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    Clinical Trial Results:
    Valproate dose reduction and its clinical evaluation by introducing lamotrigine in Japanese women with epilepsy – single arm, multicenter, and open-label study

    Summary
    EudraCT number
    2017-001515-36
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    11 May 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    20 Oct 2017
    First version publication date
    20 Oct 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    200776
    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
    17 Jul 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 May 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To examine whether the VPA dose can be reduced by additional administration of LTG (up to 200 mg/d if there are no safety concerns) in Japanese pre-menopausal female epilepsy patients aged 15 years or older, whose seizures are well controlled by VPA monotherapy (fixed maintenance dose of 400-1200 mg/d).
    Protection of trial subjects
    Not applicable
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    12 Apr 2014
    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: 33
    Worldwide total number of subjects
    33
    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)
    0
    Adolescents (12-17 years)
    6
    Adults (18-64 years)
    27
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants (par.) receiving monotherapy treatment with sodium valproate (VPA) maintenance dose of 400-1200 milligrams/day [mg/d]) due to a history of partial seizures (including secondary generalized seizures) or tonic-clonic seizures, and whose seizures had been controlled for 12 weeks (wk) prior to start of treatment were enrolled in the study.

    Pre-assignment
    Screening details
    A total of 33 participants were enrolled into the study and 20 participants completed the study.

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

    Arms
    Arm title
    Escalation Phase: LTG plus VPA
    Arm description
    Participants received a fixed maintenance dose of VPA (400-1200 mg/d) along with lamotrigine (LTG) which was gradually escalated to 200 mg/d in accordance with the information of package insert: i.e. 25 mg of LTG was orally administered once every other day for the first 2 weeks and then once daily for the following 2 weeks. Thereafter, LTG was gradually escalated by 25 to 50 mg every 1 to 2 weeks for once or twice daily administration. If there were safety concerns, the LTG dose was decreased to 100 mg/d at the discretion of the investigator or sub-investigator. If there were still safety concerns despite the dose reduction to 100 mg/d, LTG was discontinued. The total duration of this phase was 8 to18 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Lamotrigine 25 mg tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg of Lamotrigine tablet was orally administered once every other day for the first two weeks and then once daily for the next 2 weeks.

    Investigational medicinal product name
    Lamotrigine 100 mg tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg of Lamotrigine tablet was orally administered in dose escalation phase once or twice daily depending on the dose escalation.

    Investigational medicinal product name
    Sodium Valproate 100 mg tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sodium Valproate 100 mg tablets were administered as per the dosage instruction on package insert by oral route.

    Investigational medicinal product name
    Sodium Valproate 200 mg tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sodium Valproate 200 mg tablets were administered as per the dosage instruction on package insert by oral route.

    Investigational medicinal product name
    Sodium Valproate extended release 100 mg tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sodium Valproate 100 mg extended release tablets were administered as per the dosage instruction on package insert by oral route

    Investigational medicinal product name
    Sodium Valproate extended release 200 mg tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sodium Valproate 200 mg extended release tablets were administered as per the dosage instruction on package insert by oral route.

    Investigational medicinal product name
    Sodium Valproate extended release 400 mg tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sodium Valproate 400 mg extended release tablets were administered as per the dosage instruction on package insert by oral route.

    Number of subjects in period 1
    Escalation Phase: LTG plus VPA
    Started
    33
    Completed
    20
    Not completed
    13
         Protocol-defined Stopping Criteria
    1
         Adverse event, non-fatal
    9
         Consent withdrawn by subject
    3
    Period 2
    Period 2 title
    VPA Reduction Phase
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Reduction Phase: LTG plus VPA
    Arm description
    Participants received a range of VPA dose reduction as follows: When VPA was reduced to 300 mg/d, the range of reduction was determined at the discretion of the investigator or sub-investigator: e.g., 1000 mg/d (2 weeks), 800 mg/d (2 weeks), 600 mg/d (2 weeks), 400 mg/d (2 weeks), 300 mg/d OR 1000 mg/d (4 weeks), 600 mg/d (4 weeks), 300 mg/d and when VPA was reduced to less than 300 mg/d, the dose was reduced to 300, 200, 100, and 0 mg/d in 100 mg decrements in steps of at least one week duration. When VPA was concomitantly used, LTG was administered twice daily with 200 mg/d as a maintenance dose. If there were safety concerns during the LTG Escalation Phase, a fixed maintenance dose of 100 to 200 mg/d of LTG was administered twice daily. When VPA was withdrawn (that is, VPA was reduced to 0 mg/d), LTG was required to be increased by 50-100 mg/d. If there were any safety concern, 25 mg increment was also available. The total duration of this phase was 4 to16 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Lamotrigine 25 mg tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg of Lamotrigine tablet was orally administered once every other day for the first two weeks and then once daily for the next 2 weeks.

    Investigational medicinal product name
    Lamotrigine 100 mg tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg of Lamotrigine tablet was orally administered in dose escalation phase once or twice daily depending on the dose escalation.

    Investigational medicinal product name
    Sodium Valproate 100 mg tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sodium Valproate 100 mg tablets were administered as per the dosage instruction on package insert by oral route.

    Investigational medicinal product name
    Sodium Valproate 200 mg tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sodium Valproate 200 mg tablets were administered as per the dosage instruction on package insert by oral route.

    Investigational medicinal product name
    Sodium Valproate extended release 100 mg tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sodium Valproate 100 mg extended release tablets were administered as per the dosage instruction on package insert by oral route

    Investigational medicinal product name
    Sodium Valproate extended release 200 mg tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sodium Valproate 200 mg extended release tablets were administered as per the dosage instruction on package insert by oral route.

    Investigational medicinal product name
    Sodium Valproate extended release 400 mg tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sodium Valproate 400 mg extended release tablets were administered as per the dosage instruction on package insert by oral route.

    Number of subjects in period 2
    Reduction Phase: LTG plus VPA
    Started
    20
    Completed
    20
    Period 3
    Period 3 title
    LTG and VPA Maintenance Phase
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Maintenance Phase: LTG plus VPA
    Arm description
    Participants received two different treatments. In one group, participants received a fixed maintenance dose of LTG 200 mg/d (or 100 to 200 mg/d if there were safety concerns during the LTG Escalation Phase) and VPA 100 mg/d (or higher if seizures occurred during the VPA Reduction Phase) were administered twice and 1-3 times daily, respectively, for 12 weeks. The frequency of administration was not changed. If seizures occurred, VPA dose could be increased/re-introduced. On the other group, after VPA was withdrawn, LTG dose was escalated up to 300 mg/d with 50-100 mg increment per 1-2 weeks. If there was safety concern or if remaining dose to 300 mg/d was below 50 mg, 25 mg increment was also available. If seizures occurred, LTG dose was increased up to 400 mg/d. If there was safety concern, LTG dose was decreased to 100 mg/d. If there was still safety concern at 100 mg/d, the participants were discontinued from the study. The total duration of this phase was 12 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Lamotrigine 25 mg tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg of Lamotrigine tablet was orally administered once every other day for the first two weeks and then once daily for the next 2 weeks.

    Investigational medicinal product name
    Lamotrigine 100 mg tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg of Lamotrigine tablet was orally administered in dose escalation phase once or twice daily depending on the dose escalation.

    Investigational medicinal product name
    Sodium Valproate 100 mg tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sodium Valproate 100 mg tablets were administered as per the dosage instruction on package insert by oral route.

    Investigational medicinal product name
    Sodium Valproate 200 mg tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sodium Valproate 200 mg tablets were administered as per the dosage instruction on package insert by oral route.

    Investigational medicinal product name
    Sodium Valproate extended release 100 mg tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sodium Valproate 100 mg extended release tablets were administered as per the dosage instruction on package insert by oral route

    Investigational medicinal product name
    Sodium Valproate extended release 200 mg tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sodium Valproate 200 mg extended release tablets were administered as per the dosage instruction on package insert by oral route.

    Investigational medicinal product name
    Sodium Valproate extended release 400 mg tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sodium Valproate 400 mg extended release tablets were administered as per the dosage instruction on package insert by oral route.

    Number of subjects in period 3
    Maintenance Phase: LTG plus VPA
    Started
    20
    Completed
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LTG Escalation Phase
    Reporting group description
    LTG Escalation Phase

    Reporting group values
    LTG Escalation Phase Total
    Number of subjects
    33
    Age categorical
    Units: Subjects
    Age continuous
    Age continuous description
    Units: years
        arithmetic mean (standard deviation)
    25.6 ± 7.73 -
    Gender categorical
    Gender categorical description
    Units: Subjects
        Female
    33 33
        Male
    0 0
    Race/Ethnicity, Customized
    Units: Subjects
        Asian- Japanese Heritage
    33 33

    End points

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    End points reporting groups
    Reporting group title
    Escalation Phase: LTG plus VPA
    Reporting group description
    Participants received a fixed maintenance dose of VPA (400-1200 mg/d) along with lamotrigine (LTG) which was gradually escalated to 200 mg/d in accordance with the information of package insert: i.e. 25 mg of LTG was orally administered once every other day for the first 2 weeks and then once daily for the following 2 weeks. Thereafter, LTG was gradually escalated by 25 to 50 mg every 1 to 2 weeks for once or twice daily administration. If there were safety concerns, the LTG dose was decreased to 100 mg/d at the discretion of the investigator or sub-investigator. If there were still safety concerns despite the dose reduction to 100 mg/d, LTG was discontinued. The total duration of this phase was 8 to18 weeks.
    Reporting group title
    Reduction Phase: LTG plus VPA
    Reporting group description
    Participants received a range of VPA dose reduction as follows: When VPA was reduced to 300 mg/d, the range of reduction was determined at the discretion of the investigator or sub-investigator: e.g., 1000 mg/d (2 weeks), 800 mg/d (2 weeks), 600 mg/d (2 weeks), 400 mg/d (2 weeks), 300 mg/d OR 1000 mg/d (4 weeks), 600 mg/d (4 weeks), 300 mg/d and when VPA was reduced to less than 300 mg/d, the dose was reduced to 300, 200, 100, and 0 mg/d in 100 mg decrements in steps of at least one week duration. When VPA was concomitantly used, LTG was administered twice daily with 200 mg/d as a maintenance dose. If there were safety concerns during the LTG Escalation Phase, a fixed maintenance dose of 100 to 200 mg/d of LTG was administered twice daily. When VPA was withdrawn (that is, VPA was reduced to 0 mg/d), LTG was required to be increased by 50-100 mg/d. If there were any safety concern, 25 mg increment was also available. The total duration of this phase was 4 to16 weeks.
    Reporting group title
    Maintenance Phase: LTG plus VPA
    Reporting group description
    Participants received two different treatments. In one group, participants received a fixed maintenance dose of LTG 200 mg/d (or 100 to 200 mg/d if there were safety concerns during the LTG Escalation Phase) and VPA 100 mg/d (or higher if seizures occurred during the VPA Reduction Phase) were administered twice and 1-3 times daily, respectively, for 12 weeks. The frequency of administration was not changed. If seizures occurred, VPA dose could be increased/re-introduced. On the other group, after VPA was withdrawn, LTG dose was escalated up to 300 mg/d with 50-100 mg increment per 1-2 weeks. If there was safety concern or if remaining dose to 300 mg/d was below 50 mg, 25 mg increment was also available. If seizures occurred, LTG dose was increased up to 400 mg/d. If there was safety concern, LTG dose was decreased to 100 mg/d. If there was still safety concern at 100 mg/d, the participants were discontinued from the study. The total duration of this phase was 12 weeks.

    Subject analysis set title
    LTG plus VPA (Phase 1, 2 and 3)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Par. received a fixed maintenance (maint) dose of VPA (400-1200 mg/d) along with LTG gradually escalated to 200 mg/d in accordance with the package insert information: i.e. 25 mg of LTG was orally administered once every other day for the first 2 wk and then once daily for the following 2 wk. Thereafter, LTG was gradually escalated by 25 to 50 mg every 1 to 2 wk for once or twice daily administration. Par. received a range of VPA dose reduction as follows: When VPA was reduced to 300 mg/d, the range of reduction was as follows: 1000 mg/d (2 wk), 800 mg/d (2 wk), 600 mg/d (2 wk), 400 mg/d (2 wk), 300 mg/d OR 1000 mg/d (4 wk), 600 mg/d (4 wk), 300 mg/d and when VPA was reduced to < 300 mg/d, the dose was reduced to 300, 200, 100 and 0 mg/d in 100 mg decrements in steps of at least one wk duration. Par. received a fixed maint dose of LTG 200 mg/d and VPA 100 mg/d or a maint dose of LTG 200-400 mg/d were administered twice and 1-3 times daily for LTG and VPA, respectively, for 12 wk.

    Primary: Percentage of participants who achieved reduction in daily VPA dose

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    End point title
    Percentage of participants who achieved reduction in daily VPA dose [1]
    End point description
    The VPA dose reduction from Baseline is defined as post VPA dose minus the Baseline VPA dose < 0. Baseline VPA dose is the dose at the Baseline visit (Week 0) and the post VPA dose is the last VPA dose during the LTG and VPA Maintenance Phase. Percentage of participants with dose reduction during the LTG and VPA Maintenance Phase is presented. Full analysis set (FAS): comprised of all participants in the Safety Population who provided at least one efficacy data after the first dose of the investigational product during the LTG Escalation Phase.
    End point type
    Primary
    End point timeframe
    Baseline and at the end of the LTG and VPA Maintenance Phase, 24-46 weeks that can be varied by durations of the LTG Escalation Phase and VPA Reduction Phase
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: There are no statistical data to report.
    End point values
    LTG plus VPA (Phase 1, 2 and 3)
    Number of subjects analysed
    33 [2]
    Units: Percentage of participants
        number (confidence interval 95%)
    60.6 (42.14 to 77.09)
    Notes
    [2] - FAs population
    No statistical analyses for this end point

    Primary: Percent change in the VPA dose

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    End point title
    Percent change in the VPA dose [3]
    End point description
    Percent change in VPA dose is calculated as (pre-dose - post-dose) / pre-dose x 100. Pre-dose is the VPA dose at the Baseline visit and post-dose is the last VPA dose during the LTG and VPA Maintenance Phase.
    End point type
    Primary
    End point timeframe
    Baseline and at the end of the LTG and VPA Maintenance Phase, 24-46 weeks that can be varied by durations of the LTG Escalation Phase and VPA Reduction Phase
    Notes
    [3] - 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
    LTG plus VPA (Phase 1, 2 and 3)
    Number of subjects analysed
    33 [4]
    Units: Percentage of reduction
        arithmetic mean (standard deviation)
    -60.10 ± 49.290
    Notes
    [4] - FAS population
    No statistical analyses for this end point

    Secondary: Number of days in total that epileptic seizures occurred up to the LTG and VPA Maintenance Phase

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    End point title
    Number of days in total that epileptic seizures occurred up to the LTG and VPA Maintenance Phase
    End point description
    The participants with no seizure, had no record in seizure dairy. Only those participants with more than one seizure were assessed for this Outcome Measure.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 46 weeks
    End point values
    LTG plus VPA (Phase 1, 2 and 3)
    Number of subjects analysed
    33 [5]
    Units: Days
    2
    Notes
    [5] - FAS population
    No statistical analyses for this end point

    Secondary: Change from Baseline in quality of life in epilepsy-31-P (QOLIE-31-P) in participants aged 18 years and older

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    End point title
    Change from Baseline in quality of life in epilepsy-31-P (QOLIE-31-P) in participants aged 18 years and older
    End point description
    QOLIE-31-P is a questionnaire analyzed according to the scoring manual at Baseline, at the end of LTG/VPA Maintenance Phase and withdrawals for the participants aged 18 years and older (n=26, excluding 1 participant withdrawn due to protocol violation). Overall score was calculated as an average of sub scores that were normalized to 0 to 100. QOLIE-31-P has 7 subscale items (energy, mood, daily activities, cognition, medication effect, seizure worry and overall QOL). Higher score presents higher quality of life. Epileptic symptoms generally affect the QOL of participants, and so QOLIE-31-P is world widely used for the QOL assessment of adult participants. Baseline is defined as Day 1 (pre-dose) value. Change from Baseline is calculated as post-dose visit value minus Baseline value. Only those participants available at the indicated phase were analyzed (represented by n=X in the category titles).
    End point type
    Secondary
    End point timeframe
    Baseline and up to 46 weeks
    End point values
    LTG plus VPA (Phase 1, 2 and 3)
    Number of subjects analysed
    33 [6]
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        LTG Escalation-Withdrawal, n=10
    -7.19 ± 7.531
        LTG and VPA Maintenance-Visit 5, n=16
    0.19 ± 9.082
    Notes
    [6] - FAS population
    No statistical analyses for this end point

    Secondary: Change from Baseline in quality of life in epilepsy for adolescents (QOLIE-AD-48) in participants aged 15-17 years

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    End point title
    Change from Baseline in quality of life in epilepsy for adolescents (QOLIE-AD-48) in participants aged 15-17 years
    End point description
    QOLIE-AD-48 is a questionnaire analyzed according to the scoring manual at Baseline, at the end of the LTG/VPA Maintenance Phase and withdrawals for participants aged 15-17 years (n=6). Particpants who has started by QOLIE-AD-48 were using the same questionnaire even after 18 years old. Overall score was calculated as an average of sub scores that were normalized to 0 to 100. QOLIE-AD-48 has 8 subscale items (epilepsy impact, memory/concentration, physical fuctioning, stigma, social support, school behavior, attitudes towards epilepsy and health perceptions). Higher score presents higher quality of life. Epileptic symptoms generally affect the QOL of participants, and so QOLIE-AD-48 is world widely used for the QOL assessment of non-adult participants. Baseline is defined as Day 1 (pre-dose) value. Change from Baseline is calculated as post-dose visit value minus Baseline value.
    End point type
    Secondary
    End point timeframe
    Baseline and up to 46 weeks
    End point values
    LTG plus VPA (Phase 1, 2 and 3)
    Number of subjects analysed
    33 [7]
    Units: Units on a scale
    arithmetic mean (standard deviation)
        LTG Escalation-Withdrawal, n=2
    -10.83 ± 11.862
        LTG and VPA Maintenance-Visit 5, n=4
    -2.67 ± 6.356
    Notes
    [7] - FAS population
    No statistical analyses for this end point

    Secondary: Percentage of participants who completed or discontinued from the study

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    End point title
    Percentage of participants who completed or discontinued from the study
    End point description
    Following cases were considered for participants to have completed a part of or whole of the study. For whole period completion: participants who completed the last LTG and VPA Maintenance Phase visit (M5) in the LTG and VPA Maintenance Phase and follow-up examination. For LTG Escalation Phase completion: participants who reached 200 mg/d of LTG (or 100-200 mg/d of LTG if there were safety concerns) within 8-18 weeks of the phase. For VPA Reduction Phase completion: participants who completed the last fixed dose of VPA Reduction Phase visit (0 mg/d) (FR4) of the phase. For LTG and VPA Maintenance Phase completion: participants who completed M5 of the phase. Participants who met any of the withdrawal criteria after the start of investigational product were considered to have discontinued the study. Percentage of participants who completed or discontinued/withdrawn from the study is presented. Enrolled Population: comprised of all participants who had a Baseline (Week 0) visit.
    End point type
    Secondary
    End point timeframe
    Up to 50 weeks
    End point values
    LTG plus VPA (Phase 1, 2 and 3)
    Number of subjects analysed
    33 [8]
    Units: Percentage of participants
        Completed
    61
        Withdrawn
    39
    Notes
    [8] - Enrolled Population
    No statistical analyses for this end point

    Secondary: Number of participants with adverse events (AEs), AEs leading to discontinuation of the investigational product and/or withdrawal from the study, drug-related AEs, deaths and serious adverse events (SAEs) throughout the study

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    End point title
    Number of participants with adverse events (AEs), AEs leading to discontinuation of the investigational product and/or withdrawal from the study, drug-related AEs, deaths and serious adverse events (SAEs) throughout the study
    End point description
    An AE is defined as untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A SAE is any untoward medical occurrence that, at any dose results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in disability/incapacity, is a congenital anomaly/birth defect, based on medical or scientific judgement and all events of possible drug-induced liver injury. Safety Population: comprised of participants who received at least one dose of the investigational product during the LTG Escalation Phase.
    End point type
    Secondary
    End point timeframe
    From the start of study treatment until follow-up (up to 50 weeks)
    End point values
    LTG plus VPA (Phase 1, 2 and 3)
    Number of subjects analysed
    33 [9]
    Units: Participants
        Any AEs
    30
        Drug-related AEs
    17
        Any SAEs
    4
        AEs leading to discontinuation/withdrawal
    9
        AEs leading to death
    0
    Notes
    [9] - Safety Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) and serious adverse events (SAEs) were collected from the start of study treatment and until the follow-up contact (up to 50 weeks).
    Adverse event reporting additional description
    AEs and SAEs were collected from participants of the safety population, comprised of all participants who received atleast one dose of the investigational product during the LTG Escalation Phase.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    LTG plus VPA (Phase 1, 2 and 3)
    Reporting group description
    Par. received a fixed maintenance (maint) dose of VPA (400-1200 mg/d) along with LTG gradually escalated to 200 mg/d in accordance with the package insert information: i.e. 25 mg of LTG was orally administered once every other day for the first 2 wk and then once daily for the following 2 wk. Thereafter, LTG was gradually escalated by 25 to 50 mg every 1 to 2 wk for once or twice daily administration. Par. received a range of VPA dose reduction as follows: When VPA was reduced to 300 mg/d, the range of reduction was as follows: 1000 mg/d (2 wk), 800 mg/d (2 wk), 600 mg/d (2 wk), 400 mg/d (2 wk), 300 mg/d OR 1000 mg/d (4 wk), 600 mg/d (4 wk), 300 mg/d and when VPA was reduced to &lt; 300 mg/d, the dose was reduced to 300, 200, 100 and 0 mg/d in 100 mg decrements in steps of at least one wk duration. Par. received a fixed maint dose of LTG 200 mg/d and VPA 100 mg/d or a maint dose of LTG 200-400 mg/d were administered twice and 1-3 times daily for LTG and VPA, respectively, for 12 wk.

    Serious adverse events
    LTG plus VPA (Phase 1, 2 and 3)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 33 (12.12%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Histiocytic necrotising lymphadenitis
         subjects affected / exposed
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    3 / 33 (9.09%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    LTG plus VPA (Phase 1, 2 and 3)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 33 (69.70%)
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    5 / 33 (15.15%)
         occurrences all number
    5
    Dizziness
         subjects affected / exposed
    3 / 33 (9.09%)
         occurrences all number
    4
    Headache
         subjects affected / exposed
    3 / 33 (9.09%)
         occurrences all number
    5
    Tremor
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 33 (9.09%)
         occurrences all number
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    5 / 33 (15.15%)
         occurrences all number
    6
    Drug eruption
         subjects affected / exposed
    2 / 33 (6.06%)
         occurrences all number
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 33 (27.27%)
         occurrences all number
    13
    Gastroenteritis
         subjects affected / exposed
    4 / 33 (12.12%)
         occurrences all number
    5
    Influenza
         subjects affected / exposed
    3 / 33 (9.09%)
         occurrences all number
    3

    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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