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    Clinical Trial Results:
    An Open-label, Single-arm, Multicenter Study to Evaluate the Efficacy and Safety of Adjunctive Treatment With Levetiracetam in Japanese Patients (≥4 to <16 Years) With Uncontrolled Generalized Tonic-clonic (GTC) Seizures Despite Treatment With 1 or 2 Antiepileptic Drug(s)

    Summary
    EudraCT number
    2014-004382-25
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    04 Jun 2013

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

    Trial information

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    Trial identification
    Sponsor protocol code
    N01363
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01292837
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB Japan Co. Ltd.
    Sponsor organisation address
    8-17-1 Nishi-Shinjuku, Tokyo, Japan, 160-0023
    Public contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, 0049 2173 4815 15, clinicaltrials@ucb.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, 0049 2173 48 15 15, 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
    09 Sep 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jun 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy and safety of Levetiracetam (LEV) dry syrup at doses up to 60 mg/kg/day or 3000 mg/day used as adjunctive therapy in Japanese pediatric subjects aged ≥ 4 to < 16 years with uncontrolled generalized tonic-clonic (GTC) seizures, despite treatment with 1 or 2 Antiepileptic Drugs (AEDs).
    Protection of trial subjects
    Reduced the number of laboratory test to minimise pain and distress. The pregnancy test performed by urinalysis instead of blood biochemistry, to minimise the blood volume.
    Background therapy
    One or two antiepileptic drug(s)
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    09 Feb 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Japan: 13
    Worldwide total number of subjects
    13
    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)
    6
    Adolescents (12-17 years)
    7
    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
    This multicenter study started to enroll subjects in Februray 2011 in order to end up with 8 sites in Japan with enrolled subjects. Participant Flow refers to the Enrolled Set (ES). ES consists of all subjects who signed the consent form and participated in the Prospective Baseline Period.

    Pre-assignment
    Screening details
    Subjects were screened at 8 sites in Japan. Overall, 13 subjects were screened and enrolled in N01363; there were no screen failures.

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

    Arms
    Arm title
    Levetiracetam
    Arm description
    Twice daily (morning and evening) orally Levetiracetam: The initial dose is 20 mg/kg/day or 1000 mg/day, divided into two equal dose for the first two weeks, followed by 40 mg/kg/day or 2000 mg/day for two weeks. After reaching 60 mg/kg/day or 3000 mg/day, treatment will continue for 20 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Levetiracetam
    Investigational medicinal product code
    ucb L059
    Other name
    EKeppra
    Pharmaceutical forms
    Powder for syrup
    Routes of administration
    Oral use
    Dosage and administration details
    The initial dose is 20 mg/kg/day or 1000 mg/day, divided into two equal dose for the first two weeks, followed by 40 mg/kg/day or 2000 mg/day for two weeks. After reaching 60 mg/kg/day or 3000 mg/day, treatment will continue for 20 weeks.

    Number of subjects in period 1
    Levetiracetam
    Started
    13
    Completed
    11
    Not completed
    2
         Further treatment determined
    1
         AE, non-serious non-fatal
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Levetiracetam
    Reporting group description
    Twice daily (morning and evening) orally Levetiracetam: The initial dose is 20 mg/kg/day or 1000 mg/day, divided into two equal dose for the first two weeks, followed by 40 mg/kg/day or 2000 mg/day for two weeks. After reaching 60 mg/kg/day or 3000 mg/day, treatment will continue for 20 weeks.

    Reporting group values
    Levetiracetam Total
    Number of subjects
    13 13
    Age categorical
    Units: Subjects
        ≥4 to <8 years
    4 4
        ≥8 to <12 years
    2 2
        ≥12 to <16 years
    7 7
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    9.7 ± 4.1 -
    Gender Categorical
    Units: Subjects
        Female
    4 4
        Male
    9 9
    Region of Enrollment
    Units: Subjects
        Japan
    13 13
    Weight
    Units: kilogram
        arithmetic mean (standard deviation)
    32.22 ± 16.56 -
    Body Mass Index
    Units: kilogram per squaremeter (kg/m^2)
        arithmetic mean (standard deviation)
    17.89 ± 3.75 -
    Height
    Units: centimeter
        arithmetic mean (standard deviation)
    129.36 ± 26.32 -

    End points

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    End points reporting groups
    Reporting group title
    Levetiracetam
    Reporting group description
    Twice daily (morning and evening) orally Levetiracetam: The initial dose is 20 mg/kg/day or 1000 mg/day, divided into two equal dose for the first two weeks, followed by 40 mg/kg/day or 2000 mg/day for two weeks. After reaching 60 mg/kg/day or 3000 mg/day, treatment will continue for 20 weeks.

    Primary: The percent change from the Combined Baseline (4-week Retrospective Baseline and 4-week Prospective Baseline) in the generalized tonic-clonic seizure frequency per week over the 24-week Treatment Period (Up-Titration and Evaluation Periods)

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    End point title
    The percent change from the Combined Baseline (4-week Retrospective Baseline and 4-week Prospective Baseline) in the generalized tonic-clonic seizure frequency per week over the 24-week Treatment Period (Up-Titration and Evaluation Periods) [1]
    End point description
    The percent change from Combined Baseline over Treatment Period was calculated from the Generalized Tonic-Clonic (GTC) seizure frequency per week during the Treatment Period (T) and during the Baseline Period (B, Combined Baseline, ie, Retrospective and Prospective Baseline Periods) using the equation below. The percent change from Baseline = (B - T)/B x 100 The seizure frequency per week was calculated using the following formula: Frequency per week of GTC seizures = total number of GTC seizures in the corresponding period / number of days for observation in the corresponding period x 7
    End point type
    Primary
    End point timeframe
    From Baseline (Week -8) to Treatment Period (Week 0 to Week 24)
    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 was no formal statistical hypothesis testing for this endpoint in this open-label, single-arm study. Results were summarized in tables as descriptive statistics only.
    End point values
    Levetiracetam
    Number of subjects analysed
    13
    Units: percent change
    arithmetic mean (standard deviation)
        mean (standard deviation)
    45.47 ± 50.34
    No statistical analyses for this end point

    Secondary: The percent change in generalized tonic-clonic seizure frequency per week from the Combined Baseline Period over the Evaluation Period

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    End point title
    The percent change in generalized tonic-clonic seizure frequency per week from the Combined Baseline Period over the Evaluation Period
    End point description
    The percent change from Combined Baseline over Evaluation Period was calculated from the Generalized Tonic-Clonic (GTC) seizure frequency per week during the Evaluation Period (E) and during the Baseline Period (B, Combined Baseline, ie, Retrospective and Prospective Baseline Periods) using the equation below. The percent change from Baseline = (B - E)/B x 100 The seizure frequency per week was calculated using the following formula: Frequency per week of GTC seizures = total number of GTC seizures in the corresponding period / number of days for observation in the corresponding period x 7
    End point type
    Secondary
    End point timeframe
    From Baseline (Week -8) to Evaluation Period (Week 4 to Week 24)
    End point values
    Levetiracetam
    Number of subjects analysed
    12
    Units: percent change
    arithmetic mean (standard deviation)
        mean (standard deviation)
    44.93 ± 51.86
    No statistical analyses for this end point

    Secondary: Generalized tonic-clonic seizures 50 % responder rate (the proportion of subjects with 50 % or more reduction from the Combined Baseline in the frequency of generalized tonic-clonic seizures) during the Treatment Period

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    End point title
    Generalized tonic-clonic seizures 50 % responder rate (the proportion of subjects with 50 % or more reduction from the Combined Baseline in the frequency of generalized tonic-clonic seizures) during the Treatment Period
    End point description
    The 50 % responder rate during the Treatment Period was the proportion of subjects who reported a ≥ 50 % reduction in seizure frequency per week from Baseline during the Treatment Period.
    End point type
    Secondary
    End point timeframe
    From Baseline (Week -8) to Treatment Period (Week 0 to Week 24)
    End point values
    Levetiracetam
    Number of subjects analysed
    13
    Units: percentage of participants
    number (not applicable)
        percentage of participants
    53.8
    No statistical analyses for this end point

    Secondary: Generalized tonic-clonic seizures 50 % responder rate during the Evaluation Period

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    End point title
    Generalized tonic-clonic seizures 50 % responder rate during the Evaluation Period
    End point description
    The 50 % responder rate during the Evaluation Period was the proportion of subjects who reported a ≥50 % reduction in seizure frequency per week from Baseline during the Evaluation Period.
    End point type
    Secondary
    End point timeframe
    From Baseline (Week -8) to Evaluation Period (Week 4 to Week 24)
    End point values
    Levetiracetam
    Number of subjects analysed
    12
    Units: percentage of participants
    number (not applicable)
        percentage of participants
    58.3
    No statistical analyses for this end point

    Secondary: Generalized tonic-clonic seizure freedom over the Treatment Period

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    End point title
    Generalized tonic-clonic seizure freedom over the Treatment Period
    End point description
    A subject with a generalized tonic-clonic seizure frequency of 0 per week throughout the Treatment Period was considered a seizure-free subject for that period.
    End point type
    Secondary
    End point timeframe
    Treatment Period (Week 0 to Week 24)
    End point values
    Levetiracetam
    Number of subjects analysed
    13
    Units: participants
        participants
    2
    No statistical analyses for this end point

    Secondary: Generalized tonic-clonic seizure freedom over the Evaluation Period

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    End point title
    Generalized tonic-clonic seizure freedom over the Evaluation Period
    End point description
    A subject with a generalized tonic-clonic seizure frequency of 0 per week throughout the Evaluation Period was considered a seizure-free subject for that period.
    End point type
    Secondary
    End point timeframe
    Evaluation Period (Week 4 to Week 24)
    End point values
    Levetiracetam
    Number of subjects analysed
    12
    Units: participants
        participants
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment Emergent Adverse Events were reported from Baseline up to Week 30.
    Adverse event reporting additional description
    The Analysis Population refers to the Safety Set. The Safety Set was a subset of the Enrolled Set and consisted of all subjects taking at least 1 dose of the study medication.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Levetiracetam
    Reporting group description
    Twice daily (morning and evening) orally Levetiracetam: The initial dose is 20 mg/kg/day or 1000 mg/day, divided into two equal dose for the first two weeks, followed by 40 mg/kg/day or 2000 mg/day for two weeks. After reaching 60 mg/kg/day or 3000 mg/day, treatment will continue for 20 weeks.

    Serious adverse events
    Levetiracetam
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 13 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Levetiracetam
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 13 (100.00%)
    Injury, poisoning and procedural complications
    Arthropod sting
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Contusion
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Laceration
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Subcutaneous haematoma
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Respiratory tract haemorrhage
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    2
    Rhinitis allergic
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    3
    Convulsion
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    5
    Bradykinesia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    5
    Dental caries
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Stomatitis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Excessive granulation tissue
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    5
    Impetigo
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Otitis media
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Pneumonia mycoplasmal
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Aug 2010
    • UCB changed the number of the categories for causal relationship of AEs to the study medication to 2 from 4. • UCB changed the standard module of the CRF so that the clinical relevance of the “laboratory abnormalities” was not recorded in the eCRF. • Errors in writing and incorrect information were corrected. • A new Clinical Project Manager was appointed. • There was a need to add some drugs in the list of restricted concomitant drugs and drug brand names were deleted from the lists. • Clarification was provided that the pregnancy test was performed at the investigational site. • The introduction section was updated to reflect that LEV was granted the regulatory approval in Japan after the final protocol was approved.
    28 Feb 2012
    The primary purpose of the substantial Protocol Amendment 2 was to extend the study duration and clarify the visit window during the Baseline Period. Changes to the previous edition were required for clarification. The amendment also provided the following changes: • Administrative information was updated. • Two additional prohibited concomitant medications, 1 restricted concomitant medication, and 1 rescue medication, were added. • An additional reference was added.
    29 Jan 2013
    The primary purpose of the substantial Protocol Amendment 3 was to extend the study duration and mention the update in approval status by the Food and Drug Administration. The amendment also provided the following changes: • Administrative information was updated. • One additional concomitant antiepileptic medication and 1 restricted concomitant medication were added.

    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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