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    Clinical Trial Results:
    A 50-Week Open-Label, Flexible-Dose Trial of Asenapine Extension Treatment to P06107 in Pediatric Subjects with Acute Manic or Mixed Episodes Associated With Bipolar I Disorder

    Summary
    EudraCT number
    2010-022648-19
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    05 Sep 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    29 Sep 2016
    First version publication date
    11 Mar 2015
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    P05898
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01349907
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000228-PIP01-08
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 Sep 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Sep 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study will investigate the safety and tolerability of a flexible dosing regimen of asenapine for the long term treatment of manic or mixed episodes associated with bipolar I disorder in children and adolescents who completed the 3-week treatment base trial P06107 (NCT01244815).
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research. The following additional measures defined for this individual study were in place for the protection of trial subjects: For participants whose symptoms worsen or are not adequately controlled on assigned treatment, rescue medication may be administered during the trial in the following circumstances. For the control of agitation, anxiety, insomnia, restlessness, or akathisia and extrapyramidal symptoms (EPS) some benzodiazepines (i.e. lorazepam up to 4 mg/day or an equivalent dose of short-acting benzodiazepines) and EPS medications (i.e. anticholinergics) are allowed. Benadryl (dipenhydramine) and beta blockers are also permitted, provided that they are not taken within 8 hours of efficacy assessments.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    16 Jun 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 303
    Country: Number of subjects enrolled
    Russian Federation: 19
    Worldwide total number of subjects
    322
    EEA total number of subjects
    0
    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)
    53
    Adolescents (12-17 years)
    268
    Adults (18-64 years)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Participants were chosen from children and adolescents with a manic or mixed episode associated with bipolar I disorder who completed the 3-week efficacy and safety base trial P06107.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo/Asenapine
    Arm description
    Participants treated with placebo in base trial P06107 were first treated with open-label flavored asenapine 2.5 mg twice per day (BID), then up-titrated to 5 mg BID at Day 4, then up-titrated to 10 mg BID at Day 7. After Day 7, flexible dosing of asenapine was continued for up to 50 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Rescue medication
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For participants whose symptoms worsen or are not adequately controlled on assigned treatment, rescue medication may be administered during the trial in the following circumstances. For the control of agitation, anxiety, insomnia, restlessness, or akathisia and extrapyramidal symptoms (EPS) some benzodiazepines (i.e. lorazepam up to 4 mg/day or an equivalent dose of short-acting benzodiazepines) and EPS medications (i.e. anticholinergics) are allowed. Benadryl (dipenhydramine) and beta blockers are also permitted, provided that they are not taken within 8 hours of efficacy assessments.

    Investigational medicinal product name
    Asenapine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Sublingual tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One flavored asenapine sublingual tablet BID (either 2.5, 5 or 10 mg) starting at 2.5 mg on Day 1 for three consecutive days. Normally on Day 4, the dose will increase to 5 mg BID beginning with the evening dose. Normally on Day 7, the dose will increase to 10 mg BID beginning with the evening dose. The dose may be up-titrated earlier than Days 4 and 7 at the investigator's discretion. Beginning on Day 8 (or after at least 1 day on 10 mg asenapine BID) dosing will be flexible (2.5, 5, or 10 mg BID) until up to Week 50.

    Arm title
    Asenapine/Asenapine
    Arm description
    Participants treated with asenapine in base trial P06107 were first treated with open-label flavored asenapine 2.5 mg BID, then up-titrated to 5 mg BID at Day 4, then up-titrated to 10 mg BID at Day 7. After Day 7, flexible dosing of asenapine was continued for up to 50 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Asenapine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Sublingual tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One flavored asenapine sublingual tablet BID (either 2.5, 5 or 10 mg) starting at 2.5 mg on Day 1 for three consecutive days. Normally on Day 4, the dose will increase to 5 mg BID beginning with the evening dose. Normally on Day 7, the dose will increase to 10 mg BID beginning with the evening dose. The dose may be up-titrated earlier than Days 4 and 7 at the investigator's discretion. Beginning on Day 8 (or after at least 1 day on 10 mg asenapine BID) dosing will be flexible (2.5, 5, or 10 mg BID) until up to Week 50.

    Investigational medicinal product name
    Rescue medication
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For participants whose symptoms worsen or are not adequately controlled on assigned treatment, rescue medication may be administered during the trial in the following circumstances. For the control of agitation, anxiety, insomnia, restlessness, or akathisia and extrapyramidal symptoms (EPS) some benzodiazepines (i.e. lorazepam up to 4 mg/day or an equivalent dose of short-acting benzodiazepines) and EPS medications (i.e. anticholinergics) are allowed. Benadryl (dipenhydramine) and beta blockers are also permitted, provided that they are not taken within 8 hours of efficacy assessments.

    Number of subjects in period 1
    Placebo/Asenapine Asenapine/Asenapine
    Started
    81
    241
    Completed
    38
    102
    Not completed
    43
    139
         Protocol deviation
    13
    33
         Treatment failure
    4
    13
         Adverse event, non-fatal
    11
    37
         Consent withdrawn by subject
    8
    30
         Administrative
    1
    1
         Lost to follow-up
    6
    25

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo/Asenapine
    Reporting group description
    Participants treated with placebo in base trial P06107 were first treated with open-label flavored asenapine 2.5 mg twice per day (BID), then up-titrated to 5 mg BID at Day 4, then up-titrated to 10 mg BID at Day 7. After Day 7, flexible dosing of asenapine was continued for up to 50 weeks.

    Reporting group title
    Asenapine/Asenapine
    Reporting group description
    Participants treated with asenapine in base trial P06107 were first treated with open-label flavored asenapine 2.5 mg BID, then up-titrated to 5 mg BID at Day 4, then up-titrated to 10 mg BID at Day 7. After Day 7, flexible dosing of asenapine was continued for up to 50 weeks.

    Reporting group values
    Placebo/Asenapine Asenapine/Asenapine Total
    Number of subjects
    81 241 322
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    13 40 53
        Adolescents (12-17 years)
    67 201 268
        Adults (18-64 years)
    1 0 1
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    13.7 ± 2 13.8 ± 2 -
    Gender categorical
    Units: Subjects
        Female
    48 113 161
        Male
    33 128 161

    End points

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    End points reporting groups
    Reporting group title
    Placebo/Asenapine
    Reporting group description
    Participants treated with placebo in base trial P06107 were first treated with open-label flavored asenapine 2.5 mg twice per day (BID), then up-titrated to 5 mg BID at Day 4, then up-titrated to 10 mg BID at Day 7. After Day 7, flexible dosing of asenapine was continued for up to 50 weeks.

    Reporting group title
    Asenapine/Asenapine
    Reporting group description
    Participants treated with asenapine in base trial P06107 were first treated with open-label flavored asenapine 2.5 mg BID, then up-titrated to 5 mg BID at Day 4, then up-titrated to 10 mg BID at Day 7. After Day 7, flexible dosing of asenapine was continued for up to 50 weeks.

    Primary: Number of participants who experienced clinical or laboratory adverse events

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    End point title
    Number of participants who experienced clinical or laboratory adverse events [1]
    End point description
    A clinical or laboratory adverse event is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to this medicinal product. Participants analyzed received at least one dose of trial medication, and were 17 years old or younger. One treated participant from the Placebo/Asenapine group, who was 18 years old, was excluded from this analysis.
    End point type
    Primary
    End point timeframe
    Day 1 of treatment to 30 days after the last dose of study drug (up to approximately 54 weeks)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned or performed for this primary endpoint; or for any other endpoint in this study.
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    80 [2]
    241
    Units: Participants
        number (not applicable)
    74
    197
    Notes
    [2] - One participant who was 18 years old was excluded from this analysis.
    No statistical analyses for this end point

    Secondary: Change from baseline in Young Mania Rating Scale (Y-MRS) total score at Day 182

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    End point title
    Change from baseline in Young Mania Rating Scale (Y-MRS) total score at Day 182
    End point description
    The Y-MRS assesses the severity of manic episodes by assigning a severity rating to each of 11 items (Elevated mood, Increased motor activity-energy, Sexual interest, Sleep, Irritability, Speech, Language-thought disorder, Thought content, Disruptive-aggressive behavior, Appearance, Insight). Seven of the 11 items are rated on a scale of 0-4, and 4 of the items are rated on a scale of 0-8. The Y-MRS total score, observed cases (OC), the assessment closest to the scheduled assessment day within the allowed window, is the sum of the ratings for the 11 individual items, and can range from 0-60, with higher scores indicating greater severity of symptoms. Improvement in symptoms is represented by change from baseline values that are negative. The Full Analysis Set (FAS) is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 182
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    37 [3]
    112 [4]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -13 ± 8.3
    -4.9 ± 7.8
    Notes
    [3] - Full Analysis Set (FAS)
    [4] - FAS
    No statistical analyses for this end point

    Secondary: Change from baseline in Y-MRS total score at Day 350

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    End point title
    Change from baseline in Y-MRS total score at Day 350
    End point description
    The Y-MRS assesses the severity of manic episodes by assigning a severity rating to each of 11 items (Elevated mood, Increased motor activity-energy, Sexual interest, Sleep, Irritability, Speech, Language-thought disorder, Thought content, Disruptive-aggressive behavior, Appearance, Insight). Seven of the 11 items are rated on a scale of 0-4, and 4 of the items are rated on a scale of 0-8. The Y-MRS total score, OC, is the sum of the ratings for the 11 individual items, and can range from 0-60, with higher scores indicating greater severity of symptoms. Improvement in symptoms is represented by change from baseline values that are negative. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 350
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    20 [5]
    45 [6]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -15.2 ± 5.8
    -6.5 ± 10.5
    Notes
    [5] - FAS at Day 350
    [6] - FAS at Day 350
    No statistical analyses for this end point

    Secondary: Percentage of participants who were Y-MRS total score remitters (Y-MRS =<12) at Day 182

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    End point title
    Percentage of participants who were Y-MRS total score remitters (Y-MRS =<12) at Day 182
    End point description
    The Y-MRS is an 11-item clinician-rated instrument for assessing the severity of manic episodes. The Y-MRS total score, OC for each participant is the sum of the ratings for the 11 individual items, and can range from 0-60, with higher scores indicating greater severity of symptoms. A remitter is a participant with a Y-MRS total score of 12 or lower. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Day 182
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    37 [7]
    112 [8]
    Units: Percentage of participants
        number (not applicable)
    83.8
    63.4
    Notes
    [7] - FAS at Day 182
    [8] - FAS at Day 182
    No statistical analyses for this end point

    Secondary: Percentage of participants who were Y-MRS total score remitters (Y-MRS =<12) at Day 350

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    End point title
    Percentage of participants who were Y-MRS total score remitters (Y-MRS =<12) at Day 350
    End point description
    The Y-MRS is an 11-item clinician-rated instrument for assessing the severity of manic episodes. The Y-MRS total score, OC for each participant is the sum of the ratings for the 11 individual items, and can range from 0-60, with higher scores indicating greater severity of symptoms. A remitter is a participant with a Y-MRS total score of 12 or lower. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Day 350
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    20 [9]
    45 [10]
    Units: Percentage of participants
        number (not applicable)
    90
    75.6
    Notes
    [9] - FAS at Day 350
    [10] - FAS at Day 350
    No statistical analyses for this end point

    Secondary: Percentage of participants who were Y-MRS total score responders at Day 182

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    End point title
    Percentage of participants who were Y-MRS total score responders at Day 182
    End point description
    The Y-MRS is an 11-item clinician-rated instrument for assessing the severity of manic episodes.The Y-MRS total score, OC for each participant is the sum of the ratings for the 11 individual items, and can range from 0-60, with higher scores indicating greater severity of symptoms. A Y-MRS responder experiences a 50% or more decrease from baseline in Y-MRS total score. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Day 182
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    37 [11]
    111 [12]
    Units: Percentage of participants
        number (not applicable)
    64.9
    37.8
    Notes
    [11] - FAS at Day 182
    [12] - FAS at Day 182
    No statistical analyses for this end point

    Secondary: Percentage of participants who were Y-MRS total score responders at Day 350

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    End point title
    Percentage of participants who were Y-MRS total score responders at Day 350
    End point description
    The Y-MRS is an 11-item clinician-rated instrument for assessing the severity of manic episodes.The Y-MRS total score, OC for each participant is the sum of the ratings for the 11 individual items, and can range from 0-60, with higher scores indicating greater severity of symptoms. A Y-MRS responder experiences a 50% or more decrease from baseline in Y-MRS total score. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Day 350
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    20 [13]
    43 [14]
    Units: Percentage of participants
        number (not applicable)
    80
    53.5
    Notes
    [13] - FAS at Day 350
    [14] - FAS at Day 350
    No statistical analyses for this end point

    Secondary: Time to first total Y-MRS 50% response

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    End point title
    Time to first total Y-MRS 50% response
    End point description
    The Y-MRS is an 11-item clinician-rated instrument for assessing the severity of manic episodes. The Y-MRS total score, OC for each participant is the sum of the ratings for the 11 individual items, ranging from 0-60, with higher scores indicating more severe symptoms. The time to 50% response is the number of days on treatment to achieve a 50% decrease from baseline in Y-MRS total score. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Up to Week 50
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    72 [15]
    227 [16]
    Units: Days
        median (confidence interval 95%)
    49 (44 to 50)
    15 (14 to 21)
    Notes
    [15] - FAS population
    [16] - FAS population
    No statistical analyses for this end point

    Secondary: Time to failure to maintain response in Y-MRS total score

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    End point title
    Time to failure to maintain response in Y-MRS total score
    End point description
    The Y-MRS is an 11-item clinician-rated instrument for assessing the severity of manic episodes. The Y-MRS total score, OC for each participant is the sum of the ratings for the 11 individual items, ranging from 0-60, with higher scores indicating more severe symptoms. The time to failure is the number of days from first achieving a 50% or more decrease from baseline in Y-MRS total score to the first subsequent day of a less than 50% decrease from baseline in Y-MRS total score. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment. Results were shown as "0" because either time to failure or the 95% Confidence Interval (CI) were unable to be determined even after 362 days of follow-up (NA). For the Asenapine/Asenapine arm: Median - NA, 95% CI - 268.0 to NA. For the Placebo/Asenapine arm: Median -194.0, 95% CI - 78.0 to NA.
    End point type
    Secondary
    End point timeframe
    Up to Week 50
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    21 [17]
    120 [18]
    Units: Days
        median (confidence interval 95%)
    0 (0 to 0)
    0 (0 to 0)
    Notes
    [17] - Y-MRS 50% responders in base trial P06107, who were also FAS population in P05898
    [18] - Y-MRS 50% responders in base trial P06107, who were also FAS population in P05898
    No statistical analyses for this end point

    Secondary: Change from baseline in Clinical Global Impression Scale for assessing overall Bipolar Illness (CGI-BP overall) at Day 182

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    End point title
    Change from baseline in Clinical Global Impression Scale for assessing overall Bipolar Illness (CGI-BP overall) at Day 182
    End point description
    The CGI-BP overall OC is a single value score for assessing overall bipolar illness, recorded on a 7-point scale ranging from 1 for normal/not ill, to 7 for very severely ill. An improvement in symptoms is represented by change from baseline values that are negative. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 182
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    37 [19]
    113 [20]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -1.8 ± 1.1
    -0.9 ± 1
    Notes
    [19] - FAS at Day 182
    [20] - FAS at Day 182
    No statistical analyses for this end point

    Secondary: Change from baseline in Clinical Global Impression Scale for assessing overall Bipolar Illness (CGI-BP overall) at Day 350

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    End point title
    Change from baseline in Clinical Global Impression Scale for assessing overall Bipolar Illness (CGI-BP overall) at Day 350
    End point description
    The CGI-BP overall OC is a single value score for assessing overall bipolar illness, recorded on a 7-point scale ranging from 1 for normal/not ill, to 7 for very severely ill. An improvement in symptoms is represented by change from baseline values that are negative. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 350
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    20 [21]
    46 [22]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -2.4 ± 1.2
    -1.2 ± 1.3
    Notes
    [21] - FAS at Day 350
    [22] - FAS at Day 350
    No statistical analyses for this end point

    Secondary: Change from baseline in Clinical Global Impression Scale for assessing depression (CGI-BP depression) at Day 182

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    End point title
    Change from baseline in Clinical Global Impression Scale for assessing depression (CGI-BP depression) at Day 182
    End point description
    The CGI-BP depression OC is a single value score for assessing depression, recorded on a 7-point scale ranging from 1 for normal/not ill, to 7 for very severely ill. An improvement in symptoms is represented by change from baseline values that are negative. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 182
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    37 [23]
    113 [24]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -0.8 ± 1.2
    -0.5 ± 0.9
    Notes
    [23] - FAS at Day 182
    [24] - FAS at Day 182
    No statistical analyses for this end point

    Secondary: Change from baseline in Clinical Global Impression Scale for assessing depression (CGI-BP depression) at Day 350

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    End point title
    Change from baseline in Clinical Global Impression Scale for assessing depression (CGI-BP depression) at Day 350
    End point description
    The CGI-BP depression OC is a single value score for assessing depression, recorded on a 7-point scale ranging from 1 for normal/not ill, to 7 for very severely ill. An improvement in symptoms is represented by change from baseline values that are negative. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 350
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    20 [25]
    46 [26]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -1.2 ± 1.3
    -0.4 ± 1
    Notes
    [25] - FAS at day 350
    [26] - FAS at Day 350
    No statistical analyses for this end point

    Secondary: Change from baseline in Clinical Global Impression Scale for assessing mania (CGI-BP mania) at Day 182

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    End point title
    Change from baseline in Clinical Global Impression Scale for assessing mania (CGI-BP mania) at Day 182
    End point description
    The CGI-BP mania OC is a single value score for assessing mania, recorded on a 7-point scale ranging from 1 for normal/not ill, to 7 for very severely ill. An improvement in symptoms is represented by change from baseline values that are negative. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 182
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    37 [27]
    113 [28]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -1.9 ± 1.1
    -1 ± 1
    Notes
    [27] - FAS at Day 182
    [28] - FAS at Day 182
    No statistical analyses for this end point

    Secondary: Change from baseline in Clinical Global Impression Scale for assessing mania (CGI-BP mania) at Day 350

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    End point title
    Change from baseline in Clinical Global Impression Scale for assessing mania (CGI-BP mania) at Day 350
    End point description
    The CGI-BP mania OC is a single value score for assessing mania, recorded on a 7-point scale ranging from 1 for normal/not ill, to 7 for very severely ill. An improvement in symptoms is represented by change from baseline values that are negative. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 350
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    20 [29]
    46 [30]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -2.3 ± 1.2
    -1.2 ± 1.3
    Notes
    [29] - FAS at Day 350
    [30] - FAS at Day 350
    No statistical analyses for this end point

    Secondary: Change from baseline in Children's Depression Rating Scale, Revised (CDRS-R) total score at Day 182

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    End point title
    Change from baseline in Children's Depression Rating Scale, Revised (CDRS-R) total score at Day 182
    End point description
    The CDRS-R is a 17-item clinician-rated instrument for assessing the presence and severity of depressive symptoms in children. Fourteen of the 17 items are rated on a scale of 1-7, and 3 of the items are rated on a scale of 1-5, with higher scores indicating greater severity of symptoms. The CDRS-R total score, OC for each participant is the sum of the ratings for the 17 individual items, and can range from 17-113, with higher scores indicating greater severity of symptoms. Iimprovement in symptoms is represented by change from baseline values that are negative. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 182
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    37 [31]
    112 [32]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -5.4 ± 7.5
    -1.4 ± 6.4
    Notes
    [31] - FAS at Day 182
    [32] - FAS at Day 182
    No statistical analyses for this end point

    Secondary: Change from baseline in Children's Depression Rating Scale, Revised (CDRS-R) total score at Day 350

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    End point title
    Change from baseline in Children's Depression Rating Scale, Revised (CDRS-R) total score at Day 350
    End point description
    The CDRS-R is a 17-item clinician-rated instrument for assessing the presence and severity of depressive symptoms in children. Fourteen of the 17 items are rated on a scale of 1-7, and 3 of the items are rated on a scale of 1-5, with higher scores indicating greater severity of symptoms. The CDRS-R total score, OC for each participant is the sum of the ratings for the 17 individual items, and can range from 17-113, with higher scores indicating greater severity of symptoms. Iimprovement in symptoms is represented by change from baseline values that are negative. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 350
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    20 [33]
    44 [34]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    -4.3 ± 6.6
    -1.1 ± 5.5
    Notes
    [33] - FAS at Day 350
    [34] - FAS at Day 350
    No statistical analyses for this end point

    Secondary: Percentage of CDRS-R responders at Day 182

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    End point title
    Percentage of CDRS-R responders at Day 182
    End point description
    The CDRS-R is a 17-item clinician-rated instrument for assessing the presence and severity of depressive symptoms in children. The CDRS-R total score, OC for each participant is the sum of the ratings for the 17 individual items, and can range from 17-113, with higher scores indicating greater severity of symptoms. A CDRS-R responder experiences a 50% or more decrease from baseline in CDRS-R total score. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Day 182
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    37 [35]
    111 [36]
    Units: Percentage of participants
        number (not applicable)
    56.8
    36
    Notes
    [35] - FAS at Day 182
    [36] - FAS at Day 182
    No statistical analyses for this end point

    Secondary: Percentage of CDRS-R responders at Day 350

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    End point title
    Percentage of CDRS-R responders at Day 350
    End point description
    The CDRS-R is a 17-item clinician-rated instrument for assessing the presence and severity of depressive symptoms in children. The CDRS-R total score, OC for each participant is the sum of the ratings for the 17 individual items, and can range from 17-113, with higher scores indicating greater severity of symptoms. A CDRS-R responder experiences a 50% or more decrease from baseline in CDRS-R total score. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Day 350
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    20 [37]
    43 [38]
    Units: Percentage of participants
        number (not applicable)
    65
    32.6
    Notes
    [37] - FAS at Day 350
    [38] - FAS at Day 350
    No statistical analyses for this end point

    Secondary: Percentage of participants with emergent depression based on CDRS-R at Day 182

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    End point title
    Percentage of participants with emergent depression based on CDRS-R at Day 182
    End point description
    The CDRS-R is a 17-item clinician-rated instrument for assessing the presence and severity of depressive symptoms in children. The CDRS-R total score, OC for each participant is the sum of the ratings for the 17 individual items, and can range from 17-113, with higher scores indicating greater severity of symptoms. Participants with a CDRS-R score of 40 or greater (whose baseline CDRS-R less than 40) are defined as exhibiting emergent depression which is a strong indicator of the presence or potential for a major depressive disorder. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Day 182
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    37 [39]
    112 [40]
    Units: Percentage of participants
        number (not applicable)
    0
    2.7
    Notes
    [39] - FAS at Day 182
    [40] - FAS at Day 182
    No statistical analyses for this end point

    Secondary: Percentage of participants with emergent depression based on CDRS-R at Day 350

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    End point title
    Percentage of participants with emergent depression based on CDRS-R at Day 350
    End point description
    The CDRS-R is a 17-item clinician-rated instrument for assessing the presence and severity of depressive symptoms in children. The CDRS-R total score, OC for each participant is the sum of the ratings for the 17 individual items, and can range from 17-113, with higher scores indicating greater severity of symptoms. Participants with a CDRS-R score of 40 or greater (whose baseline CDRS-R less than 40) are defined as exhibiting emergent depression which is a strong indicator of the presence or potential for a major depressive disorder. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Day 350
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    20 [41]
    44 [42]
    Units: Percentage of participants
        number (not applicable)
    5
    2.3
    Notes
    [41] - FAS at Day 350
    [42] - FAS at Day 350
    No statistical analyses for this end point

    Secondary: Change from baseline in Children's Global Assessment Scale (CGAS) at Day 182

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    End point title
    Change from baseline in Children's Global Assessment Scale (CGAS) at Day 182
    End point description
    CGAS is a scale with a possible range of 1 to 100, measuring psychological, social, and school functioning in children. Minimum scores, OC range from 1-10, representing the need for constant supervision (worse result) to maximum scores of 91-100, representing superior functioning (better result). An improvement in function is represented by a change from baseline value that is positive. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 182
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    37 [43]
    114 [44]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    17.4 ± 9.9
    9.7 ± 10.1
    Notes
    [43] - FAS at Day 182
    [44] - FAS at Day 182
    No statistical analyses for this end point

    Secondary: Change from baseline in Children's Global Assessment Scale (CGAS) at Day 350

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    End point title
    Change from baseline in Children's Global Assessment Scale (CGAS) at Day 350
    End point description
    CGAS is a scale with a possible range of 1 to 100, measuring psychological, social, and school functioning in children. Minimum scores, OC range from 1-10, representing the need for constant supervision (worse result) to maximum scores of 91-100, representing superior functioning ( better result). An improvement in function is represented by a change from baseline value that is positive. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 350
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    20 [45]
    46 [46]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    22.5 ± 8
    13.1 ± 13.6
    Notes
    [45] - FAS at Day 350
    [46] - FAS at Day 350
    No statistical analyses for this end point

    Secondary: Percentage of participants with a CGAS score of equal or greater than 70 at Day 350

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    End point title
    Percentage of participants with a CGAS score of equal or greater than 70 at Day 350
    End point description
    CGAS is a scale with a possible range of 1 to 100, measuring psychological, social, and school functioning in children. Minimum scores, OC range from 1-10, representing the need for constant supervision (worse result) to maximum scores of 91-100, representing superior functioning (better result). The percentage of participants with a score of 70 or greater, represent those with normal or superior social functioning. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Day 350
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    20 [47]
    46 [48]
    Units: Percentage of participants
        number (not applicable)
    85
    73.9
    Notes
    [47] - FAS at Day 350
    [48] - FAS at Day 350
    No statistical analyses for this end point

    Secondary: Percentage of participants with a CGAS score of equal or greater than 70 at Day 182

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    End point title
    Percentage of participants with a CGAS score of equal or greater than 70 at Day 182
    End point description
    CGAS is a scale with a possible range of 1 to 100, measuring psychological, social, and school functioning in children. Minimum scores, OC range from 1-10, representing the need for constant supervision (worse result) to maximum scores of 91-100, representing superior functioning (better result). The percentage of participants with a score of 70 or greater, represent those with normal to superior social functioning. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Day 182
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    37 [49]
    114 [50]
    Units: Percentage of participants
        number (not applicable)
    73
    55.3
    Notes
    [49] - FAS at Day 182
    [50] - FAS at Day 182
    No statistical analyses for this end point

    Secondary: Change from baseline in Pediatric Quality of Life Enjoyment and Satisfaction Questionnaires (PQ-LES-Q) total score at Day 182

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    End point title
    Change from baseline in Pediatric Quality of Life Enjoyment and Satisfaction Questionnaires (PQ-LES-Q) total score at Day 182
    End point description
    PQ-LES-Q is a questionnaire to assess quality of life enjoyment and satisfaction in children and adolescents. The participant rates 15 items reflecting quality of life from the previous week on a scale of 1=very poor to 5=very good. Items 1-14 assess specific areas (e.g., health, mood or feelings); item 15 is a global assessment of overall quality of life. The PQ-LES-Q total score for each participant, OC is the sum of the rating assigned to each of the first 14 items, and ranges from 14 to 70, with a higher score indicating better quality of life. An improvement in quality of life is represented by change from baseline values that are positive. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 182
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    36 [51]
    111 [52]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    4.4 ± 8.3
    1 ± 7.1
    Notes
    [51] - FAS at Day 182
    [52] - FAS at Day 182
    No statistical analyses for this end point

    Secondary: Change from baseline in PQ-LES-Q total score at Day 350

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    End point title
    Change from baseline in PQ-LES-Q total score at Day 350
    End point description
    PQ-LES-Q is a questionnaire to assess quality of life enjoyment and satisfaction in children and adolescents. The participant rates 15 items reflecting quality of life from the previous week on a scale of 1=very poor to 5=very good. Items 1-14 assess specific areas (e.g., health, mood or feelings); item 15 is a global assessment of overall quality of life. The PQ-LES-Q total score for each participant, OC is the sum of the rating assigned to each of the first 14 items, and ranges from 14 to 70, with a higher score indicating better quality of life. An improvement in quality of life is represented by change from baseline values that are positive. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 350
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    20 [53]
    45 [54]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    3.4 ± 10.9
    0.5 ± 7.3
    Notes
    [53] - FAS at Day 350
    [54] - FAS at Day 350
    No statistical analyses for this end point

    Secondary: Change from baseline in PQ-LES-Q overall score at Day 182

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    End point title
    Change from baseline in PQ-LES-Q overall score at Day 182
    End point description
    PQ-LES-Q is a questionnaire to assess quality of life enjoyment and satisfaction in children and adolescents. The participant rates 15 items reflecting quality of life from the previous week. Item 15, the PQ-LES-Q overall score, OC is a global assessment of overall quality of life, and ranges from 1 to 5, with a higher score indicating better quality of life. An improvement in quality of life is represented by change from baseline values that are positive. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 182
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    36 [55]
    111 [56]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    0.3 ± 0.8
    0.1 ± 0.8
    Notes
    [55] - FAS at Day 182
    [56] - FAS at Day 182
    No statistical analyses for this end point

    Secondary: Change from baseline in PQ-LES-Q overall score at Day 350

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    End point title
    Change from baseline in PQ-LES-Q overall score at Day 350
    End point description
    PQ-LES-Q is a questionnaire to assess quality of life enjoyment and satisfaction in children and adolescents. The participant rates 15 items reflecting quality of life from the previous week. Item 15, the PQ-LES-Q overall score, OC is a global assessment of overall quality of life, and ranges from 1 to 5, with a higher score indicating better quality of life. An improvement in quality of life is represented by change from baseline values that are positive. The FAS is analyzed consisting of participants 17 years old or younger, who have taken at least one dose of trial medication, and have a baseline and at least one post-baseline Y-MRS assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and Day 350
    End point values
    Placebo/Asenapine Asenapine/Asenapine
    Number of subjects analysed
    20 [57]
    45 [58]
    Units: Score on a scale
        arithmetic mean (standard deviation)
    0.3 ± 0.9
    0.4 ± 1
    Notes
    [57] - FAS at Day 350
    [58] - FAS at Day 350
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    30 days after the last dose of study drug (up to approximately 54 weeks)
    Adverse event reporting additional description
    All enrolled and treated participants
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Asenapine/Asenapine
    Reporting group description
    Participants treated with asenapine in base trial P06107 were first treated with open-label flavored asenapine 2.5 mg twice per day (BID), then up-titrated to 5 mg BID at day 4, then up-titrated to 10 mg BID at day 7. After day 7, flexible dosing of asenapine was continued for up to 50 weeks.

    Reporting group title
    Placebo/Asenapine
    Reporting group description
    Participants treated with placebo in base trial P06107 were first treated with open-label flavored asenapine 2.5 mg twice per day (BID), then up-titrated to 5 mg BID at day 4, then up-titrated to 10 mg BID at day 7. After day 7, flexible dosing of asenapine was continued for up to 50 weeks.

    Serious adverse events
    Asenapine/Asenapine Placebo/Asenapine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 241 (7.05%)
    6 / 81 (7.41%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dystonia
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    2 / 241 (0.83%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    1 / 241 (0.41%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bipolar disorder
         subjects affected / exposed
    2 / 241 (0.83%)
    2 / 81 (2.47%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    3 / 241 (1.24%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disturbance in social behaviour
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Exhibitionism
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impulsive behaviour
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Self-injurious ideation
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal behaviour
         subjects affected / exposed
    1 / 241 (0.41%)
    0 / 81 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    7 / 241 (2.90%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    1 / 8
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Swollen tongue
         subjects affected / exposed
    0 / 241 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Asenapine/Asenapine Placebo/Asenapine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    135 / 241 (56.02%)
    65 / 81 (80.25%)
    Investigations
    Weight increased
         subjects affected / exposed
    42 / 241 (17.43%)
    16 / 81 (19.75%)
         occurrences all number
    43
    16
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 241 (2.07%)
    8 / 81 (9.88%)
         occurrences all number
    6
    10
    Dysgeusia
         subjects affected / exposed
    4 / 241 (1.66%)
    5 / 81 (6.17%)
         occurrences all number
    4
    5
    Headache
         subjects affected / exposed
    21 / 241 (8.71%)
    11 / 81 (13.58%)
         occurrences all number
    30
    21
    Sedation
         subjects affected / exposed
    23 / 241 (9.54%)
    19 / 81 (23.46%)
         occurrences all number
    29
    27
    Somnolence
         subjects affected / exposed
    44 / 241 (18.26%)
    29 / 81 (35.80%)
         occurrences all number
    50
    36
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    15 / 241 (6.22%)
    6 / 81 (7.41%)
         occurrences all number
    17
    7
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    10 / 241 (4.15%)
    6 / 81 (7.41%)
         occurrences all number
    15
    6
    Hypoaesthesia oral
         subjects affected / exposed
    2 / 241 (0.83%)
    11 / 81 (13.58%)
         occurrences all number
    2
    11
    Nausea
         subjects affected / exposed
    15 / 241 (6.22%)
    9 / 81 (11.11%)
         occurrences all number
    17
    9
    Paraesthesia oral
         subjects affected / exposed
    3 / 241 (1.24%)
    8 / 81 (9.88%)
         occurrences all number
    3
    10
    Vomiting
         subjects affected / exposed
    16 / 241 (6.64%)
    4 / 81 (4.94%)
         occurrences all number
    18
    4
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    16 / 241 (6.64%)
    6 / 81 (7.41%)
         occurrences all number
    18
    6
    Infections and infestations
    Gastroenteritis viral
         subjects affected / exposed
    4 / 241 (1.66%)
    5 / 81 (6.17%)
         occurrences all number
    4
    5

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 May 2011
    Amendment 1: Raised the lower age limit to greater than or equal to 12 years of age, and allowed participants who turned 18 years of age during acute trial (P06107) to continue into extension trial (P05898).
    02 Dec 2011
    Amendment 2: Addition of new investigators, and revised information for one investigator
    12 Jan 2012
    Amendment 3: Inclusion of 10 and 11 year olds; revision of options for conducting visits; updated text on non-sexually active females; updating of allowed rescue therapy; updated to clarify safety follow-up visit; added drug hypersensitivity reactions as a closely monitored event; updated monitoring of liver enzymes; clarified definition of "clinically important at any time"; updated reference section.
    28 Jun 2012
    Amendment 4:Extended length of trial to 50 weeks of treatment; added Cognition Battery and laboratory tests at Days 182 and 350; updated sponsor in title page; updated text for monitoring participants; updated footnote for date of informed consent; added text to clarify visit windows; deleted subgroup analysis; deleted efficacy parameter "sustained Y-MRS remitter".
    15 May 2013
    Amendment 5: Added clarification about growth analysis for Russia; added subgroup analysis by geographic region; provided guidance for interim analysis, and interim CSR

    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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