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    Clinical Trial Results:
    A Double-blind, Multicenter, Randomized, Placebo-controlled Study to Evaluate the Efficacy and Safety of Adjunctive Treatment With Oral Levetiracetam, in Epilepsy Patients Aged ≥ 16 Years, With Generalized Tonic-clonic (GTC) Seizures

    Summary
    EudraCT number
    2014-004401-32
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    27 May 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    N01159
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01228747
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB Japan Co. Ltd.
    Sponsor organisation address
    Shinjuku Grand Tower, 8-17-1, Nishi-shinjuku, Shinjuku-ku, Tokyo, Japan, 160-0023
    Public contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, +49 2173 48 15 15, clinicaltrials@ucb.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, +49 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
    30 Jul 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 May 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of Levetiracetam treatment used as adjunctive therapy in Japanese and Chinese epilepsy patients aged ≥ 16 years with uncontrolled generalized tonic-clonic seizures despite treatment with 1 or 2 antiepileptic drug(s).
    Protection of trial subjects
    Close monitoring of subjects safety status.
    Background therapy
    Anti Epileptic Drugs (AED), as indicated and predefined in the protocol, were allowed as oral administration of 1 or 2 stable concomitant AEDs. For sudden aggravation or cluster seizures and if the subject's condition require rescue medication(s) during minor surgical procedures rescue medication was permitted as specified per protocol.
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    21 Oct 2010
    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
    China: 208
    Country: Number of subjects enrolled
    Japan: 43
    Worldwide total number of subjects
    251
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    15
    Adults (18-64 years)
    234
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study started to enroll subjects in Japan and China in October 2010.

    Pre-assignment
    Screening details
    Participant Flow refers to the Randomized Set consisting of all screened subjects who signed the Informed Consent form, participated in the prospective Baseline Period and were randomized at Visit 2.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Matching placebo for 28 weeks Placebo: Matching oral placebo tablets twice daily for 28 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PL1
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo for 28 weeks Placebo: Matching oral placebo tablets twice daily for 28 weeks

    Arm title
    Levetiracetam
    Arm description
    Levetiracetam treatment with dosing of 1000 mg/day or 2000 mg/day or 3000 mg/day for 28 weeks Levetiracetam: Oral dose tablets, twice daily
    Arm type
    Experimental

    Investigational medicinal product name
    Levetiracetam
    Investigational medicinal product code
    PR1
    Other name
    Keppra
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Levetiracetam treatment with dosing of 1000 mg/day or 2000 mg/day or 3000 mg/day for 28 weeks Levetiracetam: Oral dose tablets, twice daily

    Number of subjects in period 1
    Placebo Levetiracetam
    Started
    125
    126
    Completed
    60
    81
    Not completed
    65
    45
         Other Reason
    2
    5
         Protocol deviation
    6
    5
         Serious adverse event, non-fatal
    1
    -
         Lack of efficacy
    40
    27
         Adverse event, serious fatal
    3
    -
         Consent withdrawn by subject
    5
    1
         Adverse event, non-serious non-fatal
    4
    4
         Lost to follow-up
    4
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Matching placebo for 28 weeks Placebo: Matching oral placebo tablets twice daily for 28 weeks

    Reporting group title
    Levetiracetam
    Reporting group description
    Levetiracetam treatment with dosing of 1000 mg/day or 2000 mg/day or 3000 mg/day for 28 weeks Levetiracetam: Oral dose tablets, twice daily

    Reporting group values
    Placebo Levetiracetam Total
    Number of subjects
    125 126 251
    Age Categorical
    Units: Subjects
        <=18 years
    11 10 21
        Between 18 and 65 years
    113 115 228
        >=65 years
    1 1 2
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    32.8 ± 12.5 31.5 ± 11.3 -
    Gender Categorical
    Units: Subjects
        Female
    49 47 96
        Male
    76 79 155
    Region of Enrollment
    Units: Subjects
        China
    104 104 208
        Japan
    21 22 43

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Matching placebo for 28 weeks Placebo: Matching oral placebo tablets twice daily for 28 weeks

    Reporting group title
    Levetiracetam
    Reporting group description
    Levetiracetam treatment with dosing of 1000 mg/day or 2000 mg/day or 3000 mg/day for 28 weeks Levetiracetam: Oral dose tablets, twice daily

    Subject analysis set title
    Placebo Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Full Analysis Set consisted of all subjects in the Safety Set who had an evaluable Baseline and at least 1 post-Baseline GTC seizure count data point for the primary efficacy analysis excluding those who had seriously violated GCP (Good Clinical Practice). Evaluable Baseline for the primary efficacy analysis: at least 1 GTC seizure was documented for the Combined Baseline.

    Subject analysis set title
    Levetiracetam Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Full Analysis Set consisted of all subjects in the Safety Set who had an evaluable Baseline and at least 1 post-Baseline GTC seizure count data point for the primary efficacy analysis excluding those who had seriously violated GCP. Evaluable Baseline for the primary efficacy analysis: at least 1 GTC seizure was documented for the Combined Baseline.

    Primary: Percentage change from the Combined Baseline in the generalized tonic-clonic seizure frequency per week over the 28-week Treatment Period (Dose Adjustment + Evaluation Periods)

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    End point title
    Percentage change from the Combined Baseline in the generalized tonic-clonic seizure frequency per week over the 28-week Treatment Period (Dose Adjustment + Evaluation Periods)
    End point description
    Percentage change in generalized tonic-clonic (GTC) seizure frequency per week from Combined Baseline B over the Treatment Period A is calculated using the equation: Percentage change from Baseline = ((A-B)/B)*100. Percentage change from baseline is not defined for subjects whose baseline information is missing / unknown or equal to zero, or whose seizure frequency per week is missing / unknown. A negative value in change in generalized tonic-clonic (GTC) seizure frequency indicates a reduction of generalized tonic-clonic (GTC) seizure frequency over the 28-week treatment Period. Combined Baseline means: a 4-week Retrospective Baseline + 4-week Prospective Baseline or 8-week Prospective Baseline
    End point type
    Primary
    End point timeframe
    From Baseline to Week 28
    End point values
    Placebo Full Analysis Set Levetiracetam Full Analysis Set
    Number of subjects analysed
    109
    117
    Units: Percentage Change
    arithmetic mean (standard deviation)
        Overall
    -13.19 ± 55.54
    -68.22 ± 34.95
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The statistical hypotheses, null hypothesis (H0) and alternate hypothesis (H1), are stated below: H0: μLEV = μPBO vs. H1: μLEV ≠ μPBO ANCOVA on the endpoint “percentage change from Combined Baseline of GTC seizures per week” using “treatment” and “country” as factors (categorical predictors) and “Combined Baseline GTC seizure frequency per week” as a covariate (a continuous predictor) where μLEV and μPBO are adjusted means for LEV and PBO, respectively.
    Comparison groups
    Placebo Full Analysis Set v Levetiracetam Full Analysis Set
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -56.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -68.24
         upper limit
    -44.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.15

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

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    End point title
    The percentage change in generalized tonic-clonic seizure frequency per week from the Combined Baseline over the Evaluation Period
    End point description
    Percentage change in generalized tonic-clonic (GTC) seizure frequency per week from combined baseline B over the Evaluation Period A is calculated using the equation: Percentage change from Baseline = ((A-B)/B)*100. Percentage change from baseline is not defined for subjects whose baseline Information is missing / unknown or equal to zero, or whose seizure frequency per week is missing / unknown. A negative value in change in generalized tonic-clonic (GTC) seizure frequency indicates a reduction of generalized tonic-clonic (GTC) seizure frequency. Combined Baseline means: a 4-week Retrospective Baseline + 4-week Prospective Baseline or 8-week Prospective Baseline.
    End point type
    Secondary
    End point timeframe
    From Baseline to Evaluation Period (Week 12 to Week 28)
    End point values
    Placebo Full Analysis Set Levetiracetam Full Analysis Set
    Number of subjects analysed
    97
    108
    Units: Percentage Change
    arithmetic mean (standard deviation)
        Overall
    -4.44 ± 153.82
    -68.27 ± 42.63
    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
    A subject with an at least 50 % reduction in weekly generalized tonic-clonic (GTC) seizure frequency from Combined Baseline Period to the Treatment Period is considered a GTC 50 % responder. Combined Baseline means: a 4-week Retrospective Baseline + 4-week Prospective Baseline or 8-week Prospective Baseline
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 28
    End point values
    Placebo Full Analysis Set Levetiracetam Full Analysis Set
    Number of subjects analysed
    109
    117
    Units: participants
        Overall
    31
    91
    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 Evaluation 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 Evaluation Period
    End point description
    A subject with an at least 50 % reduction in weekly generalized tonic-clonic (GTC) seizure frequency from Combined Baseline Period to the Evaluation Period is considered a GTC 50 % responder. Combined Baseline means: a 4-week Retrospective Baseline + 4-week Prospective Baseline or 8-week Prospective Baseline
    End point type
    Secondary
    End point timeframe
    From Baseline to Evaluation Period (Week 12 to Week 28)
    End point values
    Placebo Full Analysis Set Levetiracetam Full Analysis Set
    Number of subjects analysed
    97
    108
    Units: participants
        Overall
    33
    82
    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 non-missing weekly generalized tonic-clonic (GTC) baseline seizure frequency and a weekly GTC seizure frequency of zero throughout the Evaluation Period, is considered as a GTC seizure-free subject on the Evaluation Period.
    End point type
    Secondary
    End point timeframe
    Evaluation Period (Week 12 to Week 28)
    End point values
    Placebo Full Analysis Set Levetiracetam Full Analysis Set
    Number of subjects analysed
    97
    108
    Units: participants
        Overall
    3
    32
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events were collected from the Prospective Baseline Period ( Week -8 to Week 0) over Dose Adjustment (12 weeks) and Evaluation Period (16 weeks) until Conversion or Withdrawal Period (4-6 weeks).
    Adverse event reporting additional description
    Adverse Events refer to the Safety Set (SS), which is a subset of the Randomized Set and consisted of all subjects who received at least 1 dose of study medication after randomization, either Placebo or Levetiracetam. Adverse Events were presented for the Dose Adjustment and Evaluation Period.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    Levetiracetam
    Reporting group description
    Levetiracetam treatment with dosing of 1000 mg/day or 2000 mg/day or 3000 mg/day for 28 weeks Levetiracetam: Oral dose tablets, twice daily

    Reporting group title
    Placebo
    Reporting group description
    Matching placebo for 28 weeks Placebo: Matching oral placebo tablets twice daily for 28 weeks

    Serious adverse events
    Levetiracetam Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 126 (0.79%)
    4 / 125 (3.20%)
         number of deaths (all causes)
    0
    3
         number of deaths resulting from adverse events
    0
    1
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Drowning
         subjects affected / exposed
    0 / 126 (0.00%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Sudden unexplained death in epilepsy
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 125 (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 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    40 / 126 (31.75%)
    32 / 125 (25.60%)
    Investigations
    Platelet count decreased
         subjects affected / exposed
    7 / 126 (5.56%)
    4 / 125 (3.20%)
         occurrences all number
    8
    4
    Protein urine present
         subjects affected / exposed
    10 / 126 (7.94%)
    1 / 125 (0.80%)
         occurrences all number
    11
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 126 (3.17%)
    9 / 125 (7.20%)
         occurrences all number
    7
    14
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    7 / 126 (5.56%)
    5 / 125 (4.00%)
         occurrences all number
    8
    5
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    24 / 126 (19.05%)
    20 / 125 (16.00%)
         occurrences all number
    33
    36

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jul 2010
    The substantial Protocol Amendment 1 provided the following major changes: • To detect pregnancy, the sample utilized for the test to detect the level of beta human chorionic gonadotropin (β-hCG) was changed to blood from urine due to issues found in preparation for the central measurements that led to an increase in the volume of the blood sample. • UCB changed the number of the categories for causal relationship of AEs to the study medication from 4 to 2 (“related” or “not related”). • UCB changed the standard module of the eCRF; because of this change, 'laboratory abnormalities that the investigator judges clinically relevant' no longer needed to be recorded in the eCRF. • LEV was granted regulatory approval in Japan after the final protocol was approved.
    27 Oct 2011
    The substantial Protocol Amendment 2 provided the following change: the use of commercial Keppra in the Named Patient Program for subjects in China who completed N01159 was clarified. Changes to the previous amendment were required for clarification.
    16 Feb 2012
    The substantial Protocol Amendment 3 provided the following changes: the study duration was extended (originally planned from the fourth quarter of 2010 to the first quarter of 2013, extended to the fourth quarter of 2013) and the visit window during the Baseline Period was clarified. Ilepcimide was included in the list of permitted concomitant AEDs.
    03 Sep 2012
    The substantial Protocol Amendment 4 provided the following change: the required sample size in Japan was changed based on the progress assessment of the recruitment of the Japanese subjects (originally, 78 subjects were planned for Japan [and 154 subjects in China] and this was changed to 26 subjects in Japan [and 206 subjects in China]). In addition, the study duration was extended to the second quarter of 2014.

    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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