 (n=120,113,125)
    -1.4 ± 0.11
    -1.5 ± 0.12
    -1.1 ± 0.11
    Statistical analysis title
    CGI-BP-S Mania Day 2: Asenapine 5 mg - Placebo
    Statistical analysis description
    Number of participants analyzed = 240
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0005
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    CGI-BP-S Mania Day 2: Asenapine 10 mg - Placebo
    Statistical analysis description
    Number of participants analyzed = 233
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0026
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    CGI-BP-S Mania Day 4: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0007
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    CGI-BP-S Mania Day 4: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0002
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    CGI-BP-S Mania Day 7: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0387
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    CGI-BP-S Mania Day 7: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0059
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    CGI-BP-S Mania Day 14: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.311
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    CGI-BP-S Mania Day 14: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0613
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    CGI-BP-S Mania Day 21: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.064
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    CGI-BP-S Mania Day 21: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0139
    Method
    ANCOVA
    Confidence interval

    Secondary: Change from baseline in CGI-BP-S depression score

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    End point title
    Change from baseline in CGI-BP-S depression score
    End point description
    The CGI-BP-S depression is a score that assesses the severity of the depression component of bipolar illness. The score ranges on a scale from 1 to 7, where 1 is normal, and 7 is very severely ill. Results reported for all randomized participants who received at least one dose of trial medication and had at least one baseline and post-baseline measurement, and had evaluable post-baseline measurement at timepoint. Missing data were imputed by LOCF. An improvement in symptoms is represented by change from baseline values that are negative.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 2, Day 4, Day 7, Day 14, and Day 21
    End point values
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo
    Number of subjects analysed
    120
    113
    125
    Units: Score on a scale
    least squares mean (standard error)
        Day 2 (n=118,111,122)
    -0.2 ± 0.06
    -0.2 ± 0.06
    -0.2 ± 0.06
        Day 4 (n=120,113,125)
    -0.3 ± 0.06
    -0.3 ± 0.06
    -0.3 ± 0.06
        Day 7 (n=120,113,125)
    -0.3 ± 0.07
    -0.4 ± 0.07
    -0.1 ± 0.07
        Day 14 (n=120,113,125)
    -0.4 ± 0.07
    -0.5 ± 0.07
    -0.2 ± 0.07
        Day 21 (n=120,113,125)
    -0.4 ± 0.08
    -0.5 ± 0.08
    -0.1 ± 0.08
    Statistical analysis title
    CGI-BP-S Depression Day 2: Asenapine 5 mg-Placebo
    Statistical analysis description
    Number of participants analyzed = 240
    Comparison groups
    Placebo v Asenapine 5 mg BID
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9708
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    CGI-BP-S Depression Day 2: Asenapine 10 mg-Placebo
    Statistical analysis description
    Number of participants analyzed = 233
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7891
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    CGI-BP-S Depression Day 4: Asenapine 5 mg-Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5222
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    CGI-BP-S Depression Day 4: Asenapine 10 mg-Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8686
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    CGI-BP-S Depression Day 7: Asenapine 5 mg-Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0696
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    CGI-BP-S Depression Day 7: Asenapine 10 mg-Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0049
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    CGI-BP-S Depression Day 14: Asenapine 5 mg-Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0196
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    CGI-BP-S Depression Day 14:Asenapine 10 mg-Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0032
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    CGI-BP-S Depression Day 21: Asenapine 5 mg-Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0061
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    CGI-BP-S Depression Day 21:Asenapine 10 mg-Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0012
    Method
    ANCOVA
    Confidence interval

    Secondary: Percentage of participants who are CGI-BP Improvement (CGI-BP-I) Responders of Overall Bipolar Illness Score

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    End point title
    Percentage of participants who are CGI-BP Improvement (CGI-BP-I) Responders of Overall Bipolar Illness Score
    End point description
    The CGI-BP-I overall is a score on a 7-point scale for assessing the change from preceding phase of overall symptoms of bipolar disorder during the treatment of an acute episode or in longer term illness prophylaxis. Compared to the baseline, the CGI-BP-I overall score ranges from 1 = very much improved since initiating treatment, to 7 = very much worse since initiating treatment. Results reported for all randomized participants who received at least one dose of trial medication and had at least one post-baseline measurement, and had evaluable post-baseline measurement at timepoint. Missing data were imputed by LOCF. A CGI-BP-I responder had a score of 3 (minimally improved) or lower.
    End point type
    Secondary
    End point timeframe
    Day 2, Day 4, Day 7, Day 14, and Day 21
    End point values
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo
    Number of subjects analysed
    120
    113
    126
    Units: Percentage of participants
    number (not applicable)
        Day 2 (n=118,111,123)
    50.8
    45.9
    37.4
        Day 4 (n=120,113,126)
    64.2
    64.6
    55.6
        Day 7 (n=120,113,126)
    73.3
    78.8
    61.1
        Day 14 (n=120,113,126)
    70.8
    83.2
    65.1
        Day 21 (n=120,113,126)
    74.2
    82.3
    64.3
    Statistical analysis title
    CGI-BP-I Resp.Overall Day 2:Asenapine 5 mg-Placebo
    Statistical analysis description
    Number of participants analyzed = 241
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0147
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp.Overall Day 2:Asenapine 10mg-Placebo
    Statistical analysis description
    Number of participants analyzed = 234
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.072
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp.Overall Day 4:Asenapine 5 mg-Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1213
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp.Overall Day 4:Asenapine 10mg-Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0588
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp.Overall Day 7:Asenapine 5 mg-Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.02
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp.Overall Day 7:Asenapine 10mg-Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0017
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp.Overall Day 14:Asenapine 5mg-Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2401
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp.Overall Day 14:Asenapine10mg-Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0009
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp.Overall Day 21:Asenapine 5mg-Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0525
    Method
    Chi-squared corrected
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp.Overall Day 21:Asenapine10mg-Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0025
    Method
    Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Percentage of participants who are CGI-BP-I Responders of Mania Score

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    End point title
    Percentage of participants who are CGI-BP-I Responders of Mania Score
    End point description
    The CGI-BP-I mania is a score on a 7-point scale for assessing the change from preceding phase of mania symptoms of bipolar disorder during the treatment of an acute episode or in longer term illness prophylaxis. Compared to the baseline, the CGI-BP-I mania score ranges from 1 = very much improved since initiating treatment, to 7 = very much worse since initiating treatment. Results reported for all randomized participants who received at least one dose of trial medication and had at least one post-baseline measurement, and had evaluable post-baseline measurement at timepoint. Missing data were imputed by LOCF. A CGI-BP-I responder had a score of 3 (minimally improved) or lower.
    End point type
    Secondary
    End point timeframe
    Day 2, Day 4, Day 7, Day 14, and Day 21
    End point values
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo
    Number of subjects analysed
    120
    113
    126
    Units: Percentage of participants
    number (not applicable)
        Day 2 (n=118,111,123)
    49.2
    45.9
    37.4
        Day 4 (n=120,113,126)
    64.2
    66.4
    55.6
        Day 7 (n=120,113,126)
    74.2
    80.5
    63.5
        Day 14 (n=120,113,126)
    75.8
    82.3
    66.7
        Day 21 (n=120,113,126)
    79.2
    84.1
    66.7
    Statistical analysis title
    CGI-BP-I Resp. Mania Day 2:Asenapine 5 mg-Placebo
    Statistical analysis description
    Number of participants analyzed = 241
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0377
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp. Mania Day 2:Asenapine 10 mg-Placebo
    Statistical analysis description
    Number of participants analyzed = 234
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0771
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp. Mania Day 4:Asenapine 5 mg-Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1264
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp. Mania Day 4:Asenapine 10 mg-Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.028
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp. Mania Day 7:Asenapine 5 mg-Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0583
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp. Mania Day 7:Asenapine 10 mg-Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0021
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp. Mania Day 14:Asenapine 5 mg-Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0866
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp. Mania Day 14:Asenapine 10mg-Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0048
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp. Mania Day 21:Asenapine 5 mg-Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0147
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp. Mania Day 21:Asenapine 10mg-Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.003
    Method
    Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Percentage of participants who are CGI-BP-I Responders of Depression Score

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    End point title
    Percentage of participants who are CGI-BP-I Responders of Depression Score
    End point description
    The CGI-BP-I depression is a score on a 7-point scale for assessing the change from preceding phase of depression symptoms of bipolar disorder during the treatment of an acute episode or in longer term illness prophylaxis. Compared to the baseline, the CGI-BP-I depression score ranges from 1 = very much improved since initiating treatment, to 7 = very much worse since initiating treatment. Results reported for all randomized participants who received at least one dose of trial medication and had at least one post-baseline measurement, and had evaluable post-baseline measurement at timepoint. Missing data were imputed by LOCF. A CGI-BP-I responder had a score of 3 (minimally improved) or lower.
    End point type
    Secondary
    End point timeframe
    Day 2, Day 4, Day 7, Day 14, and Day 21
    End point values
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo
    Number of subjects analysed
    117
    106
    121
    Units: Percentage of participants
    number (not applicable)
        Day 2 (n=113, 103, 116)
    21.2
    28.2
    11.2
        Day 4 (n=116, 106, 119)
    26.7
    32.1
    19.3
        Day 7 (n=117, 106, 119)
    31.6
    35.8
    23.5
        Day 14 (n=117, 106, 120)
    31.6
    42.5
    26.7
        Day 21 (n=117, 106, 121)
    32.5
    44.3
    28.9
    Statistical analysis title
    CGI-BP-I Resp. Depr. Day 2: Asenapine 5 mg-Placebo
    Statistical analysis description
    Number of participants analyzed = 229
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0104
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp. Depr. Day 2:Asenapine 10 mg-Placebo
    Statistical analysis description
    Number of participants analyzed = 219
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    227
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0005
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp. Depr. Day 4:Asenapine 5 mg-Placebo
    Statistical analysis description
    Number of participants analyzed = 235
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0692
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp. Depr. Day 4:Asenapine 10 mg-Placebo
    Statistical analysis description
    Number of participants analyzed = 225
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    227
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0128
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp. Depr. Day 7:Asenapine 5 mg-Placebo
    Statistical analysis description
    Number of participants analyzed = 236
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0809
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp. Depr. Day 7:Asenapine 10 mg-Placebo
    Statistical analysis description
    Number of participants analyzed = 225
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    227
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.026
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp. Depr. Day 14:Asenapine 5 mg-Placebo
    Statistical analysis description
    Number of participants analyzed = 237
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2576
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp. Depr. Day 14:Asenapine 10mg-Placebo
    Statistical analysis description
    Number of participants analyzed = 226
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    227
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0077
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp. Depr. Day 21:Asenapine 5 mg-Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.396
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Statistical analysis title
    CGI-BP-I Resp. Depr. Day 21:Asenapine 10mg-Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    227
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0141
    Method
    Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Change from baseline in Positive And Negative Syndrome Scale (PANSS) total score

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    End point title
    Change from baseline in Positive And Negative Syndrome Scale (PANSS) total score
    End point description
    PANSS total score measures symptoms of schizophrenia and consists of responses to 30 items: 7 items from the positive subscale (P1-P7), 7 items from the negative subscale (N1-N7) and 16 items from the general psychopathology subscale (G1-G16). Responses to each item range from 1 = absence of symptom, to 7 = most extreme symptoms. The PANSS total score sums the scores from all 30 items, and ranges from 30 to 210, with a higher score indicating greater severity of symptoms. Results reported for all randomized participants who received at least one dose of trial medication and had at least one baseline and post-baseline measurement. The analysis is based on a MMRM model. An improvement in symptoms is represented by change from baseline values that are negative.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 7, Day 14, Day 21
    End point values
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo
    Number of subjects analysed
    115
    110
    123
    Units: Score on a scale
    least squares mean (standard error)
        Day 7
    -6.9 ± 0.77
    -6.9 ± 0.79
    -3.9 ± 0.76
        Day 14
    -7.5 ± 0.96
    -8.4 ± 0.99
    -5.2 ± 0.94
        Day 21
    -9.3 ± 1.02
    -8.8 ± 1.05
    -5.5 ± 1
    Statistical analysis title
    PANSS Total Day 7: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0056
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.1
         upper limit
    -0.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.06
    Statistical analysis title
    PANSS Total Day 7: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0068
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -2.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5
         upper limit
    -0.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.08
    Statistical analysis title
    PANSS Total Day 14: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0743
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -2.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5
         upper limit
    0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.33
    Statistical analysis title
    PANSS Total Day 14: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0177
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -3.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.9
         upper limit
    -0.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.35
    Statistical analysis title
    PANSS Total Day 21: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0081
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -3.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.6
         upper limit
    -1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.41
    Statistical analysis title
    PANSS Total Day 21: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0247
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -3.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.1
         upper limit
    -0.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.43

    Secondary: Change from baseline in PANSS Negative subscale score

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    End point title
    Change from baseline in PANSS Negative subscale score
    End point description
    PANSS Negative subscale measures symptoms of schizophrenia and consists of responses to 7 items (N1-N7). Responses to each item range from 1 = absence of symptom, to 7 = most extreme symptoms. The PANSS Negative subscale sums the scores from all 7 items and ranges from 7 to 49, with a higher score indicating greater severity of symptoms. Results reported for all randomized participants who received at least one dose of trial medication and had at least one baseline and post-baseline measurement. The analysis is based on a MMRM model. An improvement in symptoms is represented by change from baseline values that are negative.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 7, Day 14, Day 21
    End point values
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo
    Number of subjects analysed
    115
    110
    123
    Units: Score on a scale
    least squares mean (standard error)
        Day 7
    -0.5 ± 0.22
    -0.8 ± 0.22
    -0.5 ± 0.21
        Day 14
    -0.8 ± 0.23
    -0.7 ± 0.24
    -0.8 ± 0.23
        Day 21
    -0.4 ± 0.28
    0 ± 0.29
    -0.4 ± 0.27
    Statistical analysis title
    PANSS Negative Day 7: Asenapine 5 mg - Placebo
    Comparison groups
    Placebo v Asenapine 5 mg BID
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9808
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    0.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3
    Statistical analysis title
    PANSS Negative Day 7: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.283
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.9
         upper limit
    0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.31
    Statistical analysis title
    PANSS Negative Day 14: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9751
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    0.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.32
    Statistical analysis title
    PANSS Negative Day 14: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7879
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    0.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.33
    Statistical analysis title
    PANSS Negative Day 21: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9654
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.8
         upper limit
    0.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.38
    Statistical analysis title
    PANSS Negative Day 21: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3917
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    1.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.39

    Secondary: Change from baseline in PANSS Positive subscale score

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    End point title
    Change from baseline in PANSS Positive subscale score
    End point description
    PANSS Positive subscale measures symptoms of schizophrenia and consists of responses to 7 items (P1-P7). Responses to each item range from 1 = absence of symptom, to 7 = most extreme symptoms. The PANSS Positive subscale sums the scores from all 7 items and ranges from 7 to 49, with a higher score indicating greater severity of symptoms. Results reported for all randomized participants who received at least one dose of trial medication and had at least one baseline and post-baseline measurement. The analysis is based on a MMRM model. An improvement in symptoms is represented by change from baseline values that are negative.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 7, Day 14, Day 21
    End point values
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo
    Number of subjects analysed
    115
    110
    123
    Units: Score on a scale
    least squares mean (standard error)
        Day 7
    -2.4 ± 0.3
    -2.8 ± 0.31
    -1.4 ± 0.29
        Day 14
    -2.3 ± 0.37
    -3.2 ± 0.38
    -2.1 ± 0.36
        Day 21
    -3.5 ± 0.37
    -3.9 ± 0.38
    -2.4 ± 0.36
    Statistical analysis title
    PANSS Positive Day 7: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.012
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.8
         upper limit
    -0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.41
    Statistical analysis title
    PANSS Positive Day 7: Asenapine 10 mg - Placebo
    Comparison groups
    Placebo v Asenapine 10 mg BID
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0011
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.2
         upper limit
    -0.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.42
    Statistical analysis title
    PANSS Positive Day 14: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6885
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    0.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.51
    Statistical analysis title
    PANSS Positive Day 14: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0398
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.1
         upper limit
    -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.52
    Statistical analysis title
    PANSS Positive Day 21: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0258
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.1
         upper limit
    -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.51
    Statistical analysis title
    PANSS Positive Day 21: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0031
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -1.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.5
         upper limit
    -0.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.51

    Secondary: Change from baseline in PANSS General Psychopathology subscale score

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    End point title
    Change from baseline in PANSS General Psychopathology subscale score
    End point description
    PANSS General Psychopathology subscale measures symptoms of schizophrenia and consists of responses to 16 items (G1-G16). Responses to each item range from 1 = absence of symptom, to 7 = most extreme symptoms. The PANSS General Psychopathology subscale sums the scores from all 16 items and ranges from 16 to 112, with a higher score indicating greater severity of symptoms. Results reported for all randomized participants who received at least one dose of trial medication and had at least one baseline and post-baseline measurement. The analysis is based on a MMRM model. An improvement in symptoms is represented by change from baseline values that are negative.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 7, Day 14, Day 21
    End point values
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo
    Number of subjects analysed
    115
    110
    123
    Units: Score on a scale
    least squares mean (standard error)
        Day 7
    -4 ± 0.46
    -3.3 ± 0.48
    -2.1 ± 0.46
        Day 14
    -4.5 ± 0.57
    -4.6 ± 0.59
    -2.4 ± 0.56
        Day 21
    -5.5 ± 0.61
    -4.9 ± 0.62
    -2.9 ± 0.59
    Statistical analysis title
    PANSS Gen. Psych. Day 7: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0033
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -1.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.2
         upper limit
    -0.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.64
    Statistical analysis title
    PANSS Gen. Psych. Day 7: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0622
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.5
         upper limit
    0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.65
    Statistical analysis title
    PANSS Gen. Psych. Day 14: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0083
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -2.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.6
         upper limit
    -0.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.79
    Statistical analysis title
    PANSS Gen. Psych. Day 14:Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0064
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -2.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.8
         upper limit
    -0.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.8
    Statistical analysis title
    PANSS Gen. Psych. Day 21:Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0022
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -2.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.3
         upper limit
    -0.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.84
    Statistical analysis title
    PANSS Gen. Psych. Day 21:Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0196
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.7
         upper limit
    -0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.85

    Secondary: Change from baseline in PANSS Marder Factor Positive symptom score

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    End point title
    Change from baseline in PANSS Marder Factor Positive symptom score
    End point description
    PANSS Marder Factor Positive symptom score measures symptoms of schizophrenia and consists of responses to 8 items (P1,P3,P5,P6,N7,G1,G9,G12). Responses to each item range from 1 = absence of symptom, to 7 = most extreme symptoms. The PANSS Marder Factor Positive symptom score sums the scores from all 8 items and ranges from 8 to 56, with a higher score indicating greater severity of symptoms. Results reported for all randomized participants who received at least one dose of trial medication and had at least one baseline and post-baseline measurement. The analysis is based on a MMRM model. An improvement in symptoms is represented by change from baseline values that are negative.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 7, Day 14, Day 21
    End point values
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo
    Number of subjects analysed
    115
    110
    123
    Units: Score on a scale
    least squares mean (standard error)
        Day 7
    -1.9 ± 0.29
    -1.9 ± 0.29
    -1.3 ± 0.28
        Day 14
    -1.6 ± 0.33
    -2.5 ± 0.34
    -1.6 ± 0.33
        Day 21
    -2.6 ± 0.34
    -2.9 ± 0.35
    -1.7 ± 0.33
    Statistical analysis title
    PANSS Mard. Pos. Day 7: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1883
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4
    Statistical analysis title
    PANSS Mard. Pos. Day 7: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1684
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4
    Statistical analysis title
    PANSS Mard. Pos. Day 14: Asenapine 5 mg - Placebo
    Comparison groups
    Placebo v Asenapine 5 mg BID
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9522
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.9
         upper limit
    0.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.46
    Statistical analysis title
    PANSS Mard. Pos. Day 14: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0514
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.8
         upper limit
    0
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.47
    Statistical analysis title
    PANSS Mard. Pos. Day 21: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0531
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.8
         upper limit
    0
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.47
    Statistical analysis title
    PANSS Mard. Pos. Day 21: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0078
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.2
         upper limit
    -0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.48

    Secondary: Change from baseline in PANSS Marder Factor Negative symptom score

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    End point title
    Change from baseline in PANSS Marder Factor Negative symptom score
    End point description
    PANSS Marder Factor Negative symptom score measures symptoms of schizophrenia and consists of responses to 7 items (N1,N2,N3,N4,N6,G7,G16). Responses to each item range from 1 = absence of symptom, to 7 = most extreme symptoms. The PANSS Marder Factor Negative symptom score sums the scores from all 7 items and ranges from 7 to 49, with a higher score indicating greater severity of symptoms. Results reported for all randomized participants who received at least one dose of trial medication and had at least one baseline and post-baseline measurement. The analysis is based on a MMRM model. An improvement in symptoms is represented by change from baseline values that are negative.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 7, Day 14, Day 21
    End point values
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo
    Number of subjects analysed
    115
    110
    123
    Units: Score on a scale
    least squares mean (standard error)
        Day 7
    -0.5 ± 0.23
    -0.8 ± 0.24
    -0.5 ± 0.23
        Day 14
    -0.6 ± 0.24
    -0.5 ± 0.25
    -0.7 ± 0.24
        Day 21
    -0.1 ± 0.27
    0.1 ± 0.28
    -0.1 ± 0.27
    Statistical analysis title
    PANSS Mard. Neg. Day 7: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7746
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    0.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.32
    Statistical analysis title
    PANSS Mard. Neg. Day 7: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2754
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.32
    Statistical analysis title
    PANSS Mard. Neg. Day 14: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9109
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    0.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.34
    Statistical analysis title
    PANSS Mard. Neg. Day 14: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7295
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    0.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.34
    Statistical analysis title
    PANSS Mard. Neg. Day 21: Asenapine 5 mg - Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.98
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    0.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.38
    Statistical analysis title
    PANSS Mard. Neg. Day 21: Asenapine 10 mg - Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5122
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.5
         upper limit
    1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.38

    Secondary: Change from baseline in PANSS Marder Factor Disorganized Thought symptom score

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    End point title
    Change from baseline in PANSS Marder Factor Disorganized Thought symptom score
    End point description
    PANSS Marder Factor Disorganized Thought symptom score measures symptoms of schizophrenia and consists of responses to 7 items (P2,N5,G5,G10,G11,G13,G15). Responses to each item range from 1 = absence of symptom, to 7 = most extreme symptoms. The PANSS Marder Factor Disorganized Thought symptom score sums the scores from all 7 items and ranges from 7 to 49, with a higher score indicating greater severity of symptoms. Results reported for all randomized participants who received at least one dose of trial medication and had at least one baseline and post-baseline measurement. The analysis is based on a MMRM model. An improvement in symptoms is represented by change from baseline values that are negative.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 7, Day 14, Day 21
    End point values
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo
    Number of subjects analysed
    115
    110
    123
    Units: Score on a scale
    least squares mean (standard error)
        Day 7
    -1.1 ± 0.21
    -1.3 ± 0.22
    -0.7 ± 0.21
        Day 14
    -1.5 ± 0.26
    -1.8 ± 0.27
    -1.2 ± 0.26
        Day 21
    -2 ± 0.28
    -1.7 ± 0.29
    -1.5 ± 0.27
    Statistical analysis title
    PANSS Mard. Disorg. Day 7:Asenapine 5mg-Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2191
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.9
         upper limit
    0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.29
    Statistical analysis title
    PANSS Mard. Disorg. Day 7:Asenapine 10 mg-Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0589
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.1
         upper limit
    0
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.29
    Statistical analysis title
    PANSS Mard. Disorg. Day 14:Asenapine 5 mg-Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3683
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    0.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.36
    Statistical analysis title
    PANSS Mard. Disorg. Day 14:Asenapine 10 mg-Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0982
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.37
    Statistical analysis title
    PANSS Mard. Disorg. Day 21:Asenapine 5 mg-Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1969
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.38
    Statistical analysis title
    PANSS Mard. Disorg. Day 21:Asenapine 10 mg-Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5615
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1
         upper limit
    0.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.39

    Secondary: Change from baseline in PANSS Marder Factor Hostility/Excitement symptom score

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    End point title
    Change from baseline in PANSS Marder Factor Hostility/Excitement symptom score
    End point description
    PANSS Marder Factor Hostility/Excitement symptom score measures symptoms of schizophrenia and consists of responses to 4 items (P4,P7,G8,G14). Responses to each item range from 1 = absence of symptom, to 7 = most extreme symptoms. The PANSS Marder Factor Hostility/Excitement symptom score sums the score from all 4 items and ranges from 4 to 28, with a higher score indicating greater severity of symptoms. Results reported for all randomized participants who received at least one dose of trial medication and had at least one baseline and post-baseline measurement. The analysis is based on a MMRM model. An improvement in symptoms is represented by change from baseline values that are negative.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 7, Day 14, Day 21
    End point values
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo
    Number of subjects analysed
    115
    110
    123
    Units: Score on a scale
    least squares mean (standard error)
        Day 7
    -1.7 ± 0.24
    -1.7 ± 0.25
    -0.9 ± 0.24
        Day 14
    -1.8 ± 0.28
    -2 ± 0.29
    -1.2 ± 0.27
        Day 21
    -2.6 ± 0.29
    -2.5 ± 0.3
    -1.5 ± 0.28
    Statistical analysis title
    PANSS Mard. Hostil. Day 7:Asenapine 5 mg-Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0101
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.5
         upper limit
    -0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.33
    Statistical analysis title
    PANSS Mard. Hostil. Day 7:Asenapine 10 mg-Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0146
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.5
         upper limit
    -0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.34
    Statistical analysis title
    PANSS Mard. Hostil. Day 14:Asenapine 5 mg-Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0861
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.4
         upper limit
    0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.39
    Statistical analysis title
    PANSS Mard. Hostil. Day 14:Asenapine 10 mg-Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0342
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.6
         upper limit
    -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.39
    Statistical analysis title
    PANSS Mard. Hostil. Day 21:Asenapine 5 mg-Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0037
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2
         upper limit
    -0.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4
    Statistical analysis title
    PANSS Mard. Hostil. Day 21:Asenapine 10 mg-Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0096
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.9
         upper limit
    -0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.41

    Secondary: Change from baseline in PANSS Marder Factor Anxiety/Depression symptom score

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    End point title
    Change from baseline in PANSS Marder Factor Anxiety/Depression symptom score
    End point description
    PANSS Marder Factor Anxiety/Depression symptom score measures symptoms of schizophrenia and consists of responses to 4 items (G2,G3,G4,G6). Responses to each item range from 1 = absence of symptom, to 7 = most extreme symptoms. The PANSS Marder Factor Anxiety/Depression symptom score sums the scores from all 4 items and ranges from 4 to 28, with a higher score indicating greater severity of symptoms. Results reported for all randomized participants who received at least one dose of trial medication and had at least one baseline and post-baseline measurement. The analysis is based on a MMRM model. An improvement in symptoms is represented by change from baseline values that are negative.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 7, Day14, Day 21
    End point values
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo
    Number of subjects analysed
    115
    110
    123
    Units: Score on a scale
    least squares mean (standard error)
        Day 7
    -1.7 ± 0.24
    -1.3 ± 0.24
    -0.7 ± 0.23
        Day 14
    -2 ± 0.26
    -1.7 ± 0.27
    -0.7 ± 0.26
        Day 21
    -2.1 ± 0.3
    -1.9 ± 0.3
    -1 ± 0.29
    Statistical analysis title
    PANSS Mard. Anxiety Day 7:Asenapine 5 mg-Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0019
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.7
         upper limit
    -0.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.32
    Statistical analysis title
    PANSS Mard. Anxiety Day 7:Asenapine 10 mg-Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0791
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.33
    Statistical analysis title
    PANSS Mard. Anxiety Day 14:Asenapine 5 mg-Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0006
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -1.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2
         upper limit
    -0.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.36
    Statistical analysis title
    PANSS Mard. Anxiety Day 14:Asenapine 10 mg-Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0123
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.6
         upper limit
    -0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.37
    Statistical analysis title
    PANSS Mard. Anxiety Day 21:Asenapine 5 mg-Placebo
    Comparison groups
    Asenapine 5 mg BID v Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0054
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2
         upper limit
    -0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.41
    Statistical analysis title
    PANSS Mard. Anxiety Day 21:Asenapine 10 mg-Placebo
    Comparison groups
    Asenapine 10 mg BID v Placebo
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.035
    Method
    MMRM
    Parameter type
    LS means difference
    Point estimate
    -0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.7
         upper limit
    -0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.41

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 33 days after end of treatment (up to 54 days)
    Adverse event reporting additional description
    Randomized participants who received at least one dose of trial medication
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Asenapine 5 mg BID
    Reporting group description
    Participants were administered one asenapine 5 mg tablet, sublingually twice daily (BID) for 21.

    Reporting group title
    Asenapine 10 mg BID
    Reporting group description
    Participants were administered one asenapine 10 mg tablet, sublingually BID for 21 days.

    Reporting group title
    Placebo
    Reporting group description
    Participants were administered one asenapine-matched placebo tablet sublingually BID for 21 days.

    Serious adverse events
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 122 (2.46%)
    1 / 119 (0.84%)
    2 / 126 (1.59%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Facial bones fracture
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 119 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Bipolar I disorder
         subjects affected / exposed
    2 / 122 (1.64%)
    0 / 119 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 119 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 119 (0.84%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 119 (0.00%)
    0 / 126 (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
    Asenapine 5 mg BID Asenapine 10 mg BID Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 122 (35.25%)
    67 / 119 (56.30%)
    24 / 126 (19.05%)
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    5 / 122 (4.10%)
    18 / 119 (15.13%)
    1 / 126 (0.79%)
         occurrences all number
    5
    25
    1
    Dizziness
         subjects affected / exposed
    4 / 122 (3.28%)
    6 / 119 (5.04%)
    6 / 126 (4.76%)
         occurrences all number
    5
    6
    6
    Dysgeusia
         subjects affected / exposed
    4 / 122 (3.28%)
    11 / 119 (9.24%)
    0 / 126 (0.00%)
         occurrences all number
    4
    11
    0
    Headache
         subjects affected / exposed
    9 / 122 (7.38%)
    6 / 119 (5.04%)
    9 / 126 (7.14%)
         occurrences all number
    10
    7
    11
    Sedation
         subjects affected / exposed
    12 / 122 (9.84%)
    18 / 119 (15.13%)
    2 / 126 (1.59%)
         occurrences all number
    12
    19
    2
    Somnolence
         subjects affected / exposed
    12 / 122 (9.84%)
    14 / 119 (11.76%)
    3 / 126 (2.38%)
         occurrences all number
    12
    15
    3
    Gastrointestinal disorders
    Hypoaesthesia oral
         subjects affected / exposed
    15 / 122 (12.30%)
    27 / 119 (22.69%)
    2 / 126 (1.59%)
         occurrences all number
    15
    28
    2
    Nausea
         subjects affected / exposed
    4 / 122 (3.28%)
    6 / 119 (5.04%)
    4 / 126 (3.17%)
         occurrences all number
    4
    6
    6
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    1 / 122 (0.82%)
    7 / 119 (5.88%)
    3 / 126 (2.38%)
         occurrences all number
    1
    7
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Feb 2012
    Amendment 3: clarified fasting blood draw requirement; updated Closely Monitored Event to include Drug Hyperesensitivity Reactions; updated Monitoring Liver Enzymes to be consistent with guidance; updated Pharmacogenetic Specimen Handling and Shipping Instructions; Antiemetics containing dopamine agonist was changed to : Antiemetics containing dopamine antagonists.

    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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