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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Fixed-Dose, 6-Week, In-Patient Study to Assess Efficacy and Safety of HP-3070 in Subjects Diagnosed with Schizophrenia

    Summary
    EudraCT number
    		 2015-005134-21
    Trial protocol
    		 SK  
    Global end of trial date
    21 Nov 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    14 Mar 2020
    First version publication date
    15 Mar 2019
    Other versions
    		 v1
    Version creation reason

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    HP-3070-GL-04
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02876900
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Noven Pharmaceuticals, Inc.
    Sponsor organisation address
    100 Town Square Place, 5th Floor, Jersey City, New Jersey, United States, 07310
    Public contact
    Monica Lara, Noven Pharmaceuticals, Inc., +1 305 964 3569, mlara@noven.com
    Scientific contact
    George Harb, MD, MPH, Noven Pharmaceuticals, Inc., +1 551 233 2656, gharb@noven.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Nov 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate efficacy of HP-3070 [asenapine transdermal patch] compared with placebo for the treatment of schizophrenia as evaluated by Positive and Negative Syndrome Scale (PANSS) total score.
    Protection of trial subjects
    The study was conducted in accordance with the protocol, the ethical principles derived from international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences International Ethical Guidelines, applicable International Council for Harmonisation Good Clinical Practice Guidelines, and applicable laws and regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Aug 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Russian Federation: 181
    Country: Number of subjects enrolled
    Serbia: 57
    Country: Number of subjects enrolled
    Ukraine: 106
    Country: Number of subjects enrolled
    United States: 185
    Country: Number of subjects enrolled
    Bulgaria: 88
    Worldwide total number of subjects
    617
    EEA total number of subjects
    88
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    607
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This study was conducted in 59 centers across 5 countries between 22 Aug 2016 and 21 Nov 2017. Participants with a diagnosis of schizophrenia who were in an acute exacerbation, had a PANSS total score >=80 and Clinical Global Impression - Severity of Illness Scale (CGI-S) score >=4 were recruited.

    Pre-assignment
    Screening details
    		 This study consisted of a screening/run-in period of 3 to 14 days, followed by a 6-week double-blind treatment period and a 30-day follow-up period. A total of 617 participants were enrolled in the study and randomized to study treatment.

    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
    		 High Dose Asenapine Maleate Transdermal Patch
    Arm description
    		 Participants in the high dose asenapine maleate transdermal patch treatment arm received 2 asenapine maleate transdermal patches, once daily for 42 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    HP-3070-High Dose
    Investigational medicinal product code
    Other name
    asenapine maleate
    Pharmaceutical forms
    Transdermal patch
    Routes of administration
    Transdermal use
    Dosage and administration details
    Two HP‑3070 patches with each patch containing asenapine maleate consisting of a plastic film, adhesive matrix, and backing film.

    Arm title
    		 Low Dose Asenapine Maleate Transdermal Patch
    Arm description
    		 Participants in the low dose asenapine maleate transdermal patch treatment arm received 1 asenapine maleate transdermal patch and 1 placebo (matching with HP-3070) transdermal patch, once daily for 42 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    HP-3070-Low Dose
    Investigational medicinal product code
    Other name
    asenapine maleate
    Pharmaceutical forms
    Transdermal patch
    Routes of administration
    Transdermal use
    Dosage and administration details
    One HP‑3070 patch containing asenapine maleate consisting of a plastic film, adhesive matrix, and backing film.

    Investigational medicinal product name
    HP-3070 Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Transdermal patch
    Routes of administration
    Transdermal use
    Dosage and administration details
    One HP‑3070 Placebo patch containing 0.0 mg asenapine maleate consisting of a plastic film, adhesive matrix, and backing film.

    Arm title
    		 Placebo
    Arm description
    		 Participants in the Placebo arm received 2 placebo (matching with HP-3070) transdermal patches, once daily for 42 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    HP-3070 Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Transdermal patch
    Routes of administration
    Transdermal use
    Dosage and administration details
    Two HP‑3070 Placebo patches with each patch containing 0.0 mg asenapine maleate consisting of a plastic film, adhesive matrix, and backing film.

    Number of subjects in period 1
    		High Dose Asenapine Maleate Transdermal Patch Low Dose Asenapine Maleate Transdermal Patch Placebo
    Started
    206
    205
    206
    Received treatment
    204
    204
    206
    Completed
    158
    166
    162
    Not completed
    48
    39
    44
         Consent withdrawn by subject
    18
    20
    14
         Physician decision
    -
    1
    2
         Adverse event, non-fatal
    16
    10
    14
         Incorrectly randomised
    -
    1
    -
         Unspecified
    3
    3
    1
         Did not receive treatment
    2
    -
    -
         Lack of efficacy
    8
    4
    12
         Protocol deviation
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    High Dose Asenapine Maleate Transdermal Patch
    Reporting group description
    		 Participants in the high dose asenapine maleate transdermal patch treatment arm received 2 asenapine maleate transdermal patches, once daily for 42 days.

    Reporting group title
    Low Dose Asenapine Maleate Transdermal Patch
    Reporting group description
    		 Participants in the low dose asenapine maleate transdermal patch treatment arm received 1 asenapine maleate transdermal patch and 1 placebo (matching with HP-3070) transdermal patch, once daily for 42 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants in the Placebo arm received 2 placebo (matching with HP-3070) transdermal patches, once daily for 42 days.

    Reporting group values
    		 High Dose Asenapine Maleate Transdermal Patch Low Dose Asenapine Maleate Transdermal Patch Placebo Total
    Number of subjects
    		 206 205 206 617
    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 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 200 203 204 607
        From 65-84 years
    		 6 2 2 10
        85 years and over
    		 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 95 74 75 244
        Male
    		 111 131 131 373

    End points

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    End points reporting groups
    Reporting group title
    High Dose Asenapine Maleate Transdermal Patch
    Reporting group description
    		 Participants in the high dose asenapine maleate transdermal patch treatment arm received 2 asenapine maleate transdermal patches, once daily for 42 days.

    Reporting group title
    Low Dose Asenapine Maleate Transdermal Patch
    Reporting group description
    		 Participants in the low dose asenapine maleate transdermal patch treatment arm received 1 asenapine maleate transdermal patch and 1 placebo (matching with HP-3070) transdermal patch, once daily for 42 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants in the Placebo arm received 2 placebo (matching with HP-3070) transdermal patches, once daily for 42 days.

    Primary: Change From Baseline in PANSS Total Score at Week 6

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    End point title
    		 Change From Baseline in PANSS Total Score at Week 6
    End point description
    The PANSS total score is the sum of all 30 items (7 positive items, 7 negative items, and 16 general psychopathology items). For each item, severity was rated on an anchored 7-point scale, with a score of 1 indicating the absence of symptoms and a score of 7 indicating extremely severe symptoms. If one or more items are missing at a given assessment, the total score is set to missing. Baseline is defined as the last non-missing measurement taken prior to first dose of double-blind study medication. Results were presented for participants in the full analysis set (FAS) who had data available for analysis. The FAS included all randomized participants who had at least 1 patch of double-blind study medication applied and who have a baseline PANSS total score and at least 1 post baseline assessment of the primary efficacy measure (PANSS total score).
    End point type
    Primary
    End point timeframe
    Baseline (Day 0) and Week 6
    End point values
    		 High Dose Asenapine Maleate Transdermal Patch Low Dose Asenapine Maleate Transdermal Patch Placebo
    Number of subjects analysed
    164
    168
    163
    Units: Units on a scale
        least squares mean (standard error)
    -20.4 ± 1.162
    -22.1 ± 1.158
    -15.5 ± 1.166
    Statistical analysis title
    		 Treatment Comparison PANSS Total Score at Week 6
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    327
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.003 [2]
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -4.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.06
         upper limit
    		 -1.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.634
    Notes
    [1] - Assuming an effect size of 0.35 on the change in PANSS total score from baseline to Week 6 for the 2 pairwise comparisons between each active asenapine maleate transdermal patch treatment arm and placebo, the power for detecting a statistically significant HP-3070 advantage was approximately 0.90, having 204 evaluable participants per each treatment arm using a 2-sided alpha level of 0.025 for each comparison.
    [2] - Adjusted p-value was calculated according to the truncated Hochberg procedure with a truncation factor y=0.9. Adjustment for multiple comparisons uses a parallel gatekeeping procedure.
    Statistical analysis title
    		 Treatment Comparison PANSS Total Score at Week 6
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    331
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.001 [4]
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -6.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.81
         upper limit
    		 -3.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.63
    Notes
    [3] - Assuming an effect size of 0.35 on the change in PANSS total score from baseline to Week 6 for the 2 pairwise comparisons between each active asenapine maleate transdermal patch treatment arm and placebo, the power for detecting a statistically significant HP-3070 advantage was approximately 0.90, having 204 evaluable participants per each treatment arm using a 2-sided alpha level of 0.025 for each comparison.
    [4] - Adjusted p-value was calculated according to the truncated Hochberg procedure with a truncation factor y=0.9. Adjustment for multiple comparisons uses a parallel gatekeeping procedure.

    Secondary: Change From Baseline in CGI-S Scores at Week 6

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    End point title
    		 Change From Baseline in CGI-S Scores at Week 6
    End point description
    The severity of illness for each participant was rated using the CGI-S. The rater or Investigator answered the following question: “Considering your total clinical experience with this particular population, how mentally ill is the participant at this time?”. Response choices included: 0 = not assessed; 1 = normal, not at all ill, 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants. Baseline is defined as the last non-missing measurement taken prior to first dose of double-blind study medication. Results were presented for participants in the FAS who had data available for analysis. The FAS included all randomized participants who had at least 1 patch of double-blind study medication applied and who have a baseline PANSS total score and at least 1 post baseline assessment of the primary efficacy measure (PANSS total score).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) and Week 6
    End point values
    		 High Dose Asenapine Maleate Transdermal Patch Low Dose Asenapine Maleate Transdermal Patch Placebo
    Number of subjects analysed
    164
    168
    164
    Units: Units on a scale
        least squares mean (standard error)
    -1.1 ± 0.071
    -1.2 ± 0.071
    -0.8 ± 0.071
    Statistical analysis title
    		 Treatment Comparison CGI-S at Week 6
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    328
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [5]
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.55
         upper limit
    		 -0.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1
    Notes
    [5] - Adjusted p-value was calculated according to the Hochberg procedure. Adjustment for multiple comparisons uses a parallel gatekeeping procedure.
    Statistical analysis title
    		 Treatment Comparison CGI-S at Week 6
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    332
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [6]
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.64
         upper limit
    		 -0.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.099
    Notes
    [6] - Adjusted p-value was calculated according to the Hochberg procedure. Adjustment for multiple comparisons uses a parallel gatekeeping procedure.

    Secondary: Change From Baseline in PANSS Total Score at Each Time Point in Addition to Week 6

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    End point title
    		 Change From Baseline in PANSS Total Score at Each Time Point in Addition to Week 6
    End point description
    The PANSS total score is the sum of all 30 items (7 positive items, 7 negative items, and 16 general psychopathology items). For each item, severity was rated on an anchored 7-point scale, with a score of 1 indicating the absence of symptoms and a score of 7 indicating extremely severe symptoms. If one or more items are missing at a given assessment, the total score is set to missing. Baseline is defined as the last non-missing measurement taken prior to first dose of double-blind study medication. Results were presented for participants in the FAS who had data available for analysis. The FAS included all randomized participants who had at least 1 patch of double-blind study medication applied and who have a baseline PANSS total score and at least 1 post baseline assessment of the primary efficacy measure (PANSS total score). Here, "n" denotes number of participants analysed at each specific time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) through Week 6
    End point values
    		 High Dose Asenapine Maleate Transdermal Patch Low Dose Asenapine Maleate Transdermal Patch Placebo
    Number of subjects analysed
    203
    201
    201
    Units: Units on a scale
    least squares mean (standard error)
        Change from baseline at Week 1 (n=203, 201, 201)
    -5.7 ± 0.558
    -5.5 ± 0.559
    -4.8 ± 0.560
        Change from baseline at Week 2 (n=194, 196, 193)
    -10.3 ± 0.741
    -10.9 ± 0.739
    -8.3 ± 0.742
        Change from baseline at Week 3 (n=188, 186, 185)
    -13.5 ± 0.860
    -13.9 ± 0.861
    -10.9 ± 0.863
        Change from baseline at Week 4 (n=182, 180, 179)
    -16.0 ± 0.963
    -18.1 ± 0.963
    -13.3 ± 0.967
        Change from baseline at Week 5 (n=174, 178, 174)
    -18.3 ± 1.073
    -20.5 ± 1.071
    -14.5 ± 1.077
        Change from baseline at Week 6 (n=164, 168, 165)
    -20.4 ± 1.159
    -22.1 ± 1.155
    -15.6 ± 1.163
    Statistical analysis title
    		 Treatment Comparison PANSS Total Score at Week 1
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.226
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.43
         upper limit
    		 0.57
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.764
    Statistical analysis title
    		 Treatment Comparison PANSS Total Score at Week 1
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.332
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.24
         upper limit
    		 0.76
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.764
    Statistical analysis title
    		 Treatment Comparison PANSS Total Score at Week 2
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.052
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.02
         upper limit
    		 0.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.028
    Notes
    [7] - Subjects in this analysis = 387.
    Statistical analysis title
    		 Treatment Comparison PANSS Total Score at Week 2
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.013
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.57
         upper limit
    		 -0.53
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.026
    Notes
    [8] - Subjects in this analysis = 389.
    Statistical analysis title
    		 Treatment Comparison PANSS Total Score at Week 3
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.036
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.89
         upper limit
    		 -0.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.202
    Notes
    [9] - Subjects in this analysis = 373.
    Statistical analysis title
    		 Treatment Comparison PANSS Total Score at Week 3
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.013
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.36
         upper limit
    		 -0.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.201
    Notes
    [10] - Subjects in this analysis = 371.
    Statistical analysis title
    		 Treatment Comparison PANSS Total Score at Week 4
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.05
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.31
         upper limit
    		 0
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.35
    Notes
    [11] - Subjects in this analysis = 361.
    Statistical analysis title
    		 Treatment Comparison PANSS Total Score at Week 4
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [12]
    P-value
    		 < 0.001
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -4.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.46
         upper limit
    		 -2.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.349
    Notes
    [12] - Subjects in this analysis = 359.
    Statistical analysis title
    		 Treatment Comparison PANSS Total Score at Week 5
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.012
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -3.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.77
         upper limit
    		 -0.84
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.507
    Notes
    [13] - Subjects in this analysis = 348.
    Statistical analysis title
    		 Treatment Comparison PANSS Total Score at Week 5
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [14]
    P-value
    		 < 0.001
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.96
         upper limit
    		 -3.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.505
    Notes
    [14] - Subjects in this analysis = 352.
    Statistical analysis title
    		 Treatment Comparison PANSS Total Score at Week 6
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.003
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -4.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.99
         upper limit
    		 -1.59
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.63
    Notes
    [15] - Subjects in this analysis = 329.
    Statistical analysis title
    		 Treatment Comparison PANSS Total Score at Week 6
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [16]
    P-value
    		 < 0.001
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -6.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.74
         upper limit
    		 -3.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.626
    Notes
    [16] - Subjects in this analysis = 333.

    Secondary: Change From Baseline in CGI-S at Each Time Point in Addition to Week 6

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    End point title
    		 Change From Baseline in CGI-S at Each Time Point in Addition to Week 6
    End point description
    The severity of illness for each participant was rated using CGI-S. The rater or Investigator answered following question: “Considering your total clinical experience with this particular population, how mentally ill is the participant at this time?”. Response choices included: 0 = not assessed; 1 = normal, not at all ill, 2 = borderline mentally ill; 3 = mildly ill; 4 = moderately ill; 5 = markedly ill; 6 = severely ill; and 7 = among the most extremely ill participants. Baseline is defined as last non-missing measurement taken prior to first dose of double-blind study medication. Results were presented for participants in the FAS who had data available for analysis. The FAS included all randomized participants who had at least 1 patch of double-blind study medication applied and who have a baseline PANSS total score and at least 1 post baseline assessment of primary efficacy measure (PANSS total score). Here, "n" denotes number of participants analysed at each specific time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) through Week 6
    End point values
    		 High Dose Asenapine Maleate Transdermal Patch Low Dose Asenapine Maleate Transdermal Patch Placebo
    Number of subjects analysed
    203
    200
    201
    Units: Units on a scale
    least squares mean (standard error)
        Change from baseline at Week 1 (n=203, 200, 201)
    -0.2 ± 0.034
    -0.2 ± 0.034
    -0.1 ± 0.034
        Change from baseline at Week 2 (n=194, 196, 193)
    -0.5 ± 0.047
    -0.5 ± 0.047
    -0.3 ± 0.047
        Change from baseline at Week 3 (n=188, 186, 185)
    -0.8 ± 0.056
    -0.7 ± 0.056
    -0.5 ± 0.056
        Change from baseline at Week 4 (n=182, 180, 179)
    -0.9 ± 0.062
    -1.0 ± 0.062
    -0.6 ± 0.062
        Change from baseline at Week 5 (n=174, 178, 173)
    -1.1 ± 0.064
    -1.1 ± 0.064
    -0.7 ± 0.065
        Change from baseline at Week 6 (n=164, 168, 164)
    -1.1 ± 0.071
    -1.2 ± 0.071
    -0.8 ± 0.071
    Statistical analysis title
    		 Treatment Comparison CGI-S at Week 1
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.128
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.16
         upper limit
    		 0.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.046
    Statistical analysis title
    		 Treatment Comparison CGI-S at Week 1
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.156
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.16
         upper limit
    		 0.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.047
    Statistical analysis title
    		 Treatment Comparison CGI-S at Week 2
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.017
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.29
         upper limit
    		 -0.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.066
    Notes
    [17] - Subjects in this analysis = 387.
    Statistical analysis title
    		 Treatment Comparison CGI-S at Week 2
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 = 0.002
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.33
         upper limit
    		 -0.07
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.066
    Notes
    [18] - Subjects in this analysis = 389.
    Statistical analysis title
    		 Treatment Comparison CGI-S at Week 3
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.002
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 -0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.078
    Notes
    [19] - Subjects in this analysis = 373.
    Statistical analysis title
    		 Treatment Comparison CGI-S at Week 3
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 = 0.005
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.38
         upper limit
    		 -0.07
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.079
    Notes
    [20] - Subjects in this analysis = 371.
    Statistical analysis title
    		 Treatment Comparison CGI-S at Week 4
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 < 0.001
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.46
         upper limit
    		 -0.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.087
    Notes
    [21] - Subjects in this analysis = 361.
    Statistical analysis title
    		 Treatment Comparison CGI-S at Week 4
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [22]
    P-value
    		 < 0.001
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.52
         upper limit
    		 -0.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.087
    Notes
    [22] - Subjects in this analysis = 359.
    Statistical analysis title
    		 Treatment Comparison CGI-S at Week 5
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [23]
    P-value
    		 < 0.001
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.52
         upper limit
    		 -0.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.09
    Notes
    [23] - Subjects in this analysis = 347.
    Statistical analysis title
    		 Treatment Comparison CGI-S at Week 5
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [24]
    P-value
    		 < 0.001
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.56
         upper limit
    		 -0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.09
    Notes
    [24] - Subjects in this analysis = 351.
    Statistical analysis title
    		 Treatment Comparison CGI-S at Week 6
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 < 0.001
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.55
         upper limit
    		 -0.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.1
    Notes
    [25] - Subjects in this analysis = 328.
    Statistical analysis title
    		 Treatment Comparison CGI-S at Week 6
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [26]
    P-value
    		 < 0.001
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.64
         upper limit
    		 -0.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.099
    Notes
    [26] - Subjects in this analysis = 332.

    Secondary: Clinical Global Impression - Improvement Scale (CGI-I) Score at Each Time Point

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    End point title
    		 Clinical Global Impression - Improvement Scale (CGI-I) Score at Each Time Point
    End point description
    The efficacy of study medication was rated for each participant using the CGI-I. The rater or Investigator rated whether or not the participant’s total improvement was due entirely to drug treatment. All responses were compared with the participant’s condition at baseline prior to the first dose of double-blind study medication. Response choices included: 0 = not assessed, 1 = very much improved, 2 = much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, and 7 = very much worse. Results were presented for participants in the FAS who had data available for analysis. The FAS included all randomized participants who had at least 1 patch of double-blind study medication applied and who have a baseline PANSS total score and at least 1 post baseline assessment of the primary efficacy measure (PANSS total score). Here, "n" denotes number of participants analysed at each specific time point.
    End point type
    Secondary
    End point timeframe
    Up to Week 6
    End point values
    		 High Dose Asenapine Maleate Transdermal Patch Low Dose Asenapine Maleate Transdermal Patch Placebo
    Number of subjects analysed
    203
    201
    201
    Units: Units on a scale
    arithmetic mean (standard deviation)
        At Week 1 (n=203, 201, 201)
    3.6 ± 0.68
    3.6 ± 0.66
    3.7 ± 0.69
        At Week 2 (n=194, 196, 193)
    3.3 ± 0.86
    3.3 ± 0.85
    3.5 ± 0.88
        At Week 3 (n=188, 186, 185)
    3.0 ± 0.89
    3.1 ± 0.86
    3.2 ± 1.03
        At Week 4 (n=182, 180, 179)
    2.9 ± 1.00
    2.7 ± 0.87
    3.1 ± 1.01
        At Week 5 (n=174, 178, 173)
    2.7 ± 0.95
    2.7 ± 0.94
    3.0 ± 1.06
        At Week 6 (n=163, 168, 163)
    2.6 ± 1.03
    2.5 ± 0.96
    2.8 ± 1.06
    Statistical analysis title
    		 Treatment Comparison CGI-I at Week 1
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value of CGI-S as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.355
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.091
    Statistical analysis title
    		 Treatment Comparison CGI-I at Week 1
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value of CGI-S as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.346
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.27
         upper limit
    		 0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.091
    Statistical analysis title
    		 Treatment Comparison CGI-I at Week 2
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value of CGI-S as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 = 0.055
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.36
         upper limit
    		 0
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.093
    Notes
    [27] - Subjects in this analysis = 387.
    Statistical analysis title
    		 Treatment Comparison CGI-I at Week 2
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value of CGI-S as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [28]
    P-value
    		 = 0.02
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 -0.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.092
    Notes
    [28] - Subjects in this analysis = 389.
    Statistical analysis title
    		 Treatment Comparison CGI-I at Week 3
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value of CGI-S as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 = 0.035
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.38
         upper limit
    		 -0.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.094
    Notes
    [29] - Subjects in this analysis = 373.
    Statistical analysis title
    		 Treatment Comparison CGI-I at Week 3
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value of CGI-S as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [30]
    P-value
    		 = 0.144
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.32
         upper limit
    		 0.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.094
    Notes
    [30] - Subjects in this analysis = 371.
    Statistical analysis title
    		 Treatment Comparison CGI-I at Week 4
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value of CGI-S as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 = 0.008
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.44
         upper limit
    		 -0.07
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.094
    Notes
    [31] - Subjects in this analysis = 361.
    Statistical analysis title
    		 Treatment Comparison CGI-I at Week 4
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value of CGI-S as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [32]
    P-value
    		 < 0.001
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 -0.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.095
    Notes
    [32] - Subjects in this analysis = 359.
    Statistical analysis title
    		 Treatment Comparison CGI-I at Week 5
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value of CGI-S as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [33]
    P-value
    		 < 0.001
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.53
         upper limit
    		 -0.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.095
    Notes
    [33] - Subjects in this analysis = 347.
    Statistical analysis title
    		 Treatment Comparison CGI-I at Week 5
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value of CGI-S as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [34]
    P-value
    		 < 0.001
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.55
         upper limit
    		 -0.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.095
    Notes
    [34] - Subjects in this analysis = 351.
    Statistical analysis title
    		 Treatment Comparison CGI-I at Week 6
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value of CGI-S as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [35]
    P-value
    		 = 0.005
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.46
         upper limit
    		 -0.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.097
    Notes
    [35] - Subjects in this analysis = 326.
    Statistical analysis title
    		 Treatment Comparison CGI-I at Week 6
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value of CGI-S as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [36]
    P-value
    		 < 0.001
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.58
         upper limit
    		 -0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.097
    Notes
    [36] - Subjects in this analysis = 331.

    Secondary: Percentage of CGI-I Responders at Each Time Point Including Week 6

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    End point title
    		 Percentage of CGI-I Responders at Each Time Point Including Week 6
    End point description
    The CGI-I responders are defined as participants who have a score of 1 (very much improved) or a score of 2 (much improved). Results were presented for participants in the FAS who had data available for analysis. The FAS included all randomized participants who had at least 1 patch of double-blind study medication applied and who have a baseline PANSS total score and at least 1 post baseline assessment of the primary efficacy measure (PANSS total score).
    End point type
    Secondary
    End point timeframe
    Up to Week 6
    End point values
    		 High Dose Asenapine Maleate Transdermal Patch Low Dose Asenapine Maleate Transdermal Patch Placebo
    Number of subjects analysed
    203
    201
    203
    Units: Percentage of participants
    number (not applicable)
        At Week 1
    4.4
    4.0
    3.4
        At Week 2
    17.7
    12.4
    12.3
        At Week 3
    27.1
    20.4
    21.2
        At Week 4
    36.0
    38.8
    25.6
        At Week 5
    42.9
    46.3
    29.1
        At Week 6
    43.3
    49.8
    34.0
    Statistical analysis title
    		 Treatment Comparison CGI-I Responders at Week 1
    Statistical analysis description
    Estimates of the percentage of responders in each treatment group and differences of percentage between the treatment groups are based on the standard method based on the binomial distribution. 95% CIs for percentage estimates are based on the Wilson method. 95% CIs for the differences of percentage are based on the Newcombe method.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.61
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference of Responders
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.27
         upper limit
    		 0.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.127
    Statistical analysis title
    		 Treatment Comparison CGI-I Responders at Week 1
    Statistical analysis description
    Estimates of the percentage of responders in each treatment group and differences of percentage between the treatment groups are based on the standard method based on the binomial distribution. 95% CIs for percentage estimates are based on the Wilson method. 95% CIs for the differences of percentage are based on the Newcombe method.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.803
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference of Responders
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.131
    Statistical analysis title
    		 Treatment Comparison CGI-I Responders at Week 2
    Statistical analysis description
    Estimates of the percentage of responders in each treatment group and differences of percentage between the treatment groups are based on the standard method based on the binomial distribution. 95% CIs for percentage estimates are based on the Wilson method. 95% CIs for the differences of percentage are based on the Newcombe method.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.118
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference of Responders
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 0.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.069
    Statistical analysis title
    		 Treatment Comparison CGI-I Responders at Week 2
    Statistical analysis description
    Estimates of the percentage of responders in each treatment group and differences of percentage between the treatment groups are based on the standard method based on the binomial distribution. 95% CIs for percentage estimates are based on the Wilson method. 95% CIs for the differences of percentage are based on the Newcombe method.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.958
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference of Responders
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.14
         upper limit
    		 0.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.076
    Statistical analysis title
    		 Treatment Comparison CGI-I Responders at Week 3
    Statistical analysis description
    Estimates of the percentage of responders in each treatment group and differences of percentage between the treatment groups are based on the standard method based on the binomial distribution. 95% CIs for percentage estimates are based on the Wilson method. 95% CIs for the differences of percentage are based on the Newcombe method.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.173
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference of Responders
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.19
         upper limit
    		 0.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.058
    Statistical analysis title
    		 Treatment Comparison CGI-I Responders at Week 3
    Statistical analysis description
    Estimates of the percentage of responders in each treatment group and differences of percentage between the treatment groups are based on the standard method based on the binomial distribution. 95% CIs for percentage estimates are based on the Wilson method. 95% CIs for the differences of percentage are based on the Newcombe method.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.785
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference of Responders
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.062
    Statistical analysis title
    		 Treatment Comparison CGI-I Responders at Week 4
    Statistical analysis description
    Estimates of the percentage of responders in each treatment group and differences of percentage between the treatment groups are based on the standard method based on the binomial distribution. 95% CIs for percentage estimates are based on the Wilson method. 95% CIs for the differences of percentage are based on the Newcombe method.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.027
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference of Responders
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 -0.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.055
    Statistical analysis title
    		 Treatment Comparison CGI-I Responders at Week 4
    Statistical analysis description
    Estimates of the percentage of responders in each treatment group and differences of percentage between the treatment groups are based on the standard method based on the binomial distribution. 95% CIs for percentage estimates are based on the Wilson method. 95% CIs for the differences of percentage are based on the Newcombe method.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.005
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference of Responders
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 -0.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.054
    Statistical analysis title
    		 Treatment Comparison CGI-I Responders at Week 5
    Statistical analysis description
    Estimates of the percentage of responders in each treatment group and differences of percentage between the treatment groups are based on the standard method based on the binomial distribution. 95% CIs for percentage estimates are based on the Wilson method. 95% CIs for the differences of percentage are based on the Newcombe method.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference of Responders
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 -0.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.054
    Statistical analysis title
    		 Treatment Comparison CGI-I Responders at Week 5
    Statistical analysis description
    Estimates of the percentage of responders in each treatment group and differences of percentage between the treatment groups are based on the standard method based on the binomial distribution. 95% CIs for percentage estimates are based on the Wilson method. 95% CIs for the differences of percentage are based on the Newcombe method.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference of Responders
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.28
         upper limit
    		 -0.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.053
    Statistical analysis title
    		 Treatment Comparison CGI-I Responders at Week 6
    Statistical analysis description
    Estimates of the percentage of responders in each treatment group and differences of percentage between the treatment groups are based on the standard method based on the binomial distribution. 95% CIs for percentage estimates are based on the Wilson method. 95% CIs for the differences of percentage are based on the Newcombe method.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.044
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference of Responders
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.22
         upper limit
    		 -0.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.055
    Statistical analysis title
    		 Treatment Comparison CGI-I Responders at Week 6
    Statistical analysis description
    Estimates of the percentage of responders in each treatment group and differences of percentage between the treatment groups are based on the standard method based on the binomial distribution. 95% CIs for percentage estimates are based on the Wilson method. 95% CIs for the differences of percentage are based on the Newcombe method.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference of Responders
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.27
         upper limit
    		 -0.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.054

    Secondary: Change From Baseline in Positive, Negative, and General Pathology Subscores of PANSS at Each Time Point

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    End point title
    		 Change From Baseline in Positive, Negative, and General Pathology Subscores of PANSS at Each Time Point
    End point description
    The PANSS consists of 3 subscales containing a total of 30 items. For each item, severity was rated on an anchored 7-point scale, with a score of 1 indicating absence of symptoms and a score of 7 indicating extremely severe symptoms. The subscales were as follows: Positive subscale (PS; 7 items), Negative subscale (NS; 7 items), and General psychopathology subscale (GP; 16 items). Results were presented for participants in the FAS who had data available for analysis. The FAS included all randomized participants who had at least 1 patch of double-blind study medication applied and who have a baseline PANSS total score and at least 1 post baseline assessment of the primary efficacy measure (PANSS total score). Here, "n" denotes number of participants analysed at each specific time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) through Week 6
    End point values
    		 High Dose Asenapine Maleate Transdermal Patch Low Dose Asenapine Maleate Transdermal Patch Placebo
    Number of subjects analysed
    203
    201
    201
    Units: Units on a scale
    arithmetic mean (standard deviation)
        PS: Change from baseline at Week 1 (n=203,201,201)
    -1.8 ± 2.83
    -1.9 ± 2.60
    -1.6 ± 2.97
        PS: Change from baseline at Week 2 (n=194,196,193)
    -3.4 ± 3.68
    -3.8 ± 3.42
    -2.8 ± 3.65
        PS: Change from baseline at Week 3 (n=188,186,185)
    -4.8 ± 4.18
    -5.0 ± 3.62
    -4.1 ± 4.17
        PS: Change from baseline at Week 4 (n=182,180,179)
    -5.4 ± 4.76
    -6.1 ± 4.27
    -4.9 ± 4.46
        PS: Change from baseline at Week 5 (n=174,178,174)
    -6.5 ± 4.99
    -7.1 ± 4.62
    -5.5 ± 4.80
        PS: Change from baseline at Week 6 (n=164,168,165)
    -7.5 ± 5.04
    -7.7 ± 4.70
    -6.1 ± 4.94
        NS: Change from baseline at Week 1 (n=203,201,201)
    -1.0 ± 1.93
    -0.9 ± 2.22
    -0.9 ± 2.20
        NS: Change from baseline at Week 2 (n=194,196,193)
    -1.9 ± 2.72
    -1.9 ± 2.85
    -1.6 ± 2.64
        NS: Change from baseline at Week 3 (n=188,186,185)
    -2.2 ± 2.89
    -2.6 ± 3.26
    -2.1 ± 3.15
        NS: Change from baseline at Week 4 (n=182,180,179)
    -2.9 ± 3.17
    -3.5 ± 3.32
    -2.7 ± 3.51
        NS: Change from baseline at Week 5 (n=174,178,174)
    -3.2 ± 3.56
    -4.1 ± 3.83
    -2.9 ± 3.84
        NS: Change from baseline at Week 6 (n=164,168,165)
    -3.6 ± 3.91
    -4.2 ± 3.89
    -3.4 ± 4.02
        GP: Change from baseline at Week 1 (n=203,201,201)
    -3.0 ± 4.52
    -2.8 ± 4.30
    -2.4 ± 4.99
        GP: Change from baseline at Week 2 (n=194,196,193)
    -5.3 ± 5.80
    -5.7 ± 5.46
    -4.4 ± 5.68
        GP: Change from baseline at Week 3 (n=188,186,185)
    -6.8 ± 6.09
    -6.8 ± 6.01
    -5.8 ± 6.57
        GP: Change from baseline at Week 4 (n=182,180,179)
    -8.0 ± 6.53
    -9.2 ± 6.58
    -7.3 ± 7.30
        GP: Change from baseline at Week 5 (n=174,178,174)
    -9.1 ± 7.15
    -10.2 ± 6.95
    -8.1 ± 7.85
        GP: Change from baseline at Week 6 (n=164,168,165)
    -10.6 ± 7.49
    -11.5 ± 7.32
    -9.2 ± 7.59
    Statistical analysis title
    		 Treatment Comparison PANSS PS at Week 1
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.49
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.73
         upper limit
    		 0.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.273
    Statistical analysis title
    		 Treatment Comparison PANSS PS at Week 1
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.182
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.9
         upper limit
    		 0.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.274
    Statistical analysis title
    		 Treatment Comparison PANSS PS at Week 2
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [37]
    P-value
    		 = 0.062
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.4
         upper limit
    		 0.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.364
    Notes
    [37] - Subjects in this analysis = 387.
    Statistical analysis title
    		 Treatment Comparison PANSS PS at Week 2
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [38]
    P-value
    		 = 0.006
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.73
         upper limit
    		 -0.29
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.364
    Notes
    [38] - Subjects in this analysis = 389.
    Statistical analysis title
    		 Treatment Comparison PANSS PS at Week 3
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [39]
    P-value
    		 = 0.012
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.87
         upper limit
    		 -0.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.416
    Notes
    [39] - Subjects in this analysis = 373.
    Statistical analysis title
    		 Treatment Comparison PANSS PS at Week 3
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [40]
    P-value
    		 = 0.004
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.01
         upper limit
    		 -0.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.417
    Notes
    [40] - Subjects in this analysis = 371.
    Statistical analysis title
    		 Treatment Comparison PANSS PS at Week 4
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [41]
    P-value
    		 = 0.048
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.87
         upper limit
    		 -0.01
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.473
    Notes
    [41] - Subjects in this analysis = 361.
    Statistical analysis title
    		 Treatment Comparison PANSS PS at Week 4
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [42]
    P-value
    		 = 0.001
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.47
         upper limit
    		 -0.61
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.474
    Notes
    [42] - Subjects in this analysis = 359.
    Statistical analysis title
    		 Treatment Comparison PANSS PS at Week 5
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [43]
    P-value
    		 = 0.002
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.58
         upper limit
    		 -0.56
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.516
    Notes
    [43] - Subjects in this analysis = 348.
    Statistical analysis title
    		 Treatment Comparison PANSS PS at Week 5
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [44]
    P-value
    		 < 0.001
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.06
         upper limit
    		 -1.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.516
    Notes
    [44] - Subjects in this analysis = 352.
    Statistical analysis title
    		 Treatment Comparison PANSS PS at Week 6
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [45]
    P-value
    		 < 0.001
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.03
         upper limit
    		 -0.86
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.55
    Notes
    [45] - Subjects in this analysis = 329.
    Statistical analysis title
    		 Treatment Comparison PANSS PS at Week 6
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [46]
    P-value
    		 < 0.001
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -2.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.28
         upper limit
    		 -1.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.55
    Notes
    [46] - Subjects in this analysis = 333.
    Statistical analysis title
    		 Treatment Comparison PANSS NS at Week 1
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.316
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.61
         upper limit
    		 0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.205
    Statistical analysis title
    		 Treatment Comparison PANSS NS at Week 1
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.653
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.49
         upper limit
    		 0.31
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.204
    Statistical analysis title
    		 Treatment Comparison PANSS NS at Week 2
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [47]
    P-value
    		 = 0.12
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.94
         upper limit
    		 0.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.266
    Notes
    [47] - Subjects in this analysis = 387.
    Statistical analysis title
    		 Treatment Comparison PANSS NS at Week 2
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [48]
    P-value
    		 = 0.232
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.84
         upper limit
    		 0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.265
    Notes
    [48] - Subjects in this analysis = 389.
    Statistical analysis title
    		 Treatment Comparison PANSS NS at Week 3
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [49]
    P-value
    		 = 0.49
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.82
         upper limit
    		 0.39
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.309
    Notes
    [49] - Subjects in this analysis = 373.
    Statistical analysis title
    		 Treatment Comparison PANSS NS at Week 3
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [50]
    P-value
    		 = 0.039
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.24
         upper limit
    		 -0.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.308
    Notes
    [50] - Subjects in this analysis = 371.
    Statistical analysis title
    		 Treatment Comparison PANSS NS at Week 4
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [51]
    P-value
    		 = 0.173
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.1
         upper limit
    		 0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.331
    Notes
    [51] - Subjects in this analysis = 361.
    Statistical analysis title
    		 Treatment Comparison PANSS NS at Week 4
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [52]
    P-value
    		 = 0.005
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.58
         upper limit
    		 -0.27
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.331
    Notes
    [52] - Subjects in this analysis = 359.
    Statistical analysis title
    		 Treatment Comparison PANSS NS at Week 5
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [53]
    P-value
    		 = 0.137
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 0.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.378
    Notes
    [53] - Subjects in this analysis = 348.
    Statistical analysis title
    		 Treatment Comparison PANSS NS at Week 5
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [54]
    P-value
    		 = 0.001
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.98
         upper limit
    		 -0.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.377
    Notes
    [54] - Subjects in this analysis = 352.
    Statistical analysis title
    		 Treatment Comparison PANSS NS at Week 6
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [55]
    P-value
    		 = 0.181
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.34
         upper limit
    		 0.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.405
    Notes
    [55] - Subjects in this analysis = 329.
    Statistical analysis title
    		 Treatment Comparison PANSS NS at Week 6
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [56]
    P-value
    		 = 0.01
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.84
         upper limit
    		 -0.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.404
    Notes
    [56] - Subjects in this analysis = 333.
    Statistical analysis title
    		 Treatment Comparison PANSS GP at Week 1
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.147
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.53
         upper limit
    		 0.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.447
    Statistical analysis title
    		 Treatment Comparison PANSS GP at Week 1
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.502
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.18
         upper limit
    		 0.58
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.448
    Statistical analysis title
    		 Treatment Comparison PANSS GP at Week 2
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [57]
    P-value
    		 = 0.071
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.14
         upper limit
    		 0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.569
    Notes
    [57] - Subjects in this analysis = 387.
    Statistical analysis title
    		 Treatment Comparison PANSS GP at Week 2
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [58]
    P-value
    		 = 0.028
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.37
         upper limit
    		 -0.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.569
    Notes
    [58] - Subjects in this analysis = 389.
    Statistical analysis title
    		 Treatment Comparison PANSS GP at Week 3
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [59]
    P-value
    		 = 0.032
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.62
         upper limit
    		 -0.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.638
    Notes
    [59] - Subjects in this analysis = 373.
    Statistical analysis title
    		 Treatment Comparison PANSS GP at Week 3
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [60]
    P-value
    		 = 0.062
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.45
         upper limit
    		 0.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.638
    Notes
    [60] - Subjects in this analysis = 371.
    Statistical analysis title
    		 Treatment Comparison PANSS GP at Week 4
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [61]
    P-value
    		 = 0.058
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -1.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.73
         upper limit
    		 0.05
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.708
    Notes
    [61] - Subjects in this analysis = 361.
    Statistical analysis title
    		 Treatment Comparison PANSS GP at Week 4
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [62]
    P-value
    		 = 0.001
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.73
         upper limit
    		 -0.95
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.708
    Notes
    [62] - Subjects in this analysis = 359.
    Statistical analysis title
    		 Treatment Comparison PANSS GP at Week 5
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [63]
    P-value
    		 = 0.031
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.22
         upper limit
    		 -0.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.781
    Notes
    [63] - Subjects in this analysis = 348.
    Statistical analysis title
    		 Treatment Comparison PANSS GP at Week 5
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [64]
    P-value
    		 < 0.001
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.19
         upper limit
    		 -1.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.78
    Notes
    [64] - Subjects in this analysis = 352.
    Statistical analysis title
    		 Treatment Comparison PANSS GP at Week 6
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [65]
    P-value
    		 = 0.006
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.91
         upper limit
    		 -0.65
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.831
    Notes
    [65] - Subjects in this analysis = 329.
    Statistical analysis title
    		 Treatment Comparison PANSS GP at Week 6
    Statistical analysis description
    The mixed model for repeated measures includes treatment, country, visit, treatment by visit interaction, and baseline value as covariates, and participant as random effect. The correlation of repeated measures within a participant is estimated with an unstructured covariance matrix. The Kenward-Rogers method is used to estimate the denominator degrees of freedom.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    402
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [66]
    P-value
    		 < 0.001
    Method
    		 Mixed Model Repeated Measures Analysis
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.79
         upper limit
    		 -1.54
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.829
    Notes
    [66] - Subjects in this analysis = 333.

    Secondary: Percentage of PANSS Responders

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    End point title
    		 Percentage of PANSS Responders
    End point description
    The PANSS responders were defined as participants who have a >=30% reduction in PANSS total score between baseline and at each time point including Week 6. Results were presented for participants in the FAS who had data available for analysis. The FAS included all randomized participants who had at least 1 patch of double-blind study medication applied and who have a baseline PANSS total score and at least 1 post baseline assessment of the primary efficacy measure (PANSS total score).
    End point type
    Secondary
    End point timeframe
    Up to Week 6
    End point values
    		 High Dose Asenapine Maleate Transdermal Patch Low Dose Asenapine Maleate Transdermal Patch Placebo
    Number of subjects analysed
    203
    201
    203
    Units: Percentage of participants
    number (not applicable)
        At Week 1
    2.5
    1.5
    2.5
        At Week 2
    4.9
    5.0
    4.4
        At Week 3
    10.3
    10.4
    7.9
        At Week 4
    15.8
    15.4
    13.3
        At Week 5
    22.2
    25.4
    17.2
        At Week 6
    29.6
    30.8
    18.7
    Statistical analysis title
    		 Treatment Comparison PANSS Responders at Week 1
    Statistical analysis description
    Estimates of the percentage of responders in each treatment group and differences of percentages between the treatment groups are based on the standard method based on the binomial distribution. 95% CIs for percentage estimates are based on the Wilson method. 95% CIs for the differences of percentage are based on the Newcombe method.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.993
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference of Responders
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.27
         upper limit
    		 0.27
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.16
    Statistical analysis title
    		 Treatment Comparison PANSS Responders at Week 1
    Statistical analysis description
    Estimates of the percentage of responders in each treatment group and differences of percentages between the treatment groups are based on the standard method based on the binomial distribution. 95% CIs for percentage estimates are based on the Wilson method. 95% CIs for the differences of percentage are based on the Newcombe method.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.481
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference of Responders
    Point estimate
    -0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.173
    Statistical analysis title
    		 Treatment Comparison PANSS Responders at Week 2
    Statistical analysis description
    Estimates of the percentage of responders in each treatment group and differences of percentages between the treatment groups are based on the standard method based on the binomial distribution. 95% CIs for percentage estimates are based on the Wilson method. 95% CIs for the differences of percentage are based on the Newcombe method.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.784
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference of Responders
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 0.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.117
    Statistical analysis title
    		 Treatment Comparison PANSS Responders at Week 2
    Statistical analysis description
    Estimates of the percentage of responders in each treatment group and differences of percentages between the treatment groups are based on the standard method based on the binomial distribution. 95% CIs for percentage estimates are based on the Wilson method. 95% CIs for the differences of percentage are based on the Newcombe method.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.837
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference of Responders
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 0.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.117
    Statistical analysis title
    		 Treatment Comparison PANSS Responders at Week 3
    Statistical analysis description
    Estimates of the percentage of responders in each treatment group and differences of percentages between the treatment groups are based on the standard method based on the binomial distribution. 95% CIs for percentage estimates are based on the Wilson method. 95% CIs for the differences of percentage are based on the Newcombe method.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.375
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference of Responders
    Point estimate
    0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.086
    Statistical analysis title
    		 Treatment Comparison PANSS Responders at Week 3
    Statistical analysis description
    Estimates of the percentage of responders in each treatment group and differences of percentages between the treatment groups are based on the standard method based on the binomial distribution. 95% CIs for percentage estimates are based on the Wilson method. 95% CIs for the differences of percentage are based on the Newcombe method.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.381
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference of Responders
    Point estimate
    0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.23
         upper limit
    		 0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.086
    Statistical analysis title
    		 Treatment Comparison PANSS Responders at Week 4
    Statistical analysis description
    Estimates of the percentage of responders in each treatment group and differences of percentages between the treatment groups are based on the standard method based on the binomial distribution. 95% CIs for percentage estimates are based on the Wilson method. 95% CIs for the differences of percentage are based on the Newcombe method.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.419
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference of Responders
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.18
         upper limit
    		 0.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.071
    Statistical analysis title
    		 Treatment Comparison PANSS Responders at Week 4
    Statistical analysis description
    Estimates of the percentage of responders in each treatment group and differences of percentages between the treatment groups are based on the standard method based on the binomial distribution. 95% CIs for percentage estimates are based on the Wilson method. 95% CIs for the differences of percentage are based on the Newcombe method.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.554
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference of Responders
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.17
         upper limit
    		 0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.072
    Statistical analysis title
    		 Treatment Comparison PANSS Responders at Week 5
    Statistical analysis description
    Estimates of the percentage of responders in each treatment group and differences of percentages between the treatment groups are based on the standard method based on the binomial distribution. 95% CIs for percentage estimates are based on the Wilson method. 95% CIs for the differences of percentage are based on the Newcombe method.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.162
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference of Responders
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.063
    Statistical analysis title
    		 Treatment Comparison PANSS Responders at Week 5
    Statistical analysis description
    Estimates of the percentage of responders in each treatment group and differences of percentages between the treatment groups are based on the standard method based on the binomial distribution. 95% CIs for percentage estimates are based on the Wilson method. 95% CIs for the differences of percentage are based on the Newcombe method.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.05
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference of Responders
    Point estimate
    0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.01
         upper limit
    		 0.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.061
    Statistical analysis title
    		 Treatment Comparison PANSS Responders at Week 6
    Statistical analysis description
    Estimates of the percentage of responders in each treatment group and differences of percentages between the treatment groups are based on the standard method based on the binomial distribution. 95% CIs for percentage estimates are based on the Wilson method. 95% CIs for the differences of percentage are based on the Newcombe method.
    Comparison groups
    High Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference of Responders
    Point estimate
    0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 0.27
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.059
    Statistical analysis title
    		 Treatment Comparison PANSS Responders at Week 6
    Statistical analysis description
    Estimates of the percentage of responders in each treatment group and differences of percentages between the treatment groups are based on the standard method based on the binomial distribution. 95% CIs for percentage estimates are based on the Wilson method. 95% CIs for the differences of percentage are based on the Newcombe method.
    Comparison groups
    Low Dose Asenapine Maleate Transdermal Patch v Placebo
    Number of subjects included in analysis
    404
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Percentage Difference of Responders
    Point estimate
    0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.05
         upper limit
    		 0.27
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.058

    Secondary: Change From Baseline in Calgary Depression Scale for Schizophrenia (CDSS) Score at Each Time Point

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    End point title
    		 Change From Baseline in Calgary Depression Scale for Schizophrenia (CDSS) Score at Each Time Point
    End point description
    The CDSS is a 9-item scale designed for assessment of level of depression in patients with schizophrenia. Each of 9 items was rated on a 4-point scale, scored from 0 to 3. The first 8 items were rated on basis of responses during a semistructured interview conducted by a qualified clinician. The ninth item (Observed Depression) was rated by evaluating signs and symptoms over course of interview. ‎The total score was derived by adding each of 9 items together. Total scores of 6 or more identify presence of treatment emergent depression predictive of major depressive episodes. Results were presented for participants in the FAS who had data available for analysis. The FAS included all randomized participants who had at least 1 patch of double-blind study medication applied and who have a baseline PANSS total score and at least 1 post baseline assessment of the primary efficacy measure (PANSS total score). Here, "n" denotes number of participants analysed at each specific time point.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 0) through Week 6
    End point values
    		 High Dose Asenapine Maleate Transdermal Patch Low Dose Asenapine Maleate Transdermal Patch Placebo
    Number of subjects analysed
    203
    201
    201
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Change from baseline at Week 1 (n=203, 201, 201)
    -0.4 ± 1.82
    -0.4 ± 1.59
    -0.3 ± 1.58
        Change from baseline at Week 2 (n=194, 196, 193)
    -0.6 ± 1.87
    -0.7 ± 2.06
    -0.4 ± 1.99
        Change from baseline at Week 3 (n=187, 186, 185)
    -0.7 ± 2.03
    -0.7 ± 1.98
    -0.5 ± 1.97
        Change from baseline at Week 4 (n=182, 180, 179)
    -0.8 ± 2.05
    -1.0 ± 2.10
    -0.5 ± 2.36
        Change from baseline at Week 5 (n=174, 178, 173)
    -0.8 ± 1.99
    -0.9 ± 2.04
    -0.6 ± 2.14
        Change from baseline at Week 6 (n=164, 168, 164)
    -1.0 ± 1.93
    -1.0 ± 2.19
    -0.8 ± 1.73
    No statistical analyses for this end point

    Secondary: Medication Satisfaction Questionnaire (MSQ) Score at Each Time Point

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    End point title
    		 Medication Satisfaction Questionnaire (MSQ) Score at Each Time Point
    End point description
    The MSQ includes 1 simple question to ask patients about their satisfaction with their medication. A literature publication has evaluated of the psychometric properties in psychotic populations of the MSQ and found that responses to this 1 question were able to separate patients receiving active drug from those receiving placebo and was a good proxy for efficacy. As such, it was determined that a 1-point change on the MSQ may be considered clinically meaningful. Results were presented for participants in the FAS who had data available for analysis. The FAS included all randomized participants who had at least 1 patch of double-blind study medication applied and who have a baseline PANSS total score and at least 1 post baseline assessment of the primary efficacy measure (PANSS total score). Here, "n" denotes number of participants analysed at each specific time point.
    End point type
    Secondary
    End point timeframe
    Week 2, 4 and 6
    End point values
    		 High Dose Asenapine Maleate Transdermal Patch Low Dose Asenapine Maleate Transdermal Patch Placebo
    Number of subjects analysed
    199
    194
    192
    Units: Units on a scale
    arithmetic mean (standard deviation)
        At Week 2 (n=199, 194, 192)
    4.7 ± 1.30
    4.7 ± 1.28
    4.5 ± 1.34
        At Week 4 (n=184, 182, 181)
    5.1 ± 1.16
    5.0 ± 1.28
    4.7 ± 1.47
        At Week 6 (n=160, 169, 164)
    5.2 ± 1.29
    5.3 ± 1.26
    4.9 ± 1.46
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From date of first dose of double‑blind study medication (Day 1) through the 30 day follow-up period, approximately 72 days.
    Adverse event reporting additional description
    The safety analysis set included all participants who had at least 1 patch of double-blind study medication applied and who have at least 1 post dose safety measurement during the double-blind treatment period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    High Dose Asenapine Maleate Transdermal Patch
    Reporting group description
    		 Participants in the high dose asenapine maleate transdermal patch treatment arm received 2 asenapine maleate transdermal patches, once daily for 42 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants in the Placebo arm received 2 placebo (matching with HP-3070) transdermal patches, once daily for 42 days.

    Reporting group title
    Low Dose Asenapine Maleate Transdermal Patch
    Reporting group description
    		 Participants in the low dose asenapine maleate transdermal patch treatment arm received 1 asenapine maleate transdermal patch and 1 placebo (matching with HP-3070) transdermal patch, once daily for 42 days.

    Serious adverse events
    		 High Dose Asenapine Maleate Transdermal Patch Placebo Low Dose Asenapine Maleate Transdermal Patch
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 204 (0.98%)
    4 / 206 (1.94%)
    3 / 204 (1.47%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 204 (0.00%)
    1 / 206 (0.49%)
    0 / 204 (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
    Overdose
         subjects affected / exposed
    0 / 204 (0.00%)
    1 / 206 (0.49%)
    0 / 204 (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
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 204 (0.00%)
    0 / 206 (0.00%)
    1 / 204 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal ulcer haemorrhage
         subjects affected / exposed
    1 / 204 (0.49%)
    0 / 206 (0.00%)
    0 / 204 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Schizophrenia
         subjects affected / exposed
    1 / 204 (0.49%)
    2 / 206 (0.97%)
    2 / 204 (0.98%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 2
         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
    		 High Dose Asenapine Maleate Transdermal Patch Placebo Low Dose Asenapine Maleate Transdermal Patch
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    113 / 204 (55.39%)
    106 / 206 (51.46%)
    110 / 204 (53.92%)
    Investigations
    Weight increased
         subjects affected / exposed
    12 / 204 (5.88%)
    4 / 206 (1.94%)
    8 / 204 (3.92%)
         occurrences all number
    12
    4
    8
    Nervous system disorders
    Headache
         subjects affected / exposed
    19 / 204 (9.31%)
    13 / 206 (6.31%)
    18 / 204 (8.82%)
         occurrences all number
    21
    13
    23
    Extrapyramidal disorder
         subjects affected / exposed
    19 / 204 (9.31%)
    3 / 206 (1.46%)
    13 / 204 (6.37%)
         occurrences all number
    22
    4
    16
    General disorders and administration site conditions
    Application site erythema
         subjects affected / exposed
    20 / 204 (9.80%)
    3 / 206 (1.46%)
    19 / 204 (9.31%)
         occurrences all number
    57
    14
    105
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    9 / 204 (4.41%)
    9 / 206 (4.37%)
    11 / 204 (5.39%)
         occurrences all number
    11
    10
    12
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    14 / 204 (6.86%)
    23 / 206 (11.17%)
    15 / 204 (7.35%)
         occurrences all number
    16
    28
    21
    Anxiety
         subjects affected / exposed
    11 / 204 (5.39%)
    13 / 206 (6.31%)
    10 / 204 (4.90%)
         occurrences all number
    13
    19
    14
    Agitation
         subjects affected / exposed
    6 / 204 (2.94%)
    11 / 206 (5.34%)
    5 / 204 (2.45%)
         occurrences all number
    7
    14
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jan 2016
    Removal of the proportion of CGI-I responders from the key secondary efficacy objectives and endpoints, and related statistical analysis sections. Addition of an irritation assessment at the site of patch application performed daily between 30 and 60 minutes after patch removal. Clarification to the potential advantages of HP 3070 over the current sublingual formulation of asenapine.
    21 Nov 2016
    Update of the exclusion criteria and key personnel. Clarification of the study procedures.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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