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    Clinical Trial Results:
    A Multicenter, Double-Blind, Fixed-Dose, Long-Term Extension Trial of the Safety of Asenapine using Olanzapine as an Active Control in Subjects Diagnosed with Schizophrenia who Completed Protocol P05688 (formerly 041038) (Phase 3B, Protocol P05689 [formerly 041039])

    Summary
    EudraCT number
    		 2010-018408-96
    Trial protocol
    		 BG  
    Global end of trial date
    06 Mar 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Jan 2019
    First version publication date
    31 Jan 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    P05689
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01617200
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Forest Research Institute, Inc., an affiliate of Allergan, plc
    Sponsor organisation address
    185 Hudson Street, Jersey City, United States, NJ 07302
    Public contact
    Willie Earley, Forest Research Institute, Inc., an affiliate of Allergan, plc, Willie.Earley@Allergan.com
    Scientific contact
    Willie Earley, Forest Research Institute, Inc., an affiliate of Allergan, plc, Willie.Earley@Allergan.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
    06 Mar 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Mar 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Mar 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial was to evaluate the long-term safety of 2.5 and 5 milligram (mg) twice daily (BID) asenapine in schizophrenia subjects.
    Protection of trial subjects
    This trial was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 This was a long-term extension trial for subjects who had completed the 6-week short-term trial P05688. In the previous short-term trial, subjects had been randomly assigned to receive a fixed dose of asenapine (either 2.5 mg or 5 mg BID) or olanzapine 15 mg once daily (QD) or placebo (BID) for 6 weeks.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Mar 2013
    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: 33
    Country: Number of subjects enrolled
    Ukraine: 26
    Country: Number of subjects enrolled
    Bulgaria: 23
    Country: Number of subjects enrolled
    United States: 18
    Country: Number of subjects enrolled
    Romania: 13
    Country: Number of subjects enrolled
    Croatia: 7
    Worldwide total number of subjects
    120
    EEA total number of subjects
    43
    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)
    120
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 First participant enrolled: 12 March 2013; last participant completed: 6 Mar 2015. This study was performed at 39 sites across the United States, Bulgaria, Romania, Russian Federation, Croatia, and the Ukraine.

    Pre-assignment
    Screening details
    		 A total of 120 participants who had previously completed the short-term randomized trial P05688 continued in the current extension trial (P05689). Participants randomly assigned to asenapine or olanzapine in P05688 were assigned the same treatment regimen in P05689; participants randomly assigned to placebo were assigned to asenapine 2.5 mg BID.

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Placebo / Asenapine 2.5 mg
    Arm description
    		 In the previous short-term trial PO5688, participants were administered placebo for 42 days; in the current extension trial (PO5689), participants were administered one 2.5 mg asenapine tablet BID for 26 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Asenapine
    Investigational medicinal product code
    Asenapine
    Other name
    Pharmaceutical forms
    Sublingual tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    2.5 mg fast-dissolving active asenapine tablets administered sublingually

    Investigational medicinal product name
    Placebo Olanzapine
    Investigational medicinal product code
    Placebo Olanzapine
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Film-coated placebo olanzapine tablets (to match 5 and 10 mg active olanzapine tablets) administered orally

    Arm title
    		 Asenapine 2.5 mg / Asenapine 2.5 mg
    Arm description
    		 In the previous short-term trial PO5688, participants were administered one 2.5 mg asenapine tablet BID for 42 days; in the current extension trial (PO5689), participants were assigned to the same treatment regimen (ie, one 2.5 mg asenapine tablet BID) for 26 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Asenapine
    Investigational medicinal product code
    Asenapine
    Other name
    Pharmaceutical forms
    Sublingual tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    2.5 mg fast-dissolving active asenapine tablets administered sublingually

    Investigational medicinal product name
    Placebo Olanzapine
    Investigational medicinal product code
    Placebo Olanzapine
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Film-coated placebo olanzapine tablets (to match 5 and 10 mg active olanzapine tablets) administered orally

    Arm title
    		 Asenapine 2.5 mg Overall
    Arm description
    		 In the previous short-term trial PO5688, participants were administered either placebo or one 2.5 mg asenapine tablet BID for 42 days; in the current extension trial (PO5689), participants were administered one 2.5 mg asenapine tablet BID for 26 weeks. The 'asenapine 2.5 mg overall' arm represents the 'placebo / asenapine 2.5 mg' and 'asenapine 2.5 mg / asenapine 2.5 mg' arms combined.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Asenapine
    Investigational medicinal product code
    Asenapine
    Other name
    Pharmaceutical forms
    Sublingual tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    2.5 mg fast-dissolving active asenapine tablets administered sublingually

    Investigational medicinal product name
    Placebo Olanzapine
    Investigational medicinal product code
    Placebo Olanzapine
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Film-coated placebo olanzapine tablets (to match 5 and 10 mg active olanzapine tablets) administered orally

    Arm title
    		 Asenapine 5 mg / Asenapine 5 mg
    Arm description
    		 In the previous short-term trial PO5688, participants were administered one 5 mg asenapine tablet BID for 42 days; in the current extension trial (PO5689), participants were assigned to the same treatment regimen (ie, one 5 mg asenapine tablet BID) for 26 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Asenapine
    Investigational medicinal product code
    Asenapine
    Other name
    Pharmaceutical forms
    Sublingual tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    5 mg fast-dissolving active asenapine tablets administered sublingually

    Investigational medicinal product name
    Placebo Olanzapine
    Investigational medicinal product code
    Placebo Olanzapine
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Film-coated placebo olanzapine tablets (to match 5 and 10 mg active olanzapine tablets) administered orally

    Arm title
    		 Olanzapine 15 mg / Olanzapine 15 mg
    Arm description
    		 In the previous short-term trial PO5688, participants were administered 15 mg olanzapine (as one 10 mg and one 5 mg tablet) QD for 42 days (except during Week 1 when olanzapine 10 mg QD was administered); in the current extension trial (PO5689), participants were assigned to the same treatment regimen (ie, 15 mg olanzapine) for 26 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Olanzapine
    Investigational medicinal product code
    Olanzapine
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5 and 10 mg film-coated active olanzapine tablets administered orally QD. The time of the active olanzapine dose (either morning or evening) was not disclosed in order to preserve blinding

    Investigational medicinal product name
    Placebo Olanzapine
    Investigational medicinal product code
    Placebo Olanzapine
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Film-coated placebo olanzapine tablets (to match 5 and 10 mg active olanzapine tablets) administered orally

    Investigational medicinal product name
    Placebo Asenapine
    Investigational medicinal product code
    Placebo Asenapine
    Other name
    Pharmaceutical forms
    Sublingual tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    Fast dissolving placebo asenapine tablets (to match 2.5 mg and 5 mg active asenapine tablets) administered sublingually

    Number of subjects in period 1
    		Placebo / Asenapine 2.5 mg Asenapine 2.5 mg / Asenapine 2.5 mg Asenapine 2.5 mg Overall Asenapine 5 mg / Asenapine 5 mg Olanzapine 15 mg / Olanzapine 15 mg
    Started
    31
    31
    62
    42
    16
    Completed
    31
    28
    59
    32
    12
    Not completed
    0
    3
    3
    10
    4
         Consent withdrawn by subject
    -
    3
    3
    6
    1
         Adverse event, non-fatal
    -
    -
    -
    -
    2
         Lost to follow-up
    -
    -
    -
    1
    1
         Protocol deviation
    -
    -
    -
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo / Asenapine 2.5 mg
    Reporting group description
    		 In the previous short-term trial PO5688, participants were administered placebo for 42 days; in the current extension trial (PO5689), participants were administered one 2.5 mg asenapine tablet BID for 26 weeks.

    Reporting group title
    Asenapine 2.5 mg / Asenapine 2.5 mg
    Reporting group description
    		 In the previous short-term trial PO5688, participants were administered one 2.5 mg asenapine tablet BID for 42 days; in the current extension trial (PO5689), participants were assigned to the same treatment regimen (ie, one 2.5 mg asenapine tablet BID) for 26 weeks.

    Reporting group title
    Asenapine 2.5 mg Overall
    Reporting group description
    		 In the previous short-term trial PO5688, participants were administered either placebo or one 2.5 mg asenapine tablet BID for 42 days; in the current extension trial (PO5689), participants were administered one 2.5 mg asenapine tablet BID for 26 weeks. The 'asenapine 2.5 mg overall' arm represents the 'placebo / asenapine 2.5 mg' and 'asenapine 2.5 mg / asenapine 2.5 mg' arms combined.

    Reporting group title
    Asenapine 5 mg / Asenapine 5 mg
    Reporting group description
    		 In the previous short-term trial PO5688, participants were administered one 5 mg asenapine tablet BID for 42 days; in the current extension trial (PO5689), participants were assigned to the same treatment regimen (ie, one 5 mg asenapine tablet BID) for 26 weeks.

    Reporting group title
    Olanzapine 15 mg / Olanzapine 15 mg
    Reporting group description
    		 In the previous short-term trial PO5688, participants were administered 15 mg olanzapine (as one 10 mg and one 5 mg tablet) QD for 42 days (except during Week 1 when olanzapine 10 mg QD was administered); in the current extension trial (PO5689), participants were assigned to the same treatment regimen (ie, 15 mg olanzapine) for 26 weeks.

    Reporting group values
    		 Placebo / Asenapine 2.5 mg Asenapine 2.5 mg / Asenapine 2.5 mg Asenapine 2.5 mg Overall Asenapine 5 mg / Asenapine 5 mg Olanzapine 15 mg / Olanzapine 15 mg Total
    Number of subjects
    		 31 31 62 42 16
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 39.5 ± 10.05 41.1 ± 9.75 40.3 ± 9.86 39.5 ± 9.99 37.4 ± 12.45 -
    Gender Categorical
    Units: Subjects
        Male
    		 18 18 36 25 10 71
        Female
    		 13 13 26 17 6 49
    Weight
    Units: kilograms
        arithmetic mean (standard deviation)
    		 76.03 ± 16.102 79.72 ± 16.069 77.87 ± 16.061 75.08 ± 18.889 79.42 ± 16.481 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo / Asenapine 2.5 mg
    Reporting group description
    		 In the previous short-term trial PO5688, participants were administered placebo for 42 days; in the current extension trial (PO5689), participants were administered one 2.5 mg asenapine tablet BID for 26 weeks.

    Reporting group title
    Asenapine 2.5 mg / Asenapine 2.5 mg
    Reporting group description
    		 In the previous short-term trial PO5688, participants were administered one 2.5 mg asenapine tablet BID for 42 days; in the current extension trial (PO5689), participants were assigned to the same treatment regimen (ie, one 2.5 mg asenapine tablet BID) for 26 weeks.

    Reporting group title
    Asenapine 2.5 mg Overall
    Reporting group description
    		 In the previous short-term trial PO5688, participants were administered either placebo or one 2.5 mg asenapine tablet BID for 42 days; in the current extension trial (PO5689), participants were administered one 2.5 mg asenapine tablet BID for 26 weeks. The 'asenapine 2.5 mg overall' arm represents the 'placebo / asenapine 2.5 mg' and 'asenapine 2.5 mg / asenapine 2.5 mg' arms combined.

    Reporting group title
    Asenapine 5 mg / Asenapine 5 mg
    Reporting group description
    		 In the previous short-term trial PO5688, participants were administered one 5 mg asenapine tablet BID for 42 days; in the current extension trial (PO5689), participants were assigned to the same treatment regimen (ie, one 5 mg asenapine tablet BID) for 26 weeks.

    Reporting group title
    Olanzapine 15 mg / Olanzapine 15 mg
    Reporting group description
    		 In the previous short-term trial PO5688, participants were administered 15 mg olanzapine (as one 10 mg and one 5 mg tablet) QD for 42 days (except during Week 1 when olanzapine 10 mg QD was administered); in the current extension trial (PO5689), participants were assigned to the same treatment regimen (ie, 15 mg olanzapine) for 26 weeks.

    Primary: Change From Trial P05688 Baseline in Body Weight at Day 182

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    End point title
    		 Change From Trial P05688 Baseline in Body Weight at Day 182
    End point description
    Change from short-term trial (P05688) baseline in body weight at Day 182. Population for this analysis was the All Treated Set (ATS), defined as all randomized participants from the short-term trial who received ≥1 dose study drug in the current extension trial (P05689).
    End point type
    Primary
    End point timeframe
    Baseline (P05688) to Day 182
    End point values
    		 Placebo / Asenapine 2.5 mg Asenapine 2.5 mg / Asenapine 2.5 mg Asenapine 2.5 mg Overall Asenapine 5 mg / Asenapine 5 mg Olanzapine 15 mg / Olanzapine 15 mg
    Number of subjects analysed
    31
    31
    62
    42
    16
    Units: kilogram(s)
        least squares mean (standard error)
    1.2 ± 0.88
    0.1 ± 0.9
    0.6 ± 0.63
    0.8 ± 0.82
    1.2 ± 1.36
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Analysis was performed using a Mixed Model Repeated Measures (MMRM) for the ATS population. The model included change from short-term baseline (Trial P05688) score at each visit as the dependent variable, and terms for treatment, center, visit, treatment by visit interaction, and baseline weight as covariates. There was no multiple hypotheses testing for multiple comparisons.
    Comparison groups
    Asenapine 2.5 mg Overall v Olanzapine 15 mg / Olanzapine 15 mg
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS means difference
    Point estimate
    -0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.6
         upper limit
    		 2.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.49
    Statistical analysis title
    		 Comparison by Treatment Group
    Statistical analysis description
    Analysis was performed using MMRM for the ATS population. The model included change from short-term baseline (Trial P05688) score at each visit as the dependent variable, and terms for treatment, center, visit, treatment by visit interaction, and baseline weight as covariates. There was no multiple hypotheses testing for multiple comparisons.
    Comparison groups
    Asenapine 5 mg / Asenapine 5 mg v Olanzapine 15 mg / Olanzapine 15 mg
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 LS means difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.6
         upper limit
    		 2.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.59

    Secondary: Change From Trial P05688 Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Days 7, 28, 84, 182, and Study Endpoint

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    End point title
    		 Change From Trial P05688 Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at Days 7, 28, 84, 182, and Study Endpoint [1]
    End point description
    The PANSS is a 30-item clinician-rated instrument for assessing schizophrenia symptoms. It consists of 3 subscales: positive subscale (7 items), negative subscale (7 items), and general psychopathology subscale (16 items). For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS Total Score for each participant was sum of the rating assigned to each of the 30 PANSS items, and ranged from 30 to 210 with a higher score indicating greater severity of symptoms. The measure reports change from short-term trial baseline (P05688) at each specified visit, analysed using an analysis of covariance (ANCOVA) model adjusted for pooled investigative site and baseline values; improvement in symptoms is represented by negative values. Population for analysis was the Full Analysis Set (FAS), defined as all randomized participants from PO5688 who received ≥1 dose of study drug in PO5689 and had ≥1 post- PANSS Total Score measurement.
    End point type
    Secondary
    End point timeframe
    Baseline (P05688) and Days 7, 28, 84, 182, and Study Endpoint
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point "Change From Trial P05688 Baseline in PANSS Total Score" was assessed in each of the individual treatment arms: "Placebo / Asenapine 2.5 mg"; "Asenapine 2.5 mg / Asenapine 2.5 mg"; "Asenapine 5 mg / Asenapine 5 mg" and "Olanzapine 15 mg / Olanzapine 15 mg". The 'Asenapine 2.5 mg Overall' arm represents the 'Placebo / Asenapine 2.5 mg' and 'Asenapine 2.5 mg / Asenapine 2.5 mg' arms combined and this combined arm was not included for analysis of this secondary end point.
    End point values
    		 Placebo / Asenapine 2.5 mg Asenapine 2.5 mg / Asenapine 2.5 mg Asenapine 5 mg / Asenapine 5 mg Olanzapine 15 mg / Olanzapine 15 mg
    Number of subjects analysed
    31
    31
    42
    15
    Units: units on a scale
    least squares mean (standard error)
        Day 7 (n=28, 31, 40, 15)
    -24.7 ± 2.61
    -25.3 ± 2.5
    -27.7 ± 2.17
    -29.9 ± 3.56
        Day 28 (n=26, 27, 35, 13)
    -26.7 ± 2.55
    -28.3 ± 2.52
    -30.1 ± 2.2
    -28.8 ± 3.63
        Day 84 (n=24, 23, 30, 11)
    -28.1 ± 2.6
    -29.9 ± 2.69
    -30 ± 2.39
    -29.9 ± 3.95
        Day 182 (n=21, 19, 22, 8)
    -30.2 ± 2.51
    -28.5 ± 2.69
    -32.7 ± 2.53
    -36.4 ± 4.11
        Study Endpoint (n=31, 31, 42, 15)
    -25.3 ± 3.03
    -28.5 ± 3.02
    -28.2 ± 2.57
    -30.6 ± 4.32
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Are PANSS Responders (≥30% Reduction From Trial P05688 Baseline in PANSS Total Score) at Days 7, 28, 84, 182, and Study Endpoint

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    End point title
    		 Percentage of Participants Who Are PANSS Responders (≥30% Reduction From Trial P05688 Baseline in PANSS Total Score) at Days 7, 28, 84, 182, and Study Endpoint [2]
    End point description
    A PANSS responder was defined as a participant who had a reduction from baseline of at least 30% in the PANSS Total Score at a post-baseline assessment. Responder status was assessed relative to the short-term trial baseline (P05688). The PANSS is a 30-item clinician-rated instrument for assessing schizophrenia symptoms. For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The Total Score is the sum of the ratings for the individual items, and ranged from 30 to 210 with a higher score indicating greater severity of symptoms. Population for analysis was the FAS, defined as all randomized participants from PO5688 who received ≥1 dose of study drug in PO5689 and had ≥1 post- PANSS Total Score measurement.
    End point type
    Secondary
    End point timeframe
    Days 7, 28, 84, 182, and Study Endpoint
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point "Percentage of Participants Who Are PANSS Responders" was assessed in each of the individual treatment arms: "Placebo / Asenapine 2.5 mg"; "Asenapine 2.5 mg / Asenapine 2.5 mg"; "Asenapine 5 mg / Asenapine 5 mg" and "Olanzapine 15 mg / Olanzapine 15 mg". The 'Asenapine 2.5 mg Overall' arm represents the 'Placebo / Asenapine 2.5 mg' and 'Asenapine 2.5 mg / Asenapine 2.5 mg' arms combined and this combined arm was not included for analysis of this secondary end point.
    End point values
    		 Placebo / Asenapine 2.5 mg Asenapine 2.5 mg / Asenapine 2.5 mg Asenapine 5 mg / Asenapine 5 mg Olanzapine 15 mg / Olanzapine 15 mg
    Number of subjects analysed
    31
    31
    42
    15
    Units: Percentage of responders
    number (not applicable)
        Day 7 (n=28, 31, 40, 15)
    39.3
    45.2
    42.5
    53.3
        Day 28 (n=26, 27, 35, 13)
    50
    48.1
    57.1
    53.8
        Day 84 (n=24, 23, 30, 11)
    58.3
    52.2
    63.3
    63.6
        Day 182 (n=21, 19, 22, 8)
    66.7
    47.4
    68.2
    62.5
        Study Endpoint (n=31, 31, 42, 15)
    48.4
    51.6
    47.6
    46.7
    No statistical analyses for this end point

    Secondary: Change From Trial P05688 Baseline in Clinical Global Impression Scale-Severity (CGI-S) Score at Days 7, 14, 28, 56, 84, 112, 182, and Study Endpoint

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    End point title
    		 Change From Trial P05688 Baseline in Clinical Global Impression Scale-Severity (CGI-S) Score at Days 7, 14, 28, 56, 84, 112, 182, and Study Endpoint [3]
    End point description
    The CGI-S is a 7-point scale for assessing the global severity of the participant’s illness, with ratings from 1=normal, not ill to 7=very severely ill. The reported measure is the change from short-term trial baseline (P05688) at each specified visit, analysed using an ANCOVA model adjusted for pooled investigative site and baseline values; improvement in symptoms is represented by negative values. Population for analysis was the FAS, defined as all randomized participants from PO5688 who received ≥1 dose of study drug in PO5689 and had ≥1 post- PANSS Total Score measurement.
    End point type
    Secondary
    End point timeframe
    Baseline (P05688 ) and Days 7, 14, 28, 56, 84, 112, 182, and Study Endpoint
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point "Change From Trial P05688 Baseline in CGI-S Score" was assessed in each of the individual treatment arms: "Placebo / Asenapine 2.5 mg"; "Asenapine 2.5 mg / Asenapine 2.5 mg"; "Asenapine 5 mg / Asenapine 5 mg" and "Olanzapine 15 mg / Olanzapine 15 mg". The 'Asenapine 2.5 mg Overall' arm represents the 'Placebo / Asenapine 2.5 mg' and 'Asenapine 2.5 mg / Asenapine 2.5 mg' arms combined and this combined arm was not included for analysis of this secondary end point.
    End point values
    		 Placebo / Asenapine 2.5 mg Asenapine 2.5 mg / Asenapine 2.5 mg Asenapine 5 mg / Asenapine 5 mg Olanzapine 15 mg / Olanzapine 15 mg
    Number of subjects analysed
    31
    31
    42
    15
    Units: units on a scale
    least squares mean (standard error)
        Day 7 (n=28, 31, 40, 15)
    -1.6 ± 0.17
    -1.4 ± 0.16
    -1.5 ± 0.14
    -1.3 ± 0.23
        Day 14 (n=28, 30, 40, 14)
    -1.4 ± 0.16
    -1.2 ± 0.15
    -1.5 ± 0.13
    -1 ± 0.22
        Day 28 (n=26, 27, 35, 13)
    -1.6 ± 0.17
    -1.3 ± 0.17
    -1.4 ± 0.15
    -1.4 ± 0.24
        Day 56 (n=28, 28, 32, 11)
    -1.6 ± 0.16
    -1.4 ± 0.16
    -1.3 ± 0.15
    -1.6 ± 0.26
        Day 84 (n=24, 23, 30, 11)
    -1.6 ± 0.17
    -1.4 ± 0.18
    -1.5 ± 0.16
    -1.5 ± 0.26
        Day 112 (n=24, 22, 29, 10)
    -1.8 ± 0.17
    -1.5 ± 0.19
    -1.5 ± 0.17
    -1.9 ± 0.28
        Day 182 (n=21, 19, 22, 8)
    -1.9 ± 0.2
    -1.4 ± 0.22
    -1.5 ± 0.21
    -1.8 ± 0.33
        Study Endpoint (n=31, 31, 42, 15)
    -1.5 ± 0.21
    -1.4 ± 0.21
    -1.3 ± 0.18
    -1.3 ± 0.29
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Are Clinical Global Impression Scale-Improvement (CGI-I) Responders at Days 7, 14, 28, 56, 84, 112, 182, and Study Endpoint

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    End point title
    		 Percentage of Participants Who Are Clinical Global Impression Scale-Improvement (CGI-I) Responders at Days 7, 14, 28, 56, 84, 112, 182, and Study Endpoint [4]
    End point description
    A CGI-I responder was defined as a participant who had a CGI-I score of 1 (very much improved) or 2 (much improved) at a post-baseline assessment. Responder status was assessed relative to the short-term trial baseline (P05688). CGI-I is a 7-point scale for assessing the global improvement of the participant’s illness relative to baseline, with ratings from 1=very much improved to 7=very much worse. Population for analysis was the FAS, defined as all randomized participants from PO5688 who received ≥1 dose of study drug in PO5689 and had ≥1 post- PANSS Total Score measurement.
    End point type
    Secondary
    End point timeframe
    Days 7, 14, 28, 56, 84, 112, 182, and Study Endpoint
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point "Percentage of Participants Who Are CGI-I Responders" was assessed in each of the individual treatment arms: "Placebo / Asenapine 2.5 mg"; "Asenapine 2.5 mg / Asenapine 2.5 mg"; "Asenapine 5 mg / Asenapine 5 mg" and "Olanzapine 15 mg / Olanzapine 15 mg". The 'Asenapine 2.5 mg Overall' arm represents the 'Placebo / Asenapine 2.5 mg' and 'Asenapine 2.5 mg / Asenapine 2.5 mg' arms combined and this combined arm was not included for analysis of this secondary end point.
    End point values
    		 Placebo / Asenapine 2.5 mg Asenapine 2.5 mg / Asenapine 2.5 mg Asenapine 5 mg / Asenapine 5 mg Olanzapine 15 mg / Olanzapine 15 mg
    Number of subjects analysed
    31
    31
    42
    15
    Units: Percentage of responders
    number (not applicable)
        Day 7 (n=28, 31, 40, 15)
    71.4
    77.4
    70
    80
        Day 14 (n=28, 30, 40, 14)
    64.3
    76.7
    80
    71.4
        Day 28 (n=26, 27, 35, 13)
    76.9
    85.2
    82.9
    84.6
        Day 56 (n=28, 28, 32, 11)
    78.6
    92.9
    75
    81.8
        Day 84 (n=24, 23, 30, 11)
    79.2
    87
    80
    90.9
        Day 112 (n=24, 22, 29, 10)
    83.3
    86.4
    86.2
    90
        Day 182 (n=21, 19, 22, 8)
    85.7
    94.7
    86.4
    87.5
        Study Endpoint (n=31, 31, 42, 15)
    64.5
    90.3
    69
    80
    No statistical analyses for this end point

    Secondary: PANSS Negative Subscale Score at Days 7, 28, 84, 182, and Study Endpoint

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    End point title
    		 PANSS Negative Subscale Score at Days 7, 28, 84, 182, and Study Endpoint [5]
    End point description
    This measure reports results for the 7 items of the negative subscale of the PANSS, which is a 30-item clinician-rated instrument used to assess schizophrenia symptoms. Negative symptoms represent a diminution or loss of normal functions (e.g., emotional withdrawal). For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. PANSS negative subscale score for each participant was sum of the rating assigned to each of the 7 subscale items, and ranged from 7 to 49 with a higher score indicating greater severity of symptoms. Population for analysis was the FAS, defined as all randomized participants from PO5688 who received ≥1 dose of study drug in PO5689 and had ≥1 post- PANSS Total Score measurement.
    End point type
    Secondary
    End point timeframe
    Days 7, 28, 84, 182, and Study Endpoint
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point "PANSS Negative Subscale Score" was assessed in each of the individual treatment arms: "Placebo / Asenapine 2.5 mg"; "Asenapine 2.5 mg / Asenapine 2.5 mg"; "Asenapine 5 mg / Asenapine 5 mg" and "Olanzapine 15 mg / Olanzapine 15 mg". The 'Asenapine 2.5 mg Overall' arm represents the 'Placebo / Asenapine 2.5 mg' and 'Asenapine 2.5 mg / Asenapine 2.5 mg' arms combined and this combined arm was not included for analysis of this secondary end point.
    End point values
    		 Placebo / Asenapine 2.5 mg Asenapine 2.5 mg / Asenapine 2.5 mg Asenapine 5 mg / Asenapine 5 mg Olanzapine 15 mg / Olanzapine 15 mg
    Number of subjects analysed
    31
    31
    42
    15
    Units: units on a scale
    arithmetic mean (standard deviation)
        Day 7 (n=28, 31, 40, 15)
    19.8 ± 4.53
    18.5 ± 5.15
    18.7 ± 5.94
    18.2 ± 5.7
        Day 28 (n=26, 27, 35, 13)
    19.3 ± 5
    17.8 ± 4.59
    18.2 ± 5.33
    18.2 ± 5.34
        Day 84 (n=24, 23, 30, 11)
    19.1 ± 4.78
    19.2 ± 3.31
    18 ± 5.05
    18.5 ± 4.99
        Day 182 (n=21, 19, 22, 8)
    18.1 ± 4.13
    18.9 ± 3.83
    16.6 ± 5.72
    18.6 ± 3.78
        Study Endpoint (n=31, 31, 42, 15)
    18.6 ± 4.72
    19.1 ± 5.42
    18.2 ± 6.1
    18.4 ± 5.25
    No statistical analyses for this end point

    Secondary: PANSS Positive Subscale Score at Days 7, 28, 84, 182, and Study Endpoint

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    End point title
    		 PANSS Positive Subscale Score at Days 7, 28, 84, 182, and Study Endpoint [6]
    End point description
    This measure reports results for the 7 items of the positive subscale of the PANSS, which is a 30-item clinician-rated instrument used to assess schizophrenia symptoms. Positive symptoms refer to an excess or distortion of normal mental status (e.g., delusions). For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. PANSS positive subscale score for each participant was sum of the rating assigned to each of the 7 subscale items, and ranged from 7 to 49 with a higher score indicating greater severity of symptoms. Population for analysis was the FAS, defined as all randomized participants from PO5688 who received ≥1 dose of study drug in PO5689 and had ≥1 post- PANSS Total Score measurement.
    End point type
    Secondary
    End point timeframe
    Days 7, 28, 84, 182, and Study Endpoint
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point "PANSS Positive Subscale Score" was assessed in each of the individual treatment arms: "Placebo / Asenapine 2.5 mg"; "Asenapine 2.5 mg / Asenapine 2.5 mg"; "Asenapine 5 mg / Asenapine 5 mg" and "Olanzapine 15 mg / Olanzapine 15 mg". The 'Asenapine 2.5 mg Overall' arm represents the 'Placebo / Asenapine 2.5 mg' and 'Asenapine 2.5 mg / Asenapine 2.5 mg' arms combined and this combined arm was not included for analysis of this secondary end point.
    End point values
    		 Placebo / Asenapine 2.5 mg Asenapine 2.5 mg / Asenapine 2.5 mg Asenapine 5 mg / Asenapine 5 mg Olanzapine 15 mg / Olanzapine 15 mg
    Number of subjects analysed
    31
    31
    42
    15
    Units: units on a scale
    arithmetic mean (standard deviation)
        Day 7 (n=28, 31, 40, 15)
    15.5 ± 4.86
    15.8 ± 5.36
    15 ± 3.88
    14.9 ± 3.92
        Day 28 (n=26, 27, 35, 13)
    15 ± 4.19
    14.5 ± 4.26
    14.7 ± 4.08
    14.8 ± 3.78
        Day 84 (n=24, 23, 30, 11)
    14.3 ± 3.6
    13.3 ± 4.1
    14 ± 4.44
    13.5 ± 2.25
        Day 182 (n=21, 19, 22, 8)
    13.9 ± 4.39
    13.9 ± 4.08
    13.6 ± 4.63
    11.1 ± 2.1
        Study Endpoint (n=31, 31, 42, 15)
    16.2 ± 5.91
    14.5 ± 5.69
    15.5 ± 5
    14.2 ± 4.93
    No statistical analyses for this end point

    Secondary: PANSS General Psychopathology Subscale Score at Days 7, 28, 84, 182, and Study Endpoint

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    End point title
    		 PANSS General Psychopathology Subscale Score at Days 7, 28, 84, 182, and Study Endpoint [7]
    End point description
    This measure reports results for the 16 items of the general psychopathology subscale of the PANSS, which is a 30-item clinician-rated instrument used to assess the symptoms of schizophrenia. For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. The PANSS general psychopathology subscale score for each participant was calculated as the sum of the rating assigned to each of the 16 subscale items, and ranged from 16 to 112 with a higher score indicating greater severity of symptoms. Population for analysis was the FAS, defined as all randomized participants from PO5688 who received ≥1 dose of study drug in PO5689 and had ≥1 post- PANSS Total Score measurement.
    End point type
    Secondary
    End point timeframe
    Days 7, 28, 84, 182, and Study Endpoint
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point "PANSS General Psychopathology Subscale Score" was assessed in each of the individual treatment arms: "Placebo / Asenapine 2.5 mg"; "Asenapine 2.5 mg / Asenapine 2.5 mg"; "Asenapine 5 mg / Asenapine 5 mg" and "Olanzapine 15 mg / Olanzapine 15 mg". The 'Asenapine 2.5 mg Overall' arm represents the 'Placebo / Asenapine 2.5 mg' and 'Asenapine 2.5 mg / Asenapine 2.5 mg' arms combined and this combined arm was not included for analysis of this secondary end point.
    End point values
    		 Placebo / Asenapine 2.5 mg Asenapine 2.5 mg / Asenapine 2.5 mg Asenapine 5 mg / Asenapine 5 mg Olanzapine 15 mg / Olanzapine 15 mg
    Number of subjects analysed
    31
    31
    42
    15
    Units: units on a scale
    arithmetic mean (standard deviation)
        Day 7 (n=28, 31, 40, 15)
    32.5 ± 7.07
    34.4 ± 8.88
    32.8 ± 7.87
    28.7 ± 5.47
        Day 28 (n=26, 27, 35, 13)
    31.5 ± 7.21
    31.8 ± 7.05
    31.3 ± 7.55
    29.3 ± 5.3
        Day 84 (n=24, 23, 30, 11)
    31.3 ± 6.59
    31.1 ± 8.52
    31.8 ± 8.12
    28.8 ± 4.14
        Day 182 (n=21, 19, 22, 8)
    29.9 ± 7.24
    31.4 ± 6.65
    30.7 ± 8.73
    25.6 ± 3.25
        Study Endpoint (n=31, 31, 42, 15)
    32.9 ± 9.23
    31.7 ± 9.14
    32.8 ± 9.15
    28.3 ± 7.72
    No statistical analyses for this end point

    Secondary: PANSS Marder Factor Positive Symptom Score at Days 7, 28, 84, 182, and Study Endpoint

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    End point title
    		 PANSS Marder Factor Positive Symptom Score at Days 7, 28, 84, 182, and Study Endpoint [8]
    End point description
    This measure reports results for the 8 items of the Marder positive symptom factor of the PANSS, which is a 30-item clinician-rated instrument used to assess schizophrenia symptoms. Marder factors are a modified grouping of the 30 PANSS items. For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. PANSS Marder factor positive symptom score for each participant was sum of rating assigned to each of the 8 applicable Marder factor items, and ranged from 8 to 56 with a higher score indicating greater severity of symptoms. Population for analysis was the FAS, defined as all randomized participants from PO5688 who received ≥1 dose of study drug in PO5689 and had ≥1 post- PANSS Total Score measurement.
    End point type
    Secondary
    End point timeframe
    Days 7, 28, 84, 182, and Study Endpoint
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point "PANSS Marder Factor Positive Symptom Score" was assessed in each of the individual treatment arms: "Placebo / Asenapine 2.5 mg"; "Asenapine 2.5 mg / Asenapine 2.5 mg"; "Asenapine 5 mg / Asenapine 5 mg" and "Olanzapine 15 mg / Olanzapine 15 mg". The 'Asenapine 2.5 mg Overall' arm represents the 'Placebo / Asenapine 2.5 mg' and 'Asenapine 2.5 mg / Asenapine 2.5 mg' arms combined and this combined arm was not included for analysis of this secondary end point.
    End point values
    		 Placebo / Asenapine 2.5 mg Asenapine 2.5 mg / Asenapine 2.5 mg Asenapine 5 mg / Asenapine 5 mg Olanzapine 15 mg / Olanzapine 15 mg
    Number of subjects analysed
    31
    31
    42
    15
    Units: units on a scale
    arithmetic mean (standard deviation)
        Day 7 (n=28, 31, 40, 15)
    19.1 ± 5.43
    19.5 ± 6.31
    19 ± 5.29
    18.9 ± 4.81
        Day 28 (n=26, 27, 35, 13)
    18.7 ± 5.31
    18 ± 5.18
    18.3 ± 5.27
    18.6 ± 5.06
        Day 84 (n=24, 23, 30, 11)
    17.9 ± 5.08
    16.6 ± 5.44
    17.9 ± 5.93
    17.1 ± 2.84
        Day 182 (n=21, 19, 22, 8)
    17.3 ± 5.62
    17.7 ± 4.78
    17.5 ± 6.22
    14 ± 2.56
        Study Endpoint (n=31, 31, 42, 15)
    19.4 ± 6.52
    17.9 ± 6.12
    19.2 ± 6.13
    17.7 ± 6.07
    No statistical analyses for this end point

    Secondary: PANSS Marder Factor Negative Symptom Score at Days 7, 28, 84, 182, and Study Endpoint

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    End point title
    		 PANSS Marder Factor Negative Symptom Score at Days 7, 28, 84, 182, and Study Endpoint [9]
    End point description
    This measure reports results for the 7 items of the Marder negative symptoms factor of the PANSS, which is a 30-item clinician-rated instrument used to assess schizophrenia symptoms. Marder factors are a modified grouping of the 30 PANSS items. For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. PANSS Marder factor negative symptom score for each participant was sum of the rating assigned to each of the 7 applicable Marder factor items, and ranged from 7 to 49 with a higher score indicating greater severity of symptoms. Population for analysis was the FAS, defined as all randomized participants from PO5688 who received ≥1 dose of study drug in PO5689 and had ≥1 post- PANSS Total Score measurement.
    End point type
    Secondary
    End point timeframe
    Days 7, 28, 84, 182, and Study Endpoint
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point "PANSS Marder Factor Negative Symptom Score" was assessed in each of the individual treatment arms: "Placebo / Asenapine 2.5 mg"; "Asenapine 2.5 mg / Asenapine 2.5 mg"; "Asenapine 5 mg / Asenapine 5 mg" and "Olanzapine 15 mg / Olanzapine 15 mg". The 'Asenapine 2.5 mg Overall' arm represents the 'Placebo / Asenapine 2.5 mg' and 'Asenapine 2.5 mg / Asenapine 2.5 mg' arms combined and this combined arm was not included for analysis of this secondary end point.
    End point values
    		 Placebo / Asenapine 2.5 mg Asenapine 2.5 mg / Asenapine 2.5 mg Asenapine 5 mg / Asenapine 5 mg Olanzapine 15 mg / Olanzapine 15 mg
    Number of subjects analysed
    31
    31
    42
    15
    Units: units on a scale
    arithmetic mean (standard deviation)
        Day 7 (n=28, 31, 40, 15)
    18.6 ± 4.1
    17.4 ± 5.45
    17.2 ± 5.48
    16.4 ± 5.6
        Day 28 (n=26, 27, 35, 13)
    17.9 ± 4.29
    16.7 ± 4.88
    16.7 ± 4.97
    16.6 ± 5.24
        Day 84 (n=24, 23, 30, 11)
    17.5 ± 4.66
    18 ± 3.78
    16.4 ± 4.67
    16.5 ± 5.72
        Day 182 (n=21, 19, 22, 8)
    16.5 ± 3.76
    17.3 ± 4.18
    15.5 ± 5.28
    17 ± 4.14
        Study Endpoint (n=31, 31, 42, 15)
    17 ± 4.66
    17.7 ± 5.41
    16.6 ± 5.71
    16.8 ± 5.16
    No statistical analyses for this end point

    Secondary: PANSS Marder Factor Disorganized Thought Symptom Score at Days 7, 28, 84, 182, and Study Endpoint

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    End point title
    		 PANSS Marder Factor Disorganized Thought Symptom Score at Days 7, 28, 84, 182, and Study Endpoint [10]
    End point description
    This measure reports results for the 7 items of the Marder disorganized thoughts factor of the PANSS, which is a 30-item clinician-rated instrument used to assess schizophrenia symptoms. Marder factors are a modified grouping of the 30 PANSS items. For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. PANSS Marder factor disorganized thought symptom score for each participant was sum of rating assigned to each of the 7 applicable Marder factor items, and ranged from 7 to 49 with a higher score indicating greater severity of symptoms. Population for analysis was the FAS, defined as all randomized participants from PO5688 who received ≥1 dose of study drug in PO5689 and had ≥1 post- PANSS Total Score measurement.
    End point type
    Secondary
    End point timeframe
    Days 7, 28, 84, 182, and Study Endpoint
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point "PANSS Marder Factor Disorganized Thought Symptom Score" was assessed in each of the individual treatment arms: "Placebo / Asenapine 2.5 mg"; "Asenapine 2.5 mg / Asenapine 2.5 mg"; "Asenapine 5 mg / Asenapine 5 mg" and "Olanzapine 15 mg / Olanzapine 15 mg". The 'Asenapine 2.5 mg Overall' arm represents the 'Placebo / Asenapine 2.5 mg' and 'Asenapine 2.5 mg / Asenapine 2.5 mg' arms combined and this combined arm was not included for analysis of this secondary end point.
    End point values
    		 Placebo / Asenapine 2.5 mg Asenapine 2.5 mg / Asenapine 2.5 mg Asenapine 5 mg / Asenapine 5 mg Olanzapine 15 mg / Olanzapine 15 mg
    Number of subjects analysed
    31
    31
    42
    15
    Units: units on a scale
    arithmetic mean (standard deviation)
        Day 7 (n=28, 31, 40, 15)
    17.2 ± 4.63
    17.4 ± 4.45
    16.6 ± 4.24
    16.1 ± 4.23
        Day 28 (n=26, 27, 35, 13)
    16.4 ± 4.54
    16.3 ± 4.01
    16.3 ± 3.98
    16.1 ± 3.38
        Day 84 (n=24, 23, 30, 11)
    16.8 ± 4.41
    16 ± 3.59
    16.3 ± 4.3
    15.7 ± 3.1
        Day 182 (n=21, 19, 22, 8)
    15.7 ± 4.49
    16.1 ± 3.54
    15.5 ± 4.87
    14.6 ± 2.72
        Study Endpoint (n=31, 31, 42, 15)
    16.7 ± 4.52
    16.4 ± 4.94
    16.5 ± 4.52
    15.1 ± 4.36
    No statistical analyses for this end point

    Secondary: PANSS Marder Factor Hostility/Excitement Symptom Score at Days 7, 28, 84, 182, and Study Endpoint

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    End point title
    		 PANSS Marder Factor Hostility/Excitement Symptom Score at Days 7, 28, 84, 182, and Study Endpoint [11]
    End point description
    This measure reports results for the 4 items of the Marder hostility/excitement factor of the PANSS, which is a 30-item clinician-rated instrument used to assess schizophrenia symptoms. Marder factors are a modified grouping of the 30 PANSS items. For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. PANSS Marder factor hostility/excitement symptom score for each participant was sum of rating assigned to each of the 4 applicable Marder factor items, and ranged from 4 to 28 with a higher score indicating greater severity of symptoms. Population for analysis was the FAS, defined as all randomized participants from PO5688 who received ≥1 dose of study drug in PO5689 and had ≥1 post- PANSS Total Score measurement.
    End point type
    Secondary
    End point timeframe
    Days 7, 28, 84, 182, and Study Endpoint
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point "PANSS Marder Factor Hostility/Excitement Symptom Score" was assessed in each of the individual treatment arms: "Placebo / Asenapine 2.5 mg"; "Asenapine 2.5 mg / Asenapine 2.5 mg"; "Asenapine 5 mg / Asenapine 5 mg" and "Olanzapine 15 mg / Olanzapine 15 mg". The 'Asenapine 2.5 mg Overall' arm represents the 'Placebo / Asenapine 2.5 mg' and 'Asenapine 2.5 mg / Asenapine 2.5 mg' arms combined and this combined arm was not included for analysis of this secondary end point.
    End point values
    		 Placebo / Asenapine 2.5 mg Asenapine 2.5 mg / Asenapine 2.5 mg Asenapine 5 mg / Asenapine 5 mg Olanzapine 15 mg / Olanzapine 15 mg
    Number of subjects analysed
    31
    31
    42
    15
    Units: units on a scale
    arithmetic mean (standard deviation)
        Day 7 (n=28, 31, 40, 15)
    6 ± 2.46
    6.9 ± 3.26
    6.9 ± 2.67
    5.3 ± 1.44
        Day 28 (n=26, 27, 35, 13)
    6.2 ± 2.43
    6.3 ± 2.05
    6.6 ± 2.6
    5.5 ± 1.61
        Day 84 (n=24, 23, 30, 11)
    6.2 ± 2.5
    5.9 ± 1.86
    6.2 ± 2.42
    5.8 ± 1.72
        Day 182 (n=21, 19, 22, 8)
    5.9 ± 2.39
    5.8 ± 1.72
    6.5 ± 2.52
    4.9 ± 0.99
        Study Endpoint (n=31, 31, 42, 15)
    6.8 ± 3.66
    6.1 ± 2.66
    7 ± 2.85
    5.4 ± 1.76
    No statistical analyses for this end point

    Secondary: PANSS Marder Factor Anxiety/Depression Symptom Score at Days 7, 28, 84, 182, and Study Endpoint

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    End point title
    		 PANSS Marder Factor Anxiety/Depression Symptom Score at Days 7, 28, 84, 182, and Study Endpoint [12]
    End point description
    This measure reports results for the 4 items of the Marder anxiety/depression factor of the PANSS, which is a 30-item clinician-rated instrument used to assess schizophrenia symptoms. Marder factors are a modified grouping of the 30 PANSS items. For each item, symptom severity was rated on a 7-point scale, from 1=absent to 7=extreme. PANSS Marder factor anxiety/depression symptom score for each participant was sum of rating assigned to each of the 4 applicable Marder factor items, and ranged from 4 to 28 with a higher score indicating greater severity of symptoms. Population for analysis was the FAS, defined as all randomized participants from PO5688 who received ≥1 dose of study drug in PO5689 and had ≥1 post- PANSS Total Score measurement.
    End point type
    Secondary
    End point timeframe
    Days 7, 28, 84, 182, and Study Endpoint
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point "PANSS Marder Factor Anxiety/Depression Symptom Score" was assessed in each of the individual treatment arms: "Placebo / Asenapine 2.5 mg"; "Asenapine 2.5 mg / Asenapine 2.5 mg"; "Asenapine 5 mg / Asenapine 5 mg" and "Olanzapine 15 mg / Olanzapine 15 mg". The 'Asenapine 2.5 mg Overall' arm represents the 'Placebo / Asenapine 2.5 mg' and 'Asenapine 2.5 mg / Asenapine 2.5 mg' arms combined and this combined arm was not included for analysis of this secondary end point.
    End point values
    		 Placebo / Asenapine 2.5 mg Asenapine 2.5 mg / Asenapine 2.5 mg Asenapine 5 mg / Asenapine 5 mg Olanzapine 15 mg / Olanzapine 15 mg
    Number of subjects analysed
    31
    31
    42
    15
    Units: units on a scale
    arithmetic mean (standard deviation)
        Day 7 (n=28, 31, 40, 15)
    6.9 ± 2.38
    7.5 ± 3.35
    6.9 ± 2.94
    5.3 ± 1.53
        Day 28 (n=26, 27, 35, 13)
    6.6 ± 2.71
    6.8 ± 3.15
    6.4 ± 2.95
    5.5 ± 1.85
        Day 84 (n=24, 23, 30, 11)
    6.3 ± 2.22
    7 ± 3.4
    6.9 ± 3.27
    5.7 ± 1.56
        Day 182 (n=21, 19, 22, 8)
    6.5 ± 2.75
    7.3 ± 3.58
    6.1 ± 2.62
    4.9 ± 1.36
        Study Endpoint (n=31, 31, 42, 15)
    7.8 ± 3.57
    7.1 ± 3.6
    7.1 ± 3.62
    5.9 ± 2.55
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 30 days after last dose of study drug (up to approximately 30 weeks)
    Adverse event reporting additional description
    Analysis population was the ATS which included all randomized subjects from the short-term trial (PO5688) who received ≥1 dose of study drug in the current extension trial (PO5689).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Placebo / Asenapine 2.5 mg
    Reporting group description
    		 In the previous short-term trial PO5688, participants were administered placebo for 42 days; in the current extension trial (PO5689), participants were administered one 2.5 mg asenapine tablet BID for 26 weeks.

    Reporting group title
    Asenapine 2.5 mg / Asenapine 2.5 mg
    Reporting group description
    		 In the previous short-term trial PO5688, participants were administered one 2.5 mg asenapine tablet BID for 42 days; in the current extension trial (PO5689), participants were assigned to the same treatment regimen (ie, one 2.5 mg asenapine tablet BID) for 26 weeks.

    Reporting group title
    Asenapine 2.5 mg Overall
    Reporting group description
    		 In the previous short-term trial PO5688, participants were administered either placebo or one 2.5 mg asenapine tablet BID for 42 days; in the current extension trial (PO5689), participants were administered one 2.5 mg asenapine tablet BID for 26 weeks.

    Reporting group title
    Asenapine 5 mg / Asenapine 5 mg
    Reporting group description
    		 In the previous short-term trial PO5688, participants were administered one 5 mg asenapine tablet BID for 42 days; in the current extension trial (PO5689), participants were assigned to the same treatment regimen (ie, one 5 mg asenapine tablet BID) for 26 weeks.

    Reporting group title
    Olanzapine 15 mg / Olanzapine 15 mg
    Reporting group description
    		 In the previous short-term trial PO5688, participants were administered 15 mg olanzapine (as one 10 mg and one 5 mg tablet) QD for 42 days (except during Week 1 when olanzapine 10 mg QD was administered); in the current extension trial (PO5689), participants were assigned to the same treatment regimen (ie, 15 mg olanzapine) for 26 weeks.

    Serious adverse events
    		 Placebo / Asenapine 2.5 mg Asenapine 2.5 mg / Asenapine 2.5 mg Asenapine 2.5 mg Overall Asenapine 5 mg / Asenapine 5 mg Olanzapine 15 mg / Olanzapine 15 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 31 (16.13%)
    3 / 31 (9.68%)
    8 / 62 (12.90%)
    6 / 42 (14.29%)
    2 / 16 (12.50%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Nervous system disorders
    Psychomotor Hyperactivity
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    1 / 62 (1.61%)
    0 / 42 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    1 / 62 (1.61%)
    0 / 42 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Schizophrenia
         subjects affected / exposed
    1 / 31 (3.23%)
    3 / 31 (9.68%)
    4 / 62 (6.45%)
    5 / 42 (11.90%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 4
    3 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia,Paranoid Type
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 31 (0.00%)
    2 / 62 (3.23%)
    0 / 42 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal Ideation
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 62 (0.00%)
    1 / 42 (2.38%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 62 (0.00%)
    0 / 42 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    1 / 62 (1.61%)
    0 / 42 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    1 / 62 (1.61%)
    0 / 42 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo / Asenapine 2.5 mg Asenapine 2.5 mg / Asenapine 2.5 mg Asenapine 2.5 mg Overall Asenapine 5 mg / Asenapine 5 mg Olanzapine 15 mg / Olanzapine 15 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 31 (54.84%)
    9 / 31 (29.03%)
    26 / 62 (41.94%)
    12 / 42 (28.57%)
    6 / 16 (37.50%)
    Investigations
    Weight Increased
         subjects affected / exposed
    4 / 31 (12.90%)
    1 / 31 (3.23%)
    5 / 62 (8.06%)
    1 / 42 (2.38%)
    0 / 16 (0.00%)
         occurrences all number
    4
    1
    5
    1
    0
    Weight Decreased
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 31 (3.23%)
    2 / 62 (3.23%)
    0 / 42 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    1
    1
    2
    0
    1
    Blood Creatine Phosphokinase Increased
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 31 (0.00%)
    2 / 62 (3.23%)
    0 / 42 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    3
    0
    3
    0
    0
    Blood Insulin Increased
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 31 (0.00%)
    2 / 62 (3.23%)
    0 / 42 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    2
    0
    0
    Blood Pressure Increased
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 62 (0.00%)
    1 / 42 (2.38%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    1
    1
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 31 (3.23%)
    2 / 62 (3.23%)
    3 / 42 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    1
    1
    2
    3
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 31 (0.00%)
    2 / 62 (3.23%)
    1 / 42 (2.38%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    2
    1
    0
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 31 (3.23%)
    3 / 62 (4.84%)
    2 / 42 (4.76%)
    1 / 16 (6.25%)
         occurrences all number
    3
    1
    4
    2
    1
    Akathisia
         subjects affected / exposed
    3 / 31 (9.68%)
    0 / 31 (0.00%)
    3 / 62 (4.84%)
    1 / 42 (2.38%)
    0 / 16 (0.00%)
         occurrences all number
    3
    0
    3
    1
    0
    Parkinsonism
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 31 (3.23%)
    3 / 62 (4.84%)
    1 / 42 (2.38%)
    0 / 16 (0.00%)
         occurrences all number
    2
    1
    3
    1
    0
    Dyskinesia
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 62 (0.00%)
    0 / 42 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Bronchitis Chronic
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 62 (0.00%)
    0 / 42 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 62 (0.00%)
    0 / 42 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 31 (12.90%)
    3 / 31 (9.68%)
    7 / 62 (11.29%)
    2 / 42 (4.76%)
    0 / 16 (0.00%)
         occurrences all number
    4
    3
    7
    5
    0
    Anxiety
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 31 (3.23%)
    1 / 62 (1.61%)
    0 / 42 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    1
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 31 (0.00%)
    1 / 62 (1.61%)
    1 / 42 (2.38%)
    1 / 16 (6.25%)
         occurrences all number
    1
    0
    1
    1
    1
    Pulmonary Tuberculosis
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 62 (0.00%)
    0 / 42 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Urinary Tract Infection
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 31 (0.00%)
    0 / 62 (0.00%)
    0 / 42 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Jan 2012
    • In the list of medications prohibited prior to baseline and during trial, 'antiemetics containing dopamine agonist' was changed to 'antiemetics containing dopamine antagonists'. • The lists of urinalysis tests was updated to include urine pregnancy test, urine drug screen, nitrite, urobilinogen, and leukocyte esterase and deleted microscopic examination. • The Serious Adverse Event (SAE) section was updated to include 'cancer' as SAE outcome #6. • Text regarding drug induced liver injury was updated, including text on monitoring liver enzymes to align with Merck standards and latest guidance of the Food and Drug Administration. • Two additional closely monitored events were added: “suicidal ideation and/or behavior” and “drug hypersensitivity reactions”. • Text regarding medication errors in three sections of the protocol was deleted. • “Incidents associated with the device” was deleted from the list of events requiring expedited reporting of safety observations by the investigator to the sponsor. • In the Tier 3 list of safety endpoints, “heart rate” was replaced with “pulse rate”.

    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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