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    Clinical Trial Results:
    A Double-Blind, Placebo-Controlled Trial of Asenapine in the Prevention of Recurrence of a Mood Episode After Stabilization of an Acute Manic/Mixed Episode in Subjects With Bipolar 1 Disorder (Phase 3B, Protocol P06384)

    Summary
    EudraCT number
    2010-018671-20
    Trial protocol
    BG  
    Global end of trial date
    30 Apr 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Jun 2016
    First version publication date
    12 Jun 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    P06384
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01396291
    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, +1 201-427-8257, Willie.Earley@Allergan.com
    Scientific contact
    Willie Earley, Forest Research Institute, Inc., an affiliate of Allergan, plc, +1 201-427-8257, 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
    30 Apr 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Apr 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy and safety of asenapine compared with placebo in preventing the recurrence of any mood episodes.
    Protection of trial subjects
    This trial had investigator meetings at the outset to review all protocol procedures and investigator responsibilities under Good Clinical Practice (GCP). At the meeting, the conduct of the trial was explained and instructions were provided to ensure accuracy and consistency in data collection. This trial was conducted in conformance with GCP 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. One trial site participating in this trial was identified as having issues related to significant non-compliance associated with some/all requirements of GCP and hence their participation was terminated.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Jan 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Bulgaria: 57
    Country: Number of subjects enrolled
    Croatia: 25
    Country: Number of subjects enrolled
    India: 46
    Country: Number of subjects enrolled
    Philippines: 29
    Country: Number of subjects enrolled
    Romania: 34
    Country: Number of subjects enrolled
    Russian Federation: 21
    Country: Number of subjects enrolled
    Serbia: 57
    Country: Number of subjects enrolled
    Turkey: 19
    Country: Number of subjects enrolled
    Ukraine: 32
    Country: Number of subjects enrolled
    United States: 229
    Worldwide total number of subjects
    549
    EEA total number of subjects
    116
    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)
    532
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This trial was conducted at 87 trial centers: 7 in Bulgaria, 6 in Croatia, 7 in Romania, 6 in Russia, 7 in Serbia, 3 in Turkey, 7 in the Ukraine, 4 in the Philippines, 8 in India, and 32 in the United States.

    Pre-assignment
    Screening details
    This trial consisted of a Screening/2-day Wait Period; a 12-16-week, open-label, asenapine active treatment period followed by a 26-week, double-blind, placebo-controlled period; and a 30-day Follow-up Period.

    Period 1
    Period 1 title
    Open-Label Treatment Period
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    This was an open-label treatment period.

    Arms
    Arm title
    Open-Label Treatment
    Arm description
    For the Open-Label Treatment Period, participants were assigned to asenapine 10 mg BID (flexible-dosing of asenapine 5 mg BID -10 mg BID was to begin on Day 2) for a period of at least 12 and up to 16 weeks. In the event of intolerability during the Open-Label Treatment Period, down-titration to asenapine 5 mg BID was permitted. Participants who cannot tolerate an asenapine 5 mg BID dose were discontinued from the trial. For participants who were down-titrated, subsequent rechallenge with asenapine 10 mg BID was attempted as the final target dose for the stabilization phase of the Open-Label Treatment Period.
    Arm type
    Experimental

    Investigational medicinal product name
    Asenapine 10 mg BID
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    Participants were treated initially with open-label asenapine, with a starting and target dose of asenapine 10 mg BID (flexible dosing asenapine 5 -10 mg BID) for a period of at least 12 and up to 16 weeks.

    Number of subjects in period 1
    Open-Label Treatment
    Started
    549
    Completed
    253
    Not completed
    296
         Consent withdrawn by subject
    35
         Administrative
    8
         Adverse event
    91
         Lost to follow-up
    29
         Lack of efficacy
    45
         Protocol deviation
    88
    Period 2
    Period 2 title
    Double-Blind Treatment Period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Carer, Assessor, Subject
    Blinding implementation details
    The packaging and labeling of the study medication were designed to maintain the double-blind design of the trial. The study medication included active and placebo fast-dissolving asenapine tablets. Asenapine and asenapine-matched placebo tablets were made to look identical in appearance. The interactive voice response system was used to assign a starting dose of asenapine based on the participant's last dose during Open-Label Treatment Period.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Double-Blind Treatment Period - Placebo
    Arm description
    During the Double-Blind Treatment Period, participants randomized to placebo received placebo tablets. In the event of intolerability, down-titration was permitted starting at Day 2, but no subsequent rechallenge during the Double-Blind Treatment Period was permitted.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    Participants randomized to placebo received sub-lingual asenapine-matched placebo tablets 5-10 mg BID up to 26 Weeks.

    Arm title
    Double-Blind Treatment Period - Asenapine
    Arm description
    During the Double-Blind Treatment Period, participants randomized to asenapine received sub-lingual asenapine tablets 5-10 mg BID up to 26 Weeks. The starting dose of double-blind trial medication was the final asenapine dose used in the Open-Label Treatment Period. The starting dose of double-blind trial medication was the evening dose of the Double-Blind Baseline Visit. In the event of intolerability, down-titration was permitted starting at Day 2, but no subsequent rechallenge during the Double-Blind Treatment Period was permitted.
    Arm type
    Experimental

    Investigational medicinal product name
    Asenapine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Sublingual use
    Dosage and administration details
    Participants randomized to asenapine received sub-lingual asenapine tablets 5-10 mg BID up to 26 Weeks.

    Number of subjects in period 2 [1]
    Double-Blind Treatment Period - Placebo Double-Blind Treatment Period - Asenapine
    Started
    126
    126
    Completed
    70
    101
    Not completed
    56
    25
         Consent withdrawn by subject
    6
    7
         Adverse event
    25
    9
         Recurrence
    18
    4
         Lost to follow-up
    3
    3
         Protocol deviation
    4
    2
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Please note that one participant completed the Open-Label period and was randomized in the Double-Blind period. The patient discontinued the study due to an AE in the Double–Blind period however did not start Double-Blind study medication. Therefore, this participant and their AE, including the AE leading to the discontinuation is included in the Open–Label period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Open-Label Treatment
    Reporting group description
    For the Open-Label Treatment Period, participants were assigned to asenapine 10 mg BID (flexible-dosing of asenapine 5 mg BID -10 mg BID was to begin on Day 2) for a period of at least 12 and up to 16 weeks. In the event of intolerability during the Open-Label Treatment Period, down-titration to asenapine 5 mg BID was permitted. Participants who cannot tolerate an asenapine 5 mg BID dose were discontinued from the trial. For participants who were down-titrated, subsequent rechallenge with asenapine 10 mg BID was attempted as the final target dose for the stabilization phase of the Open-Label Treatment Period.

    Reporting group values
    Open-Label Treatment Total
    Number of subjects
    549 549
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    532 532
        From 65-84 years
    17 17
        85 years and over
    0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    41.8 ( 12.9 ) -
    Gender categorical
    Units: Subjects
        Female
    310 310
        Male
    239 239

    End points

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    End points reporting groups
    Reporting group title
    Open-Label Treatment
    Reporting group description
    For the Open-Label Treatment Period, participants were assigned to asenapine 10 mg BID (flexible-dosing of asenapine 5 mg BID -10 mg BID was to begin on Day 2) for a period of at least 12 and up to 16 weeks. In the event of intolerability during the Open-Label Treatment Period, down-titration to asenapine 5 mg BID was permitted. Participants who cannot tolerate an asenapine 5 mg BID dose were discontinued from the trial. For participants who were down-titrated, subsequent rechallenge with asenapine 10 mg BID was attempted as the final target dose for the stabilization phase of the Open-Label Treatment Period.
    Reporting group title
    Double-Blind Treatment Period - Placebo
    Reporting group description
    During the Double-Blind Treatment Period, participants randomized to placebo received placebo tablets. In the event of intolerability, down-titration was permitted starting at Day 2, but no subsequent rechallenge during the Double-Blind Treatment Period was permitted.

    Reporting group title
    Double-Blind Treatment Period - Asenapine
    Reporting group description
    During the Double-Blind Treatment Period, participants randomized to asenapine received sub-lingual asenapine tablets 5-10 mg BID up to 26 Weeks. The starting dose of double-blind trial medication was the final asenapine dose used in the Open-Label Treatment Period. The starting dose of double-blind trial medication was the evening dose of the Double-Blind Baseline Visit. In the event of intolerability, down-titration was permitted starting at Day 2, but no subsequent rechallenge during the Double-Blind Treatment Period was permitted.

    Primary: Percentage of participants with recurrence of any mood event during the Double-Blind (DB) Treatment Period.

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    End point title
    Percentage of participants with recurrence of any mood event during the Double-Blind (DB) Treatment Period.
    End point description
    The primary efficacy endpoint for the current trial is time to recurrence of any mood event during the Double-Blind Treatment Period, defined as any of the following: 1) Requirement or initiation of any non-study medication to treat mixed, manic, or depressive symptoms, including an antipsychotic, antidepressant, or mood-stabilizing agent; 2) Requirement or initiation of psychiatric hospitalization; 3) Discontinuation from the study because of a mood event (as determined by the investigator); or 4) Young Mania Rating Scale (Y-MRS) and/ or Montgomery Asberg Depression Rating Scale (MADRS) score ≥16. The assignment of the specific mood episode type (manic or depressed or mixed) were made by the study investigator, based on clinical judgment and verified by the rating scale data.
    End point type
    Primary
    End point timeframe
    From Week 12 or 16 to Week 38 or 42
    End point values
    Double-Blind Treatment Period - Placebo Double-Blind Treatment Period - Asenapine
    Number of subjects analysed
    126
    126
    Units: percentage of participants
    number (not applicable)
        With Recurrence
    33.3
    8.7
        Initiation of any non-study medication
    23.8
    5.6
        Initiation of psychiatric hospitalization
    4.8
    1.6
        Discontinuation from the study due to mood event
    23
    5.6
        Y-MRS and/or MADRS score ≥16
    30.2
    8.7
    Statistical analysis title
    Time to first recurrence of any mood episode
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.22
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.11
         upper limit
    0.43

    Secondary: Mean change from Baseline in Y-MRS total score by visit in Open-Label Treatment Period.

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    End point title
    Mean change from Baseline in Y-MRS total score by visit in Open-Label Treatment Period.
    End point description
    Y-MRS instrument consists of 11 items. Each item is rated on a defined step scale of 0 to 4 (Elevated mood; Increased motor activity–energy; Sexual interest; Sleep; Language thought disorder; Appearance; Insight) or 0 to 8 (Irritability; Speech; Content; Disruptive-aggressive behavior). The total score ranges from 0 (all symptoms absent) to 60 (all symptoms extreme).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Open-Label Treatment
    Number of subjects analysed
    516
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 1 (N= 447)
    -6.4 ( 6 )
        Week 2 (N= 484)
    -10.4 ( 7.6 )
        Week 4 (N= 427)
    -14.6 ( 7.6 )
        Week 6 (N= 389)
    -17.5 ( 7.4 )
        Week 8 (N= 353)
    -20.2 ( 7 )
        Week 10 (N=323)
    -21.5 ( 6.5 )
        Week 12 (N= 293)
    -22.5 ( 6.3 )
        Week 14 (N= 229)
    -23.2 ( 6.4 )
        Week 16 (N= 142)
    -23.3 ( 6.4 )
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in MADRS total score by visit in Open-Label Treatment Period.

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    End point title
    Mean change from Baseline in MADRS total score by visit in Open-Label Treatment Period.
    End point description
    MADRS is a 10-item, clinician-rated scale for assessing the severity of symptoms of depression. The MADRS interview was conducted early in each applicable visit to avoid negatively impacting diagnostic and primary outcome data due to participant fatigue. A structured interview for the MADRS (structured interview guide for the Montgomery-Åsberg Depression Rating Scale [SIGMA]) was used. The MADRS total score is the sum of the 10 items and ranges from 0 to 60. A high numeric rating implies a greater degree of symptom severity.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Open-Label Treatment
    Number of subjects analysed
    516
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 4 (N= 427)
    -4.4 ( 6.2 )
        Week 6 (N= 389)
    -5.1 ( 6.8 )
        Week 8 (N= 353)
    -5.8 ( 6.5 )
        Week 10 (N= 323)
    -6.1 ( 6.1 )
        Week 12 (N= 293)
    -6.7 ( 5.9 )
        Week 14 (N= 229)
    -6.5 ( 5.6 )
        Week 16 (N= 142)
    -7 ( 6.7 )
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in PANSS total score by visit in Open-Label Treatment Period.

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    End point title
    Mean change from Baseline in PANSS total score by visit in Open-Label Treatment Period.
    End point description
    The PANSS is a 30-item, clinician rate instrument for assessing the symptoms of schizophrenia and consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS total score was the sum of the rating scores for 7 positive scale items, 7 negative scale items, and 16 general psychopathology scale items from the PANSS panel. The PANSS total score ranged from 30 (best possible outcome) to 210 (worst possible outcome).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Open-Label Treatment
    Number of subjects analysed
    516
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 4 (N= 427)
    -9.6 ( 10.8 )
        Week 16 (N= 141)
    -15.6 ( 10.2 )
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in PANSS positive score by visit in Open-Label Treatment Period.

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    End point title
    Mean change from Baseline in PANSS positive score by visit in Open-Label Treatment Period.
    End point description
    The PANSS is a 30-item, clinician rate instrument for assessing the symptoms of schizophrenia and consisted of 3 subscales were a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicated (absence of symptoms) and a score of 7 indicated (extremely severe symptoms). The 7 positive symptom constructs were delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. The PANSS Positive Score ranged from 7 (best possible outcome) to 49 (worst possible outcome).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Open-Label Treatment
    Number of subjects analysed
    516
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 4 (N=427)
    -4.2 ( 4.4 )
        Week 16 (N=141)
    -6.3 ( 4.2 )
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in PANSS negative score by visit in Open-Label Treatment Period.

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    End point title
    Mean change from Baseline in PANSS negative score by visit in Open-Label Treatment Period.
    End point description
    The PANSS is a 30-item, clinician rate instrument for assessing the symptoms of schizophrenia and consisted of 3 subscales were a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicated (absence of symptoms) and a score of 7 indicated (extremely severe symptoms).The 7 negative symptom constructs: blunted affect, emotional withdrawal, poor rapport, passive apathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. The PANSS Negative Score ranged from 7(best possible outcome) to 49 (worst possible outcome).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Open-Label Treatment
    Number of subjects analysed
    516
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 4 (N=427)
    -0.5 ( 2.5 )
        Weel 16 (N= 141)
    -1 ( 1.9 )
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in PANSS general psychopathology score by visit in Open-Label Treatment Period.

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    End point title
    Mean change from Baseline in PANSS general psychopathology score by visit in Open-Label Treatment Period.
    End point description
    The PANSS is a 30-item, clinician rate instrument for assessing the symptoms of schizophrenia and consisted of 3 subscales were a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicated (absence of symptoms) and a score of 7 indicated (extremely severe symptoms). The 16 general psychopathology symptom constructs were Somatic concern, Anxiety, Guilt feelings, Tension, Mannerisms and posturing, Depression, Motor retardation, Uncooperativeness, Unusual thought content, Disorientation, Poor attention, Lack of judgment and insight, Disturbance of volition, Poor impulse control, Preoccupation, and Active social avoidance. The PANSS general psychopathology score ranged from 16 (best possible outcome) to 112 (worst possible outcome).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Open-Label Treatment
    Number of subjects analysed
    516
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 4 (N=427)
    -5 ( 6 )
        Week 16 (N=141)
    -8.4 ( 6 )
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in PANSS marder factor positive symptom score by visit in Open-Label Treatment Period.

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    End point title
    Mean change from Baseline in PANSS marder factor positive symptom score by visit in Open-Label Treatment Period.
    End point description
    PANSS marder factor positive symptom factor score defined by the sum of (PANSS Items P1, P3, P5, P6, N7, G1, G9, G12). If any one of the component items has a missing value then the Marder Factor Positive Symptom Score is missing. Each item is rated from 1 (absent) to 7 (extreme) and the symptom score ranges from 8 to 56. Higher scores indicate greater severity of illness.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Open-Label Treatment
    Number of subjects analysed
    516
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 4 (N=427)
    -2.9 ( 4.1 )
        Week 16 (N=141)
    -4.6 ( 4 )
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in PANSS marder factor negative symptom score by visit in Open-Label Treatment Period.

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    End point title
    Mean change from Baseline in PANSS marder factor negative symptom score by visit in Open-Label Treatment Period.
    End point description
    PANSS marder factor negative symptom factor score defined by sum of (PANSS items N1, N2, N3, N4, N6, G7, G16). If any one of the component items has a missing value then the Marder Factor Negative Symptom Score is missing. Each item is rated from 1 (absent) to 7 (extreme) and the symptom score ranges from 7 to 49. Higher scores indicate greater severity of illness.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Open-Label Treatment
    Number of subjects analysed
    516
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 4 (N=427)
    -0.3 ( 2.5 )
        Week 16 (N=141)
    -0.5 ( 2 )
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in PANSS marder factor disorganized thought symptom score by visit in Open-Label Treatment Period.

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    End point title
    Mean change from Baseline in PANSS marder factor disorganized thought symptom score by visit in Open-Label Treatment Period.
    End point description
    PANSS marder factor disorganized thought symptom factor score defined by sum of (PANSS items P2, N5, G5, G10, G11, G13, G15). If any one of the component items has a missing value then the Marder Factor Disorganized Thought Symptom Score is missing. Each item is rated from 1 (absent) to 7 (extreme) and the symptom score ranges from 7 to 49. Higher scores indicate greater severity of illness.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Open-Label Treatment
    Number of subjects analysed
    516
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 4 (N=427)
    -1.9 ( 3 )
        Week 16 (N=141)
    -3.2 ( 3.1 )
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in PANSS marder factor hostility/excitement symptom score by visit in Open-Label Treatment Period.

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    End point title
    Mean change from Baseline in PANSS marder factor hostility/excitement symptom score by visit in Open-Label Treatment Period.
    End point description
    PANSS marder factor hostility/ excitement symptom score is defined as the sum of (items P4, P7, G8, G14). If any one of the component items has a missing value then the Marder Factor Hostility/Excitement Symptom Score is missing. Each item is rated from 1 (absent) to 7 (extreme) and the symptom score ranges from 4 to 28. Higher scores indicate greater severity of illness.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Open-Label Treatment
    Number of subjects analysed
    516
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 4 (N=427)
    -3.1 ( 3 )
        Week 16 (N=141)
    -4.9 ( 3.3 )
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in PANSS marder factor anxiety/depression symptom score by visit in Open-Label Treatment Period.

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    End point title
    Mean change from Baseline in PANSS marder factor anxiety/depression symptom score by visit in Open-Label Treatment Period.
    End point description
    PANSS marder factor anxiety/depression symptom score is defined as the sum of (items G2, G3, G4, G6). If any one of the component items has a missing value then the Marder Factor Anxiety/Depression Symptom Score is missing. Each item is rated from 1 (absent) to 7 (extreme) and the symptom score ranges from 4 to 28. Higher scores indicate greater severity of illness.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Open-Label Treatment
    Number of subjects analysed
    516
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 4 (N=427)
    -1.5 ( 2.7 )
        Week 16 (N= 141)
    -2.3 ( 2.9 )
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in Clinical Global Impression Scale-Improvement for Bipolar Disorder (CGI-BP) severity of mania by visit during Open-Label Treatment Period.

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    End point title
    Mean change from Baseline in Clinical Global Impression Scale-Improvement for Bipolar Disorder (CGI-BP) severity of mania by visit during Open-Label Treatment Period.
    End point description
    It is a 7-point scale where, for each condition, 1 = Not at all ill; 2 = Borderline ill; 3 = Mildly ill; 4 = Moderately ill; 5 = Markedly ill; 6 = Severely ill; and 7 = Among the most extremely ill.
    End point type
    Secondary
    End point timeframe
    Baseline in Week 16
    End point values
    Open-Label Treatment
    Number of subjects analysed
    516
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 1 (N= 447)
    -0.6 ( 0.8 )
        Week 2 (N= 484)
    -1 ( 1 )
        Week 4 (N= 427)
    -1.6 ( 1 )
        Week 6 (N= 389)
    -2 ( 1.1 )
        Week 8 (N= 353)
    -2.4 ( 1 )
        Week 10 (N=323)
    -2.6 ( 0.9 )
        Week 12 (N= 293)
    -2.7 ( 0.9 )
        Week 14 (N= 229)
    -2.8 ( 0.9 )
        Week 16 (N= 142)
    -2.9 ( 0.9 )
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in CGI-BP severity of depression by visit during Open-Label Treatment Period.

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    End point title
    Mean change from Baseline in CGI-BP severity of depression by visit during Open-Label Treatment Period.
    End point description
    It is a 7-point scale where, for each condition, 1 = Not at all ill; 2 = Borderline ill; 3 = Mildly ill; 4 = Moderately ill; 5 = Markedly ill; 6 = Severely ill; and 7 = Among the most extremely ill.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Open-Label Treatment
    Number of subjects analysed
    516
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 1 (N= 447)
    -0.2 ( 0.7 )
        Week 2 (N= 484)
    -0.3 ( 0.9 )
        Week 4 (N= 427)
    -0.3 ( 1.1 )
        Week 6 (N= 389)
    -0.4 ( 1.1 )
        Week 8 (N= 353)
    -0.4 ( 1.1 )
        Week 10 (N=323)
    -0.4 ( 1.1 )
        Week 12 (N= 293)
    -0.4 ( 1.1 )
        Week 14 (N= 229)
    -0.4 ( 1 )
        Week 16 (N= 142)
    -0.6 ( 1.2 )
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in CGI-BP severity of overall bipolar illness by visit during Open-Label Treatment Period.

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    End point title
    Mean change from Baseline in CGI-BP severity of overall bipolar illness by visit during Open-Label Treatment Period.
    End point description
    It is a 7-point scale where, for each condition, 1 = Not at all ill; 2 = Borderline ill; 3 = Mildly ill; 4 = Moderately ill; 5 = Markedly ill; 6 = Severely ill; and 7 = Among the most extremely ill.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Open-Label Treatment
    Number of subjects analysed
    516
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Week 1 (N= 447)
    -0.6 ( 0.8 )
        Week 2 (N= 482)
    -1 ( 0.9 )
        Week 4 (N= 427)
    -1.6 ( 1 )
        Week 6 (N= 389)
    -2 ( 1 )
        Week 8 (N= 353)
    -2.3 ( 1 )
        Week 10 (N=323)
    -2.5 ( 0.9 )
        Week 12 (N= 293)
    -2.7 ( 0.9 )
        Week 14 (N= 229)
    -2.7 ( 0.9 )
        Week 16 (N= 142)
    -2.8 ( 0.9 )
    No statistical analyses for this end point

    Secondary: Percentage of participants with remission of mania by visit in Open-Label Treatment Period.

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    End point title
    Percentage of participants with remission of mania by visit in Open-Label Treatment Period.
    End point description
    Remission of mania is defined as Y-MRS total score of ≤12 at 2 consecutive post open-label baseline visits.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Open-Label Treatment
    Number of subjects analysed
    516
    Units: percentage of participants
    number (not applicable)
        Week 1 (N= 447)
    0
        Week 2 (N= 484)
    8.3
        Week 4 (N= 427)
    25.8
        Week 6 (N= 389)
    43.7
        Week 8 (N= 353)
    62.6
        Week 10 (N=323)
    88.5
        Week 12 (N= 293)
    90.8
        Week 14 (N= 229)
    90.4
        Week 16 (N= 142)
    86.6
    No statistical analyses for this end point

    Secondary: Percentage of participants of Y-MRS 50% responders by visit in Open-Label Treatment Period.

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    End point title
    Percentage of participants of Y-MRS 50% responders by visit in Open-Label Treatment Period.
    End point description
    Y-MRS 50% responder is defined as a Y-MRS total score reduction of at least 50% compared to open-label baseline.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Open-Label Treatment
    Number of subjects analysed
    516
    Units: Percentage of participants
    number (not applicable)
        Week 1 (N= 447)
    13
        Week 2 (N= 484)
    31
        Week 4 (N= 427)
    56.2
        Week 6 (N= 389)
    75.6
        Week 8 (N= 353)
    90.9
        Week 10 (N=323)
    97.2
        Week 12 (N= 293)
    96.2
        Week 14 (N= 229)
    96.9
        Week 16 (N= 142)
    97.9
    No statistical analyses for this end point

    Secondary: Percentage of participants with remission of depression by visit in Open-Label Treatment Period.

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    End point title
    Percentage of participants with remission of depression by visit in Open-Label Treatment Period.
    End point description
    Remission of depression is defined as MADRS total score of 12 or lower at 2 consecutive post open-label baseline visits during the open-label treatment period for participants with an open-label baseline MADRS of 16 or higher.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Open-Label Treatment
    Number of subjects analysed
    516
    Units: percentage of participants
    number (not applicable)
        Week 4 (N= 427)
    0
        Week 6 (N= 389)
    9.3
        Week 8 (N= 353)
    9.3
        Week 10 (N=323)
    11.8
        Week 12 (N= 293)
    11.6
        Week 14 (N= 229)
    10.9
        Week 16 (N= 142)
    12
    No statistical analyses for this end point

    Secondary: Percentage of participants of MADRS 50% responder by visit in Open-Label Treatment Period.

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    End point title
    Percentage of participants of MADRS 50% responder by visit in Open-Label Treatment Period.
    End point description
    MADRS 50% responder is defined as a MADRS total score reduction of at least 50%, compared to open-label baseline in subset of participants with open-label baseline MADRS score of 16 or higher.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Open-Label Treatment
    Number of subjects analysed
    516
    Units: percentage of participants
    number (not applicable)
        Week 4 (N= 414)
    10.1
        Week 6 (N= 377)
    11.1
        Week 8 (N= 342)
    10.8
        Week 10 (N= 314)
    11.8
        Week 12 (N= 285)
    11.6
        Week 14 (N= 221)
    10.4
        Week 16 (N= 138)
    16.7
    No statistical analyses for this end point

    Secondary: Percentage of participants in CGI-BP mania responder rates by visit in Open-Label Treatment Period.

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    End point title
    Percentage of participants in CGI-BP mania responder rates by visit in Open-Label Treatment Period.
    End point description
    CGI-BP mania responder rate is defined as change of much improved or very much improved in mania from open-label baseline.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Open-Label Treatment
    Number of subjects analysed
    516
    Units: percentage of participants
    number (not applicable)
        Week 1 (N= 447)
    24.4
        Week 2 (N= 482)
    41.7
        Week 4 (N= 427)
    69.8
        Week 6 (N= 389)
    81.7
        Week 8 (N= 353)
    91.2
        Week 10 (N=323)
    95.4
        Week 12 (N= 293)
    96.9
        Week 14 (N= 229)
    96.5
        Week 16 (N= 142)
    97.2
    No statistical analyses for this end point

    Secondary: Percentage of participants in CGI-BP depression responder rates by visit in Open-Label Treatment Period.

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    End point title
    Percentage of participants in CGI-BP depression responder rates by visit in Open-Label Treatment Period.
    End point description
    CGI-BP depression responder rate is defined as change of much improved or very much improved in depression from open-label baseline.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Open-Label Treatment
    Number of subjects analysed
    516
    Units: percentage of participants
    number (not applicable)
        Week 1 (N= 447)
    13
        Week 2 (N= 482)
    18.3
        Week 4 (N= 427)
    23.2
        Week 6 (N= 389)
    23.9
        Week 8 (N= 353)
    26.9
        Week 10 (N=323)
    28.8
        Week 12 (N= 293)
    30
        Week 14 (N= 229)
    26.6
        Week 16 (N= 142)
    29.6
    No statistical analyses for this end point

    Secondary: Percentage of participants in CGI-BP bipolar illness responder rates by visit in Open-Label Treatment Period.

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    End point title
    Percentage of participants in CGI-BP bipolar illness responder rates by visit in Open-Label Treatment Period.
    End point description
    The CGI-I is a 7-point scale where, 1 = Very much improved; 2 = Much improved; 3 = Minimally improved; 4 = No change; 5 = Minimally worse; 6 = Much worse; and 7 = Very much worse.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Open-Label Treatment
    Number of subjects analysed
    516
    Units: percentage of participants
    number (not applicable)
        Week 1 (N= 447)
    23.9
        Week 2 (N= 482)
    39.8
        Week 4 (N= 427)
    65.1
        Week 6 (N= 389)
    78.4
        Week 8 (N= 353)
    87.8
        Week 10 (N=323)
    92
        Week 12 (N= 293)
    95.6
        Week 14 (N= 229)
    94.3
        Week 16 (N= 142)
    95.8
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in Y-MRS total score by visit in DB Treatment Period.

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    End point title
    Mean change from Baseline in Y-MRS total score by visit in DB Treatment Period.
    End point description
    Y-MRS instrument consists of 11 items. Each item is rated on a defined step scale of 0 to 4 (Elevated mood; Increased motor activity–energy; Sexual interest; Sleep; Language thought disorder; Appearance; Insight) or 0 to 8 (Irritability; Speech; Content; Disruptive-aggressive behavior). The total score ranges from 0 (all symptoms absent) to 60 (all symptoms extreme).
    End point type
    Secondary
    End point timeframe
    Baseline to DB Week 26
    End point values
    Double-Blind Treatment Period - Placebo Double-Blind Treatment Period - Asenapine
    Number of subjects analysed
    126
    126
    Units: units on a scale
    least squares mean (standard error)
        DB Week 2 (N= 123, 119)
    0.1 ( 0.2 )
    0 ( 0.2 )
        DB Week 4 (N= 109, 115)
    0.4 ( 0.3 )
    0 ( 0.3 )
        DB Week 6 (N= 104, 113)
    -0.2 ( 0.3 )
    -0.3 ( 0.3 )
        DB Week 8 (N= 98, 106)
    0.3 ( 0.4 )
    -0.3 ( 0.4 )
        DB Week 10 (N= 99, 105)
    -0.1 ( 0.3 )
    -0.8 ( 0.3 )
        DB Week 12 (N= 88, 101)
    0.4 ( 0.4 )
    -0.9 ( 0.4 )
        DB Week 16 (N= 76, 101)
    -0.5 ( 0.3 )
    -1.2 ( 0.3 )
        DB Week 20 (N= 73, 103)
    -0.7 ( 0.4 )
    -0.5 ( 0.4 )
        DB Week 24 (N= 69, 98)
    -0.5 ( 0.4 )
    -0.7 ( 0.3 )
        DB Week 26 (N= 60, 92)
    -0.9 ( 0.3 )
    -0.8 ( 0.3 )
    Statistical analysis title
    Statistical analysis at DB Week 2.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9834 [1]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    0.6
    Notes
    [1] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases.
    Statistical analysis title
    Statistical analysis at DB Week 4.
    Comparison groups
    Double-Blind Treatment Period - Asenapine v Double-Blind Treatment Period - Placebo
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4427 [2]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    0.6
    Notes
    [2] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases.
    Statistical analysis title
    Statistical analysis at DB Week 6.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7512 [3]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.9
         upper limit
    0.6
    Notes
    [3] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases.
    Statistical analysis title
    Statistical analysis at DB Week 8.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3022 [4]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.5
         upper limit
    0.5
    Notes
    [4] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases.
    Statistical analysis title
    Statistical analysis at DB Week 10.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.121 [5]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.6
         upper limit
    0.2
    Notes
    [5] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases.
    Statistical analysis title
    Statistical analysis at DB Week 12.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0135 [6]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.3
         upper limit
    -0.3
    Notes
    [6] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases.
    Statistical analysis title
    Statistical analysis at DB Week 12.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0597 [7]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.4
         upper limit
    0
    Notes
    [7] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases.
    Statistical analysis title
    Statistical analysis at DB Week 20.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6801 [8]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.9
         upper limit
    1.3
    Notes
    [8] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases.
    Statistical analysis title
    Statistical analysis at DB Week 24.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7173 [9]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.1
         upper limit
    0.8
    Notes
    [9] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases.
    Statistical analysis title
    Statistical analysis at DB Week 26.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8121 [10]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    0.9
    Notes
    [10] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases.

    Secondary: Mean change from Baseline in MADRS total score by visit in DB Treatment Period.

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    End point title
    Mean change from Baseline in MADRS total score by visit in DB Treatment Period.
    End point description
    MADRS is a 10-item, clinician-rated scale for assessing the severity of symptoms of depression. The MADRS interview was conducted early in each applicable visit to avoid negatively impacting diagnostic and primary outcome data due to participant fatigue. A structured interview for the MADRS (SIGMA) was used. The MADRS total score is the sum of the 10 items and ranges from 0 to 60. A high numeric rating implies a greater degree of symptom severity.
    End point type
    Secondary
    End point timeframe
    Baseline to DB Week 26
    End point values
    Double-Blind Treatment Period - Placebo Double-Blind Treatment Period - Asenapine
    Number of subjects analysed
    126
    126
    Units: units on a scale
    least squares mean (standard error)
        DB Week 2 (N= 123, 119)
    1.5 ( 0.3 )
    0.5 ( 0.4 )
        DB Week 4 (N= 109, 115)
    1 ( 0.3 )
    0.1 ( 0.3 )
        DB Week 6 (N= 104, 113)
    0.6 ( 0.2 )
    0.1 ( 0.2 )
        DB Week 8 (N= 98, 106)
    0.6 ( 0.3 )
    0.3 ( 0.3 )
        DB Week 10 (N= 99, 105)
    0.2 ( 0.3 )
    0.3 ( 0.3 )
        DB Week 12 (N= 88, 101)
    1 ( 0.4 )
    0.2 ( 0.4 )
        DB Week 16 (N= 76, 101)
    -0.1 ( 0.3 )
    0 ( 0.3 )
        DB Week 20 (N= 73, 103)
    -0.1 ( 0.3 )
    0.3 ( 0.2 )
        DB Week 24 (N= 69, 98)
    0.1 ( 0.3 )
    0.2 ( 0.3 )
        DB Week 26 (N= 60, 92)
    -0.5 ( 0.3 )
    0.1 ( 0.2 )
    Statistical analysis title
    Statistical analysis at DB Week 2.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0473 [11]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.9
         upper limit
    0
    Notes
    [11] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases.
    Statistical analysis title
    Statistical analysis at DB Week 4.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.039 [12]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.8
         upper limit
    0
    Notes
    [12] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases.
    Statistical analysis title
    Statistical analysis at DB Week 6.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1725 [13]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.1
         upper limit
    0.2
    Notes
    [13] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases.
    Statistical analysis title
    Statistical analysis at DB Week 8.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4351 [14]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.1
         upper limit
    0.5
    Notes
    [14] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases.
    Statistical analysis title
    Statistical analysis at DB Week 10.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7124 [15]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.6
         upper limit
    0.8
    Notes
    [15] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases.
    Statistical analysis title
    Statistical analysis at DB Week 12.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1148 [16]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.9
         upper limit
    0.2
    Notes
    [16] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases.
    Statistical analysis title
    Statistical analysis at DB Week 16.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7879 [17]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    0.9
    Notes
    [17] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases.
    Statistical analysis title
    Statistical analysis at DB Week 20.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2559 [18]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    1.1
    Notes
    [18] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases.
    Statistical analysis title
    Statistical analysis at DB Week 24.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8241 [19]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.7
         upper limit
    0.9
    Notes
    [19] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases.
    Statistical analysis title
    Statistical analysis at DB Week 26.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.097 [20]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    1.2
    Notes
    [20] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases.

    Secondary: Mean change from Baseline in PANSS total score by visit in DB Treatment Period.

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    End point title
    Mean change from Baseline in PANSS total score by visit in DB Treatment Period.
    End point description
    The PANSS consisted of three subscales: a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 (absence of symptoms) and a score of 7 (extremely severe symptoms). The PANSS total score was the sum of the rating scores for 7 positive scale items, 7 negative scale items, and 16 general psychopathology scale items from the PANSS panel. The PANSS total score ranged from 30 (best possible outcome) to 210 (worst possible outcome).
    End point type
    Secondary
    End point timeframe
    Baseline to DB Week 26
    End point values
    Double-Blind Treatment Period - Placebo Double-Blind Treatment Period - Asenapine
    Number of subjects analysed
    60
    91
    Units: units on a scale
        least squares mean (standard error)
    -0.4 ( 0.6 )
    0.9 ( 0.5 )
    Statistical analysis title
    Statistcal analysis at DB Week 26.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.1225 [21]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    2.9
    Notes
    [21] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.

    Secondary: Mean change from Baseline in PANSS positive score by visit in DB Treatment Period.

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    End point title
    Mean change from Baseline in PANSS positive score by visit in DB Treatment Period.
    End point description
    The PANSS consisted of 3 subscales were a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicated (absence of symptoms) and a score of 7 indicated (extremely severe symptoms). The 7 positive symptom constructs were delusions, conceptual disorganization, hallucinatory behavior, excitement, grandiosity, suspiciousness/persecution, and hostility. The PANSS Positive Score ranged from 7(best possible outcome) to 49 (worst possible outcome).
    End point type
    Secondary
    End point timeframe
    Baseline to DB Week 26
    End point values
    Double-Blind Treatment Period - Placebo Double-Blind Treatment Period - Asenapine
    Number of subjects analysed
    60
    91
    Units: units on a scale
        least squares mean (standard error)
    -0.1 ( 0.2 )
    0.1 ( 0.2 )
    Statistical analysis title
    Statistical analysis at DB Week 26.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3326 [22]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    0.8
    Notes
    [22] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.

    Secondary: Mean change from Baseline in PANSS negative score by visit in DB Treatment Period.

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    End point title
    Mean change from Baseline in PANSS negative score by visit in DB Treatment Period.
    End point description
    The PANSS consisted of 3 subscales were a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicated (absence of symptoms) and a score of 7 indicated (extremely severe symptoms).The 7 negative symptom constructs: blunted affect, emotional withdrawal, poor rapport, passive apathetic withdrawal, difficulty in abstract thinking, lack of spontaneity and flow of conversation, stereotyped thinking. The PANSS Negative Score ranged from 7(best possible outcome) to 49 (worst possible outcome).
    End point type
    Secondary
    End point timeframe
    Baseline to DB Week 26.
    End point values
    Double-Blind Treatment Period - Placebo Double-Blind Treatment Period - Asenapine
    Number of subjects analysed
    60
    91
    Units: units on a scale
        least squares mean (standard error)
    -0.1 ( 0.2 )
    0.4 ( 0.2 )
    Statistical analysis title
    Statistical analysis at DB Week 26.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0651 [23]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    1
    Notes
    [23] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.

    Secondary: Mean change from Baseline in PANSS general psychopathology score by visit in DB Treatment Period.

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    End point title
    Mean change from Baseline in PANSS general psychopathology score by visit in DB Treatment Period.
    End point description
    The PANSS consisted of 3 subscales were a total of 30 symptom constructs. For each symptom construct, severity was rated on a 7-point scale, with a score of 1 indicated (absence of symptoms) and a score of 7 indicated (extremely severe symptoms). The 16 general psychopathology symptom constructs were Somatic concern, Anxiety, Guilt feelings, Tension, Mannerisms and posturing, Depression, Motor retardation, Uncooperativeness, Unusual thought content, Disorientation, Poor attention, Lack of judgment and insight, Disturbance of volition, Poor impulse control, Preoccupation, and Active social avoidance. The PANSS general psychopathology score ranged from 16 (best possible outcome) to 112 (worst possible outcome).
    End point type
    Secondary
    End point timeframe
    Baseline to DB Week 26
    End point values
    Double-Blind Treatment Period - Placebo Double-Blind Treatment Period - Asenapine
    Number of subjects analysed
    60
    91
    Units: units on a scale
        least squares mean (standard error)
    -0.2 ( 0.4 )
    0.3 ( 0.3 )
    Statistical analysis title
    Statistical analysis at DB Week 26.
    Comparison groups
    Double-Blind Treatment Period - Asenapine v Double-Blind Treatment Period - Placebo
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2599 [24]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    1.5
    Notes
    [24] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.

    Secondary: Mean change from Baseline in PANSS marder factor positive symptom score by visit in DB Treatment Period.

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    End point title
    Mean change from Baseline in PANSS marder factor positive symptom score by visit in DB Treatment Period.
    End point description
    PANSS marder factor positive symptom factor score defined by the sum of (PANSS Items P1, P3, P5, P6, N7, G1, G9, G12). If any one of the component items has a missing value then the Marder Factor Positive Symptom Score is missing. Each item is rated from 1 (absent) to 7 (extreme) and the symptom score ranges from 8 to 56. Higher scores indicate greater severity of illness.
    End point type
    Secondary
    End point timeframe
    Baseline to DB Week 26
    End point values
    Double-Blind Treatment Period - Placebo Double-Blind Treatment Period - Asenapine
    Number of subjects analysed
    60
    91
    Units: units on a scale
        least squares mean (standard error)
    0 ( 0.2 )
    0.3 ( 0.2 )
    Statistical analysis title
    Statistical analysis at DB Week 26.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.209 [25]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.8
    Notes
    [25] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.

    Secondary: Mean change from Baseline in PANSS marder factor negative symptom score by visit in DB Treatment Period.

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    End point title
    Mean change from Baseline in PANSS marder factor negative symptom score by visit in DB Treatment Period.
    End point description
    PANSS marder factor negative symptom factor score defined by sum of (PANSS items N1, N2, N3, N4, N6, G7, G16). If any one of the component items has a missing value then the Marder Factor Negative Symptom Score is missing. Each item is rated from 1 (absent) to 7 (extreme) and the symptom score ranges from 7 to 49. Higher scores indicate greater severity of illness.
    End point type
    Secondary
    End point timeframe
    Baseline to DB Week 26
    End point values
    Double-Blind Treatment Period - Placebo Double-Blind Treatment Period - Asenapine
    Number of subjects analysed
    60
    91
    Units: units on a scale
        least squares mean (standard error)
    0.1 ( 0.2 )
    0.4 ( 0.2 )
    Statistical analysis title
    Statistical analysis at DB Week 26.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2059 [26]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.8
    Notes
    [26] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.

    Secondary: Mean change from Baseline in PANSS marder factor disorganized thought symptom score by visit in DB Treatment Period.

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    End point title
    Mean change from Baseline in PANSS marder factor disorganized thought symptom score by visit in DB Treatment Period.
    End point description
    PANSS marder factor disorganized thought symptom factor score defined by sum of (PANSS items P2, N5, G5, G10, G11, G13, G15). If any one of the component items has a missing value then the Marder Factor Disorganized Thought Symptom Score is missing. Each item is rated from 1 (absent) to 7 (extreme) and the symptom score ranges from 7 to 49. Higher scores indicate greater severity of illness.
    End point type
    Secondary
    End point timeframe
    Baseline to DB Week 26
    End point values
    Double-Blind Treatment Period - Placebo Double-Blind Treatment Period - Asenapine
    Number of subjects analysed
    60
    91
    Units: units on a scale
        least squares mean (standard error)
    -0.3 ( 0.2 )
    -0.1 ( 0.2 )
    Statistical analysis title
    Statistical analysis at DB Week 26.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3326 [27]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.7
    Notes
    [27] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.

    Secondary: Mean change from Baseline in PANSS marder factor hostility/excitement symptom score by visit in DB Treatment Period.

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    End point title
    Mean change from Baseline in PANSS marder factor hostility/excitement symptom score by visit in DB Treatment Period.
    End point description
    PANSS marder factor hostility/ excitement symptom score is defined as the sum of (items P4, P7, G8, G14). If any one of the component items has a missing value then the Marder Factor Hostility/Excitement Symptom Score is missing. Each item is rated from 1 (absent) to 7 (extreme) and the symptom score ranges from 4 to 28. Higher scores indicate greater severity of illness.
    End point type
    Secondary
    End point timeframe
    Baseline to DB Week 26
    End point values
    Double-Blind Treatment Period - Placebo Double-Blind Treatment Period - Asenapine
    Number of subjects analysed
    60
    91
    Units: units on a scale
        least squares mean (standard error)
    -0.1 ( 0.2 )
    0 ( 0.2 )
    Statistical analysis title
    Statistical analysis at DB Week 26.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6243 [28]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    0.6
    Notes
    [28] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.

    Secondary: Mean change from Baseline in PANSS marder factor anxiety/depression symptom score by visit in DB Treatment Period.

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    End point title
    Mean change from Baseline in PANSS marder factor anxiety/depression symptom score by visit in DB Treatment Period.
    End point description
    PANSS marder factor anxiety/depression symptom score is defined as the sum of (items G2, G3, G4, G6). If any one of the component items has a missing value then the Marder Factor Anxiety/Depression Symptom Score is missing. Each item is rated from 1 (absent) to 7 (extreme) and the symptom score ranges from 4 to 28. Higher scores indicate greater severity of illness.
    End point type
    Secondary
    End point timeframe
    Baseline to DB Week 26
    End point values
    Double-Blind Treatment Period - Placebo Double-Blind Treatment Period - Asenapine
    Number of subjects analysed
    60
    91
    Units: units on a scale
        least squares mean (standard error)
    0 ( 0.2 )
    0.3 ( 0.2 )
    Statistical analysis title
    Statistical analysis at DB Week 26.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    151
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2632 [29]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.8
    Notes
    [29] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.

    Secondary: Mean change from Baseline in CGI-BP severity of mania by visit in DB Treatment Period.

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    End point title
    Mean change from Baseline in CGI-BP severity of mania by visit in DB Treatment Period.
    End point description
    CGI-BP score ranged from 1 (normal, not at all ill) to 7 (very severely ill). Decreases from baseline within a treatment group were indicative of an improvement.
    End point type
    Secondary
    End point timeframe
    Baseline to DB Week 26
    End point values
    Double-Blind Treatment Period - Placebo Double-Blind Treatment Period - Asenapine
    Number of subjects analysed
    126
    126
    Units: units on a scale
    least squares mean (standard error)
        DB Week 2 (N= 123, 119)
    0 ( 0 )
    0 ( 0 )
        DB Week 4 (N= 109, 115)
    0 ( 0.1 )
    0 ( 0.1 )
        DB Week 6 (N= 104, 113)
    -0.1 ( 0 )
    0 ( 0 )
        DB Week 8 (N= 98, 106)
    0 ( 0.1 )
    -0.1 ( 0.1 )
        DB Week 10 (N= 99, 105)
    -0.1 ( 0.1 )
    -0.1 ( 0.1 )
        DB Week 12 (N= 88, 100)
    0 ( 0.1 )
    -0.1 ( 0.1 )
        DB Week 16 (N= 76, 101)
    -0.1 ( 0.1 )
    -0.2 ( 0 )
        DB Week 20 (N= 73, 103)
    -0.2 ( 0.1 )
    -0.1 ( 0.1 )
        DB Week 24 (N= 69, 98)
    -0.1 ( 0.1 )
    -0.1 ( 0.1 )
        DB Week 26 (N= 60, 92)
    -0.2 ( 0.1 )
    -0.2 ( 0 )
    Statistical analysis title
    Statistical analysis at DB Week 2
    Comparison groups
    Double-Blind Treatment Period - Asenapine v Double-Blind Treatment Period - Placebo
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6977 [30]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    0.1
    Notes
    [30] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 4.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2568 [31]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.1
    Notes
    [31] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 6.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4852 [32]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    0.2
    Notes
    [32] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 8.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2192 [33]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    0.1
    Notes
    [33] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 10.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8268 [34]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.1
    Notes
    [34] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 12.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2266 [35]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    0.1
    Notes
    [35] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 16.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3759 [36]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.1
    Notes
    [36] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 20.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1998 [37]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    0.2
    Notes
    [37] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 24.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7865 [38]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.1
    Notes
    [38] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 26.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7952 [39]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.1
    Notes
    [39] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.

    Secondary: Mean change from Baseline in CGI-BP severity of depression by visit in DB Treatment Period.

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    End point title
    Mean change from Baseline in CGI-BP severity of depression by visit in DB Treatment Period.
    End point description
    CGI-BP score ranged from 1 (normal, not at all ill) to 7 (very severely ill). Decreases from baseline within a treatment group were indicative of an improvement.
    End point type
    Secondary
    End point timeframe
    Baseline to DB Week 26
    End point values
    Double-Blind Treatment Period - Placebo Double-Blind Treatment Period - Asenapine
    Number of subjects analysed
    126
    126
    Units: units on a scale
    least squares mean (standard error)
        DB Week 2 (N= 123, 119)
    0.2 ( 0.1 )
    0.1 ( 0.1 )
        DB Week 4 (N= 109, 115)
    0.1 ( 0 )
    0 ( 0 )
        DB Week 6 (N= 104, 113)
    0 ( 0 )
    0 ( 0 )
        DB Week 8 (N= 98, 106)
    0.1 ( 0 )
    0 ( 0 )
        DB Week 10 (N= 99, 105)
    0 ( 0 )
    0.1 ( 0 )
        DB Week 12 (N= 88, 100)
    0.1 ( 0.1 )
    0.1 ( 0.1 )
        DB Week 16 (N= 76, 101)
    0 ( 0.1 )
    0.1 ( 0 )
        DB Week 20 (N= 73, 103)
    0 ( 0 )
    0 ( 0 )
        DB Week 24 (N= 69, 98)
    0.1 ( 0.1 )
    0.1 ( 0 )
        DB Week 26 (N= 60, 92)
    -0.1 ( 0 )
    0 ( 0 )
    Statistical analysis title
    Statistical analysis at DB Week 2.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4488 [40]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.1
    Notes
    [40] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 4.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9279 [41]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    0.1
    Notes
    [41] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 6.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7011 [42]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    0.1
    Notes
    [42] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 8.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.6188 [43]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.1
    Notes
    [43] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 10.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.258 [44]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    0.2
    Notes
    [44] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 12.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5861 [45]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.1
    Notes
    [45] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 16.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4592 [46]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    0.2
    Notes
    [46] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 20.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8219 [47]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    0.1
    Notes
    [47] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 24.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9939 [48]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    0.1
    Notes
    [48] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 26.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1157 [49]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    0.2
    Notes
    [49] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.

    Secondary: Mean change from Baseline in CGI-BP severity of overall bipolar illness by visit in DB Treatment Period.

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    End point title
    Mean change from Baseline in CGI-BP severity of overall bipolar illness by visit in DB Treatment Period.
    End point description
    CGI-BP score ranged from 1 (normal, not at all ill) to 7 (very severely ill). Decreases from baseline within a treatment group were indicative of an improvement.
    End point type
    Secondary
    End point timeframe
    Baseline to DB Week 26
    End point values
    Double-Blind Treatment Period - Placebo Double-Blind Treatment Period - Asenapine
    Number of subjects analysed
    126
    126
    Units: units on a scale
    least squares mean (standard error)
        DB Week 2 (N= 123, 119)
    0.1 ( 0.1 )
    0.1 ( 0.1 )
        DB Week 4 (N= 109, 115)
    0 ( 0.1 )
    0 ( 0.1 )
        DB Week 6 (N= 104, 113)
    -0.1 ( 0 )
    0 ( 0 )
        DB Week 8 (N= 98, 106)
    0 ( 0.1 )
    -0.1 ( 0.1 )
        DB Week 10 (N= 99, 105)
    0 ( 0.1 )
    0 ( 0.1 )
        DB Week 12 (N= 88, 100)
    0.1 ( 0.1 )
    -0.1 ( 0.1 )
        DB Week 16 (N= 76, 101)
    -0.1 ( 0.1 )
    -0.1 ( 0.1 )
        DB Week 20 (N= 73, 103)
    -0.1 ( 0.1 )
    -0.1 ( 0.1 )
        DB Week 24 (N= 69, 98)
    -0.1 ( 0.1 )
    -0.1 ( 0.1 )
        DB Week 26 (N= 60, 92)
    -0.2 ( 0.1 )
    -0.2 ( 0 )
    Statistical analysis title
    Statistical analysis at DB Week 2.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5974 [50]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.1
    Notes
    [50] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 4.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5887 [51]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.1
    Notes
    [51] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 6.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.342 [52]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    0.2
    Notes
    [52] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 8.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2196 [53]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    0.1
    Notes
    [53] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 10.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.9776 [54]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.1
    Notes
    [54] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 12.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.1241 [55]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    0
    Notes
    [55] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 16.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8295 [56]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.1
    Notes
    [56] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 20.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4173 [57]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    0.2
    Notes
    [57] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 24.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3891 [58]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.1
    Notes
    [58] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.
    Statistical analysis title
    Statistical analysis at DB Week 26.
    Comparison groups
    Double-Blind Treatment Period - Placebo v Double-Blind Treatment Period - Asenapine
    Number of subjects included in analysis
    252
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8337 [59]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    0.2
    Notes
    [59] - Based on ANCOVA model with treatment and pooled site as fixed effects and double-blind baseline as a covariate for the observed cases data.

    Secondary: Percentage of participants in CGI-BP mania responder rates by visit in DB Treatment Period.

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    End point title
    Percentage of participants in CGI-BP mania responder rates by visit in DB Treatment Period.
    End point description
    CGI-BP mania responder rate is defined as change of much improved or very much improved in mania from double-blind baseline.
    End point type
    Secondary
    End point timeframe
    DB Week 2 to DB Week 16
    End point values
    Double-Blind Treatment Period - Placebo Double-Blind Treatment Period - Asenapine
    Number of subjects analysed
    126
    126
    Units: percentage of participants
    number (not applicable)
        DB Week 2
    39
    46.2
        DB Week 4
    37.6
    46.1
        DB Week 6
    38.5
    46
        DB Week 8
    33.7
    47.2
        DB Week 10
    36.4
    43.8
        DB Week 12
    33
    48
        DB Week 16
    36.8
    50.5
        DB Week 20
    35.6
    51.5
        DB Week 24
    33.3
    57.1
        DB Week 26
    31.7
    55.4
    No statistical analyses for this end point

    Secondary: Percentage of participants in CGI-BP depression responder rates by visit in DB Treatment Period.

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    End point title
    Percentage of participants in CGI-BP depression responder rates by visit in DB Treatment Period.
    End point description
    CGI-BP depression responder rate is defined as change of much improved or very much improved in depression from double-blind baseline.
    End point type
    Secondary
    End point timeframe
    DB Week 2 to DB Week 26
    End point values
    Double-Blind Treatment Period - Placebo Double-Blind Treatment Period - Asenapine
    Number of subjects analysed
    126
    126
    Units: percentage of participants
    number (not applicable)
        DB Week 2
    7.3
    13.4
        DB Week 4
    5.5
    15.7
        DB Week 6
    5.8
    15
        DB Week 8
    5.1
    16
        DB Week 10
    6.1
    14.3
        DB Week 12
    4.5
    15
        DB Week 16
    9.2
    12.9
        DB Week 20
    9.6
    15.5
        DB Week 24
    7.2
    16.3
        DB Week 26
    8.3
    15.2
    No statistical analyses for this end point

    Secondary: Percentage of participants in CGI-BP overall bipolar illness responder rates by visit in DB Treatment Period.

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    End point title
    Percentage of participants in CGI-BP overall bipolar illness responder rates by visit in DB Treatment Period.
    End point description
    CGI-BP overall bipolar illness responder rate is defined as change of much improved or very much improved in overall bipolar illness from double-blind baseline.
    End point type
    Secondary
    End point timeframe
    DB Week 2 to DB Week 26
    End point values
    Double-Blind Treatment Period - Placebo Double-Blind Treatment Period - Asenapine
    Number of subjects analysed
    126
    126
    Units: percentage of participants
    number (not applicable)
        DB Week 2
    36.6
    45.4
        DB Week 4
    36.7
    43.5
        DB Week 6
    38.5
    44.2
        DB Week 8
    32.7
    46.2
        DB Week 10
    36.4
    41.9
        DB Week 12
    31.8
    47
        DB Week 16
    36.8
    47.5
        DB Week 20
    35.6
    51.5
        DB Week 24
    30.4
    58.2
        DB Week 26
    31.7
    56.5
    No statistical analyses for this end point

    Secondary: Overall recurrence rate of any mood episode by visit in DB Treatment Period.

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    End point title
    Overall recurrence rate of any mood episode by visit in DB Treatment Period.
    End point description
    Overall recurrence rates (any mood episode) defined as number of participants with recurrences divided by the number of participants in full analysis set.
    End point type
    Secondary
    End point timeframe
    DB Visit 10 to DB Visit 19
    End point values
    Double-Blind Treatment Period - Placebo Double-Blind Treatment Period - Asenapine
    Number of subjects analysed
    126
    126
    Units: percentage of participants
    number (not applicable)
        Visit 10 (1 ≤ Day ≤ 21)
    7.1
    2.4
        Visit 11 (22 ≤ Day ≤ 35)
    3.5
    2.5
        Visit 12 (36 ≤ Day ≤ 49)
    3.7
    0.8
        Visit 13 (50 ≤ Day ≤ 63)
    2.9
    0.9
        Visit 14 (64 ≤ Day ≤ 77)
    5
    0.9
        Visit 15 (78 ≤ Day ≤ 98)
    8.6
    0
        Visit 16 (99 ≤ Day ≤ 126)
    4.8
    0.9
        Visit 17 (127 ≤ Day ≤ 154)
    3.9
    0.9
        Visit 18 (155 ≤ Day ≤ 175)
    2.7
    0
        Visit 19 (176 ≤ Day)
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from the signing of the informed consent through the study until the follow-up visit at least 7 days after last dose of study medication; For serious adverse events, at least 30 days after last dose of study medication.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Open-Label Treatment Period
    Reporting group description
    For the Open-Label Treatment Period, participants were assigned to asenapine 10 mg BID (flexible-dosing of asenapine 5 mg BID -10 mg BID was to begin on Day 2) for a period of at least 12 and up to 16 weeks. In the event of intolerability during the Open-Label Treatment Period, down-titration to asenapine 5 mg BID was permitted. Participants who cannot tolerate an asenapine 5 mg BID dose were discontinued from the trial. For participants who were down-titrated, subsequent rechallenge with asenapine 10 mg BID was attempted as the final target dose for the stabilization phase of the Open-Label Treatment Period.

    Reporting group title
    Placebo - Double-Blind Treatment Period
    Reporting group description
    During the Double-Blind Treatment Period, participants randomized to placebo received placebo tablets. In the event of intolerability, down-titration was permitted starting at Day 2, but no subsequent rechallenge during the Double-Blind Treatment Period was permitted.

    Reporting group title
    Asenapine - Double-Blind Treatment Period
    Reporting group description
    During the Double-Blind Treatment Period, participants randomized to asenapine received sub-lingual asenapine tablets 5-10 mg BID up to 26 Weeks. The starting dose of double-blind trial medication was the final asenapine dose used in the Open-Label Treatment Period. The starting dose of double-blind trial medication was the evening dose of the Double-Blind Baseline Visit. In the event of intolerability, down-titration was permitted starting at Day 2, but no subsequent rechallenge during the Double-Blind Treatment Period was permitted.

    Serious adverse events
    Open-Label Treatment Period Placebo - Double-Blind Treatment Period Asenapine - Double-Blind Treatment Period
    Total subjects affected by serious adverse events
         subjects affected / exposed
    30 / 549 (5.46%)
    11 / 126 (8.73%)
    6 / 126 (4.76%)
         number of deaths (all causes)
    1
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    1 / 549 (0.18%)
    0 / 126 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 549 (0.18%)
    0 / 126 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 549 (0.18%)
    0 / 126 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    0 / 549 (0.00%)
    1 / 126 (0.79%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 549 (0.18%)
    0 / 126 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 549 (0.00%)
    0 / 126 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 549 (0.18%)
    0 / 126 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 549 (0.18%)
    0 / 126 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 549 (0.18%)
    0 / 126 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 549 (0.18%)
    0 / 126 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 549 (0.18%)
    0 / 126 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis chronic
         subjects affected / exposed
    0 / 549 (0.00%)
    0 / 126 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mania
         subjects affected / exposed
    6 / 549 (1.09%)
    1 / 126 (0.79%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    4 / 549 (0.73%)
    1 / 126 (0.79%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bipolar disorder
         subjects affected / exposed
    3 / 549 (0.55%)
    0 / 126 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depressive symptom
         subjects affected / exposed
    3 / 549 (0.55%)
    0 / 126 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bipolar I disorder
         subjects affected / exposed
    2 / 549 (0.36%)
    1 / 126 (0.79%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 549 (0.18%)
    0 / 126 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 549 (0.18%)
    0 / 126 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 549 (0.18%)
    0 / 126 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug dependence
         subjects affected / exposed
    1 / 549 (0.18%)
    0 / 126 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    1 / 549 (0.18%)
    0 / 126 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 549 (0.18%)
    1 / 126 (0.79%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Substance-induced psychotic disorder
         subjects affected / exposed
    0 / 549 (0.00%)
    1 / 126 (0.79%)
    0 / 126 (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
    Infections and infestations
    Appendicitis perforated
         subjects affected / exposed
    1 / 549 (0.18%)
    0 / 126 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 549 (0.18%)
    0 / 126 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Open-Label Treatment Period Placebo - Double-Blind Treatment Period Asenapine - Double-Blind Treatment Period
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    192 / 549 (34.97%)
    14 / 126 (11.11%)
    4 / 126 (3.17%)
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    39 / 549 (7.10%)
    0 / 126 (0.00%)
    0 / 126 (0.00%)
         occurrences all number
    47
    0
    0
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    55 / 549 (10.02%)
    0 / 126 (0.00%)
    0 / 126 (0.00%)
         occurrences all number
    65
    0
    0
    Akathisia
         subjects affected / exposed
    42 / 549 (7.65%)
    0 / 126 (0.00%)
    0 / 126 (0.00%)
         occurrences all number
    45
    0
    0
    Sedation
         subjects affected / exposed
    42 / 549 (7.65%)
    0 / 126 (0.00%)
    0 / 126 (0.00%)
         occurrences all number
    46
    0
    0
    Headache
         subjects affected / exposed
    32 / 549 (5.83%)
    0 / 126 (0.00%)
    0 / 126 (0.00%)
         occurrences all number
    40
    0
    0
    Gastrointestinal disorders
    Hypoaesthesia oral
         subjects affected / exposed
    33 / 549 (6.01%)
    0 / 126 (0.00%)
    0 / 126 (0.00%)
         occurrences all number
    34
    0
    0
    Psychiatric disorders
    Mania
         subjects affected / exposed
    0 / 549 (0.00%)
    14 / 126 (11.11%)
    4 / 126 (3.17%)
         occurrences all number
    0
    15
    4

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Oct 2010
    The first protocol amendment, included the following changes: Key secondary trial objectives were deleted; Specification that there would be no hypothesis testing of safety data; Added exclusion criteria related to hepatic condition to exclusion criterion #4; Added previous diagnosis of epilepsy or seizure disorder to exclusion criterion #7; Added previous or current diagnosis of schizophrenia or schizoaffective disorder or other psychotic disorder to exclusion criterion #10; Added diagnosis of primary Axis I disorder other than bipolar I disorder to exclusion criterion #11; Added previous allergy to asenapine to exclusion criterion #22; Added inability of the participant to reduce his/her benzodiazepine intake as specified in the protocol to exclusion criterion #24; Added time points (at least 8 weeks) related to the failure to respond to marketed antipsychotic agents and the intake of an investigational drug to exclusion criterion #25; Added discontinuation criteria related to absolute neutrophil count; Changes and additional information were added to Table 4 (allowed medications); Additional details were added to trial procedures; Key secondary efficacy endpoints were deleted; Added Table 6; Changes and additional information to endpoints and analyses were added; Additional details were added to the timing of dose administration (Section 7.4.1.3.2), labeling (Section 7.4.1.5.3), and packaging (Section 7.7.1.2); Additional details were added to statistical analysis sections of protocol; Other editorial corrections, minor clarifications, and additional information were provided.
    03 Aug 2011
    The second protocol amendment, included the following changes: Trial Flow Charts, Open-Label Treatment Period, removed the “x” for the Columbia Suicidal Severity Rating Scale (C-SSRS) at Day 1; Participant Exclusion Criteria, 7.3.2.1 Open-Label Treatment Period, Medical, under criteria #3, the second paragraph was given a new designation: 3A; Subject Exclusion Criteria, 7.3.2.1 Open-Label Treatment Period, Psychiatric, under criterion #17: revision to C-SSRS text; Participant Discontinuation Criteria, inclusion of new criterion #4 (Y-MRS/MADRS ≥16) for participant discontinuation from treatment; Concomitant Medications, Supplements, and Other Substances Allowed During Trial, Table 4, text for benzodiazepine and diazepam dosing was revised and clarified; Screening and Administrative Procedures Not Including Safety and Efficacy Baseline Measurements, had new text added to item #10 header; Procedures for Safety Assessments, Table 5 Laboratory Tests to include the following tests under Urinalysis: urine pregnancy test, urine drug screen, nitrite, urobilinogen, leukocyte esterase, and the deletion of microscopic exam; Serious Adverse Event, had “cancer” added as serious adverse event outcome #6; CME, #1, replacement of Drug Induced Liver Injury (DILI) text per Sponsor standards and latest Food and Drug Administration (FDA) guidance; CME, #5, a new event (suicidal ideation and/or behavior) was added; Deletion of the following sections: Section 7.7.2.2.7, Medication Error; 7.7.2.2.8; Potential Medication Error; and 7.7.2.2.9, Incident; Expedited Reporting of Safety Observations by the Investigator to the Sponsor,“5. Incidents associated with the device” was deleted; Statistical Method for Exploratory Safety Analysis, Table 6, Tier 3, the safety endpoint “heart rate” was replaced with “pulse rate.”
    06 Oct 2011
    The third protocol amendment, included the following changes: Trial Flow Chart, Open-Label Treatment Period, footnote b example was corrected; Trial Flow Chart, Open-Label Treatment Period, footnote i was deleted; Trial Flow Chart, Open-Label Treatment Period, footnote j was clarified by adding text specific to urine drug screen requirements for participants who meet stabilization and enter double-blind period; Trial Flow Chart, Open-Label Treatment Period, footnote o was clarified by adding text specific to C-SSRS completion on Day 3 of open-label; Trial Flow Chart, Open-Label Treatment Period, footnote q was revised to clarify fasting blood draw requirements; Trial Flow Chart, Double-Blind Treatment Period, footnote e was deleted; Procedures for Efficacy Assessments, text specific to monitoring of the Mini International Neuropsychiatric Interview (MINI), the Y-MRS, and the MADRS was removed; Monitoring Liver Enzymes was updated to be consistent with FDA DILI guidance and; Pharmacogenetic Specimen Handling and Shipping Instructions were updated in Appendix 1 to reflect ambient shipping on the day of collection.
    20 Aug 2014
    The fourth protocol amendment, included the following changes: Sponsor’s name, Schering Plough, Schering, Schering Plough Research Institute, and Merck was changed to Forest Research Institute, Inc. (as well as Sponsor address where required); Global Pharmacovigilance was changed to Pharmacovigilance and Risk Management and; Section 12 was amended to clarify the specimen sampling, processing, labeling, storage, and shipment according to Forest Research Institute, Inc. SOPs due to the Sponsor change.
    05 Dec 2014
    The fifth protocol amendment included the following changes: Title Page, trial physician/director was changed from Maju Mathews to Armin Szegedi, MD, due to personnel changes; Amended Section 2 to reflect changes to the sample size within Statistical Methods; Added three additional references and; Sections 7.3.4 and 8.4 were updated to reflect the changes in the sample size.

    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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