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    Clinical Trial Results:
    An 8-week, Placebo-Controlled, Double-Blind, Randomized, Fixed-Dose Efficacy and Safety Trial of Asenapine in Adolescent Subjects with Schizophrenia

    Summary
    EudraCT number
    		 2009-017971-10
    Trial protocol
    		 RO   Outside EU/EEA  
    Global end of trial date
    01 Apr 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 May 2016
    First version publication date
    23 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    P05896
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01190254
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Merck Protocol number: MK-8274-020
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Apr 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Apr 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study is designed to evaluate whether asenapine, which is approved by the United States Food and Drug Administration (US FDA) for acute treatment of schizophrenia in adults, is also effective in adolescents with schizophrenia. Participants who qualify for the study will be randomly assigned to receive a fixed dose of asenapine (either 2.5 mg or 5 mg twice daily [BID]) or placebo for 8 weeks. Throughout the study, observations will be made on each participant at various times to assess the efficacy and safety of the study treatment. The primary objective of the trial is to demonstrate significant superiority of at least one asenapine dose to placebo, as measured by the change from baseline of the Positive and Negative Syndrome Scale (PANSS) total score at Day 56.
    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. The following additional measure defined for this individual study was in place for the protection of trial subjects: For participants whose symptoms worsen or are not adequately controlled on assigned treatment, rescue medication may be administered during the trial in the following circumstances. For the control of agitation, anxiety, insomnia, restlessness, or akathisia and extrapyramidal symptoms (EPS) some benzodiazepines and EPS medications (i.e., anticholinergics) are allowed. Benadryl (diphenhydramine) and beta blockers are also permitted, provided that they are not taken within 8 hours of efficacy assessments.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Sep 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Colombia: 8
    Country: Number of subjects enrolled
    Croatia: 6
    Country: Number of subjects enrolled
    Romania: 6
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 2
    Country: Number of subjects enrolled
    India: 100
    Country: Number of subjects enrolled
    Korea, Republic of: 3
    Country: Number of subjects enrolled
    Mexico: 1
    Country: Number of subjects enrolled
    Philippines: 1
    Country: Number of subjects enrolled
    Russian Federation: 101
    Country: Number of subjects enrolled
    Serbia: 9
    Country: Number of subjects enrolled
    Ukraine: 17
    Country: Number of subjects enrolled
    United States: 49
    Country: Number of subjects enrolled
    South Africa: 3
    Worldwide total number of subjects
    306
    EEA total number of subjects
    12
    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)
    1
    Adolescents (12-17 years)
    304
    Adults (18-64 years)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 306 subjects were randomized to treatment with placebo (N=102), asenapine 2.5 mg BID (N=98) or asenapine 5.0 mg BID (N=106).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants receive placebo asenapine tablets sublingually BID for 8 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Sublingual tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    Asenapine-matched placebo tablets for sublingual administration

    Arm title
    		 Asenapine 2.5 mg BID
    Arm description
    		 Participants receive active asenapine 2.5 mg tablets sublingually BID for 8 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    asenapine 2.5 mg
    Investigational medicinal product code
    Other name
    Saphris®, SCH 900274, Org 5222
    Pharmaceutical forms
    Sublingual tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    Asenapine 2.5 mg tablets for sublingual administration

    Arm title
    		 Asenapine 5.0 mg BID
    Arm description
    		 Participants receive active asenapine 2.5 mg tablets sublingually BID through Day 3. On Day 4 participants receive asenapine 2.5 mg in the morning and 5.0 mg in the evening. Participants receive active asenapine 5.0 mg tablets sublingually BID for the remainder of the 8-week treatment period
    Arm type
    		 Experimental

    Investigational medicinal product name
    asenapine 2.5 mg
    Investigational medicinal product code
    Other name
    Saphris®, SCH 900274, Org 5222
    Pharmaceutical forms
    Sublingual tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    Asenapine 2.5 mg tablets for sublingual administration

    Investigational medicinal product name
    asenapine 5.0 mg
    Investigational medicinal product code
    Other name
    Saphris®, SCH 900274, Org 5222
    Pharmaceutical forms
    Sublingual tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    Asenapine 5.0 mg tablets for sublingual administration

    Number of subjects in period 1
    		Placebo Asenapine 2.5 mg BID Asenapine 5.0 mg BID
    Started
    102
    98
    106
    Treated
    102
    98
    106
    Completed
    81
    81
    84
    Not completed
    21
    17
    22
         Did not meet protocol eligibility
    1
    -
    -
         Consent withdrawn by subject
    4
    5
    7
         Adverse event, non-fatal
    3
    6
    8
         Lost to follow-up
    4
    2
    -
         Lack of efficacy
    7
    4
    5
         Protocol deviation
    2
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants receive placebo asenapine tablets sublingually BID for 8 weeks

    Reporting group title
    Asenapine 2.5 mg BID
    Reporting group description
    		 Participants receive active asenapine 2.5 mg tablets sublingually BID for 8 weeks

    Reporting group title
    Asenapine 5.0 mg BID
    Reporting group description
    		 Participants receive active asenapine 2.5 mg tablets sublingually BID through Day 3. On Day 4 participants receive asenapine 2.5 mg in the morning and 5.0 mg in the evening. Participants receive active asenapine 5.0 mg tablets sublingually BID for the remainder of the 8-week treatment period

    Reporting group values
    		 Placebo Asenapine 2.5 mg BID Asenapine 5.0 mg BID Total
    Number of subjects
    		 102 98 106 306
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 1 1
        Adolescents (12-17 years)
    		 102 98 104 304
        Adults (18-64 years)
    		 0 0 1 1
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 15.4 ( 1.4 ) 15.2 ( 1.5 ) 15.4 ( 1.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 40 36 39 115
        Male
    		 62 62 67 191
    Positive and Negative Syndrome Scale (PANSS) total score
    The PANSS is a 30-item scale for assessing the symptoms of schizophrenia. For each PANSS item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS total score (30 items) ranged from 30 to 210 with a higher score indicating greater severity of symptoms. Summary statistics presented are for efficacy population (Full Analysis Set [FAS]): N=100, 96 and 104 for placebo, asenapine 2.5 mg BID and asenapine 5.0 mg BID groups, respectively.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 97.5 ( 10.3 ) 97.4 ( 10.2 ) 98.6 ( 13.4 ) -
    Clinical Global Impression of Severity (CGI-S) score
    CGI-S is a 7-point scale for assessing the global severity of the participant’s illness, with ratings from 1=normal, not ill to 7=very severely ill. Summary statistics presented are for efficacy population (FAS): N=100, 96 and 104 for placebo, asenapine 2.5 mg BID and asenapine 5.0 mg BID groups, respectively.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 4.6 ( 0.6 ) 4.6 ( 0.6 ) 4.7 ( 0.6 ) -
    PANSS positive subscale score
    The PANSS is a 30-item scale for assessing the symptoms of schizophrenia. For each PANSS item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS positive subscale score (7 PANSS items) ranged from 7 to 49 with a higher score indicating greater severity of symptoms. Summary statistics presented are for efficacy population (FAS): N=100, 96 and 104 for placebo, asenapine 2.5 mg BID and asenapine 5.0 mg BID groups, respectively.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 25.5 ( 3.8 ) 25.4 ( 4.2 ) 26.2 ( 4.5 ) -
    PANSS negative subscale score
    The PANSS is a 30-item scale for assessing the symptoms of schizophrenia. For each PANSS item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS negative subscale score (7 PANSS items) ranged from 7 to 49 with a higher score indicating greater severity of symptoms. Summary statistics presented are for efficacy population (FAS): N=100, 96 and 104 for placebo, asenapine 2.5 mg BID and asenapine 5.0 mg BID groups, respectively.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 25 ( 4.5 ) 24.9 ( 4.8 ) 24.5 ( 5.4 ) -
    PANSS positive and negative subscale scores combined
    The PANSS is a 30-item scale for assessing the symptoms of schizophrenia. For each PANSS item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS positive and negative subscale scores combined (14 PANSS items) ranged from 14 to 98 with a higher score indicating greater severity of symptoms. Summary statistics presented are for efficacy population (FAS): N=100, 96 and 104 for placebo, asenapine 2.5 mg BID and asenapine 5.0 mg BID groups, respectively.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 50.5 ( 5.7 ) 50.2 ( 5.9 ) 50.7 ( 7.3 ) -
    PANSS general psychopathology subscale score
    The PANSS is a 30-item scale for assessing the symptoms of schizophrenia. For each PANSS item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS general psychopathology subscale score (16 PANSS items) ranged from 16 to 112 with a higher score indicating greater severity of symptoms. Summary statistics presented are for efficacy population (FAS): N=100, 96 and 104 for placebo, asenapine 2.5 mg BID and asenapine 5.0 mg BID groups, respectively.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 47.1 ( 6.4 ) 47.2 ( 6 ) 47.9 ( 7.7 ) -
    PANSS Marder positive symptoms factor score
    The PANSS is a 30-item scale for assessing the symptoms of schizophrenia. For each PANSS item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS Marder positive symptoms factor score (calculated from value of 8 identified PANSS items) ranged from 8 to 56 with a higher score indicating greater severity of symptoms. Summary statistics presented are for efficacy population (FAS): N=100, 96 and 104 for placebo, asenapine 2.5 mg BID and asenapine 5.0 mg BID groups, respectively.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 28.4 ( 4 ) 28.7 ( 3.6 ) 28.9 ( 4.3 ) -
    PANSS Marder negative symptoms factor score
    The PANSS is a 30-item scale for assessing the symptoms of schizophrenia. For each PANSS item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS Marder negative symptoms factor score (calculated from value of 7 identified PANSS items) ranged from 7 to 49 with a higher score indicating greater severity of symptoms. Summary statistics presented are for efficacy population (FAS): N=100, 96 and 104 for placebo, asenapine 2.5 mg BID and asenapine 5.0 mg BID groups, respectively.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 24.2 ( 4.8 ) 23.9 ( 5.4 ) 23.8 ( 5.9 ) -
    PANSS Marder disorganized thoughts factor score
    The PANSS is a 30-item scale for assessing the symptoms of schizophrenia. For each PANSS item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS Marder disorganized thoughts factor score (calculated from value of 7 identified PANSS items) ranged from 7 to 49 with a higher score indicating greater severity of symptoms. Summary statistics presented are for efficacy population (FAS): N=100, 96 and 104 for placebo, asenapine 2.5 mg BID and asenapine 5.0 mg BID groups, respectively.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 22.4 ( 3.7 ) 22.3 ( 3.4 ) 22.5 ( 4.6 ) -
    PANSS Marder hostility/excitement factor score
    The PANSS is a 30-item scale for assessing the symptoms of schizophrenia. For each PANSS item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS Marder hostility/excitement factor score (calculated from value of 4 identified PANSS items) ranged from 4 to 28 with a higher score indicating greater severity of symptoms. Summary statistics presented are for efficacy population (FAS): N=100, 96 and 104 for placebo, asenapine 2.5 mg BID and asenapine 5.0 mg BID groups, respectively.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 12.9 ( 3.5 ) 12.8 ( 3.6 ) 13.1 ( 4.3 ) -
    PANSS Marder anxiety/depression factor score
    The PANSS is a 30-item scale for assessing the symptoms of schizophrenia. For each PANSS item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS Marder anxiety/depression factor score (calculated from value of 4 identified PANSS items) ranged from 4 to 28 with a higher score indicating greater severity of symptoms. Summary statistics presented are for efficacy population (FAS): N=100, 96 and 104 for placebo, asenapine 2.5 mg BID and asenapine 5.0 mg BID groups, respectively.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 9.6 ( 3.1 ) 9.8 ( 3.1 ) 10.3 ( 3.1 ) -
    Children’s Global Assessment Scale (CGAS) score - current functioning
    CGAS is a 100-point scale measuring psychological, social, and school functioning in children aged 6-17. Minimum scores ranged from 1-10, representing the need for constant supervision (worse result) to maximum scores of 91-100, representing superior functioning (better result). Summary statistics presented are for efficacy population (FAS) except as noted: N=99 (baseline value not available for 1 FAS participant in this group), 96 and 104 for placebo, asenapine 2.5 mg BID and asenapine 5.0 mg BID groups, respectively.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 43 ( 8.4 ) 41.6 ( 9.1 ) 42.9 ( 8.5 ) -
    Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) total score
    PQ-LES-Q is a questionnaire to assess quality of life enjoyment and satisfaction in children and adolescents. The participant is asked to rate 15 items reflecting quality of life with respect to the previous week on a scale of 1=very poor to 5=very good. The PQ-LES-Q total score (sum of Items 1-14) for each participant ranged from 14 to 70 with a higher score indicating better quality of life. Summary statistics presented are for efficacy population (FAS): N=100, 96 and 104 for placebo, asenapine 2.5 mg BID and asenapine 5.0 mg BID groups, respectively.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 41.6 ( 10.7 ) 41.2 ( 10 ) 40.7 ( 9.5 ) -
    PQ-LES-Q overall score
    PQ-LES-Q is a questionnaire to assess quality of life enjoyment and satisfaction in children and adolescents. The participant is asked to rate 15 items reflecting quality of life with respect to the previous week on a scale of 1=very poor to 5=very good. The PQ-LES-Q overall score (Item 15, a global assessment of quality of life) ranged from 1 to 5 with a higher score indicating better quality of life. Summary statistics presented are for efficacy population (FAS): N=100, 96 and 104 for placebo, asenapine 2.5 mg BID and asenapine 5.0 mg BID groups, respectively.
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 3.1 ( 1 ) 3.1 ( 0.9 ) 3 ( 1 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants receive placebo asenapine tablets sublingually BID for 8 weeks

    Reporting group title
    Asenapine 2.5 mg BID
    Reporting group description
    		 Participants receive active asenapine 2.5 mg tablets sublingually BID for 8 weeks

    Reporting group title
    Asenapine 5.0 mg BID
    Reporting group description
    		 Participants receive active asenapine 2.5 mg tablets sublingually BID through Day 3. On Day 4 participants receive asenapine 2.5 mg in the morning and 5.0 mg in the evening. Participants receive active asenapine 5.0 mg tablets sublingually BID for the remainder of the 8-week treatment period

    Primary: Change From Baseline in PANSS Total Score at Day 56

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    End point title
    		 Change From Baseline in PANSS Total Score at Day 56
    End point description
    The PANSS is a 30-item clinician-rated instrument for assessing schizophrenia symptoms. It consists of 3 subscales: positive subscale (7 items), negative subscale (7 items), and general psychopathology subscale (16 items). For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS total score for each participant was sum of the rating assigned to each of the 30 PANSS items, and ranged from 30 to 210 with a higher score indicating greater severity of symptoms. The reported measure is the change from baseline at Day 56; improvement in symptoms is represented by negative values. Population for analysis was randomized participants who received ≥1 dose of study drug and had both a baseline and ≥1 post-baseline on-treatment PANSS Total Score (this group is termed the efficacy FAS); also, to be included an on-treatment Day 56 value of PANSS Total Score must be available for a participant.
    End point type
    Primary
    End point timeframe
    Baseline and Day 56
    End point values
    		 Placebo Asenapine 2.5 mg BID Asenapine 5.0 mg BID
    Number of subjects analysed
    77
    72
    79
    Units: score on a scale
        arithmetic mean (standard deviation)
    -17.8 ( 17.8 )
    -23.7 ( 18.6 )
    -25.5 ( 16.9 )
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Number of participants for calculation of reported mean ± standard deviation (SD) change from baseline is 77 for placebo and 72 for asenapine 2.5 mg (total – 149). Mixed model for repeated measures (MMRM) analysis uses FAS population (Number of participants: placebo – 100, asenapine 2.5 mg – 96, asenapine 5.0 mg – 104). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.
    Comparison groups
    Asenapine 2.5 mg BID v Placebo
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.07 [1]
    Method
    		 MMRM
    Parameter type
    		 Difference in Least Squares (LS) Means
    Point estimate
    -4.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.9
         upper limit
    		 0.4
    Notes
    [1] - p-value is adjusted by Hochberg's method for testing two asenapine groups versus the placebo group.
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Number of participants for calculation of reported mean ± SD change from baseline is 77 for placebo and 79 for asenapine 5.0 mg (total – 156). MMRM analysis uses FAS population (Number of participants: placebo – 100, asenapine 2.5 mg – 96, asenapine 5.0 mg – 104). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.
    Comparison groups
    Asenapine 5.0 mg BID v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.064 [2]
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    -5.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.7
         upper limit
    		 -0.5
    Notes
    [2] - p-value is adjusted by Hochberg's method for testing two asenapine groups versus the placebo group.
    Statistical analysis title
    		 Analysis of Dose-response: Linear Pattern
    Statistical analysis description
    Investigation of dose-response relationship of change from baseline to Day 56 in PANSS Total Score was a Secondary study endpoint. Number of participants for calculation of reported mean ± SD changes from baseline is 228 (total for 3 groups). Multiple contrast testing using MMRM model (based on FAS population, total N = 300) was used to evaluate 3 pre-defined dose-response patterns (Linear, Convex, Concave).
    Comparison groups
    Placebo v Asenapine 2.5 mg BID v Asenapine 5.0 mg BID
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.064 [3]
    Method
    		 MMRM
    Confidence interval
    Notes
    [3] - p-value (adjusted to control Type I error in multiple testing) for Linear dose-response pattern (Placebo<2.5 mg<5.0 mg)
    Statistical analysis title
    		 Analysis of Dose-response: Convex Pattern
    Statistical analysis description
    Investigation of dose-response relationship of change from baseline to Day 56 in PANSS Total Score was a Secondary study endpoint. Number of participants for calculation of reported mean ± SD changes from baseline is 228 (total for 3 groups). Multiple contrast testing using MMRM model (based on FAS population, total N = 300) was used to evaluate 3 pre-defined dose-response patterns (Linear, Convex, Concave).
    Comparison groups
    Placebo v Asenapine 2.5 mg BID v Asenapine 5.0 mg BID
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.046 [4]
    Method
    		 MMRM
    Confidence interval
    Notes
    [4] - p-value (adjusted to control Type I error in multiple testing) for Convex dose-response pattern (Placebo<2.5 mg=5.0 mg)
    Statistical analysis title
    		 Analysis of Dose-response: Concave Pattern
    Statistical analysis description
    Investigation of dose-response relationship of change from baseline to Day 56 in PANSS Total Score was a Secondary study endpoint. Number of participants for calculation of reported mean ± SD changes from baseline is 228 (total for 3 groups). Multiple contrast testing using MMRM model (based on FAS population, total N = 300) was used to evaluate 3 pre-defined dose-response patterns (Linear, Convex, Concave).
    Comparison groups
    Placebo v Asenapine 2.5 mg BID v Asenapine 5.0 mg BID
    Number of subjects included in analysis
    228
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.273 [5]
    Method
    		 MMRM
    Confidence interval
    Notes
    [5] - p-value (adjusted to control Type I error in multiple testing) for Concave dose-response pattern (Placebo=2.5 mg<5.0 mg)

    Secondary: Change From Baseline in Clinical Global Impression of Severity (CGI-S) Score at Day 56

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    End point title
    		 Change From Baseline in Clinical Global Impression of Severity (CGI-S) Score at Day 56
    End point description
    Change from baseline in CGI-S score at Day 56 is the Key Secondary Outcome Measure. CGI-S is a 7-point scale for assessing the global severity of the participant’s illness, with ratings from 1=normal, not ill to 7=very severely ill. The reported measure is the change from baseline at Day 56; improvement in symptoms is represented by negative values. Population for analysis was randomized participants who received ≥1 dose of study drug and had both a baseline and ≥1 post-baseline on-treatment PANSS Total Score (this group is termed the efficacy FAS); also, to be included a baseline and an on-treatment Day 56 value of the CGI-S score must be available for a participant.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 56
    End point values
    		 Placebo Asenapine 2.5 mg BID Asenapine 5.0 mg BID
    Number of subjects analysed
    76
    72
    79
    Units: score on a scale
        arithmetic mean (standard deviation)
    -0.8 ( 1.1 )
    -1.1 ( 1 )
    -1.3 ( 1 )
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Number of participants for calculation of reported mean ± SD change from baseline is 76 for placebo and 72 for asenapine 2.5 mg (total – 148). MMRM analysis uses FAS population (Number of participants: placebo – 100, asenapine 2.5 mg – 96, asenapine 5.0 mg – 104). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.
    Comparison groups
    Asenapine 2.5 mg BID v Placebo
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.218 [6]
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.5
         upper limit
    		 0.1
    Notes
    [6] - Confirmative testing for key secondary endpoint was to be performed only if both asenapine doses were superior to placebo in change from baseline in PANSS total score at Day 56. If this did not occur, multiplicity unadjusted p-values are provided.
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Number of participants for calculation of reported mean ± SD change from baseline is 76 for placebo and 79 for asenapine 5.0 mg (total – 155). MMRM analysis uses FAS population (Number of participants: placebo – 100, asenapine 2.5 mg – 96, asenapine 5.0 mg – 104). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.
    Comparison groups
    Asenapine 5.0 mg BID v Placebo
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.024 [7]
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 0
    Notes
    [7] - Confirmative testing for key secondary endpoint was to be performed only if both asenapine doses were superior to placebo in change from baseline in PANSS total score at Day 56. If this did not occur, multiplicity unadjusted p-values are provided.

    Secondary: Change From Baseline in PANSS Positive Subscale Score at Day 56

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    End point title
    		 Change From Baseline in PANSS Positive Subscale Score at Day 56
    End point description
    This measure reports results for the 7 items of the positive subscale of the PANSS, which is a 30-item clinician-rated instrument used to assess schizophrenia symptoms. Positive symptoms refer to an excess or distortion of normal mental status (e.g., delusions). For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. PANSS positive subscale score for each participant was sum of the rating assigned to each of the 7 subscale items, and ranged from 7 to 49 with a higher score indicating greater severity of symptoms. Measure reports change from baseline; improvement in symptoms is represented by negative values. Population for analysis was randomized participants who received ≥1 dose of study drug and had both baseline and ≥1 post-baseline on-treatment PANSS Total Score (this group is termed the efficacy FAS); also, to be included baseline and an on-treatment Day 56 value of PANSS positive subscale score must be available for a participant.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 56
    End point values
    		 Placebo Asenapine 2.5 mg BID Asenapine 5.0 mg BID
    Number of subjects analysed
    77
    72
    79
    Units: score on a scale
        arithmetic mean (standard deviation)
    -6 ( 6.1 )
    -7.9 ( 5.8 )
    -9.1 ( 5.6 )
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Number of participants for calculation of reported mean ± SD change from baseline is 77 for placebo and 72 for asenapine 2.5 mg (total – 149). MMRM analysis uses FAS population (Number of participants: placebo – 100, asenapine 2.5 mg – 96, asenapine 5.0 mg – 104). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.
    Comparison groups
    Asenapine 2.5 mg BID v Placebo
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.067
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.3
         upper limit
    		 0.1
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Number of participants for calculation of reported mean ± SD change from baseline is 77 for placebo and 79 for asenapine 5.0 mg (total – 156). MMRM analysis uses FAS population (Number of participants: placebo – 100, asenapine 2.5 mg – 96, asenapine 5.0 mg – 104). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.
    Comparison groups
    Asenapine 5.0 mg BID v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.012
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    -2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.8
         upper limit
    		 -0.5

    Secondary: Change From Baseline in PANSS Negative Subscale Score at Day 56

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    End point title
    		 Change From Baseline in PANSS Negative Subscale Score at Day 56
    End point description
    This measure reports results for the 7 items of the negative subscale of the PANSS, which is a 30-item clinician-rated instrument used to assess schizophrenia symptoms. Negative symptoms represent a diminution or loss of normal functions (e.g., emotional withdrawal). For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. PANSS negative subscale score for each participant was sum of the rating assigned to each of the 7 subscale items, and ranged from 7 to 49 with a higher score indicating greater severity of symptoms. Measure reports change from baseline; improvement in symptoms is represented by negative values. Population for analysis was randomized participants who received ≥1 dose of study drug and had both a baseline and ≥1 post-baseline on-treatment PANSS Total Score (this group is termed the efficacy FAS); also, to be included baseline and an on-treatment Day 56 value of PANSS negative subscale score must be available for a participant.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 56
    End point values
    		 Placebo Asenapine 2.5 mg BID Asenapine 5.0 mg BID
    Number of subjects analysed
    77
    72
    79
    Units: score on a scale
        arithmetic mean (standard deviation)
    -3.4 ( 5.2 )
    -4.8 ( 5.6 )
    -4.9 ( 4.5 )
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Number of participants for calculation of reported mean ± SD change from baseline is 77 for placebo and 72 for asenapine 2.5 mg (total – 149). MMRM analysis uses FAS population (Number of participants: placebo – 100, asenapine 2.5 mg – 96, asenapine 5.0 mg – 104). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.
    Comparison groups
    Asenapine 2.5 mg BID v Placebo
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.097
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 0.2
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Number of participants for calculation of reported mean ± SD change from baseline is 77 for placebo and 79 for asenapine 5.0 mg (total – 156). MMRM analysis uses FAS population (Number of participants: placebo – 100, asenapine 2.5 mg – 96, asenapine 5.0 mg – 104). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.
    Comparison groups
    Asenapine 5.0 mg BID v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.099
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 0.2

    Secondary: Change From Baseline in PANSS Positive and Negative Subscale Scores Combined at Day 56

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    End point title
    		 Change From Baseline in PANSS Positive and Negative Subscale Scores Combined at Day 56
    End point description
    This measure reports results for combined positive (7 items) and negative (7 items) subscales of the PANSS, which is a 30-item clinician-rated instrument used to assess schizophrenia symptoms. For each of the total 14 items in the combined positive and negative subscales, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS positive and negative subscale scores combined for each participant was sum of rating assigned to the 14 subscale items, and ranged from 14 to 98 with a higher score indicating greater severity of symptoms. Measure reports change from baseline; improvement in symptoms is represented by negative values. Population for analysis was randomized participants who received ≥1 dose of study drug and had both a baseline and ≥1 post-baseline on-treatment PANSS Total Score (efficacy FAS); also, to be included a baseline and an on-treatment Day 56 value of PANSS positive/negative subscale scores combined must be available for a participant.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 56
    End point values
    		 Placebo Asenapine 2.5 mg BID Asenapine 5.0 mg BID
    Number of subjects analysed
    77
    72
    79
    Units: score on a scale
        arithmetic mean (standard deviation)
    -9.4 ( 10.1 )
    -12.7 ( 10.2 )
    -14 ( 8.8 )
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Number of participants for calculation of reported mean ± SD change from baseline is 77 for placebo and 72 for asenapine 2.5 mg (total – 149). MMRM analysis uses FAS population (Number of participants: placebo – 100, asenapine 2.5 mg – 96, asenapine 5.0 mg – 104). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.
    Comparison groups
    Asenapine 2.5 mg BID v Placebo
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.062
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    -2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.6
         upper limit
    		 0.1
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Number of participants for calculation of reported mean ± SD change from baseline is 77 for placebo and 79 for asenapine 5.0 mg (total – 156). MMRM analysis uses FAS population (Number of participants: placebo – 100, asenapine 2.5 mg – 96, asenapine 5.0 mg – 104). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.
    Comparison groups
    Asenapine 5.0 mg BID v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.025
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    -3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6
         upper limit
    		 -0.4

    Secondary: Change From Baseline in PANSS General Psychopathology Subscale Score at Day 56

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    End point title
    		 Change From Baseline in PANSS General Psychopathology Subscale Score at Day 56
    End point description
    This measure reports results for the 16 items of the general psychopathology subscale of the PANSS, which is a 30-item clinician-rated instrument used to assess the symptoms of schizophrenia. For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS general psychopathology subscale score for each participant was calculated as the sum of the rating assigned to each of the 16 subscale items, and ranged from 16 to 112 with a higher score indicating greater severity of symptoms. The reported measure is the change from baseline at Day 56; improvement in symptoms is represented by negative values. Population for analysis was randomized participants who received ≥1 dose of study drug and had both a baseline and ≥1 post-baseline on-treatment PANSS Total Score (this group is termed the efficacy FAS); also, to be included a baseline and an on-treatment Day 56 value of the PANSS general psychopathology subscale score must be available for a participant.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 56
    End point values
    		 Placebo Asenapine 2.5 mg BID Asenapine 5.0 mg BID
    Number of subjects analysed
    77
    72
    79
    Units: score on a scale
        arithmetic mean (standard deviation)
    -8.5 ( 8.6 )
    -10.9 ( 9.5 )
    -11.5 ( 8.9 )
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Number of participants for calculation of reported mean ± SD change from baseline is 77 for placebo and 72 for asenapine 2.5 mg (total – 149). MMRM analysis uses FAS population (Number of participants: placebo – 100, asenapine 2.5 mg – 96, asenapine 5.0 mg – 104). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.
    Comparison groups
    Asenapine 2.5 mg BID v Placebo
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.098
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    -2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.6
         upper limit
    		 0.4
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Number of participants for calculation of reported mean ± SD change from baseline is 77 for placebo and 79 for asenapine 5.0 mg (total – 156). MMRM analysis uses FAS population (Number of participants: placebo – 100, asenapine 2.5 mg – 96, asenapine 5.0 mg – 104). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.
    Comparison groups
    Asenapine 5.0 mg BID v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.071
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    -2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.8
         upper limit
    		 0.2

    Secondary: Change From Baseline in PANSS Marder Positive Symptoms Factor Score at Day 56

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    End point title
    		 Change From Baseline in PANSS Marder Positive Symptoms Factor Score at Day 56
    End point description
    This measure reports results for the 8 items of the Marder positive symptoms factor of the PANSS, which is a 30-item clinician-rated instrument used to assess schizophrenia symptoms. Marder factors are a modified grouping of the 30 PANSS items. For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. PANSS Marder positive symptoms factor score for each participant was sum of rating assigned to each of the 8 applicable Marder factor items, and ranged from 8 to 56 with a higher score indicating greater severity of symptoms. Measure reports change from baseline; improvement in symptoms is represented by negative values. Population for analysis was randomized participants who received ≥1 dose of study drug and had both baseline and ≥1 post-baseline on-treatment PANSS Total Score (efficacy FAS); also, to be included baseline and an on-treatment Day 56 value of the PANSS Marder positive symptoms factor score must be available for a participant.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 56
    End point values
    		 Placebo Asenapine 2.5 mg BID Asenapine 5.0 mg BID
    Number of subjects analysed
    77
    72
    79
    Units: score on a scale
        arithmetic mean (standard deviation)
    -6.1 ( 6.1 )
    -7.9 ( 6.1 )
    -8.9 ( 5.5 )
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Number of participants for calculation of reported mean ± SD change from baseline is 77 for placebo and 72 for asenapine 2.5 mg (total – 149). MMRM analysis uses FAS population (Number of participants: placebo – 100, asenapine 2.5 mg – 96, asenapine 5.0 mg – 104). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.
    Comparison groups
    Asenapine 2.5 mg BID v Placebo
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.106
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.1
         upper limit
    		 0.3
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Number of participants for calculation of reported mean ± SD change from baseline is 77 for placebo and 79 for asenapine 5.0 mg (total – 156). MMRM analysis uses FAS population (Number of participants: placebo – 100, asenapine 2.5 mg – 96, asenapine 5.0 mg – 104). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.
    Comparison groups
    Asenapine 5.0 mg BID v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.026
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.6
         upper limit
    		 -0.2

    Secondary: Change From Baseline in PANSS Marder Negative Symptoms Factor Score at Day 56

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    End point title
    		 Change From Baseline in PANSS Marder Negative Symptoms Factor Score at Day 56
    End point description
    This measure reports results for the 7 items of the Marder negative symptoms factor of the PANSS, which is a 30-item clinician-rated instrument used to assess schizophrenia symptoms. Marder factors are a modified grouping of the 30 PANSS items. For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. PANSS Marder negative symptoms factor score for each participant was sum of the rating assigned to each of the 7 applicable Marder factor items, and ranged from 7 to 49 with a higher score indicating greater severity of symptoms. Measure reports change from baseline; improvement in symptoms is represented by negative values. Population for analysis was randomized participants who received ≥1 dose of study drug and had both baseline and ≥1 post-baseline on-treatment PANSS Total Score (efficacy FAS); also, to be included baseline and an on-treatment Day 56 value of the PANSS Marder negative symptoms factor score must be available for a participant.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 56
    End point values
    		 Placebo Asenapine 2.5 mg BID Asenapine 5.0 mg BID
    Number of subjects analysed
    77
    72
    79
    Units: score on a scale
        arithmetic mean (standard deviation)
    -3.7 ( 5.3 )
    -5.2 ( 5.5 )
    -5.3 ( 4.5 )
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Number of participants for calculation of reported mean ± SD change from baseline is 77 for placebo and 72 for asenapine 2.5 mg (total – 149). MMRM analysis uses FAS population (Number of participants: placebo – 100, asenapine 2.5 mg – 96, asenapine 5.0 mg – 104). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.
    Comparison groups
    Asenapine 2.5 mg BID v Placebo
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.083
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.6
         upper limit
    		 0.2
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Number of participants for calculation of reported mean ± SD change from baseline is 77 for placebo and 79 for asenapine 5.0 mg (total – 156). MMRM analysis uses FAS population (Number of participants: placebo – 100, asenapine 2.5 mg – 96, asenapine 5.0 mg – 104). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.
    Comparison groups
    Asenapine 5.0 mg BID v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.067
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.7
         upper limit
    		 0.1

    Secondary: Change From Baseline in PANSS Marder Disorganized Thoughts Factor Score at Day 56

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    End point title
    		 Change From Baseline in PANSS Marder Disorganized Thoughts Factor Score at Day 56
    End point description
    This measure reports results for the 7 items of the Marder disorganized thoughts factor of the PANSS, which is a 30-item clinician-rated instrument used to assess schizophrenia symptoms. Marder factors are a modified grouping of the 30 PANSS items. For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. PANSS Marder disorganized thoughts factor score for each participant was sum of rating assigned to each of the 7 applicable Marder factor items, and ranged from 7 to 49 with a higher score indicating greater severity of symptoms. Measure is change from baseline; improvement in symptoms is represented by negative values. Population for analysis was randomized participants who received ≥1 dose of study drug and had both baseline and ≥1 post-baseline on-treatment PANSS Total Score (efficacy FAS); also, to be included baseline and an on-treatment Day 56 value of PANSS Marder disorganized thoughts factor score must be available for a participant.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 56
    End point values
    		 Placebo Asenapine 2.5 mg BID Asenapine 5.0 mg BID
    Number of subjects analysed
    77
    72
    79
    Units: score on a scale
        arithmetic mean (standard deviation)
    -3.4 ( 4.1 )
    -4.3 ( 4.3 )
    -4.8 ( 4.3 )
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Number of participants for calculation of reported mean ± SD change from baseline is 77 for placebo and 72 for asenapine 2.5 mg (total – 149). MMRM analysis uses FAS population (Number of participants: placebo – 100, asenapine 2.5 mg – 96, asenapine 5.0 mg – 104). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.
    Comparison groups
    Asenapine 2.5 mg BID v Placebo
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.131
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 0.3
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Number of participants for calculation of reported mean ± SD change from baseline is 77 for placebo and 79 for asenapine 5.0 mg (total – 156). MMRM analysis uses FAS population (Number of participants: placebo – 100, asenapine 2.5 mg – 96, asenapine 5.0 mg – 104). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.
    Comparison groups
    Asenapine 5.0 mg BID v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.135
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.1
         upper limit
    		 0.3

    Secondary: Change From Baseline in PANSS Marder Hostility/Excitement Factor Score at Day 56

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    End point title
    		 Change From Baseline in PANSS Marder Hostility/Excitement Factor Score at Day 56
    End point description
    This measure reports results for the 4 items of the Marder hostility/excitement factor of the PANSS, which is a 30-item clinician-rated instrument used to assess schizophrenia symptoms. Marder factors are a modified grouping of the 30 PANSS items. For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. PANSS Marder hostility/excitement factor score for each participant was sum of rating assigned to each of the 4 applicable Marder factor items, and ranged from 4 to 28 with a higher score indicating greater severity of symptoms. Measure is change from baseline; improvement in symptoms is represented by negative values. Population for analysis was randomized participants who received ≥1 dose of study drug and had both baseline and ≥1 post-baseline on-treatment PANSS Total Score (efficacy FAS); also, to be included baseline and an on-treatment Day 56 value of PANSS Marder hostility/excitement factor score must be available for a participant.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 56
    End point values
    		 Placebo Asenapine 2.5 mg BID Asenapine 5.0 mg BID
    Number of subjects analysed
    77
    72
    79
    Units: score on a scale
        arithmetic mean (standard deviation)
    -2.8 ( 4 )
    -3.8 ( 3.6 )
    -3.8 ( 4.3 )
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Number of participants for calculation of reported mean ± SD change from baseline is 77 for placebo and 72 for asenapine 2.5 mg (total – 149). MMRM analysis uses FAS population (Number of participants: placebo – 100, asenapine 2.5 mg – 96, asenapine 5.0 mg – 104). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.
    Comparison groups
    Asenapine 2.5 mg BID v Placebo
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.071
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 0.1
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Number of participants for calculation of reported mean ± SD change from baseline is 77 for placebo and 79 for asenapine 5.0 mg (total – 156). MMRM analysis uses FAS population (Number of participants: placebo – 100, asenapine 2.5 mg – 96, asenapine 5.0 mg – 104). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.
    Comparison groups
    Asenapine 5.0 mg BID v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.12
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.9
         upper limit
    		 0.2

    Secondary: Change From Baseline in PANSS Marder Anxiety/Depression Factor Score at Day 56

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    End point title
    		 Change From Baseline in PANSS Marder Anxiety/Depression Factor Score at Day 56
    End point description
    This measure reports results for the 4 items of the Marder anxiety/depression factor of the PANSS, which is a 30-item clinician-rated instrument used to assess schizophrenia symptoms. Marder factors are a modified grouping of the 30 PANSS items. For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. PANSS Marder anxiety/depression factor score for each participant was sum of rating assigned to each of the 4 applicable Marder factor items, and ranged from 4 to 28 with a higher score indicating greater severity of symptoms. Measure is change from baseline; improvement in symptoms is represented by negative values. Population for analysis was randomized participants who received ≥1 dose of study drug and had both baseline and ≥1 post-baseline on-treatment PANSS Total Score (efficacy FAS); also, to be included baseline and an on-treatment Day 56 value of the PANSS Marder anxiety/depression factor score must be available for a participant.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 56
    End point values
    		 Placebo Asenapine 2.5 mg BID Asenapine 5.0 mg BID
    Number of subjects analysed
    77
    72
    79
    Units: score on a scale
        arithmetic mean (standard deviation)
    -1.8 ( 2.4 )
    -2.4 ( 2.9 )
    -2.7 ( 2.9 )
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Number of participants for calculation of reported mean ± SD change from baseline is 77 for placebo and 72 for asenapine 2.5 mg (total – 149). MMRM analysis uses FAS population (Number of participants: placebo – 100, asenapine 2.5 mg – 96, asenapine 5.0 mg – 104). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.
    Comparison groups
    Asenapine 2.5 mg BID v Placebo
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.263
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 0.3
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Number of participants for calculation of reported mean ± SD change from baseline is 77 for placebo and 79 for asenapine 5.0 mg (total – 156). MMRM analysis uses FAS population (Number of participants: placebo – 100, asenapine 2.5 mg – 96, asenapine 5.0 mg – 104). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.
    Comparison groups
    Asenapine 5.0 mg BID v Placebo
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.146
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 0.2

    Secondary: Total PANSS 30% Responders

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    End point title
    		 Total PANSS 30% Responders
    End point description
    A Total PANSS 30% responder was defined as a participant who had a reduction from baseline of at least 30% in the PANSS Total score at the last available assessment of the study for that participant (i.e., endpoint). The PANSS is a 30-item clinician-rated instrument for assessing schizophrenia symptoms. For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The Total score is the sum of the ratings for the individual items, and ranged from 30 to 210 with a higher score indicating greater severity of symptoms. Population for analysis was randomized participants who received ≥1 dose of study drug and had both baseline and ≥1 post-baseline on-treatment PANSS Total Score (this group is termed the efficacy FAS).
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 56
    End point values
    		 Placebo Asenapine 2.5 mg BID Asenapine 5.0 mg BID
    Number of subjects analysed
    100
    96
    104
    Units: participants
    36
    48
    51
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Model included terms of (pooled) site, treatment, and baseline PANSS Total Score. Odds ratio (OR) was adjusted for baseline and (pooled) site. An OR of >1 is considered to mean that asenapine has a higher probability of achieving Total PANSS 30% response.
    Comparison groups
    Asenapine 2.5 mg BID v Placebo
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.028 [8]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.1
         upper limit
    		 3.6
    Notes
    [8] - p-value and 95% Confidence Interval are based on Wald statistic
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Model included terms of (pooled) site, treatment, and baseline PANSS Total Score. OR was adjusted for baseline and (pooled) site. An OR of >1 is considered to mean that asenapine has a higher probability of achieving Total PANSS 30% response.
    Comparison groups
    Asenapine 5.0 mg BID v Placebo
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.048 [9]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 3.3
    Notes
    [9] - p-value and 95% Confidence Interval are based on Wald statistic

    Secondary: Kaplan-Meier Estimate of Cumulative Percentage of Participants With Total PANSS 30% Response at End of Study

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    End point title
    		 Kaplan-Meier Estimate of Cumulative Percentage of Participants With Total PANSS 30% Response at End of Study
    End point description
    A total PANSS 30% response was defined as a reduction from baseline of at least 30% in the PANSS Total score. The PANSS is a 30-item clinician-rated instrument for assessing schizophrenia symptoms. For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The Total score is the sum of the ratings for the individual items, and ranged from 30 to 210 with a higher score indicating greater severity of symptoms. The Kaplan-Meier estimate reports the cumulative percentage of participants with total PANSS 30% response from first drug intake up to approximately Day 59. Population for analysis was randomized participants who received ≥1 dose of study drug and had both baseline and ≥1 post-baseline on-treatment PANSS Total Score (this group is termed the efficacy FAS).
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately Day 59
    End point values
    		 Placebo Asenapine 2.5 mg BID Asenapine 5.0 mg BID
    Number of subjects analysed
    100
    96
    104
    Units: cumulative % of participants w/ Response
        number (not applicable)
    62
    64.2
    72.1
    Statistical analysis title
    		 Test of Difference in Time to Event Curves
    Comparison groups
    Placebo v Asenapine 2.5 mg BID v Asenapine 5.0 mg BID
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.576 [10]
    Method
    		 Logrank
    Confidence interval
    Notes
    [10] - p-value is for Log Rank test of difference in time to event (PANSS 30% response) curves between the three treatment groups
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Model included factors for (pooled) site, treatment and baseline PANSS Total Score. A Hazard ratio (HR) of >1 is considered to mean that asenapine has a higher likelihood of being a Total PANSS 30% Responder than placebo.
    Comparison groups
    Asenapine 2.5 mg BID v Placebo
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.171
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 2
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Model included factors for (pooled) site, treatment and baseline PANSS Total Score. A Hazard ratio (HR) of >1 is considered to mean that asenapine has a higher likelihood of being a Total PANSS 30% Responder than placebo.
    Comparison groups
    Asenapine 5.0 mg BID v Placebo
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.368
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.8

    Secondary: Clinical Global Impression of Improvement (CGI-I) Score at Day 56

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    End point title
    		 Clinical Global Impression of Improvement (CGI-I) Score at Day 56
    End point description
    CGI-I is a 7-point scale for assessing the global improvement of the participant’s illness relative to baseline, with ratings from 1=very much improved to 7=very much worse. Population for analysis was randomized participants who received ≥1 dose of study drug and had both baseline and ≥1 post-baseline on-treatment PANSS Total Score (this group is termed the efficacy FAS); also, to be included an on-treatment Day 56 value of the CGI-I score must be available for a participant.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 56
    End point values
    		 Placebo Asenapine 2.5 mg BID Asenapine 5.0 mg BID
    Number of subjects analysed
    76
    72
    79
    Units: score on a scale
        arithmetic mean (standard deviation)
    3.1 ( 1.1 )
    2.8 ( 1.1 )
    2.5 ( 1 )
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Number of participants for calculation of reported mean ± SD change from baseline is 76 for placebo and 72 for asenapine 2.5 mg (total – 148). MMRM analysis uses FAS population (Number of participants: placebo – 100, asenapine 2.5 mg – 96, asenapine 5.0 mg – 104). Model includes terms of (pooled) site, treatment, visit and the interaction of visit by treatment.
    Comparison groups
    Asenapine 2.5 mg BID v Placebo
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.094
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 0
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Number of participants for calculation of reported mean ± SD change from baseline is 76 for placebo and 79 for asenapine 5.0 mg (total – 155). MMRM analysis uses FAS population (Number of participants: placebo – 100, asenapine 2.5 mg – 96, asenapine 5.0 mg – 104). Model includes terms of (pooled) site, treatment, visit and the interaction of visit by treatment.
    Comparison groups
    Asenapine 5.0 mg BID v Placebo
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.003
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 -0.2

    Secondary: CGI-I Responders

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    End point title
    		 CGI-I Responders
    End point description
    A CGI-I responder was defined as a participant who had a CGI-I score of 1 (very much improved) or 2 (much improved) at the last available assessment of the study for that participant (i.e., endpoint). CGI-I is a 7-point scale for assessing the global improvement of the participant’s illness relative to baseline, with ratings from 1=very much improved to 7=very much worse. Population for analysis was randomized participants who received ≥1 dose of study drug and had both baseline and ≥1 post-baseline on-treatment PANSS Total Score (this group is termed the efficacy FAS).
    End point type
    Secondary
    End point timeframe
    Baseline up to Day 56
    End point values
    		 Placebo Asenapine 2.5 mg BID Asenapine 5.0 mg BID
    Number of subjects analysed
    100
    96
    104
    Units: participants
    28
    36
    41
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Model included terms of region (Asia-Pacific, North America, Eastern Europe [Africa/Latin America sites assigned to this region]) and treatment. OR was adjusted for region. An OR of >1 is considered to mean that asenapine has a higher probability of achieving CGI-I response.
    Comparison groups
    Asenapine 2.5 mg BID v Placebo
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.177 [11]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 2.8
    Notes
    [11] - p-value and 95% Confidence Interval are based on Wald statistic
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Model included terms of region (Asia-Pacific, North America, Eastern Europe [Africa/Latin America sites assigned to this region]) and treatment. OR was adjusted for region. An OR of >1 is considered to mean that asenapine has a higher probability of achieving CGI-I response.
    Comparison groups
    Asenapine 5.0 mg BID v Placebo
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.114 [12]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 2.9
    Notes
    [12] - p-value and 95% Confidence Interval are based on Wald statistic

    Secondary: Kaplan-Meier Estimate of Cumulative Percentage of Participants With CGI-I Response at End of Study

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    End point title
    		 Kaplan-Meier Estimate of Cumulative Percentage of Participants With CGI-I Response at End of Study
    End point description
    CGI-I response was defined as the occurrence of a CGI-I score of 1 (very much improved) or 2 (much improved). CGI-I is a 7-point scale for assessing the global improvement of the participant’s illness relative to baseline, with ratings from 1=very much improved to 7=very much worse. The Kaplan-Meier estimate reports the cumulative percentage of participants with CGI-I response from first drug intake up to approximately Day 58. Population for analysis was randomized participants who received ≥1 dose of study drug and had both baseline and ≥1 post-baseline on-treatment PANSS Total Score (this group is termed the efficacy FAS).
    End point type
    Secondary
    End point timeframe
    Baseline up to approximately Day 58
    End point values
    		 Placebo Asenapine 2.5 mg BID Asenapine 5.0 mg BID
    Number of subjects analysed
    100
    96
    104
    Units: cumulative % of participants w/ Response
        number (not applicable)
    54.7
    47.1
    60.1
    Statistical analysis title
    		 Test of Difference in Time to Event Curves
    Comparison groups
    Placebo v Asenapine 2.5 mg BID v Asenapine 5.0 mg BID
    Number of subjects included in analysis
    300
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.057 [13]
    Method
    		 Logrank
    Confidence interval
    Notes
    [13] - p-value is for Log Rank test of difference in time to event (CGI-I response) curves between the three treatment groups
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Model included factors for (pooled) site and treatment. An HR of >1 is considered to mean that asenapine has a higher likelihood of being a CGI-I Responder than placebo.
    Comparison groups
    Asenapine 2.5 mg BID v Placebo
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.135
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 2.3
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Model included factors for (pooled) site and treatment. An HR of >1 is considered to mean that asenapine has a higher likelihood of being a CGI-I Responder than placebo.
    Comparison groups
    Asenapine 5.0 mg BID v Placebo
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.01
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.2
         upper limit
    		 2.9

    Secondary: Change From Baseline in Children’s Global Assessment Scale (CGAS) Score at Day 56

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    End point title
    		 Change From Baseline in Children’s Global Assessment Scale (CGAS) Score at Day 56
    End point description
    CGAS is a 100-point scale measuring psychological, social, and school functioning in children aged 6-17. Minimum scores ranged from 1-10, representing the need for constant supervision (worse result) to maximum scores of 91-100, representing superior functioning (better result). The reported measure is the change from baseline at Day 56; improvement in functioning is represented by positive values. Population for analysis was randomized participants who received ≥1 dose of study drug and had both baseline and ≥1 post-baseline on-treatment PANSS Total Score (this group is termed the efficacy FAS); also, to be included a baseline and an on-treatment Day 56 value of the CGAS score must be available for a participant.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 56
    End point values
    		 Placebo Asenapine 2.5 mg BID Asenapine 5.0 mg BID
    Number of subjects analysed
    76
    72
    79
    Units: score on a scale
        arithmetic mean (standard deviation)
    10.2 ( 12.9 )
    12.8 ( 12.1 )
    15 ( 10.8 )
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Number of participants for calculation of reported mean ± SD change from baseline is 76 for placebo and 72 for asenapine 2.5 mg (total – 148). MMRM analysis uses FAS population (Number of participants: placebo – 100, asenapine 2.5 mg – 96, asenapine 5.0 mg – 104). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.
    Comparison groups
    Asenapine 2.5 mg BID v Placebo
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.417
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2
         upper limit
    		 4.8
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Number of participants for calculation of reported mean ± SD change from baseline is 76 for placebo and 79 for asenapine 5.0 mg (total – 155). MMRM analysis uses FAS population (Number of participants: placebo – 100, asenapine 2.5 mg – 96, asenapine 5.0 mg – 104). Model includes terms of (pooled) site, treatment, visit, baseline, and the interaction of visit by treatment and baseline by visit.
    Comparison groups
    Asenapine 5.0 mg BID v Placebo
    Number of subjects included in analysis
    155
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.017
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Means
    Point estimate
    4.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 7.6

    Secondary: Change From Baseline in Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) Total Score at Day 56

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    End point title
    		 Change From Baseline in Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q) Total Score at Day 56
    End point description
    PQ-LES-Q is a questionnaire to assess quality of life enjoyment and satisfaction in children and adolescents. Participant rates 15 items on a scale of 1=very poor to 5=very good. Items 1-14 assess specific areas; Item 15 is a global assessment. PQ-LES-Q total score for each participant was sum of rating assigned to first 14 items, and ranged from 14 to 70 with a higher score indicating better quality of life. Measure reports change from baseline; improvement in quality of life is represented by positive values. Last-observation-carried-forward (LOCF) approach was used; if no Day 56 value was available, the last available assessment prior to Day 56 assessment was used. Population for analysis was randomized participants who received ≥1 dose of study drug and had both baseline and ≥1 post-baseline on-treatment PANSS Total Score (efficacy FAS); also, to be included baseline and ≥1 post-baseline on-treatment value of PQ-LES-Q total score must be available for a participant.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 56
    End point values
    		 Placebo Asenapine 2.5 mg BID Asenapine 5.0 mg BID
    Number of subjects analysed
    85
    83
    82
    Units: score on a scale
        arithmetic mean (standard deviation)
    3.1 ( 8.9 )
    3.9 ( 9.3 )
    6.1 ( 8.7 )
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Analysis of covariance (ANCOVA) model includes terms of (pooled) site, treatment and baseline.
    Comparison groups
    Asenapine 2.5 mg BID v Placebo
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 2.8
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    ANCOVA model includes terms of (pooled) site, treatment and baseline.
    Comparison groups
    Asenapine 5.0 mg BID v Placebo
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.064
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    2.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 4.3

    Secondary: Change From Baseline in PQ-LES-Q Overall Score (i.e., Item 15) at Day 56

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    End point title
    		 Change From Baseline in PQ-LES-Q Overall Score (i.e., Item 15) at Day 56
    End point description
    PQ-LES-Q is a questionnaire to assess quality of life enjoyment and satisfaction in children and adolescents. Participant rates 15 items on a scale of 1=very poor to 5=very good. Items 1-14 assess specific areas; Item 15 is a global assessment. The Item 15 result is defined to be the PQ-LES-Q overall score, and ranged from 1 to 5 with a higher score indicating better quality of life. Measure reports change from baseline; improvement in quality of life is represented by positive values. LOCF approach was used; if no Day 56 value was available, the last available assessment prior to Day 56 assessment was used. Population for analysis was randomized participants who received ≥1 dose of study drug and had both a baseline and ≥1 post-baseline on-treatment PANSS Total Score (this group is termed the efficacy FAS); also, to be included a baseline and ≥1 post-baseline on-treatment value of the PQ-LES-Q overall score must be available for a participant.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 56
    End point values
    		 Placebo Asenapine 2.5 mg BID Asenapine 5.0 mg BID
    Number of subjects analysed
    85
    83
    82
    Units: score on a scale
        arithmetic mean (standard deviation)
    0.2 ( 1 )
    0.3 ( 1.1 )
    0.5 ( 0.9 )
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    ANCOVA model includes terms of (pooled) site, treatment and baseline.
    Comparison groups
    Asenapine 2.5 mg BID v Placebo
    Number of subjects included in analysis
    168
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.407
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 0.33
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    ANCOVA model includes terms of (pooled) site, treatment and baseline.
    Comparison groups
    Asenapine 5.0 mg BID v Placebo
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.111
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Means
    Point estimate
    0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.42

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 30 days after the last dose of study drug
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants receive placebo asenapine tablets sublingually BID for 8 weeks

    Reporting group title
    Asenapine 2.5 mg BID
    Reporting group description
    		 Participants receive active asenapine 2.5 mg tablets sublingually BID for 8 weeks

    Reporting group title
    Asenapine 5.0 mg BID
    Reporting group description
    		 Participants receive active asenapine 2.5 mg tablets sublingually BID through Day 3. On Day 4 participants receive asenapine 2.5 mg in the morning and 5.0 mg in the evening. Participants receive active asenapine 5.0 mg tablets sublingually BID for the remainder of the 8-week treatment period

    Serious adverse events
    		 Placebo Asenapine 2.5 mg BID Asenapine 5.0 mg BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 102 (2.94%)
    3 / 98 (3.06%)
    3 / 106 (2.83%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Psychiatric disorders
    Hallucination, Auditory
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 98 (1.02%)
    0 / 106 (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
    Schizophrenia
         subjects affected / exposed
    3 / 102 (2.94%)
    1 / 98 (1.02%)
    2 / 106 (1.89%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 98 (1.02%)
    0 / 106 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Typhoid Fever
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 98 (0.00%)
    1 / 106 (0.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         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
    		 Placebo Asenapine 2.5 mg BID Asenapine 5.0 mg BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 102 (22.55%)
    39 / 98 (39.80%)
    46 / 106 (43.40%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 102 (5.88%)
    7 / 98 (7.14%)
    8 / 106 (7.55%)
         occurrences all number
    7
    12
    11
    Sedation
         subjects affected / exposed
    2 / 102 (1.96%)
    4 / 98 (4.08%)
    12 / 106 (11.32%)
         occurrences all number
    2
    4
    14
    Somnolence
         subjects affected / exposed
    7 / 102 (6.86%)
    20 / 98 (20.41%)
    18 / 106 (16.98%)
         occurrences all number
    7
    22
    21
    Akathisia
         subjects affected / exposed
    1 / 102 (0.98%)
    4 / 98 (4.08%)
    7 / 106 (6.60%)
         occurrences all number
    1
    5
    9
    Dizziness
         subjects affected / exposed
    1 / 102 (0.98%)
    7 / 98 (7.14%)
    2 / 106 (1.89%)
         occurrences all number
    1
    7
    5
    Gastrointestinal disorders
    Hypoaesthesia Oral
         subjects affected / exposed
    1 / 102 (0.98%)
    5 / 98 (5.10%)
    5 / 106 (4.72%)
         occurrences all number
    1
    6
    5
    Nausea
         subjects affected / exposed
    8 / 102 (7.84%)
    2 / 98 (2.04%)
    2 / 106 (1.89%)
         occurrences all number
    9
    2
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 102 (5.88%)
    5 / 98 (5.10%)
    10 / 106 (9.43%)
         occurrences all number
    8
    6
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Sep 2011
    Amendment 01: Primary reason for amendment was to incorporate revisions to text presenting tapering periods for discontinuation of prohibited medications prior to study and upper limit of age range for entry into extension trial (Protocol P05897).
    03 May 2012
    Amendment 02: Primary reason for amendment was to incorporate revisions to requirements for final visit for subjects enrolling in extension trial (Protocol P05897), measures included in key secondary objectives, identification of staff qualified to administer an efficacy assessment, allowed concomitant medications/rescue therapy, list of closely monitored events, statistical analysis and procedures for liver enzyme monitoring.

    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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