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    Clinical Trial Results:
    A Multi-Center, open-label, randomized study to evaluate the long term effectiveness of Levetiracetam as monotherapy in comparison with Oxcarbazepine in subjects with newly or recently diagnosed partial epilepsy

    Summary
    EudraCT number
    2014-002713-32
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    15 Jul 2014

    Results information
    Results version number
    v2(current)
    This version publication date
    30 Jan 2016
    First version publication date
    11 Jul 2015
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Revision of full data set results to be consistent with results posted on Clinicaltrials.gov.

    Trial information

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    Trial identification
    Sponsor protocol code
    N01367
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01498822
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Korea UCB Co., Ltd.
    Sponsor organisation address
    127 Teheran-ro, Seoul, Korea, Republic of, 135-911
    Public contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, +49 2173 4815 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
    09 Oct 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the long term effectiveness of Levetiracetam (LEV) monotherapy on Treatment Failure Rate in subjects with newly diagnosed partial onset seizures with or without secondary generalized seizure, compared to Oxcarbazepine (OXC) monotherapy over 50 weeks from the first dose of study medication and to demonstrate that monotherapy with LEV (1,000 to 3,000 mg/day) is non-inferior to monotherapy with OXC (900 to 2,400 mg/day).
    Protection of trial subjects
    Subjects were informed of potential risks and discomforts from the study medications and the study procedures, and the fact that they would receive the most appropriate treatment when they suffer injuries and inform the doctor and that the doctors would make every efforts to minimize any discomforts from the study procedure, for example: needle stick, bruising at the blood sample site, reaction to the ECG patch adhesive, number of visits.
    Background therapy
    Not applicable
    Evidence for comparator
    For subjects with newly diagnosed or yet untreated epilepsy, the question still remains regarding the best choice of AED(s) with the best evidence for long term efficacy and safety as initial monotherapy. Apart from a well designed, randomized controlled trial for registration purpose, which demonstrated the non-inferiority of LEV compared to CBZ-CR in newly-diagnosed patients with partial epilepsy, KOMET study suggested broad-spectrum efficacy of LEV with tolerability similar to that of VPA-ER and CBZ-CR, and SANAD study suggested that further AED needs to be compared with LTG or possibly OXC rather than CBZ in partial onset seizures for monotherapy. In order to provide neurologists with the best evidence in selecting efficacious and tolerable long-term treatments among commonly prescribed newer AEDs, a comparison including LEV and OXC is warranted. Comparing LEV to OXC may provide evidence to support LEV use for subjects with newly diagnosed partial epilepsy, and provide reliable data for clinical practice that takes patient preference into account.
    Actual start date of recruitment
    08 Jun 2011
    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
    Korea, Republic of: 353
    Worldwide total number of subjects
    353
    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)
    14
    Adults (18-64 years)
    301
    From 65 to 84 years
    38
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study started to enroll subjects in June 2011. A total of 27 investigators enrolled 353 subjects at 23 sites in Korea.

    Pre-assignment
    Screening details
    Participant Flow refers to the Randomized Set, consisting of all subjects who were randomized in this study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Levetiracetam
    Arm description
    Levetiracetam twice a day treatment Group 250 mg and 500 mg Levetiracetam tablet, 1000 mg-3000 mg/day, maximum 50 weeks including initial up titration of 500 mg/day for 2 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    Levetiracetam
    Investigational medicinal product code
    LEV
    Other name
    Keppra
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    250 mg and 500 mg Levetiracetam tablet, 1000 mg-3000 mg/day, maximum 50 weeks including initial up titration of 500 mg/day for 2 weeks

    Arm title
    Oxcarbazepine
    Arm description
    Oxcarbazepine twice a day treatment Group 150 mg and 300 mg Oxcarbazepine tablet, 900 mg-2400 mg/day, maximum 50 weeks including 2 weeks of up titration (300 mg/day 1 week then 600 mg/day 1 week)
    Arm type
    Active comparator

    Investigational medicinal product name
    Oxcarbazepine
    Investigational medicinal product code
    OXC
    Other name
    Trileptal
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    150 mg and 300 mg Oxcarbazepine tablet, 900 mg-2400 mg/day, maximum 50 weeks including 2 weeks of up titration (300 mg/day 1 week then 600 mg/day 1 week)

    Number of subjects in period 1
    Levetiracetam Oxcarbazepine
    Started
    175
    178
    Completed
    121
    122
    Not completed
    54
    56
         Other Reason
    5
    2
         Protocol deviation
    8
    4
         Lack of efficacy
    7
    2
         SAE, non-fatal
    2
    2
         Adverse event, serious fatal
    1
    1
         AE, non-serious non-fatal
    8
    17
         Consent withdrawn by subject
    15
    25
         Lost to follow-up
    8
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Levetiracetam
    Reporting group description
    Levetiracetam twice a day treatment Group 250 mg and 500 mg Levetiracetam tablet, 1000 mg-3000 mg/day, maximum 50 weeks including initial up titration of 500 mg/day for 2 weeks

    Reporting group title
    Oxcarbazepine
    Reporting group description
    Oxcarbazepine twice a day treatment Group 150 mg and 300 mg Oxcarbazepine tablet, 900 mg-2400 mg/day, maximum 50 weeks including 2 weeks of up titration (300 mg/day 1 week then 600 mg/day 1 week)

    Reporting group values
    Levetiracetam Oxcarbazepine Total
    Number of subjects
    175 178 353
    Age categorical
    Units: Subjects
        <=18 years
    14 13 27
        Between 18 and 65 years
    145 143 288
        >=65 years
    16 22 38
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    39.5 ± 16.7 42.7 ± 17.3 -
    Gender categorical
    Units: Subjects
        Female
    84 79 163
        Male
    91 99 190
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0
        Asian
    174 178 352
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    0 0 0
        White
    1 0 1
        More than one race
    0 0 0
        Unknown or Not Reported
    0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Levetiracetam
    Reporting group description
    Levetiracetam twice a day treatment Group 250 mg and 500 mg Levetiracetam tablet, 1000 mg-3000 mg/day, maximum 50 weeks including initial up titration of 500 mg/day for 2 weeks

    Reporting group title
    Oxcarbazepine
    Reporting group description
    Oxcarbazepine twice a day treatment Group 150 mg and 300 mg Oxcarbazepine tablet, 900 mg-2400 mg/day, maximum 50 weeks including 2 weeks of up titration (300 mg/day 1 week then 600 mg/day 1 week)

    Subject analysis set title
    Per Protocol Set (OXC treated subjects)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    150 mg and 300 mg Oxcarbazepine tablet, 900 mg-2400 mg/day, maximum 50 weeks including 2 weeks of up titration (300 mg/day 1 week then 600 mg/day 1 week)

    Subject analysis set title
    Per Protocol Set (LEV treated subjects)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    250 mg and 500 mg Levetiracetam tablet, 1000 mg-3000 mg/day, maximum 50 weeks including initial up titration of 500 mg/day for 2 weeks

    Subject analysis set title
    Full Analysis Set (OXC treated subjects)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    150 mg and 300 mg Oxcarbazepine tablet, 900 mg-2400 mg/day, maximum 50 weeks including 2 weeks of up titration (300 mg/day 1 week then 600 mg/day 1 week)

    Subject analysis set title
    Full Analysis Set (LEV treated subjects)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    250 mg and 500 mg Levetiracetam tablet, 1000 mg-3000 mg/day, maximum 50 weeks including initial up titration of 500 mg/day for 2 weeks

    Primary: Percentage of subjects with a treatment failure

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    End point title
    Percentage of subjects with a treatment failure
    End point description
    Treatment failure is defined as (1) Dropout due to related intolerable adverse event, lack of efficacy or need for addition of another Antiepileptic Drug (AED), or (2) need of a 1-step down-titration, within 50 weeks from the first dose of study medication.
    End point type
    Primary
    End point timeframe
    Week 0 (First Dose) to Week 50
    End point values
    Per Protocol Set (OXC treated subjects) Per Protocol Set (LEV treated subjects)
    Number of subjects analysed
    128
    118
    Units: percentage of subjects
    number (not applicable)
        percentage of subjects
    23.4
    12.7
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Per Protocol Set (LEV treated subjects) v Per Protocol Set (OXC treated subjects)
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    Method
    Wald methodology
    Parameter type
    Absolut difference
    Point estimate
    -10.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -20.2
         upper limit
    -1.2
    Notes
    [1] - The primary analysis of this study aimed to demonstrate that LEV was noninferior to OXC with respect to the treatment failure rate in the Per Protocol Set. The noninferiority margin was 15 %.

    Secondary: Time to the first seizure defined as the time from the first dose of medication to the occurrence of the first seizure during the 48 weeks Treatment Period

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    End point title
    Time to the first seizure defined as the time from the first dose of medication to the occurrence of the first seizure during the 48 weeks Treatment Period
    End point description
    Dispersion measures for the statistic were not part of the analysis (or it’s specification). Kaplan-Meier estimation of percentage of event-free subjects does not fall to or below 50 %, therefore no median time to event could be estimated for the OXC Group.
    End point type
    Secondary
    End point timeframe
    From Week 2 to Week 50 (During Treatment Period )
    End point values
    Full Analysis Set (OXC treated subjects) Full Analysis Set (LEV treated subjects)
    Number of subjects analysed
    171 [2]
    173 [3]
    Units: months
    median (full range (min-max))
        Median (Full Range)
    99 (-999 to 999)
    7.556 (-999 to 999)
    Notes
    [2] - -999/99/999 = not estimable
    [3] - -999/999 = Dispersion measures not part of the analysis
    No statistical analyses for this end point

    Secondary: Percentage of subjects who achieved seizure freedom for 24 consecutive weeks during the 48 weeks Treatment Period at any time

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    End point title
    Percentage of subjects who achieved seizure freedom for 24 consecutive weeks during the 48 weeks Treatment Period at any time
    End point description
    24-week Seizure Freedom (rate) defined as the number and percentage of subjects who achieved seizure freedom for 24 consecutive weeks during the Treatment Period at any time
    End point type
    Secondary
    End point timeframe
    From Week 2 to Week 50 (During Treatment Period )
    End point values
    Full Analysis Set (OXC treated subjects) Full Analysis Set (LEV treated subjects)
    Number of subjects analysed
    171
    173
    Units: percentage of subjects
    number (not applicable)
        percentage of subjects
    58.5
    53.8
    No statistical analyses for this end point

    Secondary: Percentage of subjects who achieved seizure freedom during the 48 weeks Treatment Period

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    End point title
    Percentage of subjects who achieved seizure freedom during the 48 weeks Treatment Period
    End point description
    48-week Seizure Freedom (rate) defined as the number and percentage of subjects who achieved seizure freedom during the Treatment Period
    End point type
    Secondary
    End point timeframe
    From Week 2 to Week 50 (During Treatment Period )
    End point values
    Full Analysis Set (OXC treated subjects) Full Analysis Set (LEV treated subjects)
    Number of subjects analysed
    171
    173
    Units: percentage of subjects
    number (not applicable)
        percentage of subjects
    40.9
    34.7
    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 up to 57 Weeks from Visit 1 (Week -1) to the end of the post-treatment period (down-titration visit, safety follow-up visit).
    Adverse event reporting additional description
    Adverse Events refer to the Safety Set (SS). SS consisted of all subjects who were randomized and received at least 1 (partial) dose of study medication.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Oxcarbazepine
    Reporting group description
    Oxcarbazepine twice a day treatment Group 150 mg and 300 mg Oxcarbazepine tablet, 900 mg-2400 mg/day, maximum 50 weeks including 2 weeks of up titration (300 mg/day 1 week then 600 mg/day 1 week)

    Reporting group title
    Levetiracetam
    Reporting group description
    Levetiracetam twice a day treatment Group 250 mg and 500 mg Levetiracetam tablet, 1000 mg-3000 mg/day, maximum 50 weeks including initial up titration of 500 mg/day for 2 weeks

    Serious adverse events
    Oxcarbazepine Levetiracetam
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 174 (8.62%)
    15 / 173 (8.67%)
         number of deaths (all causes)
    2
    1
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Fibula fracture
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Comminuted fracture
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    1 / 174 (0.57%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    2 / 174 (1.15%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Upper airway obstruction
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    5 / 174 (2.87%)
    4 / 173 (2.31%)
         occurrences causally related to treatment / all
    0 / 5
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 174 (0.57%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Endometriosis
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    0 / 174 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 174 (0.57%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 174 (0.57%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    Oxcarbazepine Levetiracetam
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    93 / 174 (53.45%)
    67 / 173 (38.73%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    36 / 174 (20.69%)
    25 / 173 (14.45%)
         occurrences all number
    53
    29
    Dizziness
         subjects affected / exposed
    50 / 174 (28.74%)
    25 / 173 (14.45%)
         occurrences all number
    70
    30
    Somnolence
         subjects affected / exposed
    24 / 174 (13.79%)
    22 / 173 (12.72%)
         occurrences all number
    30
    30
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    13 / 174 (7.47%)
    3 / 173 (1.73%)
         occurrences all number
    16
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    19 / 174 (10.92%)
    14 / 173 (8.09%)
         occurrences all number
    21
    15

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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