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    Clinical Trial Results:
    A Randomized, Active-controlled, Open-label, Flexible-dose Study to Assess the Safety and Tolerability of Topiramate as Monotherapy Compared With Levetiracetam as Monotherapy in Pediatric Subjects With New or Recent-onset Epilepsy

    Summary
    EudraCT number
    2012-001552-19
    Trial protocol
    AT   IT   HU   BE   DE   GB   FR   PL  
    Global end of trial date
    30 Apr 2020

    Results information
    Results version number
    v2(current)
    This version publication date
    14 May 2021
    First version publication date
    14 Nov 2020
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    TOPMATEPY4067
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02201251
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    920 Route 202 NJ, Raritan, United States,
    Public contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Jun 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Apr 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of this study was to evaluate the effects of topiramate monotherapy compared with levetiracetam another standard antiepileptic drug (AED), as monotherapy for new-onset or recent-onset epilepsy (seizure disorder) on pediatric growth and maturation, bone mineralization, and kidney stone formation in children aged 2 to 15 years.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. Safety evaluations included monitoring of adverse events (AEs), vital sign measurements, electrocardiogram (ECG), clinical laboratory parameters, dual-energy X-ray absorptiometry (DEXA) scan, renal ultrasound, biochemical bone markers, hand/wrist x-ray, Tanner staging, cognitive, developmental, and behavioral assessments, and physical examinations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    30 Apr 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Hungary: 9
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Philippines: 3
    Country: Number of subjects enrolled
    Poland: 16
    Country: Number of subjects enrolled
    Russian Federation: 6
    Country: Number of subjects enrolled
    Taiwan: 17
    Country: Number of subjects enrolled
    United States: 2
    Worldwide total number of subjects
    63
    EEA total number of subjects
    34
    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)
    47
    Adolescents (12-17 years)
    16
    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
    -

    Pre-assignment
    Screening details
    A total of 114 subjects were screened. Out of 114 screened subjects, 63 subjects (topiramate group: 28 subjects, levetiracetam group: 35 subjects) were randomized in the study and received at least 1 dose of study drug.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Topiramate
    Arm description
    Subjects received topiramate weight-based sprinkle capsule and tablet, as tolerated (not to exceed 350 milligrams per day [mg/day] for subjects 2 to less than [<] 10 years of age, and not to exceed 400 mg/day for subjects 10 to 15 years of age), twice daily (BID) for up to 1 year during open-label treatment phase. Subjects were to either continue on commercially available topiramate or were tapered off of study drug over a period of up to 2 weeks during post-treatment phase of 30 days.
    Arm type
    Experimental

    Investigational medicinal product name
    Topiramate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Topiramate BID for up to 1 year during open-label treatment phase was administered.

    Arm title
    Levetiracetam
    Arm description
    Subjects received levetiracetam weight-based tablet or oral solution, as tolerated (not to exceed 60 milligrams per kilogram per day [mg/kg/day] for subjects 2 to 15 years of age). The daily dosage was increased every 2 weeks by increments of 20 mg/kg/day to the recommended daily dosage of 60 mg/kg/day. The maximum recommended daily dosage was 3000 mg (1500 mg BID) for up to 1 year during open-label treatment phase. Subjects were to either continue on commercially available levetiracetam or were tapered off of study drug over a period of up to 2 weeks during post-treatment phase of 30 days.
    Arm type
    Active comparator

    Investigational medicinal product name
    Levetiracetam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Levetiracetam every 2 weeks by increments of 20 mg/kg/day to the recommended daily dosage for up to 1 year during open-label treatment phase was administered.

    Number of subjects in period 1
    Topiramate Levetiracetam
    Started
    28
    35
    Completed
    24
    32
    Not completed
    4
    3
         Protocol deviation
    1
    -
         Noncompliance with study drug
    -
    1
         Adverse event, non-fatal
    1
    1
         Consent withdrawn by subject
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Topiramate
    Reporting group description
    Subjects received topiramate weight-based sprinkle capsule and tablet, as tolerated (not to exceed 350 milligrams per day [mg/day] for subjects 2 to less than [<] 10 years of age, and not to exceed 400 mg/day for subjects 10 to 15 years of age), twice daily (BID) for up to 1 year during open-label treatment phase. Subjects were to either continue on commercially available topiramate or were tapered off of study drug over a period of up to 2 weeks during post-treatment phase of 30 days.

    Reporting group title
    Levetiracetam
    Reporting group description
    Subjects received levetiracetam weight-based tablet or oral solution, as tolerated (not to exceed 60 milligrams per kilogram per day [mg/kg/day] for subjects 2 to 15 years of age). The daily dosage was increased every 2 weeks by increments of 20 mg/kg/day to the recommended daily dosage of 60 mg/kg/day. The maximum recommended daily dosage was 3000 mg (1500 mg BID) for up to 1 year during open-label treatment phase. Subjects were to either continue on commercially available levetiracetam or were tapered off of study drug over a period of up to 2 weeks during post-treatment phase of 30 days.

    Reporting group values
    Topiramate Levetiracetam Total
    Number of subjects
    28 35 63
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    20 27 47
        Adolescents (12-17 years)
    8 8 16
        Adults (18-64 years)
    0 0 0
        From 65 to 84 years
    0 0 0
        85 years and over
    0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    9.9 ± 2.76 9.3 ± 3.29 -
    Title for Gender
    Units: subjects
        Female
    16 18 34
        Male
    12 17 29

    End points

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    End points reporting groups
    Reporting group title
    Topiramate
    Reporting group description
    Subjects received topiramate weight-based sprinkle capsule and tablet, as tolerated (not to exceed 350 milligrams per day [mg/day] for subjects 2 to less than [<] 10 years of age, and not to exceed 400 mg/day for subjects 10 to 15 years of age), twice daily (BID) for up to 1 year during open-label treatment phase. Subjects were to either continue on commercially available topiramate or were tapered off of study drug over a period of up to 2 weeks during post-treatment phase of 30 days.

    Reporting group title
    Levetiracetam
    Reporting group description
    Subjects received levetiracetam weight-based tablet or oral solution, as tolerated (not to exceed 60 milligrams per kilogram per day [mg/kg/day] for subjects 2 to 15 years of age). The daily dosage was increased every 2 weeks by increments of 20 mg/kg/day to the recommended daily dosage of 60 mg/kg/day. The maximum recommended daily dosage was 3000 mg (1500 mg BID) for up to 1 year during open-label treatment phase. Subjects were to either continue on commercially available levetiracetam or were tapered off of study drug over a period of up to 2 weeks during post-treatment phase of 30 days.

    Primary: Change From Baseline in Weight Z-score at Month 1

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    End point title
    Change From Baseline in Weight Z-score at Month 1 [1]
    End point description
    The Z-Score indicates how many standard deviations (SD) a subject was from the population normal values. The body weight z-scores were designed to take into account the amount of weight gain that was expected due to normal growth in children and adolescents. Body weight data were converted to Z-scores using the Statistical Analysis System (SAS) programs provided by the Centers for Disease Control (CDC) for the calculation of the 2000 CDC growth charts. The mean (SD) change in Z scores from baseline by visit for the total safety population for all age cohorts combined were presented. The safety analysis set included all randomized subjects who received at least 1 dose of study drug. Here, N (Number of Subjects Analyzed) signifies number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Month 1
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistical analyses was planned to report for the primary end point.
    End point values
    Topiramate Levetiracetam
    Number of subjects analysed
    27
    34
    Units: Z-score
        arithmetic mean (standard deviation)
    -0.112 ± 0.1220
    -0.014 ± 0.1244
    No statistical analyses for this end point

    Primary: Change From Baseline in Weight Z-score at Month 3

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    End point title
    Change From Baseline in Weight Z-score at Month 3 [2]
    End point description
    The Z-Score indicates how many SD a subject was from the population normal values. The body weight z-scores were designed to take into account the amount of weight gain that was expected due to normal growth in children and adolescents. Body weight data were converted to Z-scores using the SAS programs provided by the CDC for the calculation of the 2000 CDC growth charts. The mean (SD) change in Z scores from baseline by visit for the total safety population for all age cohorts combined were presented. The safety analysis set included all randomized subjects who received at least 1 dose of study drug. Here, N (Number of Subjects Analyzed) signifies number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Month 3
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistical analyses was planned to report for the primary end point.
    End point values
    Topiramate Levetiracetam
    Number of subjects analysed
    27
    34
    Units: Z-score
        arithmetic mean (standard deviation)
    -0.201 ± 0.2094
    -0.027 ± 0.1802
    No statistical analyses for this end point

    Primary: Change From Baseline in Weight Z-score at Month 6

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    End point title
    Change From Baseline in Weight Z-score at Month 6 [3]
    End point description
    The Z-Score indicates how many SD a subject was from the population normal values. The body weight z-scores were designed to take into account the amount of weight gain that was expected due to normal growth in children and adolescents. Body weight data were converted to Z-scores using the SAS programs provided by the CDC for the calculation of the 2000 CDC growth charts. The mean (SD) change in Z scores from baseline by visit for the total safety population for all age cohorts combined were presented. The safety analysis set included all randomized subjects who received at least 1 dose of study drug. Here, N (Number of Subjects Analyzed) signifies number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Month 6
    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: No inferential statistical analyses was planned to report for the primary end point.
    End point values
    Topiramate Levetiracetam
    Number of subjects analysed
    24
    33
    Units: Z-score
        arithmetic mean (standard deviation)
    -0.319 ± 0.2496
    -0.070 ± 0.2304
    No statistical analyses for this end point

    Primary: Change From Baseline in Weight Z-score at Month 9

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    End point title
    Change From Baseline in Weight Z-score at Month 9 [4]
    End point description
    The Z-Score indicates how many SD a subject was from the population normal values. The body weight z-scores were designed to take into account the amount of weight gain that was expected due to normal growth in children and adolescents. Body weight data were converted to Z-scores using the SAS programs provided by the CDC for the calculation of the 2000 CDC growth charts. The mean (SD) change in Z scores from baseline by visit for the total safety population for all age cohorts combined were presented. The safety analysis set included all randomized subjects who received at least 1 dose of study drug. Here, N (Number of Subjects Analyzed) signifies number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Month 9
    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: No inferential statistical analyses was planned to report for the primary end point.
    End point values
    Topiramate Levetiracetam
    Number of subjects analysed
    24
    32
    Units: Z-score
        arithmetic mean (standard deviation)
    -0.326 ± 0.3235
    -0.110 ± 0.3584
    No statistical analyses for this end point

    Primary: Change From Baseline in Weight Z-score at Month 12

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    End point title
    Change From Baseline in Weight Z-score at Month 12 [5]
    End point description
    The Z-Score indicates how many SD a subject was from the population normal values. The body weight z-scores were designed to take into account the amount of weight gain that was expected due to normal growth in children and adolescents. Body weight data were converted to Z-scores using the SAS programs provided by the CDC for the calculation of the 2000 CDC growth charts. The mean (SD) change in Z scores from baseline by visit for the total safety population for all age cohorts combined were presented. The safety analysis set included all randomized subjects who received at least 1 dose of study drug. Here, N (Number of Subjects Analyzed) signifies number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Month 12
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistical analyses was planned to report for the primary end point.
    End point values
    Topiramate Levetiracetam
    Number of subjects analysed
    24
    32
    Units: Z-score
        arithmetic mean (standard deviation)
    -0.351 ± 0.3905
    -0.065 ± 0.3026
    No statistical analyses for this end point

    Primary: Change From Baseline in Height Z-score at Month 1

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    End point title
    Change From Baseline in Height Z-score at Month 1 [6]
    End point description
    Z-Score was a statistical measure to evaluate how a single data point compares to a standard. It described whether a mean was above or below the standard and how unusual the measurement is with range from minus (-) 3 to plus (+) 3; 0 equal to (=) same mean, greater than (>) 0 a greater mean, and less than (<) 0 a lesser mean than the standard. Growth parameters were compared to a standard defined by CDC growth charts. The mean (SD) change in Z scores from baseline by visit for the total safety population for all age cohorts combined were presented. The safety analysis set included all randomized subjects who received at least 1 dose of study drug. Here, N (Number of Subjects Analyzed) signifies number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Month 1
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistical analyses was planned to report for the primary end point.
    End point values
    Topiramate Levetiracetam
    Number of subjects analysed
    27
    33
    Units: Z-score
        arithmetic mean (standard deviation)
    0.004 ± 0.0870
    -0.015 ± 0.1017
    No statistical analyses for this end point

    Primary: Change From Baseline in Height Z-score at Month 3

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    End point title
    Change From Baseline in Height Z-score at Month 3 [7]
    End point description
    Z-Score was a statistical measure to evaluate how a single data point compares to a standard. It described whether a mean was above or below the standard and how unusual the measurement is with range from -3 to +3; 0 =same mean, >0 a greater mean, and <0 a lesser mean than the standard. Growth parameters were compared to a standard defined by CDC growth charts. The mean (SD) change in Z scores from baseline by visit for the total safety population for all age cohorts combined were presented. The safety analysis set included all randomized subjects who received at least 1 dose of study drug. Here, N (Number of Subjects Analyzed) signifies number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Month 3
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistical analyses was planned to report for the primary end point.
    End point values
    Topiramate Levetiracetam
    Number of subjects analysed
    27
    34
    Units: Z-score
        arithmetic mean (standard deviation)
    -0.036 ± 0.1452
    0.017 ± 0.1631
    No statistical analyses for this end point

    Primary: Change From Baseline in Height Z-score at Month 6

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    End point title
    Change From Baseline in Height Z-score at Month 6 [8]
    End point description
    Z-Score was a statistical measure to evaluate how a single data point compares to a standard. It described whether a mean was above or below the standard and how unusual the measurement is with range from -3 to +3; 0 =same mean, >0 a greater mean, and <0 a lesser mean than the standard. Growth parameters were compared to a standard defined by CDC growth charts. The mean (SD) change in Z scores from baseline by visit for the total safety population for all age cohorts combined were presented. The safety analysis set included all randomized subjects who received at least 1 dose of study drug. Here, N (Number of Subjects Analyzed) signifies number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Month 6
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistical analyses was planned to report for the primary end point.
    End point values
    Topiramate Levetiracetam
    Number of subjects analysed
    24
    33
    Units: Z-score
        arithmetic mean (standard deviation)
    -0.008 ± 0.1753
    0.077 ± 0.2670
    No statistical analyses for this end point

    Primary: Change From Baseline in Height Z-score at Month 9

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    End point title
    Change From Baseline in Height Z-score at Month 9 [9]
    End point description
    Z-Score was a statistical measure to evaluate how a single data point compares to a standard. It described whether a mean was above or below the standard and how unusual the measurement is with range from -3 to +3; 0 =same mean, >0 a greater mean, and <0 a lesser mean than the standard. Growth parameters were compared to a standard defined by CDC growth charts. The mean (SD) change in Z scores from baseline by visit for the total safety population for all age cohorts combined were presented. The safety analysis set included all randomized subjects who received at least 1 dose of study drug. Here, N (Number of Subjects Analyzed) signifies number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Month 9
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistical analyses was planned to report for the primary end point.
    End point values
    Topiramate Levetiracetam
    Number of subjects analysed
    24
    32
    Units: Z-score
        arithmetic mean (standard deviation)
    -0.059 ± 0.2337
    0.086 ± 0.2929
    No statistical analyses for this end point

    Primary: Change From Baseline in Height Z-score at Month 12

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    End point title
    Change From Baseline in Height Z-score at Month 12 [10]
    End point description
    Z-Score was a statistical measure to evaluate how a single data point compares to a standard. It described whether a mean was above or below the standard and how unusual the measurement is with range from -3 to +3; 0 =same mean, >0 a greater mean, and <0 a lesser mean than the standard. Growth parameters were compared to a standard defined by CDC growth charts. The mean (SD) change in Z scores from baseline by visit for the total safety population for all age cohorts combined were presented. The safety analysis set included all randomized subjects who received at least 1 dose of study drug. Here, N (Number of Subjects Analyzed) signifies number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Month 12
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistical analyses was planned to report for the primary end point.
    End point values
    Topiramate Levetiracetam
    Number of subjects analysed
    24
    32
    Units: Z-score
        arithmetic mean (standard deviation)
    -0.057 ± 0.2734
    0.088 ± 0.3315
    No statistical analyses for this end point

    Primary: Change from Baseline in Bone Mineral Density (BMD) Z-score at Month 6

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    End point title
    Change from Baseline in Bone Mineral Density (BMD) Z-score at Month 6 [11]
    End point description
    The BMD was measured by dual energy X-ray absorptiometry (DEXA) for the posterior-anterior lumbar spine (L1_L4) and total body less head area. The Z-Score is the number of standard deviations a subject's BMD differs from the average BMD of their age, sex and ethnicity. Positive scores indicate BMD above the mean; positive values are "best values" and negative values are "worst values". Positive changes from baseline indicated an improvement in condition. The safety analysis set included all randomized subjects who received at least 1 dose of study drug. Here, n (number analyzed) signifies number of subjects evaluable for this endpoint for specified category.
    End point type
    Primary
    End point timeframe
    Baseline, Month 6
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistical analyses was planned to report for the primary end point.
    End point values
    Topiramate Levetiracetam
    Number of subjects analysed
    28
    35
    Units: Z-score
    arithmetic mean (standard deviation)
        Lumbar spine (n= 24, 32)
    -0.181 ± 0.2590
    0.035 ± 0.2606
        Total body less head (n=25, 30)
    -0.180 ± 0.2647
    0.102 ± 0.2574
    No statistical analyses for this end point

    Primary: Change from Baseline in BMD Z-score at Month 12

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    End point title
    Change from Baseline in BMD Z-score at Month 12 [12]
    End point description
    The BMD was measured by DEXA for the posterior-anterior lumbar spine (L1_L4) and total body less head area. The Z-Score is the number of standard deviations a subject's BMD differs from the average BMD of their age, sex and ethnicity. Positive scores indicate BMD above the mean; positive values are "best values" and negative values are "worst values". Positive changes from baseline indicated an improvement in condition. The safety analysis set included all randomized subjects who received at least 1 dose of study drug. Here, n (number analyzed) signifies number of subjects evaluable for this endpoint for specified category.
    End point type
    Primary
    End point timeframe
    Baseline, Month 12
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistical analyses was planned to report for the primary end point.
    End point values
    Topiramate Levetiracetam
    Number of subjects analysed
    28
    35
    Units: Z-score
    arithmetic mean (standard deviation)
        Lumbar spine (n= 23, 30)
    -0.346 ± 0.3461
    0.084 ± 0.3552
        Total body less head (n=24, 28)
    -0.367 ± 0.3170
    0.054 ± 0.3766
    No statistical analyses for this end point

    Primary: Change From Baseline in Bone Mineral Content (BMC)-Z Score at Month 6

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    End point title
    Change From Baseline in Bone Mineral Content (BMC)-Z Score at Month 6 [13]
    End point description
    The BMC is an estimate of the amount of mineral (such as calcium) in the bone, which was assessed by DEXA scan for the posterior-anterior lumbar spine (L1_L4) and total body less head area. Positive changes from baseline indicated an improvement in condition. The safety analysis set included all randomized subjects who received at least 1 dose of study drug. Here, n (number analyzed) signifies number of subjects evaluable for this endpoint for specified category.
    End point type
    Primary
    End point timeframe
    Baseline, Month 6
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistical analyses was planned to report for the primary end point.
    End point values
    Topiramate Levetiracetam
    Number of subjects analysed
    28
    35
    Units: Z-score
    arithmetic mean (standard deviation)
        Lumbar spine (n= 14, 19)
    -0.141 ± 0.2155
    0.075 ± 0.2806
        Total body less head (n=15, 19)
    -0.242 ± 0.2516
    0.151 ± 0.2154
    No statistical analyses for this end point

    Primary: Change From Baseline in BMC-Z Score at Month 12

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    End point title
    Change From Baseline in BMC-Z Score at Month 12 [14]
    End point description
    The BMC is an estimate of the amount of mineral (such as calcium) in the bone, which was assessed by DEXA scan for the posterior-anterior lumbar spine (L1_L4) and total body less head area. Positive changes from baseline indicated an improvement in condition. The safety analysis set included all randomized subjects who received at least 1 dose of study drug. Here, n (number analyzed) signifies number of subjects evaluable for this endpoint for specified category.
    End point type
    Primary
    End point timeframe
    Baseline, Month 12
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistical analyses was planned to report for the primary end point.
    End point values
    Topiramate Levetiracetam
    Number of subjects analysed
    28
    35
    Units: Z-score
    arithmetic mean (standard deviation)
        Lumbar spine (n= 14, 18)
    -0.274 ± 0.3123
    0.124 ± 0.3584
        Total body less head (n=15, 18)
    -0.266 ± 0.6800
    0.017 ± 0.2533
    No statistical analyses for this end point

    Secondary: Number of Subjects with Treatment-emergent Adverse Events (TEAE)

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    End point title
    Number of Subjects with Treatment-emergent Adverse Events (TEAE)
    End point description
    An adverse event (AE) is any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. TEAE are defined as AEs with onset during the treatment period or that are a consequence of a pre-existing condition that has worsened since baseline. Safety analysis set included all randomized subjects who received at least 1 dose of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 1 year
    End point values
    Topiramate Levetiracetam
    Number of subjects analysed
    28
    35
    Units: Subjects
    25
    29
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Kidney Stones

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    End point title
    Percentage of Subjects with Kidney Stones
    End point description
    Percentage of subjects with kidney stones were reported.
    End point type
    Secondary
    End point timeframe
    Up to 1 year
    End point values
    Topiramate Levetiracetam
    Number of subjects analysed
    28
    35
    Units: Percentage of Subject
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Day 390
    Adverse event reporting additional description
    The safety analysis set included all randomized subjects who received at least 1 dose of study drug.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Levetiracetam
    Reporting group description
    Subjects received levetiracetam weight-based tablet or oral solution, as tolerated (not to exceed 60 milligrams per kilogram per day [mg/kg/day] for subjects 2 to 15 years of age). The daily dosage was increased every 2 weeks by increments of 20 mg/kg/day to the recommended daily dosage of 60 mg/kg/day. The maximum recommended daily dosage was 3000 mg (1500 mg BID) for up to 1 year during open-label treatment phase. Subjects were to either continue on commercially available levetiracetam or were tapered off of study drug over a period of up to 2 weeks during post-treatment phase of 30 days.

    Reporting group title
    Topiramate
    Reporting group description
    Subjects received topiramate weight-based sprinkle capsule and tablet, as tolerated (not to exceed 350 milligrams per day [mg/day] for subjects 2 to less than [<] 10 years of age, and not to exceed 400 mg/day for subjects 10 to 15 years of age), twice daily (BID) for up to 1 year during open-label treatment phase. Subjects were to either continue on commercially available topiramate or were tapered off of study drug over a period of up to 2 weeks during post-treatment phase of 30 days.

    Serious adverse events
    Levetiracetam Topiramate
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 35 (14.29%)
    0 / 28 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Skull Fracture
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised Tonic-Clonic Seizure
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Myositis
         subjects affected / exposed
    1 / 35 (2.86%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Levetiracetam Topiramate
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 35 (74.29%)
    24 / 28 (85.71%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 28 (3.57%)
         occurrences all number
    2
    1
    Epistaxis
         subjects affected / exposed
    2 / 35 (5.71%)
    2 / 28 (7.14%)
         occurrences all number
    3
    2
    Oropharyngeal Pain
         subjects affected / exposed
    3 / 35 (8.57%)
    4 / 28 (14.29%)
         occurrences all number
    5
    5
    Rhinitis Allergic
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Nervous system disorders
    Disturbance in Attention
         subjects affected / exposed
    0 / 35 (0.00%)
    4 / 28 (14.29%)
         occurrences all number
    0
    4
    Headache
         subjects affected / exposed
    9 / 35 (25.71%)
    3 / 28 (10.71%)
         occurrences all number
    25
    3
    Memory Impairment
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    Psychomotor Hyperactivity
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 28 (3.57%)
         occurrences all number
    2
    1
    Somnolence
         subjects affected / exposed
    3 / 35 (8.57%)
    2 / 28 (7.14%)
         occurrences all number
    4
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Pyrexia
         subjects affected / exposed
    3 / 35 (8.57%)
    3 / 28 (10.71%)
         occurrences all number
    9
    3
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 35 (5.71%)
    1 / 28 (3.57%)
         occurrences all number
    6
    4
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    5 / 35 (14.29%)
    0 / 28 (0.00%)
         occurrences all number
    5
    0
    Attention Deficit/Hyperactivity Disorder
         subjects affected / exposed
    0 / 35 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    2
    Nervousness
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 28 (7.14%)
         occurrences all number
    1
    4
    Abdominal Pain Upper
         subjects affected / exposed
    2 / 35 (5.71%)
    4 / 28 (14.29%)
         occurrences all number
    11
    8
    Diarrhoea
         subjects affected / exposed
    4 / 35 (11.43%)
    1 / 28 (3.57%)
         occurrences all number
    4
    1
    Nausea
         subjects affected / exposed
    2 / 35 (5.71%)
    0 / 28 (0.00%)
         occurrences all number
    4
    0
    Vomiting
         subjects affected / exposed
    5 / 35 (14.29%)
    2 / 28 (7.14%)
         occurrences all number
    8
    2
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    1 / 35 (2.86%)
    4 / 28 (14.29%)
         occurrences all number
    1
    4
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 35 (2.86%)
    3 / 28 (10.71%)
         occurrences all number
    1
    13
    Influenza
         subjects affected / exposed
    1 / 35 (2.86%)
    2 / 28 (7.14%)
         occurrences all number
    1
    2
    Nasopharyngitis
         subjects affected / exposed
    7 / 35 (20.00%)
    7 / 28 (25.00%)
         occurrences all number
    14
    15
    Pharyngitis
         subjects affected / exposed
    0 / 35 (0.00%)
    3 / 28 (10.71%)
         occurrences all number
    0
    4
    Respiratory Tract Infection Viral
         subjects affected / exposed
    3 / 35 (8.57%)
    1 / 28 (3.57%)
         occurrences all number
    5
    1
    Rhinitis
         subjects affected / exposed
    3 / 35 (8.57%)
    2 / 28 (7.14%)
         occurrences all number
    3
    2
    Sinusitis
         subjects affected / exposed
    1 / 35 (2.86%)
    3 / 28 (10.71%)
         occurrences all number
    1
    4
    Tonsillitis
         subjects affected / exposed
    1 / 35 (2.86%)
    3 / 28 (10.71%)
         occurrences all number
    1
    3
    Upper Respiratory Tract Infection
         subjects affected / exposed
    7 / 35 (20.00%)
    11 / 28 (39.29%)
         occurrences all number
    16
    22

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Mar 2014
    The overall reason for the amendment is to clarify exclusion and withdrawal criteria for subjects with a history of or significant risk of suicidal or violent behavior.
    24 Aug 2017
    The overall objective of this amendment is to improve a slower than expected study enrollment. At the current rate of subject randomization, the previously agreed upon milestone for the study completion will not be met.

    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.
    Enrollment stopped early due to futility; but all enrolled subjects completed trial except 7 subjects(reasons in subject disposition). Also, no exposure to topiramate in 2-5 years age cohort. Hence no conclusions made due to absence of comparability.
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