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    Clinical Trial Results:
    A Multi-Center, Open-Label, Long-Term, Follow-Up Study Of The Safety And Efficacy Of Levetiracetam In Children With Partial Onset Seizures

    Summary
    EudraCT number
    2004-000200-40
    Trial protocol
    CZ   GB   BE   IT   HU  
    Global end of trial date
    24 Jun 2008

    Results information
    Results version number
    v1(current)
    This version publication date
    30 Jun 2016
    First version publication date
    25 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    N01148
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00152516
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB Biosciences Inc.
    Sponsor organisation address
    8010 Arco Corporate Drive, Raleigh, United States, NC 27617
    Public contact
    CTRRD, UCB Biosciences GmbH, +49 2173481515, clinicaltrials@ucb.com
    Scientific contact
    CTRRD, UCB Biosciences GmbH, +49 2173481515, clinicaltrials@ucb.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
    08 Aug 2008
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jun 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to obtain long-term descriptive safety and efficacy data in pediatric epileptic patients with partial onset seizures receiving long-term treatment with levetiracetam at individualized doses. This study in conjunction with Study N157 (NCT00150709) (UCBs other long-term, follow-up pediatric study) will be used to fulfill the requirement from the FDA written request to determine the long-term safety of levetiracetam as adjunctive therapy in the treatment of partial onset seizures in pediatric patients.
    Protection of trial subjects
    Before any study procedures were initiated for any subject in this study, an IRB/IEC approved written informed consent form and assent form, where appropriate, were to be properly executed and documented. Selection criteria for the study were specified globally in the protocol and were further clarified in country specific amendments to the protocol.
    Background therapy
    Concomitant anti epileptic drugs and other medication were allowed as specified in the study protocol.
    Evidence for comparator
    -
    Actual start date of recruitment
    23 Oct 2004
    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
    South Africa: 7
    Country: Number of subjects enrolled
    Czech Republic: 9
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Romania: 7
    Country: Number of subjects enrolled
    Poland: 2
    Country: Number of subjects enrolled
    Russian Federation: 7
    Country: Number of subjects enrolled
    Brazil: 29
    Country: Number of subjects enrolled
    Mexico: 6
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    India: 20
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    United States: 123
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    United Kingdom: 2
    Worldwide total number of subjects
    255
    EEA total number of subjects
    52
    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)
    81
    Children (2-11 years)
    147
    Adolescents (12-17 years)
    27
    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
    102 sites in 17 countries participated in the study, of which 85 sites in 16 countries enrolled subjects in the study.

    Pre-assignment
    Screening details
    The country specific protocol amendment C2 (August 7, 2006) allowed direct enrollment from India, Australia, and New Zealand bypassing the blinded feeder studies N01009 (2004-000199-14/NCT00175890) and N01103 (2014-004396-23/NCT00105040).

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

    Arms
    Arm title
    Levetiracetam
    Arm description
    Oral tablets or oral solution at 10 to 30 mg/kg/day bid for 48 weeks, or approximately 52 weeks should a subject choose to discontinue levetiracetam (LEV) at the end of the maintenance period.
    Arm type
    Experimental

    Investigational medicinal product name
    Levetiracetam
    Investigational medicinal product code
    IMP1
    Other name
    Pharmaceutical forms
    Oral solution, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Per protocol oral tablets or oral solution at 10 to 30 mg/kg/day bid for 48 weeks, or approximately 52 weeks should a subject choose to discontinue levetiracetam (LEV) at the end of the maintenance period.

    Number of subjects in period 1
    Levetiracetam
    Started
    255
    Completed
    180
    Not completed
    75
         Protocol deviation
    3
         Other: Mother Refused To Cooperate
    1
         Other: Primary Care Physician's Decision
    1
         Other: Seizure Worsening, Seeking 2nd Opinion
    1
         SAE, non-fatal
    5
         AE, serious fatal
    2
         Consent withdrawn by subject
    8
         Other: Given Commercial Drug in Error
    2
         Unknown AE
    1
         Other: Moved Out Of State
    1
         Other: Non-Compliance
    2
         Other: Underwent Surgery for Epilepsy
    1
         Other: Parents Withdrew Consent
    2
         AE, non-serious non-fatal
    10
         Lack and Loss of Efficacy
    30
         Lost to follow-up
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Levetiracetam
    Reporting group description
    Oral tablets or oral solution at 10 to 30 mg/kg/day bid for 48 weeks, or approximately 52 weeks should a subject choose to discontinue levetiracetam (LEV) at the end of the maintenance period.

    Reporting group values
    Levetiracetam Total
    Number of subjects
    255 255
    Age Categorical
    Units: Subjects
        <=18 years
    255 255
        Between 18 and 65 years
    0 0
        >=65 years
    0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    5.28 ± 4.69 -
    Gender Categorical
    Units: Subjects
        Female
    116 116
        Male
    139 139

    End points

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    End points reporting groups
    Reporting group title
    Levetiracetam
    Reporting group description
    Oral tablets or oral solution at 10 to 30 mg/kg/day bid for 48 weeks, or approximately 52 weeks should a subject choose to discontinue levetiracetam (LEV) at the end of the maintenance period.

    Primary: Percentage change (reduction) of partial (type I) seizure frequency per week from baseline over time during treatment period

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    End point title
    Percentage change (reduction) of partial (type I) seizure frequency per week from baseline over time during treatment period [1]
    End point description
    Positive changes from Baseline indicate an improvement (i.e., a reduction) in seizure frequency per week.
    End point type
    Primary
    End point timeframe
    Up-titration/Conversion Period (2-8 weeks); Maintenance Period (2-8 weeks to 40-46 weeks)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized in tables as descriptive statistics only.
    End point values
    Levetiracetam
    Number of subjects analysed
    247
    Units: Percent reduction in seizures Per Week
    median (inter-quartile range (Q1-Q3))
        Up-titration/Conversion
    51.06 (-10.7 to 91.59)
        Maintenance
    68.87 (-3.6 to 96.61)
    No statistical analyses for this end point

    Secondary: Percentage change (reduction) of total (type I, II, III) seizure frequency per week from baseline over time during treatment period

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    End point title
    Percentage change (reduction) of total (type I, II, III) seizure frequency per week from baseline over time during treatment period
    End point description
    Positive changes from Baseline indicate an improvement (i.e., a reduction) in seizure frequency per week.
    End point type
    Secondary
    End point timeframe
    Up-titration/Conversion Period (2-8 weeks); Maintenance Period (2-8 weeks to 40-46 weeks)
    End point values
    Levetiracetam
    Number of subjects analysed
    248
    Units: Percent Reduction in Seizures per Week
    median (inter-quartile range (Q1-Q3))
        Up-titration/Conversion Period
    47.44 (-21.18 to 88.7)
        Maintenance Period
    66.02 (-3.98 to 95)
    No statistical analyses for this end point

    Secondary: Partial (type I) seizure frequency per week over time during treatment period

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    End point title
    Partial (type I) seizure frequency per week over time during treatment period
    End point description
    End point type
    Secondary
    End point timeframe
    Up-titration/Conversion Period (2-8 weeks); Maintenance Period (2-8 weeks to 40-46 weeks)
    End point values
    Levetiracetam
    Number of subjects analysed
    254
    Units: Seizures Per Week
    median (inter-quartile range (Q1-Q3))
        Up-titration/Conversion Period
    2.85 (0.23 to 26.3)
        Maintenance Period
    1.49 (0.07 to 17.89)
    No statistical analyses for this end point

    Secondary: Total (type I, II, III) seizure frequency per week over time during treatment period

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    End point title
    Total (type I, II, III) seizure frequency per week over time during treatment period
    End point description
    End point type
    Secondary
    End point timeframe
    Up-titration/Conversion Period (2-8 weeks); Maintenance Period (2-8 weeks to 40-46 weeks)
    End point values
    Levetiracetam
    Number of subjects analysed
    254
    Units: Seizures Per Week
    median (inter-quartile range (Q1-Q3))
        Up-titration/Conversion Period
    3.15 (0.25 to 31.17)
        Maintenance Period
    1.91 (0.09 to 24.86)
    No statistical analyses for this end point

    Secondary: Change (reduction) from baseline in partial (type I) seizure frequency per week over time during treatment period

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    End point title
    Change (reduction) from baseline in partial (type I) seizure frequency per week over time during treatment period
    End point description
    Positive changes from Baseline indicate an improvement (i.e., a reduction) in seizure frequency per week.
    End point type
    Secondary
    End point timeframe
    Up-titration/Conversion Period (2-8 weeks); Maintenance Period (2-8 weeks to 40-46 weeks)
    End point values
    Levetiracetam
    Number of subjects analysed
    250
    Units: Seizures Per Week
    median (inter-quartile range (Q1-Q3))
        Up-titration/Conversion Period
    0.72 (-0.81 to 7.14)
        Maintenance Period
    0.93 (-0.33 to 8.99)
    No statistical analyses for this end point

    Secondary: Change (reduction) from baseline in total (type I, II, III) seizure frequency per week over time during treatment period

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    End point title
    Change (reduction) from baseline in total (type I, II, III) seizure frequency per week over time during treatment period
    End point description
    Positive changes from Baseline indicate an improvement (i.e., a reduction) in seizure frequency per week.
    End point type
    Secondary
    End point timeframe
    Up-titration/Conversion Period (2-8 weeks); Maintenance Period (2-8 weeks to 40-46 weeks)
    End point values
    Levetiracetam
    Number of subjects analysed
    250
    Units: Seizures Per Week
    median (inter-quartile range (Q1-Q3))
        Up-titration/Conversion Period
    0.69 (-0.89 to 7.84)
        Maintenance Period
    0.93 (-0.33 to 10.7)
    No statistical analyses for this end point

    Secondary: Partial seizure (type I) Responder rate (percent) during the up-titration/conversion phase and by visit during the maintenance phase

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    End point title
    Partial seizure (type I) Responder rate (percent) during the up-titration/conversion phase and by visit during the maintenance phase
    End point description
    The responder rate is defined as the number of responders. A responder is a patient with a 50% or greater change (reduction) in partial seizure frequency per week. Note: Rates were reported as percentages.
    End point type
    Secondary
    End point timeframe
    Up-titration (4 weeks); Maintenance Visits 3-4 (weeks 4-14, 6-15, or 8-16); Visits 4-5 (weeks 14-24, 15-24, or 16-24); Visits 5-6 (weeks 24-36); Visits 6-7 (weeks 36-48)
    End point values
    Levetiracetam
    Number of subjects analysed
    247
    Units: Percentage of Participants
    number (not applicable)
        Up-titration/Conversion (4 weeks)
    50.6
        Maintenance Visits 3-4 (weeks 4-14, 6-15, or 8-16)
    59.8
        Maint. Visits 4-5 (weeks 14-24, 15-24, or 16-24);
    65.5
        Maintenance Visits 5-6 (weeks 24-36)
    68.2
        Maintenance Visits 6-7 (weeks 36-48)
    71.8
    No statistical analyses for this end point

    Secondary: Partial seizure (type I) Maximum Seizure Free Interval (percentage of days belonging to a seizure free interval of 28 days or more)

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    End point title
    Partial seizure (type I) Maximum Seizure Free Interval (percentage of days belonging to a seizure free interval of 28 days or more)
    End point description
    For subjects with up to 24 weeks in the evaluation phase the denominator for each subject is their number of days in the evaluation phase.
    End point type
    Secondary
    End point timeframe
    Subjects with up to 24 weeks of exposure
    End point values
    Levetiracetam
    Number of subjects analysed
    51
    Units: Percentage of Days
    median (inter-quartile range (Q1-Q3))
        Overall
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Partial seizure (type I) Maximum Seizure Free Interval (percentage of days belonging to a seizure free interval of 28 days or more)

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    End point title
    Partial seizure (type I) Maximum Seizure Free Interval (percentage of days belonging to a seizure free interval of 28 days or more)
    End point description
    For subjects with greater than 24 weeks in the evaluation phase the denominator for each subject is their number of days in the evaluation phase.
    End point type
    Secondary
    End point timeframe
    Subjects with greater than 24 weeks of exposure
    End point values
    Levetiracetam
    Number of subjects analysed
    203
    Units: Percentage of days
    median (inter-quartile range (Q1-Q3))
        Overall
    61.49 (0 to 94.07)
    No statistical analyses for this end point

    Secondary: Total seizure (type I, II, III) Maximum Seizure Free Interval (percentage of days belonging to a seizure free interval of 28 days or more)

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    End point title
    Total seizure (type I, II, III) Maximum Seizure Free Interval (percentage of days belonging to a seizure free interval of 28 days or more)
    End point description
    For subjects with up to 24 weeks in the evaluation phase the denominator for each subject is their number of days in the evaluation phase.
    End point type
    Secondary
    End point timeframe
    Subjects with up to 24 weeks of exposure
    End point values
    Levetiracetam
    Number of subjects analysed
    51
    Units: Percentage of Days
    median (inter-quartile range (Q1-Q3))
        Overall
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Total seizure (type I, II, III) Maximum Seizure Free Interval (percentage of days belonging to a seizure free interval of 28 days or more)

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    End point title
    Total seizure (type I, II, III) Maximum Seizure Free Interval (percentage of days belonging to a seizure free interval of 28 days or more)
    End point description
    For subjects with greater than 24 weeks in the evaluation phase the denominator for each subject is their number of days in the evaluation phase.
    End point type
    Secondary
    End point timeframe
    Subjects with greater than 24 weeks of exposure
    End point values
    Levetiracetam
    Number of subjects analysed
    203
    Units: Percentage of Days
    median (inter-quartile range (Q1-Q3))
        Overall
    58.41 (0 to 93.81)
    No statistical analyses for this end point

    Secondary: Total seizure (type I, II, III) Continuously Seizure Free during the maintenance period

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    End point title
    Total seizure (type I, II, III) Continuously Seizure Free during the maintenance period
    End point description
    The measure description is the product limit adjusted percent of subjects seizure free starting from the beginning of the maintenance period. The up-titration period is the up to 6 week period of increasing dose prior to the maintenance period. The maintenance period is the period of stable dosing, subsquent to the up-titration period, which could last from 42 to 48 weeks.
    End point type
    Secondary
    End point timeframe
    Greater than or equal to 24 weeks, greater than or equal to 40 weeks
    End point values
    Levetiracetam
    Number of subjects analysed
    233
    Units: Percentage of Participants
    number (not applicable)
        >= 24 Weeks
    16.5
        >= 40 Weeks
    14.7
    No statistical analyses for this end point

    Secondary: Percent of subjects with each seizure type during the evaluation period

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    End point title
    Percent of subjects with each seizure type during the evaluation period
    End point description
    Type I Seizure is a partial onset Seizure (see International League Against Epilepsy definitions). Type II Seizure is a Generalized Seizure (see International League Against Epilepsy definitions). Type III Seizure is a Unknown Seizure Type (see International League Against Epilepsy definitions). A subject could experience more than one seizure type.
    End point type
    Secondary
    End point timeframe
    Evaluation period (48 weeks)
    End point values
    Levetiracetam
    Number of subjects analysed
    254
    Units: Percentage of Participants
    number (not applicable)
        Type I
    88.6
        Type II
    12.9
        Type III
    7.1
    No statistical analyses for this end point

    Secondary: Investigator Global Evaluation Scale

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    End point title
    Investigator Global Evaluation Scale
    End point description
    There are 7 categories, 3 for improvement (Marked improvement, Moderate improvement, Slight improvement), 3 for worsening (Slight worsening, Moderate worsening, Marked worsening), and 1 for no change (No change).
    End point type
    Secondary
    End point timeframe
    End of Evaluation period (week 48 or at point of early discontinuation)
    End point values
    Levetiracetam
    Number of subjects analysed
    222
    Units: Percentage of Participants
    number (not applicable)
        Improved
    76.1
        No Change
    15.3
        Worsened
    8.6
    No statistical analyses for this end point

    Secondary: Parent/Guardian Global Evaluation Scale

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    End point title
    Parent/Guardian Global Evaluation Scale
    End point description
    There are 7 categories, 3 for improvement (Marked improvement, Moderate improvement, Slight improvement), 3 for worsening (Slight worsening, Moderate worsening, Marked worsening), and 1 for no change (No change).
    End point type
    Secondary
    End point timeframe
    End of Evaluation period (week 48 or at point of early discontinuation)
    End point values
    Levetiracetam
    Number of subjects analysed
    214
    Units: Percentage of Participants
    number (not applicable)
        Improved
    75.7
        No Change
    12.6
        Worsened
    11.7
    No statistical analyses for this end point

    Secondary: Subject (>=8 years old) Global Evaluation Scale

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    End point title
    Subject (>=8 years old) Global Evaluation Scale
    End point description
    There are 7 categories, 3 for improvement (Marked improvement, Moderate improvement, Slight improvement), 3 for worsening (Slight worsening, Moderate worsening, Marked worsening), and 1 for no change (No change).
    End point type
    Secondary
    End point timeframe
    End of Evaluation period (week 48 or at point of early discontinuation)
    End point values
    Levetiracetam
    Number of subjects analysed
    71
    Units: Percentage of Participants
    number (not applicable)
        Improved
    78.9
        No Change
    15.5
        Worsened
    5.6
    No statistical analyses for this end point

    Secondary: Leiter-R Associated Memory (AM) Memory Screen Composite Score Change from Baseline to Visit 5 (week 24) and Visit 7 (week 48) (4 to 16 year olds)

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    End point title
    Leiter-R Associated Memory (AM) Memory Screen Composite Score Change from Baseline to Visit 5 (week 24) and Visit 7 (week 48) (4 to 16 year olds)
    End point description
    The Leiter-R AM battery has 10 subtests. The raw scores of the subtests are converted into scaled scores. Six composite scores are constructed from the 10 subtest scaled scores. The Memory Screen is one of them. It is composed of 2 subtests the Associated Pairs and Forward Memory. The sum of the Associated Pairs and Forward Memory subtest scaled scores are converted into a Memory composite score normally distributed with a mean and standard deviation of 100 (±15). Higher scores and positive changes from baseline are better. The range of the Memory Screen composite score is 44 to 155.
    End point type
    Secondary
    End point timeframe
    Baseline to Visit 5 (Week 24) and Visit 7 (Week 48)
    End point values
    Levetiracetam
    Number of subjects analysed
    87
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Visit 5 (week 24)
    4.8 ± 12.6
        Visit 7 (week 48)
    4.5 ± 15.3
    No statistical analyses for this end point

    Secondary: Bayley Scale of Infant Development (BSID) II Mental Development Index Scores Classification Shift from Baseline at Visit 5 (week 24) (1 month to < 4 year olds)

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    End point title
    Bayley Scale of Infant Development (BSID) II Mental Development Index Scores Classification Shift from Baseline at Visit 5 (week 24) (1 month to < 4 year olds)
    End point description
    This score is obtained from a total raw score which is the sum of a battery of individual questions. It is adjusted for a child's age, has an expected mean of 100 and standard deviation of 15, and can be categorized as: (1) Accelerated Performance (>= 115), (2) Within Normal Limits (85-114), (3) Mildly Delayed Performance (70-84), and (4) Significantly Delayed Performance (<=69). Changes from baseline are then further categorized where ‘Improved’ is any positive category change, ‘Stable’ is no category change, and ‘Worsened’ is any negative category change, from baseline.
    End point type
    Secondary
    End point timeframe
    Visit 5 (Week 24)
    End point values
    Levetiracetam
    Number of subjects analysed
    30
    Units: Number of subjects
        Worsened
    5
        Stable
    21
        Improved
    4
    No statistical analyses for this end point

    Secondary: Bayley Scale of Infant Development (BSID) II Mental Development Index Scores Classification Shift from Baseline at Visit 7 (week 48) (1 month to < 4 year olds)

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    End point title
    Bayley Scale of Infant Development (BSID) II Mental Development Index Scores Classification Shift from Baseline at Visit 7 (week 48) (1 month to < 4 year olds)
    End point description
    This score is obtained from a total raw score which is the sum of a battery of individual questions. It is adjusted for a child's age, has an expected mean of 100 and standard deviation of 15, and can be categorized as: (1) Accelerated Performance (>= 115), (2) Within Normal Limits (85-114), (3) Mildly Delayed Performance (70-84), and (4) Significantly Delayed Performance (<=69). Changes from baseline are then further categorized where ‘Improved’ is any positive category change, ‘Stable’ is no category change, and ‘Worsened’ is any negative category change, from baseline.
    End point type
    Secondary
    End point timeframe
    Visit 7 (week 48)
    End point values
    Levetiracetam
    Number of subjects analysed
    25
    Units: Number of subjects
        Worsened
    7
        Stable
    17
        Improved
    1
    No statistical analyses for this end point

    Secondary: Bayley Scale of Infant Development (BSID) II Psychomotor Development Index Scores Classification Shift from Baseline at Visit 5 (week 24) (1 month to < 4 year old)

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    End point title
    Bayley Scale of Infant Development (BSID) II Psychomotor Development Index Scores Classification Shift from Baseline at Visit 5 (week 24) (1 month to < 4 year old)
    End point description
    This score is obtained from a total raw score which is the sum of a battery of individual questions. It is adjusted for a child's age, has an expected mean of 100 and standard deviation of 15, and can be categorized as: (1) Accelerated Performance (>= 115), (2) Within Normal Limits (85-114), (3) Mildly Delayed Performance (70-84), and (4) Significantly Delayed Performance (<=69). Changes from baseline are then further categorized where ‘Improved’ is any positive category change, ‘Stable’ is no category change, and ‘Worsened’ is any negative category change, from baseline.
    End point type
    Secondary
    End point timeframe
    Visit 5 (week 24)
    End point values
    Levetiracetam
    Number of subjects analysed
    29
    Units: Number of subjects
        Worsened
    1
        Stable
    20
        Improved
    8
    No statistical analyses for this end point

    Secondary: Bayley Scale of Infant Development (BSID) II Psychomotor Development Index Scores Classification Shift from Baseline at Visit 7 (week 48) (1 month to < 4 year old)

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    End point title
    Bayley Scale of Infant Development (BSID) II Psychomotor Development Index Scores Classification Shift from Baseline at Visit 7 (week 48) (1 month to < 4 year old)
    End point description
    This score is obtained from a total raw score which is the sum of a battery of individual questions. It is adjusted for a child's age, has an expected mean of 100 and standard deviation of 15, and can be categorized as: (1) Accelerated Performance (>= 115), (2) Within Normal Limits (85-114), (3) Mildly Delayed Performance (70-84), and (4) Significantly Delayed Performance (<=69). Changes from baseline are then further categorized where ‘Improved’ is any positive category change, ‘Stable’ is no category change, and ‘Worsened’ is any negative category change, from baseline.
    End point type
    Secondary
    End point timeframe
    Visit 7 (week 48)
    End point values
    Levetiracetam
    Number of subjects analysed
    24
    Units: Number of subjects
        Worsened
    1
        Stable
    15
        Improved
    8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 1 year
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    9.0
    Reporting groups
    Reporting group title
    Levetiracetam
    Reporting group description
    Oral tablets or oral solution at 10 to 30 mg/kg/day bid for 48 weeks, or approximately 52 weeks should a subject choose to discontinue levetiracetam (LEV) at the end of the maintenance period.

    Serious adverse events
    Levetiracetam
    Total subjects affected by serious adverse events
         subjects affected / exposed
    46 / 255 (18.04%)
         number of deaths (all causes)
    3
         number of deaths resulting from adverse events
    0
    Surgical and medical procedures
    Oesophagogastric fundoplasty
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    4 / 255 (1.57%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Crying
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Drug toxicity
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Feeding tube complication
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Head injury
         subjects affected / exposed
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumothorax traumatic
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Congenital, familial and genetic disorders
    Hip dysplasia
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Choking
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Tonsillar hypertrophy
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Convulsion
         subjects affected / exposed
    18 / 255 (7.06%)
         occurrences causally related to treatment / all
    9 / 22
         deaths causally related to treatment / all
    0 / 0
    Infantile spasms
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Partial seizures with secondary generalisation
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Status epilepticus
         subjects affected / exposed
    6 / 255 (2.35%)
         occurrences causally related to treatment / all
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Feeding disorder of infancy or early childhood
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Exanthema subitum
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis adenovirus
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 255 (2.35%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Viral infection
         subjects affected / exposed
    5 / 255 (1.96%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Levetiracetam
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    206 / 255 (80.78%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    29 / 255 (11.37%)
         occurrences all number
    39
    Pharyngolaryngeal pain
         subjects affected / exposed
    14 / 255 (5.49%)
         occurrences all number
    20
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    20 / 255 (7.84%)
         occurrences all number
    24
    Convulsion
         subjects affected / exposed
    17 / 255 (6.67%)
         occurrences all number
    20
    Headache
         subjects affected / exposed
    31 / 255 (12.16%)
         occurrences all number
    46
    General disorders and administration site conditions
    Irritability
         subjects affected / exposed
    27 / 255 (10.59%)
         occurrences all number
    33
    Pyrexia
         subjects affected / exposed
    81 / 255 (31.76%)
         occurrences all number
    131
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    15 / 255 (5.88%)
         occurrences all number
    17
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    18 / 255 (7.06%)
         occurrences all number
    24
    Diarrhoea
         subjects affected / exposed
    34 / 255 (13.33%)
         occurrences all number
    45
    Vomiting
         subjects affected / exposed
    41 / 255 (16.08%)
         occurrences all number
    62
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    24 / 255 (9.41%)
         occurrences all number
    28
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    14 / 255 (5.49%)
         occurrences all number
    17
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    16 / 255 (6.27%)
         occurrences all number
    22
    Ear infection
         subjects affected / exposed
    18 / 255 (7.06%)
         occurrences all number
    29
    Influenza
         subjects affected / exposed
    16 / 255 (6.27%)
         occurrences all number
    22
    Nasopharyngitis
         subjects affected / exposed
    38 / 255 (14.90%)
         occurrences all number
    53
    Otitis media
         subjects affected / exposed
    21 / 255 (8.24%)
         occurrences all number
    34
    Pharyngitis
         subjects affected / exposed
    15 / 255 (5.88%)
         occurrences all number
    30
    Rhinitis
         subjects affected / exposed
    14 / 255 (5.49%)
         occurrences all number
    20
    Upper respiratory tract infection
         subjects affected / exposed
    62 / 255 (24.31%)
         occurrences all number
    105

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Jul 2004
    The primary reason for this amendment is to allow enrollment of a homogeneous patient population for testing with the Leiter-R and CBCL and to align the inclusion/exclusion criteria for N01148 with N01103 (2014-004396-23 / NCT00105040) and N01009 (2004-000199-14 / NCT00175890). Secondarily, correction of errors, updates to the study team and central lab, addition of a visit window to allow flexibility in visit scheduling, more accurate descriptions of the titration period length, drug packaging and pregnancy testing are also provided.
    02 Sep 2005
    This amendment serves to make revisions to the protocol summary, background information, study procedures, and treatment of patients sections of the protocol. Changes in the study procedures include the incorporation of an additional height assessment at Visit 7 and the addition of thyroid testing [thyroid-stimulating hormone (TSH)] at Visit 1 and Visit 7 to satisfy requirements imparted by the European Medicines Agency (EMEA). Changes in the protocol summary reflect the addition of possibly Argentina, India, Russia, Hungary, Poland, South Africa, and Croatia. Changes to the background information reflect the recent FDA approval of Keppra® for partial onset seizures in children, ages four and above. Changes in the treatment of patient section includes the removal of an appendix related to dosing and the addition of a statement related to IVRS.

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/21095488
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