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    Clinical Trial Results:
    Clinical Evaluation of lamotrigine in Epilepsy-Mutual Recognition-D2012-6595-Study only identified as requiring Article 46 submission-30 July 2012 (as part of r/co-administration retrospective exercise)

    Summary
    EudraCT number
    		 2015-004901-18
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    26 Mar 2009

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Dec 2016
    First version publication date
    23 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LAM107844
    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
    11 Jun 2009
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Mar 2009
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Mar 2009
    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
    07 Aug 2006
    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
    Japan: 102
    Worldwide total number of subjects
    102
    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)
    35
    Adolescents (12-17 years)
    22
    Adults (18-64 years)
    45
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 102 participants were enrolled in the study. Of these, 99 participants completed the maintenance phase, and 97 participants entered the continuation phase.

    Period 1
    Period 1 title
    Escalation Phase + Maintenance Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Adults: LTG
    Arm description
    		 Adult participants were initiated on 12.5 milligrams per day (mg/day) of BW430C (lamotrigine [LTG]) (as a tablet taken orally) once daily. Participants had their dose increased to an optimal maintenance dose (escalation phase) and then were maintained at that dose for 8 weeks (maintenance phase [MP]). During the 8-week MP, participants received up to a maximum of 200 mg/day for adults taking valproeic acid (VPA) or up to a maximum of 400 mg/day for adults not taking VPA plus an inducer of LTG glucuronidation. Participants who achieved adequate seizure control at the end of the MP and for whom no alternative antiepileptic drugs (AEDs) were available were allowed to continue treatment with LTG until the drug is marketed (continuation phase).
    Arm type
    		 Experimental

    Investigational medicinal product name
    BW430C (Lamotrigine) 2 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable/dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BW430C (Lamotrigine) tablet taken orally once daily or twice daily depending on study phase and adjusted dose.

    Investigational medicinal product name
    BW430C (Lamotrigine) 5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable/dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BW430C (Lamotrigine) tablet taken orally once daily or twice daily depending on study phase and adjusted dose.

    Investigational medicinal product name
    BW430C (Lamotrigine) 25 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable/dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BW430C (Lamotrigine) tablet taken orally once daily or twice daily depending on study phase and adjusted dose.

    Investigational medicinal product name
    BW430C (Lamotrigine) 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable/dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BW430C (Lamotrigine) tablet taken orally once daily or twice daily depending on study phase and adjusted dose.

    Arm title
    		 Adolescents: LTG
    Arm description
    		 Adolescent participants were initiated on 0.15 mg/kilogram (kg)/day. Participants had their dose increased to an optimal maintenance dose (escalation phase) and then were maintained at that dose for 8 weeks (MP). During the 8-week MP, adolescents taking VPA alone received up to a maximum of 3 mg/kg/day, adolescents taking VPA with an inducer of LTG glucuronidation received up to a maximum of 5 mg/kg/day, and adolescents not taking VPA with an inducer of LTG glucuronidation received up to a maximum of 15 mg/kg/day. Participants who achieved adequate seizure control at the end of the MP and for whom no alternative AEDs were available were allowed to continue treatment with BW430C until the drug is marketed (continuation phase).
    Arm type
    		 Experimental

    Investigational medicinal product name
    BW430C (Lamotrigine) 2 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable/dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BW430C (Lamotrigine) tablet taken orally once daily or twice daily depending on study phase and adjusted dose.

    Investigational medicinal product name
    BW430C (Lamotrigine) 5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable/dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BW430C (Lamotrigine) tablet taken orally once daily or twice daily depending on study phase and adjusted dose.

    Investigational medicinal product name
    BW430C (Lamotrigine) 25 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable/dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BW430C (Lamotrigine) tablet taken orally once daily or twice daily depending on study phase and adjusted dose.

    Investigational medicinal product name
    BW430C (Lamotrigine) 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable/dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BW430C (Lamotrigine) tablet taken orally once daily or twice daily depending on study phase and adjusted dose.

    Number of subjects in period 1
    		Adults: LTG Adolescents: LTG
    Started
    51
    51
    Completed
    50
    49
    Not completed
    1
    2
         Adverse event, non-fatal
    1
    2
    Period 2
    Period 2 title
    Continuation Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Adults: LTG
    Arm description
    		 Adult participants were initiated on 12.5 milligrams per day (mg/day) of BW430C (lamotrigine [LTG]) (as a tablet taken orally) once daily. Participants had their dose increased to an optimal maintenance dose (escalation phase) and then were maintained at that dose for 8 weeks (maintenance phase [MP]). During the 8-week MP, participants received up to a maximum of 200 mg/day for adults taking valproeic acid (VPA) or up to a maximum of 400 mg/day for adults not taking VPA plus an inducer of LTG glucuronidation. Participants who achieved adequate seizure control at the end of the MP and for whom no alternative antiepileptic drugs (AEDs) were available were allowed to continue treatment with LTG until the drug is marketed (continuation phase).
    Arm type
    		 Experimental

    Investigational medicinal product name
    BW430C (Lamotrigine) 2 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable/dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BW430C (Lamotrigine) tablet taken orally once daily or twice daily depending on study phase and adjusted dose.

    Investigational medicinal product name
    BW430C (Lamotrigine) 5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable/dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BW430C (Lamotrigine) tablet taken orally once daily or twice daily depending on study phase and adjusted dose.

    Investigational medicinal product name
    BW430C (Lamotrigine) 25 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable/dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BW430C (Lamotrigine) tablet taken orally once daily or twice daily depending on study phase and adjusted dose.

    Investigational medicinal product name
    BW430C (Lamotrigine) 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable/dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BW430C (Lamotrigine) tablet taken orally once daily or twice daily depending on study phase and adjusted dose.

    Arm title
    		 Adolescents: LTG
    Arm description
    		 Adolescent participants were initiated on 0.15 mg/kilogram (kg)/day. Participants had their dose increased to an optimal maintenance dose (escalation phase) and then were maintained at that dose for 8 weeks (MP). During the 8-week MP, adolescents taking VPA alone received up to a maximum of 3 mg/kg/day, adolescents taking VPA with an inducer of LTG glucuronidation received up to a maximum of 5 mg/kg/day, and adolescents not taking VPA with an inducer of LTG glucuronidation received up to a maximum of 15 mg/kg/day. Participants who achieved adequate seizure control at the end of the MP and for whom no alternative AEDs were available were allowed to continue treatment with BW430C until the drug is marketed (continuation phase).
    Arm type
    		 Experimental

    Investigational medicinal product name
    BW430C (Lamotrigine) 2 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable/dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BW430C (Lamotrigine) tablet taken orally once daily or twice daily depending on study phase and adjusted dose.

    Investigational medicinal product name
    BW430C (Lamotrigine) 5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable/dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BW430C (Lamotrigine) tablet taken orally once daily or twice daily depending on study phase and adjusted dose.

    Investigational medicinal product name
    BW430C (Lamotrigine) 25 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable/dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BW430C (Lamotrigine) tablet taken orally once daily or twice daily depending on study phase and adjusted dose.

    Investigational medicinal product name
    BW430C (Lamotrigine) 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Chewable/dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BW430C (Lamotrigine) tablet taken orally once daily or twice daily depending on study phase and adjusted dose.

    Number of subjects in period 2 [1]
    		Adults: LTG Adolescents: LTG
    Started
    49
    48
    Completed
    34
    35
    Not completed
    15
    13
         Consent withdrawn by subject
    -
    2
         Adverse event, non-fatal
    1
    -
         Withdrawal Due to Wishes of Family
    1
    -
         Poor Compliance
    1
    -
         Lack of efficacy
    12
    11
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: A total of 99 participants (50 adults and 49 children) completed the maintenance phase. Of these, 97 participants (49 adults and 48 children) entered the continuation phase and 2 participants (1 adult and 1 child) discontinued the study due to lack of efficacy.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Adults: LTG
    Reporting group description
    		 Adult participants were initiated on 12.5 milligrams per day (mg/day) of BW430C (lamotrigine [LTG]) (as a tablet taken orally) once daily. Participants had their dose increased to an optimal maintenance dose (escalation phase) and then were maintained at that dose for 8 weeks (maintenance phase [MP]). During the 8-week MP, participants received up to a maximum of 200 mg/day for adults taking valproeic acid (VPA) or up to a maximum of 400 mg/day for adults not taking VPA plus an inducer of LTG glucuronidation. Participants who achieved adequate seizure control at the end of the MP and for whom no alternative antiepileptic drugs (AEDs) were available were allowed to continue treatment with LTG until the drug is marketed (continuation phase).

    Reporting group title
    Adolescents: LTG
    Reporting group description
    		 Adolescent participants were initiated on 0.15 mg/kilogram (kg)/day. Participants had their dose increased to an optimal maintenance dose (escalation phase) and then were maintained at that dose for 8 weeks (MP). During the 8-week MP, adolescents taking VPA alone received up to a maximum of 3 mg/kg/day, adolescents taking VPA with an inducer of LTG glucuronidation received up to a maximum of 5 mg/kg/day, and adolescents not taking VPA with an inducer of LTG glucuronidation received up to a maximum of 15 mg/kg/day. Participants who achieved adequate seizure control at the end of the MP and for whom no alternative AEDs were available were allowed to continue treatment with BW430C until the drug is marketed (continuation phase).

    Reporting group values
    		 Adults: LTG Adolescents: LTG Total
    Number of subjects
    		 51 51
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 29 ± 9.9 8.2 ± 4.1 -
    Gender categorical
    Units: Subjects
        Female
    		 23 25 48
        Male
    		 28 26 54
    Race/Ethnicity, Customized
    Units: Subjects
        Asian–Japanese
    		 51 51 102

    End points

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    End points reporting groups
    Reporting group title
    Adults: LTG
    Reporting group description
    		 Adult participants were initiated on 12.5 milligrams per day (mg/day) of BW430C (lamotrigine [LTG]) (as a tablet taken orally) once daily. Participants had their dose increased to an optimal maintenance dose (escalation phase) and then were maintained at that dose for 8 weeks (maintenance phase [MP]). During the 8-week MP, participants received up to a maximum of 200 mg/day for adults taking valproeic acid (VPA) or up to a maximum of 400 mg/day for adults not taking VPA plus an inducer of LTG glucuronidation. Participants who achieved adequate seizure control at the end of the MP and for whom no alternative antiepileptic drugs (AEDs) were available were allowed to continue treatment with LTG until the drug is marketed (continuation phase).

    Reporting group title
    Adolescents: LTG
    Reporting group description
    		 Adolescent participants were initiated on 0.15 mg/kilogram (kg)/day. Participants had their dose increased to an optimal maintenance dose (escalation phase) and then were maintained at that dose for 8 weeks (MP). During the 8-week MP, adolescents taking VPA alone received up to a maximum of 3 mg/kg/day, adolescents taking VPA with an inducer of LTG glucuronidation received up to a maximum of 5 mg/kg/day, and adolescents not taking VPA with an inducer of LTG glucuronidation received up to a maximum of 15 mg/kg/day. Participants who achieved adequate seizure control at the end of the MP and for whom no alternative AEDs were available were allowed to continue treatment with BW430C until the drug is marketed (continuation phase).
    Reporting group title
    Adults: LTG
    Reporting group description
    		 Adult participants were initiated on 12.5 milligrams per day (mg/day) of BW430C (lamotrigine [LTG]) (as a tablet taken orally) once daily. Participants had their dose increased to an optimal maintenance dose (escalation phase) and then were maintained at that dose for 8 weeks (maintenance phase [MP]). During the 8-week MP, participants received up to a maximum of 200 mg/day for adults taking valproeic acid (VPA) or up to a maximum of 400 mg/day for adults not taking VPA plus an inducer of LTG glucuronidation. Participants who achieved adequate seizure control at the end of the MP and for whom no alternative antiepileptic drugs (AEDs) were available were allowed to continue treatment with LTG until the drug is marketed (continuation phase).

    Reporting group title
    Adolescents: LTG
    Reporting group description
    		 Adolescent participants were initiated on 0.15 mg/kilogram (kg)/day. Participants had their dose increased to an optimal maintenance dose (escalation phase) and then were maintained at that dose for 8 weeks (MP). During the 8-week MP, adolescents taking VPA alone received up to a maximum of 3 mg/kg/day, adolescents taking VPA with an inducer of LTG glucuronidation received up to a maximum of 5 mg/kg/day, and adolescents not taking VPA with an inducer of LTG glucuronidation received up to a maximum of 15 mg/kg/day. Participants who achieved adequate seizure control at the end of the MP and for whom no alternative AEDs were available were allowed to continue treatment with BW430C until the drug is marketed (continuation phase).

    Subject analysis set title
    Total: LTG
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Adult participants were initiated on 12.5 mg/day, and adolescents were initiated on 0.15 mg/kg/day. Participants had their dose increased to an optimal maintenance dose (escalation phase) and then were maintained at that dose for 8 weeks (MP). During the 8-week MP, participants received up to a maximum of 200 mg/day for adults taking VPA or up to a maximum of 400 mg/day for adults not taking VPA plus an inducer of LTG glucuronidation. During the MP, adolescents taking VPA alone received up to a maximum of 3 mg/kg/day, adolescents taking VPA with an inducer of LTG glucuronidation received up to a maximum of 5 mg/kg/day, and adolescents not taking VPA with an inducer of LTG glucuronidation received up to a maximum of 15 mg/kg/day. Participants who achieved adequate seizure control at the end of the MP and for whom no alternative AEDs were available were allowed to continue treatment with BW430C until the drug is marketed (continuation phase).

    Primary: Number of participants with any rash event (including Stevens–Johnson syndrome [SJS] and any other serious drug eruption) during the initial 8 weeks of study treatment

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    End point title
    		 Number of participants with any rash event (including Stevens–Johnson syndrome [SJS] and any other serious drug eruption) during the initial 8 weeks of study treatment
    End point description
    Any rash event (including SJS or any other serious drug eruption) includes: all event terms containing "rash"; drug eruption; SJS; toxic epidermal necrolysis; rash generalized; and events grouped into the "Skin and Subcutaneous Tissue Disorders" system organ class per the Medical Dictionary for Regulatory Activities (MedDRA), including the above-mentioned events that the GSK medical advisors judged to be included as any rash event. SJS, also called as erythema multiforme, is a skin disorder resulting from an allergic reaction or infection. Safety Population: all participants enrolled in the study who received at least one dose of study medication
    End point type
    Primary
    End point timeframe
    8 weeks
    End point values
    		 Adults: LTG Adolescents: LTG Total: LTG
    Number of subjects analysed
    51 [1]
    51 [2]
    102 [3]
    Units: participants
    2
    3
    5
    Notes
    [1] - Safety Population
    [2] - Safety Population
    [3] - Safety Population
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    The estimated value represents the percentage of participants with rash events.
    Comparison groups
    Adults: LTG v Adolescents: LTG v Total: LTG
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Percentage of participants
    Point estimate
    4.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.6
         upper limit
    		 11.1

    Primary: Number of participants with any rash event (including SJS and any other serious drug eruption) up to the end of the maintenance phase

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    End point title
    		 Number of participants with any rash event (including SJS and any other serious drug eruption) up to the end of the maintenance phase [4]
    End point description
    Any rash event (including SJS or any other serious drug eruption) includes: all event terms containing "rash"; drug eruption; SJS; toxic epidermal necrolysis; rash generalized; and events grouped into the "Skin and Subcutaneous Tissue Disorders" system organ class per the Medical Dictionary for Regulatory Activities (MedDRA), including the above-mentioned events that the GSK medical advisors judged to be included as any rash event. SJS, also called as erythema multiforme, is a skin disorder resulting from an allergic reaction or infection.
    End point type
    Primary
    End point timeframe
    Up to Week 8 of the Maintenance Phase (Study Week 14)
    Notes
    [4] - 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: There are no statistical data to report
    End point values
    		 Adults: LTG Adolescents: LTG Total: LTG
    Number of subjects analysed
    51 [5]
    51 [6]
    102 [7]
    Units: participants
    2
    3
    5
    Notes
    [5] - Safety Population
    [6] - Safety Population
    [7] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of rash events experienced (including SJS and any other serious drug eruption) during the initial 8 weeks of study treatment

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    End point title
    		 Number of rash events experienced (including SJS and any other serious drug eruption) during the initial 8 weeks of study treatment
    End point description
    Any rash event (including SJS or any other serious drug eruption) includes: all event terms containing "rash"; drug eruption; SJS; toxic epidermal necrolysis; rash generalized; and events grouped into the "Skin and Subcutaneous Tissue Disorders" system organ class per the Medical Dictionary for Regulatory Activities (MedDRA), including the above-mentioned events that the GSK medical advisors judged to be included as any rash event. SJS, also called as erythema multiforme, is a skin disorder resulting from an allergic reaction or infection.
    End point type
    Secondary
    End point timeframe
    8 weeks
    End point values
    		 Adults: LTG Adolescents: LTG Total: LTG
    Number of subjects analysed
    2 [8]
    3 [9]
    5 [10]
    Units: rash events
    3
    4
    7
    Notes
    [8] - Safety Population
    [9] - Safety Population
    [10] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated intensity of rash (including SJS and any other serious drug eruption) during the initial 8 weeks of study treatment

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    End point title
    		 Number of participants with the indicated intensity of rash (including SJS and any other serious drug eruption) during the initial 8 weeks of study treatment
    End point description
    The rash events (including SJS and any other serious drug eruption) were classified into severe (rash prevents participant from leading a normal life), moderate (participant's discomfort due to rash interferes with daily life), and mild (no interference with participant's daily life due to rash), based on the intesity of the event.
    End point type
    Secondary
    End point timeframe
    8 weeks
    End point values
    		 Total: LTG
    Number of subjects analysed
    5 [11]
    Units: participants
        Severe
    0
        Moderate
    2
        Mild
    3
    Notes
    [11] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of drug-related and not related rash events (including SJS and any other serious drug eruption) during the initial 8 weeks of study treatment

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    End point title
    		 Number of drug-related and not related rash events (including SJS and any other serious drug eruption) during the initial 8 weeks of study treatment
    End point description
    The adverse event of rash was considered to be drug-related when the Investigator answered "Yes" to the following question: "Is there a reasonable possibility that the adverse event may have been caused by the investigational product?".
    End point type
    Secondary
    End point timeframe
    8 weeks
    End point values
    		 Total: LTG
    Number of subjects analysed
    5 [12]
    Units: rash events
        Drug related
    3
        Not related to drug
    4
    Notes
    [12] - Safety Population
    No statistical analyses for this end point

    Secondary: Percentage of participants with at least a 50 percent reduction in seizure frequency for the indicated types of seizures

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    End point title
    		 Percentage of participants with at least a 50 percent reduction in seizure frequency for the indicated types of seizures
    End point description
    Partial seizures are seizures that affect only a part of the brain at onset. Tonic-clonic seizures (grand mal seizures) affect the entire brain and are characterized by a generalized involuntary muscular contraction and cessation of respiration followed by tonic and clonic spasms of the muscles. Lennox-Gastaut syndrome (LGS) is a pediatric epilepsy syndrome characterized by multiple seizure types; mental retardation or regression; and abnormal findings on an electroencephalogram (EEG), with paroxysms of fast activity and generalized slow spike-and-wave discharges. Full Analysis Set (FAS) Population: all enrolled participants except those who had no assessments of the main efficacy variable (percent reduction in seizure frequency).
    End point type
    Secondary
    End point timeframe
    8 weeks
    End point values
    		 Adults: LTG Adolescents: LTG Total: LTG
    Number of subjects analysed
    28 [13]
    25 [14]
    53 [15]
    Units: percentage of participants
    number (not applicable)
        All Partial Seizures, n=28, 25, 53
    17.9
    20
    18.9
        Tonic-clonic Seizures, n=5, 4, 9
    60
    0
    33.3
        Generalized Seizures with LGS, n=25, 25, 50
    16
    20
    18
    Notes
    [13] - FAS
    [14] - FAS
    [15] - FAS
    No statistical analyses for this end point

    Secondary: Percent change in seizure frequency of the indicated types of seizures

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    End point title
    		 Percent change in seizure frequency of the indicated types of seizures
    End point description
    Percent change in seizure frequency was calculated as 100 * (pre-treatment seizures minus MP seizures)/pre-treatment seizures. Partial seizures are seizures that affect only a part of the brain at onset. Tonic-clonic seizures (grand mal seizures) affect the entire brain and are characterized by a generalized involuntary muscular contraction and cessation of respiration followed by tonic and clonic spasms of the muscles. Lennox-Gastaut syndrome (LGS) is a pediatric epilepsy syndrome characterized by multiple seizure types, mental retardation or regression, and abnormal findings on an ECG.
    End point type
    Secondary
    End point timeframe
    Pre-treatment (Day 0) and Week 8 of the Maintenance Phase (Study Week 14)
    End point values
    		 Adults: LTG Adolescents: LTG Total: LTG
    Number of subjects analysed
    28 [16]
    25 [17]
    53 [18]
    Units: percent change
    median (confidence interval 95%)
        All Partial Seizures, n=28, 25, 53
    6.3 (-44.8 to 28.7)
    -11.1 (-46.6 to 34.6)
    -9.8 (-42.3 to 28.6)
        Tonic-clonic Seizures, n=5, 4, 9
    83.3 (-99999 to 99999)
    27.4 (-99999 to 99999)
    36.5 (-47.9 to 100)
        Generalized Seizures with LGS, n=25, 25, 50
    18.6 (-16.2 to 32.2)
    10.1 (-24.9 to 28.8)
    12.4 (5.8 to 27.6)
    Notes
    [16] - FAS Population
    [17] - FAS Population
    [18] - FAS Population
    No statistical analyses for this end point

    Secondary: Number of rash events experienced (including SJS and any other serious drug eruption) up to the end of the maintenance phase

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    End point title
    		 Number of rash events experienced (including SJS and any other serious drug eruption) up to the end of the maintenance phase
    End point description
    Any rash event (including SJS or any other serious drug eruption) includes: all event terms containing "rash"; drug eruption; SJS; toxic epidermal necrolysis; rash generalized; and events grouped into the "Skin and Subcutaneous Tissue Disorders" system organ class per the Medical Dictionary for Regulatory Activities (MedDRA), including the above-mentioned events that the GSK medical advisors judged to be included as any rash event. SJS, also called as erythema multiforme, is a skin disorder resulting from an allergic reaction or infection. Safety Population. Only those participants who had experienced any rash event were evaluated.
    End point type
    Secondary
    End point timeframe
    Up to Week 8 of the Maintenance Phase (Study Week 14)
    End point values
    		 Adults: LTG Adolescents: LTG Total: LTG
    Number of subjects analysed
    2 [19]
    3 [20]
    5 [21]
    Units: rash events
    3
    4
    7
    Notes
    [19] - Safety Population
    [20] - Safety Population
    [21] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated intensity of rash (including SJS and any other serious drug eruption) up to the end of the maintenance phase

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    End point title
    		 Number of participants with the indicated intensity of rash (including SJS and any other serious drug eruption) up to the end of the maintenance phase
    End point description
    The rash events (including SJS and any other serious drug eruption) were classified into severe (rash prevents participant from leading a normal life), moderate (participant's discomfort due to rash interferes with daily life), and mild (no interference with participant's daily life due to rash), based on the intesity of the event.
    End point type
    Secondary
    End point timeframe
    Up to Week 8 of the Maintenance Phase (Study Week 14)
    End point values
    		 Total: LTG
    Number of subjects analysed
    5 [22]
    Units: participants
        Severe
    0
        Moderate
    2
        Mild
    3
    Notes
    [22] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of drug-related and not related rash events (including SJS and any other serious drug eruption) up to the end of the maintenance phase

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    End point title
    		 Number of drug-related and not related rash events (including SJS and any other serious drug eruption) up to the end of the maintenance phase
    End point description
    The adverse event of rash was considered to be drug-related when the Investigator answered "Yes" to the following question: "Is there a reasonable possibility that the adverse event may have been caused by the investigational product?".
    End point type
    Secondary
    End point timeframe
    Up to Week 8 of the Maintenance Phase (Study Week 14)
    End point values
    		 Total: LTG
    Number of subjects analysed
    5 [23]
    Units: rash events
        Drug related
    3
        Not related to drug
    4
    Notes
    [23] - Safety Population
    No statistical analyses for this end point

    Secondary: Number of rash events (including SJS and any other serious drug eruption) adjudicated by the rash adjudication committee in participants taking VPA

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    End point title
    		 Number of rash events (including SJS and any other serious drug eruption) adjudicated by the rash adjudication committee in participants taking VPA
    End point description
    The rash adjudication committee reviewed all rash events from a dermatologic standpoint based on the nature, onset site, affected area, time to onset, outcome, and the investigator's comments to adjudicate whether or not the reported event was a drug eruption. A drug eruption is an eruption or a solitary lesion caused by a drug taken internally, often a result of allergic sensitization.
    End point type
    Secondary
    End point timeframe
    Up to Week 8 of the Maintenance Phase (Study Week 14)
    End point values
    		 Adults: LTG Adolescents: LTG Total: LTG
    Number of subjects analysed
    2 [24]
    3 [25]
    5 [26]
    Units: adjudicated rash events
    1
    2
    3
    Notes
    [24] - Safety Population
    [25] - Safety Population
    [26] - Safety Population
    No statistical analyses for this end point

    Secondary: Percentage of participants with monocyte values outside the normal range (shifted high) at Weeks 4 and 8

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    End point title
    		 Percentage of participants with monocyte values outside the normal range (shifted high) at Weeks 4 and 8
    End point description
    Monocytes are a type of white blood cell (WBC; typically comprising 2%-8% of total WBCs) and are a part of the immune system. The normal range for adults is 0.2 to 0.95 * 10^3 cells per microliter (µL); the normal range for adolescents is 0 to 0.8 * 10^3 cells per µL. The monocyte count may increase during chronic inflammation, stress response, immune-mediated disease, viral fever, etc. The percentage of participants (par.) with monocyte values outside the normal range was calculated as 100 * (number of par. with monocyte values outside the normal range) divided by the total number of par.
    End point type
    Secondary
    End point timeframe
    Week 4 and Week 8
    End point values
    		 Total: LTG
    Number of subjects analysed
    102 [27]
    Units: percentage of participants
    number (not applicable)
        Week 4
    15.2
        Week 8
    16.2
    Notes
    [27] - Safety Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First day of study drug administration and the end of the maintenance phase-Week 8.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    9.1
    Reporting groups
    Reporting group title
    Adults: LTG
    Reporting group description
    		 Adult participants were initiated on 12.5 milligrams per day (mg/day) of BW430C (lamotrigine [LTG]) (as a tablet taken orally) once daily. Participants had their dose increased to an optimal maintenance dose (escalation phase) and then were maintained at that dose for 8 weeks (maintenance phase [MP]). During the 8-week MP, participants received up to a maximum of 200 mg/day for adults taking valproeic acid (VPA) or up to a maximum of 400 mg/day for adults not taking VPA plus an inducer of LTG glucuronidation. Participants who achieved adequate seizure control at the end of the MP and for whom no alternative antiepileptic drugs (AEDs) were available were allowed to continue treatment with LTG until the drug is marketed (continuation phase).

    Reporting group title
    Total: LTG
    Reporting group description
    		 Adult participants were initiated on 12.5 mg/day, and adolescents were initiated on 0.15 mg/kg/day. Participants had their dose increased to an optimal maintenance dose (escalation phase) and then were maintained at that dose for 8 weeks (MP). During the 8-week MP, participants received up to a maximum of 200 mg/day for adults taking VPA or up to a maximum of 400 mg/day for adults not taking VPA plus an inducer of LTG glucuronidation. During the MP, adolescents taking VPA alone received up to a maximum of 3 mg/kg/day, adolescents taking VPA with an inducer of LTG glucuronidation received up to a maximum of 5 mg/kg/day, and adolescents not taking VPA with an inducer of LTG glucuronidation received up to a maximum of 15 mg/kg/day. Participants who achieved adequate seizure control at the end of the MP and for whom no alternative AEDs were available were allowed to continue treatment with BW430C until the drug is marketed (continuation phase).

    Reporting group title
    Adolescents: LTG
    Reporting group description
    		 Adolescent participants were initiated on 0.15 mg/kilogram (kg)/day. Participants had their dose increased to an optimal maintenance dose (escalation phase) and then were maintained at that dose for 8 weeks (MP). During the 8-week MP, adolescents taking VPA alone received up to a maximum of 3 mg/kg/day, adolescents taking VPA with an inducer of LTG glucuronidation received up to a maximum of 5 mg/kg/day, and adolescents not taking VPA with an inducer of LTG glucuronidation received up to a maximum of 15 mg/kg/day. Participants who achieved adequate seizure control at the end of the MP and for whom no alternative AEDs were available were allowed to continue treatment with BW430C until the drug is marketed (continuation phase).

    Serious adverse events
    		 Adults: LTG Total: LTG Adolescents: LTG
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 51 (9.80%)
    7 / 102 (6.86%)
    2 / 51 (3.92%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Therapeutic agent toxicity
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 102 (0.98%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 102 (0.98%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 102 (0.98%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 102 (0.98%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 102 (0.98%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 102 (0.98%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 102 (0.98%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 102 (0.98%)
    0 / 51 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Adults: LTG Total: LTG Adolescents: LTG
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 51 (72.55%)
    83 / 102 (81.37%)
    46 / 51 (90.20%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    8 / 51 (15.69%)
    12 / 102 (11.76%)
    4 / 51 (7.84%)
         occurrences all number
    9
    13
    4
    Arthropod sting
         subjects affected / exposed
    1 / 51 (1.96%)
    10 / 102 (9.80%)
    9 / 51 (17.65%)
         occurrences all number
    1
    16
    15
    Excoriation
         subjects affected / exposed
    6 / 51 (11.76%)
    8 / 102 (7.84%)
    2 / 51 (3.92%)
         occurrences all number
    6
    8
    2
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    6 / 51 (11.76%)
    17 / 102 (16.67%)
    11 / 51 (21.57%)
         occurrences all number
    9
    20
    11
    Dizziness
         subjects affected / exposed
    10 / 51 (19.61%)
    12 / 102 (11.76%)
    2 / 51 (3.92%)
         occurrences all number
    11
    13
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    7 / 51 (13.73%)
    12 / 102 (11.76%)
    5 / 51 (9.80%)
         occurrences all number
    7
    13
    6
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 51 (5.88%)
    14 / 102 (13.73%)
    11 / 51 (21.57%)
         occurrences all number
    3
    16
    13
    Vomiting
         subjects affected / exposed
    3 / 51 (5.88%)
    10 / 102 (9.80%)
    7 / 51 (13.73%)
         occurrences all number
    3
    13
    10
    Constipation
         subjects affected / exposed
    3 / 51 (5.88%)
    7 / 102 (6.86%)
    4 / 51 (7.84%)
         occurrences all number
    3
    7
    4
    Respiratory, thoracic and mediastinal disorders
    Upper respiratory tract inflammation
         subjects affected / exposed
    5 / 51 (9.80%)
    20 / 102 (19.61%)
    15 / 51 (29.41%)
         occurrences all number
    6
    27
    21
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 51 (1.96%)
    7 / 102 (6.86%)
    6 / 51 (11.76%)
         occurrences all number
    3
    11
    8
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    10 / 51 (19.61%)
    24 / 102 (23.53%)
    14 / 51 (27.45%)
         occurrences all number
    12
    33
    21

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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