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    Clinical Trial Results:
    The Evaluation of Lamictal as an Add-on Treatment for Bipolar I Disorder in Children and Adolescents, 10 to 17 Years of Age

    Summary
    EudraCT number
    		 2015-004872-31
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    07 Aug 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Jan 2017
    First version publication date
    22 Jan 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SCA102833
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline
    Sponsor organisation address
    980 Great West Road, Brentford, Middlesex, United Kingdom,
    Public contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Scientific contact
    GSK Response Center, GlaxoSmithKline, 1 866-435-7343,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Jan 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Aug 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    TBD
    Protection of trial subjects
    Not Applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Jul 2008
    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
    United States: 301
    Worldwide total number of subjects
    301
    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)
    74
    Adolescents (12-17 years)
    227
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 301 participants were enrolled in the study, of which 298 subjects took at least one dose of lamotrigine (LTG). One hundred and seventy three participants met stabilization criteria and entered the Randomized Phase.

    Pre-assignment
    Screening details
    		 The study consisted of a 2-week Screening Phase, an 18-week Open-Label Phase, a 36-week Double-Blind Randomized Phase and a Taper and Follow-up Phase (up to 4 weeks depending on the dose the participant was taking at the last Open-Label or Randomized Phase visit), which was either open-label or double-blind depending on the phase of the study.

    Period 1
    Period 1 title
    Open-Label Phase
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 LTG: Open-Label Phase
    Arm description
    		 Participants (par.) received lamotrigine (LTG) up to a maximum dose depending on their age and concomitant bipolar medication group. Participants 10 -12 years of age received LTG up to a maximum dose of: 3 milligrams/kilograms (mg/kg)/day or 100 mg/day, whichever was less; or 6 mg/kg/day or 200 mg/day whichever was less; or 12 mg/kg/day or 300 mg/day whichever was less, depending on their bipolar medication group. Participants 13-17 years of age received LTG up to a maximum dose of 150 mg/day, 300 mg/day, or 400 mg/day depending on their bipolar medication group. Participants took LTG for a duration of up to 18 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lamictal (Lamotrigine) 5, 25, 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable/dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants 10 -12 years of age received LTG up to a maximum dose of: 3 milligrams/kilograms (mg/kg)/day or 100 mg/day, whichever was less; or 6 mg/kg/day or 200 mg/day whichever was less; or 12 mg/kg/day or 300 mg/day whichever was less, depending on their bipolar medication group. Participants 13-17 years of age received LTG up to a maximum dose of 150 mg/day, 300 mg/day, or 400 mg/day depending on their bipolar medication group. Participants took LTG for a duration of up to 18 weeks

    Number of subjects in period 1
    		LTG: Open-Label Phase
    Started
    298
    Completed
    173
    Not completed
    125
         Physician decision
    2
         Consent withdrawn by subject
    37
         Adverse event, non-fatal
    26
         Lost to follow-up
    7
         Lack of efficacy
    18
         Protocol deviation
    35
    Period 2
    Period 2 title
    Randomized Phase
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received matching placebo in the evening for participants taking one dose and for participants taking two divided doses, one dose in the morning and one dose in the evening, for a duration of up to 36 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable/dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received matching placebo in the evening for participants taking one dose and for participants taking two divided doses, one dose in the morning and one dose in the evening, for a duration of up to 36 weeks.

    Arm title
    		 Lamotrigine
    Arm description
    		 Participants received LTG equivalent to the dose established in the Open-Label Phase. Participants received LTG tablets in the evening for participants taking one dose and for participants taking two divided doses, one dose in the morning and one dose in the evening, for a duration of up to 36 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lamotrigine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable/dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received LTG equivalent to the dose established in the Open-Label Phase . Participants received LTG

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Participants (par.) received lamotrigine (LTG) up to a maximum dose depending on their age and concomitant bipolar medication group. Participants 10 -12 years of age received LTG up to a maximum dose of: 3 milligrams/kilograms (mg/kg)/day or 100 mg/day, whichever was less; or 6 mg/kg/day or 200 mg/day whichever was less; or 12 mg/kg/day or 300 mg/day whichever was less, depending on their bipolar medication group. Participants 13-17 years of age received LTG up to a maximum dose of 150 mg/day.
    Number of subjects in period 2 [2]
    		Placebo Lamotrigine
    Started
    86
    87
    Completed
    21
    20
    Not completed
    65
    67
         Physician decision
    3
    1
         Consent withdrawn by subject
    14
    22
         Adverse event, non-fatal
    26
    17
         Lost to follow-up
    2
    3
         Lack of efficacy
    11
    11
         Protocol deviation
    9
    13
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 301 participants were enrolled in the study, of which 298 subjects took at least one dose of lamotrigine (LTG). One hundred and seventy three participants met stabilization criteria and entered the Randomized Phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo in the evening for participants taking one dose and for participants taking two divided doses, one dose in the morning and one dose in the evening, for a duration of up to 36 weeks.

    Reporting group title
    Lamotrigine
    Reporting group description
    		 Participants received LTG equivalent to the dose established in the Open-Label Phase. Participants received LTG tablets in the evening for participants taking one dose and for participants taking two divided doses, one dose in the morning and one dose in the evening, for a duration of up to 36 weeks.

    Reporting group values
    		 Placebo Lamotrigine Total
    Number of subjects
    		 86 87
    Age categorical
    Units: Subjects
    Age continuous
    Age continuous description
    Units: years
        arithmetic mean (standard deviation)
    		 13.5 ± 2.22 13.4 ± 2.33 -
    Gender categorical
    Gender categorical description
    Units: Subjects
        Female
    		 39 33 72
        Male
    		 47 54 101
    Race/Ethnicity, Customized
    Units: Subjects
        African American/African Heritage
    		 9 9 18
        American Indian or Alaska Native
    		 0 1 1
        Asian - East Asian Heritage
    		 1 0 1
        White - Arabic/North African Heritage
    		 1 0 1
        White - White/Caucasian/European Heritage
    		 71 71 142
        Mixed Race
    		 4 6 10

    End points

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    End points reporting groups
    Reporting group title
    LTG: Open-Label Phase
    Reporting group description
    		 Participants (par.) received lamotrigine (LTG) up to a maximum dose depending on their age and concomitant bipolar medication group. Participants 10 -12 years of age received LTG up to a maximum dose of: 3 milligrams/kilograms (mg/kg)/day or 100 mg/day, whichever was less; or 6 mg/kg/day or 200 mg/day whichever was less; or 12 mg/kg/day or 300 mg/day whichever was less, depending on their bipolar medication group. Participants 13-17 years of age received LTG up to a maximum dose of 150 mg/day, 300 mg/day, or 400 mg/day depending on their bipolar medication group. Participants took LTG for a duration of up to 18 weeks.
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo in the evening for participants taking one dose and for participants taking two divided doses, one dose in the morning and one dose in the evening, for a duration of up to 36 weeks.

    Reporting group title
    Lamotrigine
    Reporting group description
    		 Participants received LTG equivalent to the dose established in the Open-Label Phase. Participants received LTG tablets in the evening for participants taking one dose and for participants taking two divided doses, one dose in the morning and one dose in the evening, for a duration of up to 36 weeks.

    Primary: Time from randomization to the occurrence of a bipolar event (TOBE)

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    End point title
    		 Time from randomization to the occurrence of a bipolar event (TOBE)
    End point description
    TOBE is defined as the first prescription of any additional pharmacotherapy to treat bipolar symptoms, increasing the dose(s) of the participants conventional bipolar medication(s), treatment with electroconvulsive therapy, or moving the participant to a more restricted environment for observation, safety, or treatment; or participant withdrawal from the study due to a bipolar-related adverse event (AE) or serious adverse event (SAE); or participants withdrawal from the study due to lack of efficacy as defined by rating scale threshold scores. TOBE is calculated using a log rank test with stratification for index mood state (depression, mania/hypomania, mixed mood). Randomized Intent-to-Treat (ITT) Population: all participants who were randomized to LTG or placebo and received at least one dose of investigational product.
    End point type
    Primary
    End point timeframe
    From randomization until Week 36
    End point values
    		 Placebo Lamotrigine
    Number of subjects analysed
    86 [1]
    87 [2]
    Units: Days
    arithmetic mean (standard error)
        Stratum: Depression, n=22,21
    50 ± 3.8
    155 ± 14.7
        Stratum: Mania/Hypomania, n=36, 37
    120 ± 12.2
    163 ± 12.2
        Stratum: Mixed Mood, n=28, 29
    107 ± 13.8
    136 ± 15.4
    Notes
    [1] - Randomized Intent-to-Treat (ITT) Population
    [2] - Randomized Intent-to-Treat (ITT) Population
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Placebo v Lamotrigine
    Number of subjects included in analysis
    173
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0717
    Method
    		 Logrank
    Confidence interval
         level
    		 95%

    Secondary: Time from randomization to withdrawal from the study for any cause (TTW)

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    End point title
    		 Time from randomization to withdrawal from the study for any cause (TTW)
    End point description
    The time from randomization to the withdrawal from study was analyzed. TTW was calculated using the log rank test with stratification for index mood state (depression, mania/hypomania, mixed mood).
    End point type
    Secondary
    End point timeframe
    From randomization until withdrawal from the study for any cause (up to Week 36)
    End point values
    		 Placebo Lamotrigine
    Number of subjects analysed
    86 [3]
    87 [4]
    Units: Days
    arithmetic mean (standard error)
        Stratum: Depression, n=22, 21
    113 ± 21.4
    141 ± 20
        Stratum: Mania/Hypomania, n=36, 37
    138 ± 17.3
    144 ± 15.6
        Stratum: Mixed Mood, n=28, 29
    101 ± 15.7
    106 ± 16.3
    Notes
    [3] - Randomized ITT Population.
    [4] - Randomized ITT Population.
    No statistical analyses for this end point

    Secondary: Time from randomization to intervention for a mood episode (TIME)

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    End point title
    		 Time from randomization to intervention for a mood episode (TIME)
    End point description
    The time from randomization to the intervention for a mood episode (depression, mania/hypomania or mixed mood) was analyzed. TIME was calculated using the log rank test with stratification for index mood state (depression, mania/hypomania, mixed mood).
    End point type
    Secondary
    End point timeframe
    From randomization until intervention administered for a mood episode (up to Week 36)
    End point values
    		 Placebo Lamotrigine
    Number of subjects analysed
    86 [5]
    87 [6]
    Units: Days
    arithmetic mean (standard error)
        Stratum: Depression, n=22, 21
    62 ± 5.2
    164 ± 12.7
        Stratum: Mania/Hypomania, n=36, 37
    129 ± 11.7
    179 ± 10.8
        Stratum: Mixed Mood, n=28, 29
    120 ± 13.7
    127 ± 12
    Notes
    [5] - Randomized ITT Population.
    [6] - Randomized ITT Population.
    No statistical analyses for this end point

    Secondary: Time from randomization to intervention for depression (TIDep), mania/hypomania (TIMan), or a mixed episode (TIMix)

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    End point title
    		 Time from randomization to intervention for depression (TIDep), mania/hypomania (TIMan), or a mixed episode (TIMix)
    End point description
    The time from randomization to intervention for depression (TIDep), mania/hypomania (TIMan), or a mixed episode (TIMix) was analyzed. TIDep, TIMan, and TIMix were calculated using the log rank test with stratification for index mood state (depression, mania/hypomania, mixed mood). A value of 99999 indicates that the arithmetic mean is not available.
    End point type
    Secondary
    End point timeframe
    From randomization until intervention administered for depression, mania/hypomania or a mixed episode (up to Week 36)
    End point values
    		 Placebo Lamotrigine
    Number of subjects analysed
    86 [7]
    87 [8]
    Units: Days
    arithmetic mean (standard error)
        TIDep: Depression, n=22, 21
    61 ± 1.5
    46 ± 1.5
        TIDep: Mania/Hypomania, n=36, 37
    99999 ± 99999
    99999 ± 99999
        TIDep: Mixed Mood, n=28, 29
    59 ± 2.6
    159 ± 99999
        TIMan: Depression, n=22, 21
    74 ± 3.9
    182 ± 99999
        TIMan: Mania/Hypomania, n=36, 37
    139 ± 11.5
    61 ± 2.1
        TIMan: Mixed Mood, n=28, 29
    105 ± 7.3
    148 ± 8.5
        TIMix: Depression, n=22, 21
    37 ± 1.3
    158 ± 99999
        TIMix: Mania/Hypomania, n=36, 37
    135 ± 6.3
    194 ± 7.5
        TIMix: Mixed Mood, n=28, 29
    160 ± 10.7
    57 ± 2.5
    Notes
    [7] - Randomized ITT Population.
    [8] - Randomized ITT Population.
    No statistical analyses for this end point

    Secondary: Number of participants experiencing a relapse/recurrence to depression, mania/hypomania, or mixed mood state

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    End point title
    		 Number of participants experiencing a relapse/recurrence to depression, mania/hypomania, or mixed mood state
    End point description
    The number of participants requiring intervention to treat either the emergence of or a change in bipolar symptoms that is, experiencing a relapse/recurrence to depression, mania/hypomania, or mixed mood state were analyzed. Randomized ITT Population. Only those participants requiring intervention to treat either the emergence of, or a change, in bipolar symptoms were analyzed.
    End point type
    Secondary
    End point timeframe
    From randomization until a relapse/recurrence to depression, mania/hypomania, or mixed mood state (up to Week 36)
    End point values
    		 Placebo Lamotrigine
    Number of subjects analysed
    31 [9]
    18 [10]
    Units: Participants
        Depression
    5
    3
        Mania/hypomania
    16
    6
        Mixed episode state
    10
    9
    Notes
    [9] - Randomized ITT Population
    [10] - Randomized ITT Population
    No statistical analyses for this end point

    Secondary: Number of participants experiencing a relapse/recurrence within the first 30, 90, and 180 days in the Randomized Phase

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    End point title
    		 Number of participants experiencing a relapse/recurrence within the first 30, 90, and 180 days in the Randomized Phase
    End point description
    The proportion of participants (par.) requiring intervention to treat either the emergence of or a change in bipolar symptoms, that is, experiencing a relapse/recurrence to depression, mania/hypomania, or mixed mood state at any time within the first 30, 90, and 180 days in the Randomized Phase were analyzed. Randomized ITT Population. Only those participants requiring intervention to treat either the emergence of, or a change, in bipolar symptoms were analyzed.
    End point type
    Secondary
    End point timeframe
    From randomization up to Week 36
    End point values
    		 Placebo Lamotrigine
    Number of subjects analysed
    31 [11]
    18 [12]
    Units: Participants
        Mania/hypomania, 30 days, n=16, 6
    9
    2
        Mania/hypomania, 90 days, n=16, 6
    12
    4
        Mania/hypomania, 180 days, n=16, 6
    16
    5
        Depression, 30 days, n=5, 3
    1
    1
        Depression, 90 days, n=5, 3
    5
    2
        Depression, 180 days, n=5, 3
    5
    3
        Mixed mood state, 30 days, n= 10, 9
    3
    2
        Mixed mood state, 90 days, n= 10, 9
    7
    6
        Mixed mood state, 180 days, n= 10, 9
    10
    8
    Notes
    [11] - Randomized ITT Population
    [12] - Randomized ITT Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Quick Inventory of Depressive Symptomatology – Clinician interview, semi-structured, adolescent version (QIDS- A17-C) at each visit in the Open-Label Phase

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    End point title
    		 Change from Baseline in the Quick Inventory of Depressive Symptomatology – Clinician interview, semi-structured, adolescent version (QIDS- A17-C) at each visit in the Open-Label Phase
    End point description
    The QIDS-A17-C is a 17-item scale used to assess depression severity in adolescents according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) diagnostic criteria for a major depressive episode; it is a modified version of the Quick Inventory of Depressive Symptomatology (QIDS) used for adults. Each item is scored on a 0-3 scale, yielding 9 domain scores. The range of scores is 0 (best possible outcome) to 27 (worst possible outcome). Analysis was performed using mixed model repeated measures. Open-Label ITT population: all participants who entered the Open-Label Phase and received at least one dose of LTG.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18
    End point values
    		 LTG: Open-Label Phase
    Number of subjects analysed
    298 [13]
    Units: Scores on a Scale
    least squares mean (standard error)
        Week 1
    -2.1 ± 0.22
        Week 2
    -2.9 ± 0.28
        Week 3
    -3.7 ± 0.28
        Week 4
    -3.8 ± 0.3
        Week 5
    -4.3 ± 0.3
        Week 6
    -4.7 ± 0.3
        Week 7
    -5.1 ± 0.3
        Week 8
    -4.9 ± 0.31
        Week 9
    -5.6 ± 0.3
        Week 10
    -6.1 ± 0.29
        Week 11
    -6.4 ± 0.3
        Week 12
    -6.6 ± 0.32
        Week 13
    -6.7 ± 0.32
        Week 14
    -6.8 ± 0.34
        Week 15
    -6.8 ± 0.4
        Week 16
    -6.8 ± 0.41
        Week 17
    -6.5 ± 0.53
        Week 18
    -6.5 ± 0.7
    Notes
    [13] - Open-Label ITT population
    No statistical analyses for this end point

    Secondary: Change from Randomization in the Quick Inventory of Depressive Symptomatology – Clinician interview, semi-structured, adolescent version (QIDS- A17-C) at each visit in the Randomized Phase

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    End point title
    		 Change from Randomization in the Quick Inventory of Depressive Symptomatology – Clinician interview, semi-structured, adolescent version (QIDS- A17-C) at each visit in the Randomized Phase
    End point description
    The QIDS-A17-C is a 17-item scale used to assess depression severity in adolescents according to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR) diagnostic criteria for a major depressive episode; it is a modified version of the Quick Inventory of Depressive Symptomatology (QIDS) used for adults. Each item is scored on a 0-3 scale, yielding 9 domain scores. The range of scores is 0 (best possible outcome) to 27 (worst possible outcome). Analysis was performed using mixed model repeated measures.
    End point type
    Secondary
    End point timeframe
    Randomization and Weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, and 36
    End point values
    		 Placebo Lamotrigine
    Number of subjects analysed
    86 [14]
    87 [15]
    Units: Scores on a scale
    least squares mean (standard error)
        Week 1
    0.8 ± 0.3
    0.5 ± 0.31
        Week 2
    1.5 ± 0.37
    1.1 ± 0.37
        Week 3
    1.3 ± 0.36
    0.6 ± 0.36
        Week 4
    1.2 ± 0.39
    1 ± 0.39
        Week 6
    1.9 ± 0.49
    1.5 ± 0.47
        Week 8
    1.9 ± 0.47
    1.7 ± 0.45
        Week 10
    1.4 ± 0.44
    1.5 ± 0.41
        Week 12
    1.4 ± 0.4
    1.2 ± 0.39
        Week 16
    2.2 ± 0.48
    1.8 ± 0.47
        Week 20
    1.5 ± 0.5
    2.5 ± 0.46
        Week 24
    1.7 ± 0.53
    1.8 ± 0.51
        Week 28
    1.6 ± 0.61
    2.3 ± 0.57
        Week 32
    1 ± 0.72
    1.9 ± 0.72
        Week 36
    2 ± 0.63
    1.9 ± 0.63
    Notes
    [14] - Randomized ITT Population
    [15] - Randomized ITT Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Quick Inventory of Depressive Symptomatology – self-report adolescent version (QIDS-A17-SR) at each visit in the Open-Label Phase

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    End point title
    		 Change from Baseline in the Quick Inventory of Depressive Symptomatology – self-report adolescent version (QIDS-A17-SR) at each visit in the Open-Label Phase
    End point description
    The QIDS-A17-SR is a 17-item scale used to assess depression severity in adolescents according to the DSM-IV-TR diagnostic criteria for a major depressive episode; it is a modified version of the Quick Inventory of Depressive Symptomatology (QIDS) used for adults. Each item is scored on a 0-3 scale, yielding 9 domain scores. The range of scores is 0 (best possible outcome) to 27 (worst possible outcome). The scale is completed by the participant. Analysis was performed using mixed model repeated measures.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12, 16, and 18
    End point values
    		 LTG: Open-Label Phase
    Number of subjects analysed
    298 [16]
    Units: Scores on a scale
    least squares mean (standard error)
        Week 4
    -2.7 ± 0.25
        Week 8
    -3.3 ± 0.27
        Week 12
    -4.3 ± 0.28
        Week 16
    -4.5 ± 0.33
        Week 18
    -5 ± 0.52
    Notes
    [16] - Open-Label ITT Population
    No statistical analyses for this end point

    Secondary: Change from Randomization in the Quick Inventory of Depressive Symptomatology – self-report adolescent version (QIDS-A17-SR) at each visit in the Randomized Phase

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    End point title
    		 Change from Randomization in the Quick Inventory of Depressive Symptomatology – self-report adolescent version (QIDS-A17-SR) at each visit in the Randomized Phase
    End point description
    The QIDS-A17-SR is a 17-item scale used to assess depression severity in adolescents according to the DSM-IV-TR diagnostic criteria for a major depressive episode; it is a modified version of the Quick Inventory of Depressive Symptomatology (QIDS) used for adults. Each item is scored on a 0-3 scale, yielding 9 domain scores. The range of scores is 0 (best possible outcome) to 27 (worst possible outcome). The scale is completed by the participant. Analysis was performed using mixed model repeated measures.
    End point type
    Secondary
    End point timeframe
    Randomization and Weeks 8, 16, 24, 32, and 36
    End point values
    		 Placebo Lamotrigine
    Number of subjects analysed
    86 [17]
    87 [18]
    Units: Scores on a scale
    least squares mean (standard error)
        Week 8
    1.6 ± 0.47
    1.2 ± 0.48
        Week 16
    1.6 ± 0.6
    1.4 ± 0.58
        Week 24
    1 ± 0.6
    1.5 ± 0.56
        Week 32
    0.6 ± 0.66
    0.2 ± 0.63
        Week 36
    0.9 ± 0.66
    0.8 ± 0.68
    Notes
    [17] - Randomized ITT Population
    [18] - Randomized ITT Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Clinical Global Impressions – Bipolar, Severity of Illness (CGI-BP[S]) at each visit in the Open-Label Phase

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    End point title
    		 Change from Baseline in the Clinical Global Impressions – Bipolar, Severity of Illness (CGI-BP[S]) at each visit in the Open-Label Phase
    End point description
    Severity of the bipolar illness was based on the CGI-BP(S) score which had a range from 1 (normal, not ill) to 7 (very severely ill). Analysis was performed using mixed model repeated measures.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18
    End point values
    		 LTG: Open-Label Phase
    Number of subjects analysed
    298 [19]
    Units: Scores on a scale
    least squares mean (standard error)
        Week 1
    -0.4 ± 0.05
        Week 2
    -0.6 ± 0.05
        Week 3
    -0.9 ± 0.06
        Week 4
    -1 ± 0.06
        Week 5
    -1.2 ± 0.06
        Week 6
    -1.3 ± 0.06
        Week 7
    -1.4 ± 0.07
        Week 8
    -1.5 ± 0.07
        Week 9
    -1.6 ± 0.07
        Week 10
    -1.8 ± 0.07
        Week 11
    -1.9 ± 0.07
        Week 12
    -2.1 ± 0.07
        Week 13
    -2.1 ± 0.07
        Week 14
    -2.1 ± 0.07
        Week 15
    -2.1 ± 0.08
        Week 16
    -2.1 ± 0.1
        Week 17
    -2 ± 0.12
        Week 18
    -2.1 ± 0.15
    Notes
    [19] - Open-Label ITT Population
    No statistical analyses for this end point

    Secondary: Change from Randomization in the Clinical Global Impressions – Bipolar, Severity of Illness (CGI-BP[S]) at each visit in the Randomized Phase

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    End point title
    		 Change from Randomization in the Clinical Global Impressions – Bipolar, Severity of Illness (CGI-BP[S]) at each visit in the Randomized Phase
    End point description
    Severity of the bipolar illness was based on the CGI-BP(S) score which had a range from 1 (normal, not ill) to 7 (very severely ill). Analysis was performed using mixed model repeated measures.
    End point type
    Secondary
    End point timeframe
    Randomization and Weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, and 36
    End point values
    		 Placebo Lamotrigine
    Number of subjects analysed
    86 [20]
    87 [21]
    Units: Scores on a scale
    least squares mean (standard error)
        Week 1
    0.2 ± 0.09
    0 ± 0.09
        Week 2
    0.4 ± 0.12
    0.2 ± 0.12
        Week 3
    0.4 ± 0.12
    0.2 ± 0.12
        Week 4
    0.6 ± 0.13
    0.3 ± 0.13
        Week 6
    0.8 ± 0.15
    0.4 ± 0.15
        Week 8
    0.7 ± 0.15
    0.4 ± 0.14
        Week 10
    0.4 ± 0.13
    0.6 ± 0.13
        Week 12
    0.5 ± 0.14
    0.4 ± 0.14
        Week 16
    0.6 ± 0.17
    0.6 ± 0.15
        Week 20
    0.5 ± 0.17
    0.8 ± 0.16
        Week 24
    0.4 ± 0.17
    0.6 ± 0.16
        Week 28
    0.3 ± 0.17
    0.5 ± 0.16
        Week 32
    0.2 ± 0.19
    0.5 ± 0.2
        Week 36
    0.4 ± 0.19
    0.3 ± 0.21
    Notes
    [20] - Randomized ITT Population
    [21] - Randomized ITT Population
    No statistical analyses for this end point

    Secondary: Summary of Clinical Global Impressions – Bipolar – Improvement of Illness (CGI-BP [I]) Scores during Open-label Phase

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    End point title
    		 Summary of Clinical Global Impressions – Bipolar – Improvement of Illness (CGI-BP [I]) Scores during Open-label Phase
    End point description
    Improvement of bipolar illness was based on the CGI-BP (I) score which ranged from 1 (very much improved) to 7 (very much worse). Analysis was performed using mixed model repeated measures. Open-Label ITT Population. Only those par. available at the specified time points were analyzed (represented by n=X). Different par. may have been analyzed at different time points, so the overall number of par. analyzed reflects everyone in the Open-Label Population.
    End point type
    Secondary
    End point timeframe
    Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18
    End point values
    		 LTG: Open-Label Phase
    Number of subjects analysed
    298 [22]
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Week 1, n=290
    3.6 ± 0.8
        Week 2, n=278
    3.3 ± 0.9
        Week 3, n=270
    3.1 ± 0.96
        Week 4, n=265
    3 ± 1.03
        Week 5, n=258
    2.8 ± 1.01
        Week 6, n=243
    2.7 ± 1.05
        Week 7, n=246
    2.5 ± 1.07
        Week 8, n=236
    2.5 ± 1.09
        Week 9, n=227
    2.3 ± 1.05
        Week 10, n=205
    2.2 ± 1.09
        Week 11, n=181
    2.2 ± 0.92
        Week 12, n=168
    2 ± 0.87
        Week 13, n=141
    1.9 ± 0.85
        Week 14, n=118
    1.9 ± 0.69
        Week 15, n=93
    1.8 ± 0.71
        Week 16, n=72
    2 ± 0.89
        Week 17, n=42
    2 ± 0.7
        Week 18, n=28
    2 ± 0.88
    Notes
    [22] - Open-Label ITT Population
    No statistical analyses for this end point

    Secondary: Summary of Clinical Global Impressions – Bipolar – Improvement of Illness (CGI-BP [I]) Scores during Randomized Phase

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    End point title
    		 Summary of Clinical Global Impressions – Bipolar – Improvement of Illness (CGI-BP [I]) Scores during Randomized Phase
    End point description
    Improvement of bipolar illness was based on the CGI-BP(I) score which ranged from 1 (very much improved) to 7 (very much worse). Analysis was performed using mixed model repeated measures. Randomized ITT Population. Only those par. available at the specified time points were analyzed (represented by n=X). Different par. may have been analyzed at different time points, so the overall number of par. analyzed reflects everyone in the Randomized ITT Population.
    End point type
    Secondary
    End point timeframe
    Randomization weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32 and 36
    End point values
    		 Placebo Lamotrigine
    Number of subjects analysed
    86 [23]
    87 [24]
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Week 1, n=84, 85
    3.3 ± 1.4
    3.3 ± 1.37
        Week 2, n=82, 81
    3.7 ± 1.48
    3.6 ± 1.38
        Week 3, n=74, 75
    3.6 ± 1.39
    3.6 ± 1.34
        Week 4, n=65, 70
    3.6 ± 1.51
    3.6 ± 1.35
        Week 6, n=58, 64
    3.8 ± 1.64
    3.4 ± 1.49
        Week 8, n=51, 60
    3.5 ± 1.72
    3.6 ± 1.47
        Week 10, n=45, 55
    3.3 ± 1.64
    3.8 ± 1.19
        Week 12, n=45, 49
    3.3 ± 1.52
    3.4 ± 1.29
        Week 16, n=43, 50
    3.4 ± 1.73
    3.5 ± 1.37
        Week 20, n=37, 43
    3 ± 1.48
    3.8 ± 1.36
        Week 24, n=34, 36
    3 ± 1.59
    3.4 ± 1.44
        Week 28, n=29, 32
    2.7 ± 1.56
    3.5 ± 1.44
        Week 32, n=28, 27
    3 ± 1.63
    3.5 ± 1.28
        Week 36, n=27, 24
    3 ± 1.68
    3.6 ± 1.1
    Notes
    [23] - Randomized ITT Population
    [24] - Randomized ITT Population
    No statistical analyses for this end point

    Secondary: Number of participants considered much improved or very much improved [defined as a Clinical Global Impression-Bipolar Version, Improvement of Illness (CGI-BP[I]), score of 1 or 2] at each visit compared to Baseline in the Open-Label Phase

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    End point title
    		 Number of participants considered much improved or very much improved [defined as a Clinical Global Impression-Bipolar Version, Improvement of Illness (CGI-BP[I]), score of 1 or 2] at each visit compared to Baseline in the Open-Label Phase
    End point description
    The CGI-BP(I) asks the following question: “Compared to the Baseline assessment in this trial, how much has the participant changed?”. Scores on the CGI-I range from 1 (very much improved) to 7 (very much worse). The investigator or their designee rated improvement regardless of whether the improvement to be due to drug treatment. Improvement defined as CGI-BP(I)=1 (improved) or 2 (very much improved). Missing data imputed using last-observation carried forward (LOCF). Open-Label ITT Population. Only those par. available at the specified time points were analyzed (represented by n=X). Different par. may have been analyzed at different time points, so the overall number of par. analyzed reflects everyone in the Open-Label Population.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18
    End point values
    		 LTG: Open-Label Phase
    Number of subjects analysed
    298 [25]
    Units: Participants
        Week 1, n=297
    27
        Week 2, n=297
    46
        Week 3, n=297
    72
        Week 4, n=297
    86
        Week 5, n=297
    113
        Week 6, n=297
    124
        Week 7, n=297
    138
        Week 8, n=297
    140
        Week 9, n=297
    159
        Week 10, n=297
    176
        Week 11, n=297
    182
        Week 12, n=297
    195
        Week 13, n=297
    205
        Week 14, n=297
    211
        Week 15, n=297
    210
        Week 16, n=297
    209
        Week 17, n=297
    208
        Week 18, n=297
    206
    Notes
    [25] - Open-Label ITT Population
    No statistical analyses for this end point

    Secondary: Number of participants considered much improved or very much improved [defined as a Clinical Global Impression-Bipolar Version, Improvement of Illness (CGI-BP[I]), score of 1 or 2] at each visit compared to Randomization in the Randomized Phase

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    End point title
    		 Number of participants considered much improved or very much improved [defined as a Clinical Global Impression-Bipolar Version, Improvement of Illness (CGI-BP[I]), score of 1 or 2] at each visit compared to Randomization in the Randomized Phase
    End point description
    The CGI-BP(I) asks the following question: “Compared to the Randomization assessment in this trial, how much has the participant changed?”. Scores on the CGI-I range from 1 (very much improved) to 7 (very much worse). The investigator or their designee rated improvement regardless of whether the improvement to be due to drug treatment. Improvement defined as CGI-BP(I)=1 (improved) or 2 (very much improved). Missing data imputed using last-observation carried forward (LOCF).
    End point type
    Secondary
    End point timeframe
    Randomization and Weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, and 36
    End point values
    		 Placebo Lamotrigine
    Number of subjects analysed
    86 [26]
    87 [27]
    Units: Participants
        Week 1
    31
    31
        Week 2
    25
    22
        Week 3
    24
    21
        Week 4
    22
    19
        Week 6
    20
    23
        Week 8
    22
    19
        Week 10
    22
    12
        Week 12
    21
    17
        Week 16
    21
    16
        Week 20
    21
    14
        Week 24
    21
    15
        Week 28
    22
    15
        Week 32
    19
    15
        Week 36
    20
    13
    Notes
    [26] - Randomized ITT Population
    [27] - Randomized ITT Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Young Mania Rating Scale (YMRS) at each visit in the Open-Label Phase

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    End point title
    		 Change from Baseline in the Young Mania Rating Scale (YMRS) at each visit in the Open-Label Phase
    End point description
    The YMRS consists of 11 items and is based on the participant's report of their mania symptoms. It is clinician rated. Four items (irritability, speech, thought content, and disruptive/aggressive behavior) are rated on a scale of 0 to 8, while the other seven items (elevated mood, increased motor activity-energy, sexual interest, sleep, language, appearance, and insight) are rated on a scale of 0 to 4. The range of scores for the YMRS is 0 (best possible outcome) to 60 (worst possible outcome). The YMRS was completed by the investigator or their qualified designee. Analysis was performed using mixed model repeated measures.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, and 18
    End point values
    		 LTG: Open-Label Phase
    Number of subjects analysed
    298 [28]
    Units: Scores on a scale
    least squares mean (standard error)
        Week 1
    -3.2 ± 0.39
        Week 2
    -4.8 ± 0.42
        Week 3
    -6.4 ± 0.45
        Week 4
    -6.5 ± 0.46
        Week 5
    -7.5 ± 0.5
        Week 6
    -8.4 ± 0.5
        Week 7
    -9.1 ± 0.51
        Week 8
    -8.8 ± 0.48
        Week 9
    -9.6 ± 0.48
        Week 10
    -10.3 ± 0.49
        Week 11
    -11.1 ± 0.48
        Week 12
    -11.6 ± 0.53
        Week 13
    -12 ± 0.58
        Week 14
    -12 ± 0.59
        Week 15
    -12.4 ± 0.63
        Week 16
    -12.3 ± 0.78
        Week 17
    -12.2 ± 0.88
        Week 18
    -12.1 ± 1.43
    Notes
    [28] - Open-Label ITT Population
    No statistical analyses for this end point

    Secondary: Change from Randomization in the Young Mania Rating Scale (YMRS) at each visit in the Randomized Phase

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    End point title
    		 Change from Randomization in the Young Mania Rating Scale (YMRS) at each visit in the Randomized Phase
    End point description
    The YMRS consists of 11 items and is based on the participant's report of their mania symptoms. It is clinician rated. Four items (irritability, speech, thought content, and disruptive/aggressive behavior) are rated on a scale of 0 to 8, while the other seven items (elevated mood, increased motor activity-energy, sexual interest, sleep, language, appearance, and insight) are rated on a scale of 0 to 4. The range of scores for the YMRS is 0 (best possible outcome) to 60 (worst possible outcome). The YMRS was completed by the investigator or their qualified designee. Analysis was performed using mixed model repeated measures.
    End point type
    Secondary
    End point timeframe
    Randomization and Weeks 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 28, 32, and 36
    End point values
    		 Placebo Lamotrigine
    Number of subjects analysed
    86 [29]
    87 [30]
    Units: Scores on a scale
    least squares mean (standard error)
        Week 1
    1.3 ± 0.57
    0.4 ± 0.59
        Week 2
    2.6 ± 0.72
    2.1 ± 0.72
        Week 3
    2.6 ± 0.69
    1.3 ± 0.71
        Week 4
    3.7 ± 0.85
    2 ± 0.84
        Week 6
    4.9 ± 0.96
    2.3 ± 0.93
        Week 8
    4.3 ± 0.98
    3.5 ± 0.93
        Week 10
    3.5 ± 0.87
    2.9 ± 0.82
        Week 12
    3.2 ± 0.84
    1.6 ± 0.81
        Week 16
    4.7 ± 0.93
    3 ± 0.89
        Week 20
    4.8 ± 0.99
    4.5 ± 0.92
        Week 24
    4.2 ± 1.06
    2.9 ± 1.02
        Week 28
    4.4 ± 1.04
    3.7 ± 1.01
        Week 32
    4.5 ± 1.1
    2.6 ± 1.14
        Week 36
    3.5 ± 0.92
    1.2 ± 0.95
    Notes
    [29] - Randomized ITT Population
    [30] - Randomized ITT Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Parent Version of the Young Mania Rating Scale (P-YMRS) at each visit in the Open-Label Phase

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    End point title
    		 Change from Baseline in the Parent Version of the Young Mania Rating Scale (P-YMRS) at each visit in the Open-Label Phase
    End point description
    The P-YMRS was adapted from the YMRS for completion by parents of the pediatric participants with bipolar disorder in order to assess the severity of the manic symptoms. The P-YMRS consisted of 11 items and had a total score range of 0 (best possible outcome) to 60 (worst possible outcome). The P-YMRS was completed by the participant's custodial parent or legal guardian. Analysis was performed using mixed model repeated measures.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12, 16, and 18
    End point values
    		 LTG: Open-Label Phase
    Number of subjects analysed
    298 [31]
    Units: Scores on a scale
    least squares mean (standard error)
        Week 4
    -4.7 ± 0.57
        Week 8
    -6 ± 0.62
        Week 12
    -7.4 ± 0.62
        Week 16
    -8.2 ± 0.72
        Week 18
    -9.3 ± 1.29
    Notes
    [31] - Open-Label ITT Population
    No statistical analyses for this end point

    Secondary: Change from Randomization in the Parent Version of the Young Mania Rating Scale (P-YMRS) at each visit in the Randomized Phase

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    End point title
    		 Change from Randomization in the Parent Version of the Young Mania Rating Scale (P-YMRS) at each visit in the Randomized Phase
    End point description
    The P-YMRS was adapted from the YMRS for completion by parents of the pediatric participants with bipolar disorder in order to assess the severity of the manic symptoms. The P-YMRS consisted of 11 items and had a total score range of 0 (best possible outcome) to 60 (worst possible outcome). The P-YMRS was completed by the participant's custodial parent or legal guardian. Analysis was performed using mixed model repeated measures.
    End point type
    Secondary
    End point timeframe
    Randomization and Weeks 8, 16, 24, 32, and 36
    End point values
    		 Placebo Lamotrigine
    Number of subjects analysed
    86 [32]
    87 [33]
    Units: Scores on a scale
    least squares mean (standard error)
        Week 8
    4.9 ± 0.93
    4.3 ± 0.95
        Week 16
    2.7 ± 1.13
    2.6 ± 1.09
        Week 24
    5.3 ± 1.35
    5.7 ± 1.29
        Week 32
    5.1 ± 1.33
    6 ± 1.32
        Week 36
    5.3 ± 1.33
    4.5 ± 1.6
    Notes
    [32] - Randomized ITT Population
    [33] - Randomized ITT Population
    No statistical analyses for this end point

    Secondary: Change from Baseline in the Conners’ Global Index – Parent Version (CGI-P) at each visit in the Open-Label Phase

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    End point title
    		 Change from Baseline in the Conners’ Global Index – Parent Version (CGI-P) at each visit in the Open-Label Phase
    End point description
    The CGI-P is a 10-item scale used to assess attention deficit hyperactivity disorder (ADHD) symptoms in children and adolescents aged 3-17 years of age. The scale is composed of two factors: restless-impulsive behavior and emotional lability. Each item was scored on a 0-3 scale. The range of scores for the CGI-P is 0 (best possible outcome) to 30 (worst possible outcome). The CGI-P was completed by the participant’s custodial parent or legal guardian. Analysis was performed using mixed model repeated measures.
    End point type
    Secondary
    End point timeframe
    Baseline and Weeks 4, 8, 12, 16, and 18
    End point values
    		 LTG: Open-Label Phase
    Number of subjects analysed
    298 [34]
    Units: Scores on a scale
    least squares mean (standard error)
        Week 4
    -4 ± 0.36
        Week 8
    -5.7 ± 0.43
        Week 12
    -6.7 ± 0.47
        Week 16
    -7.1 ± 0.56
        Week 18
    -8.2 ± 1.07
    Notes
    [34] - Open-Label ITT Population
    No statistical analyses for this end point

    Secondary: Change from Randomization in the Conners’ Global Index – Parent Version (CGI-P) at each visit in the Randomized Phase.

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    End point title
    		 Change from Randomization in the Conners’ Global Index – Parent Version (CGI-P) at each visit in the Randomized Phase.
    End point description
    The CGI-P is a 10-item scale used to assess attention deficit hyperactivity disorder (ADHD) symptoms in children and adolescents aged 3-17 years of age. The scale is composed of two factors: restless-impulsive behavior and emotional lability. Each item was scored on a 0-3 scale. The range of scores for the CGI-P is 0 (best possible outcome) to 30 (worst possible outcome). The CGI-P was completed by the participant’s custodial parent or legal guardian. Analysis was performed using mixed model repeated measures.
    End point type
    Secondary
    End point timeframe
    Randomization and Weeks 8, 16, 24, 32, and 36
    End point values
    		 Placebo Lamotrigine
    Number of subjects analysed
    86 [35]
    87 [36]
    Units: Scores on a scale
    least squares mean (standard error)
        Week 8
    3.1 ± 0.75
    2.1 ± 0.77
        Week 16
    3.4 ± 0.92
    1.2 ± 0.9
        Week 24
    2.4 ± 1.12
    3.1 ± 1.05
        Week 32
    2.7 ± 1.1
    2.6 ± 1.08
        Week 36
    1.5 ± 1
    0.5 ± 1.03
    Notes
    [35] - Randomized ITT Population
    [36] - Randomized ITT Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On-treatment serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from the first dose of investigational product until the last visit of the Open-Label or Double-Blind Taper and Follow-up Phase (up to Taper Week 4).
    Adverse event reporting additional description
    On-treatment SAEs and non-serious AEs, were reported for ITT population (Open-Label and Randomized Phase), comprised of all participants who were randomized to LTG or placebo (only for Randomized Phase) and received at least one dose of the investigational product.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Open-Label and Open-Label Taper Phases: LTG
    Reporting group description
    		 Participants (par.) received lamotrigine (LTG) up to a maximum dose depending on their age and concomitant bipolar medication group. Participants 10 -12 years of age received LTG up to a maximum dose of : 3 milligrams/kilograms (mg/kg)/day or 100 mg/day, whichever was less; or 6 mg/kg/day or 200 mg/day whichever was less; or 12 mg/kg/day or 300 mg/day whichever was less, depending on their bipolar medication group. Participants 13-17 years of age received LTG up to a maximum dose of 150 mg/day, 300 mg/day, or 400 mg/day depending on their bipolar medication group. Participants took LTG for a duration of up to 18 weeks. Participants discontinuing from the study during the Open-Label Phase entered an open Taper and Follow-up Phase.The Taper and Follow-up Phase may last up to 4 weeks, dependent on the dose of LTG the participant received during the Open-Label Phase.

    Reporting group title
    Randomized and Double-blind Taper Phases: Placebo
    Reporting group description
    		 Participants received matching placebo in the evening for participants taking one dose and for participants taking two divided doses, one dose in the morning and one dose in the evening, for a duration of up to 36 weeks. Participants completing the Randomized Phase entered Double-Blind Taper and Follow-up Phase. The Taper and Follow-up Phase may last up to 4 weeks. The participant received Placebo during this Phase.

    Reporting group title
    Randomized and Double-blind Taper Phases: LTG
    Reporting group description
    		 Participants received LTG equivalent to the dose established in the Open-Label Phase. Participants received LTG tablets in the evening for participants taking one dose and for participants taking two divided doses, one dose in the morning and one dose in the evening, for a duration of up to 36 weeks. Participants completing the Randomized Phase entered Double-Blind Taper and Follow-up Phase. The Taper and Follow-up Phase may last up to 4 weeks, dependent on the dose of LTG the participant received during the Randomized Phase.

    Serious adverse events
    		 Open-Label and Open-Label Taper Phases: LTG Randomized and Double-blind Taper Phases: Placebo Randomized and Double-blind Taper Phases: LTG
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 298 (6.38%)
    5 / 86 (5.81%)
    1 / 87 (1.15%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 86 (0.00%)
    0 / 87 (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
    Intentional overdose
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 86 (1.16%)
    0 / 87 (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
    General disorders and administration site conditions
    Irritability
         subjects affected / exposed
    2 / 298 (0.67%)
    0 / 86 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 86 (0.00%)
    0 / 87 (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
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 86 (0.00%)
    0 / 87 (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
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    5 / 298 (1.68%)
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    3 / 298 (1.01%)
    0 / 86 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    3 / 298 (1.01%)
    1 / 86 (1.16%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aggression
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 86 (0.00%)
    0 / 87 (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
    Anxiety
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 86 (0.00%)
    0 / 87 (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
    Bipolar I disorder
         subjects affected / exposed
    1 / 298 (0.34%)
    1 / 86 (1.16%)
    0 / 87 (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
    Bipolar disorder
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 86 (0.00%)
    0 / 87 (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
    Impulsive behaviour
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 86 (0.00%)
    0 / 87 (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
    Intentional self-injury
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 86 (0.00%)
    0 / 87 (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
    Pressure of speech
         subjects affected / exposed
    1 / 298 (0.34%)
    0 / 86 (0.00%)
    0 / 87 (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
    Emotional disorder
         subjects affected / exposed
    0 / 298 (0.00%)
    0 / 86 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Infectious mononucleosis
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 86 (1.16%)
    0 / 87 (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
    Urinary tract infection
         subjects affected / exposed
    0 / 298 (0.00%)
    1 / 86 (1.16%)
    0 / 87 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Open-Label and Open-Label Taper Phases: LTG Randomized and Double-blind Taper Phases: Placebo Randomized and Double-blind Taper Phases: LTG
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    177 / 298 (59.40%)
    41 / 86 (47.67%)
    45 / 87 (51.72%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    106 / 298 (35.57%)
    18 / 86 (20.93%)
    18 / 87 (20.69%)
         occurrences all number
    201
    38
    26
    Dizziness
         subjects affected / exposed
    24 / 298 (8.05%)
    4 / 86 (4.65%)
    3 / 87 (3.45%)
         occurrences all number
    31
    7
    3
    General disorders and administration site conditions
    Irritability
         subjects affected / exposed
    16 / 298 (5.37%)
    14 / 86 (16.28%)
    7 / 87 (8.05%)
         occurrences all number
    19
    16
    7
    Fatigue
         subjects affected / exposed
    17 / 298 (5.70%)
    2 / 86 (2.33%)
    1 / 87 (1.15%)
         occurrences all number
    19
    4
    1
    Pyrexia
         subjects affected / exposed
    14 / 298 (4.70%)
    5 / 86 (5.81%)
    2 / 87 (2.30%)
         occurrences all number
    19
    5
    3
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    47 / 298 (15.77%)
    3 / 86 (3.49%)
    5 / 87 (5.75%)
         occurrences all number
    64
    6
    7
    Nausea
         subjects affected / exposed
    39 / 298 (13.09%)
    3 / 86 (3.49%)
    2 / 87 (2.30%)
         occurrences all number
    47
    4
    2
    Diarrhoea
         subjects affected / exposed
    23 / 298 (7.72%)
    1 / 86 (1.16%)
    2 / 87 (2.30%)
         occurrences all number
    29
    1
    2
    Vomiting
         subjects affected / exposed
    25 / 298 (8.39%)
    3 / 86 (3.49%)
    5 / 87 (5.75%)
         occurrences all number
    30
    5
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    21 / 298 (7.05%)
    4 / 86 (4.65%)
    7 / 87 (8.05%)
         occurrences all number
    22
    4
    9
    Oropharyngeal pain
         subjects affected / exposed
    30 / 298 (10.07%)
    2 / 86 (2.33%)
    7 / 87 (8.05%)
         occurrences all number
    35
    3
    13
    Nasal congestion
         subjects affected / exposed
    10 / 298 (3.36%)
    6 / 86 (6.98%)
    6 / 87 (6.90%)
         occurrences all number
    11
    7
    11
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    23 / 298 (7.72%)
    5 / 86 (5.81%)
    6 / 87 (6.90%)
         occurrences all number
    35
    7
    6
    Suicidal ideation
         subjects affected / exposed
    16 / 298 (5.37%)
    1 / 86 (1.16%)
    4 / 87 (4.60%)
         occurrences all number
    18
    2
    5
    Agitation
         subjects affected / exposed
    11 / 298 (3.69%)
    1 / 86 (1.16%)
    5 / 87 (5.75%)
         occurrences all number
    11
    1
    5
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    25 / 298 (8.39%)
    5 / 86 (5.81%)
    7 / 87 (8.05%)
         occurrences all number
    31
    5
    7
    Influenza
         subjects affected / exposed
    14 / 298 (4.70%)
    2 / 86 (2.33%)
    7 / 87 (8.05%)
         occurrences all number
    14
    2
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jul 2008
    To 1) comply with the FDA’s advice to increase the lower weight limit for the 10-12 year old subjects receiving valproate; 2) clarify the mg/kg/day dosing for the 10-12 year-old subjects; 3) add and clarify the laboratory analytes; and 4) specify the availability of laboratory and ECG results prior to randomization
    08 Mar 2009
    To 1) Comply with FDA’s recommendation to add the Simpson-Angus scale to assess extrapyramidal symptoms; 2) add paliperidone to the list of acceptable bipolar medications; and, 3) to make other minor clarifications throughout the protocol.

    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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