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    Clinical Trial Results:
    A multicenter, randomized, double-blind, placebo-controlled, parallel study to evaluate the efficacy and safety of brivaracetam used as adjunctive treatment for 12 weeks in adolescent and adult patients (>=16 years) with genetically ascertained Unverricht-Lundborg disease

    Summary
    EudraCT number
    2006-001536-46
    Trial protocol
    FR   FI  
    Global end of trial date
    08 Jan 2008

    Results information
    Results version number
    v1(current)
    This version publication date
    31 Mar 2016
    First version publication date
    31 Mar 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    N01236
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00368251
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB Pharma SA
    Sponsor organisation address
    Chemin du Foriest, Braine-l'Alleud, Belgium, 1420
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Mar 2008
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jan 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to compare the efficacy of Brivaracetam 5 and 150 mg/day in bid administration with Placebo, on the symptom relief of Action Myoclonus in patients with Unverricht-Lundborg disease (ULD).
    Protection of trial subjects
    Standard safety measures to minimize pain and distress
    Background therapy
    Not applicable
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    07 Nov 2006
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    10 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Finland: 9
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Russian Federation: 8
    Country: Number of subjects enrolled
    Serbia: 6
    Country: Number of subjects enrolled
    Tunisia: 5
    Country: Number of subjects enrolled
    United States: 9
    Worldwide total number of subjects
    56
    EEA total number of subjects
    17
    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)
    2
    Adults (18-64 years)
    54
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    72 subjects were screened, 56 subjects were randomized.

    Pre-assignment
    Screening details
    Participant Flow refers to all subjects randomized who are identical with the Intent-To-Treat (ITT) Population, which consists of all randomized subjects who took at least one dose of study medication.

    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
    Investigator, Carer, Subject, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Placebo twice a day (bid), 14 weeks (2 week Up-Titration Period + 12 week Maintenance Period)
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PBO
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching Placebo Tablets

    Arm title
    Brivaracetam 5 mg/day
    Arm description
    Brivaracetam (BRV) 5 mg/day 2.5 mg twice a day (bid) using 2.5 mg tablets for 12 weeks (after 2 week Up- Titration Period)
    Arm type
    Experimental

    Investigational medicinal product name
    Brivaracetam
    Investigational medicinal product code
    BRV
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BRV 5 mg: oral tablet of 2.5 mg BRV 150 mg: oral tablet of 25 mg and 50 mg

    Arm title
    Brivaracetam 150 mg/day
    Arm description
    Brivaracetam (BRV) 150 mg/day 75 mg twice a day (bid) using 25 mg and 50 mg tablets for 12 weeks (after 2 week Up-Titration Period)
    Arm type
    Experimental

    Investigational medicinal product name
    Brivaracetam
    Investigational medicinal product code
    BRV
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BRV 5 mg: oral tablet of 2.5 mg BRV 150 mg: oral tablet of 25 mg and 50 mg

    Number of subjects in period 1
    Placebo Brivaracetam 5 mg/day Brivaracetam 150 mg/day
    Started
    18
    20
    18
    Completed
    17
    20
    17
    Not completed
    1
    0
    1
         SAE, non-fatal
    1
    -
    -
         AE, non-serious non-fatal
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo twice a day (bid), 14 weeks (2 week Up-Titration Period + 12 week Maintenance Period)

    Reporting group title
    Brivaracetam 5 mg/day
    Reporting group description
    Brivaracetam (BRV) 5 mg/day 2.5 mg twice a day (bid) using 2.5 mg tablets for 12 weeks (after 2 week Up- Titration Period)

    Reporting group title
    Brivaracetam 150 mg/day
    Reporting group description
    Brivaracetam (BRV) 150 mg/day 75 mg twice a day (bid) using 25 mg and 50 mg tablets for 12 weeks (after 2 week Up-Titration Period)

    Reporting group values
    Placebo Brivaracetam 5 mg/day Brivaracetam 150 mg/day Total
    Number of subjects
    18 20 18 56
    Age Categorical
    Units: Subjects
        <=18 years
    0 1 1 2
        Between 18 and 65 years
    18 19 17 54
        >=65 years
    0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    34.3 ± 9.2 35.8 ± 10.9 33.7 ± 11.4 -
    Gender Categorical
    Units: Subjects
        Female
    12 11 9 32
        Male
    6 9 9 24
    Region of Enrollment
    Units: Subjects
        Serbia
    2 2 2 6
        France
    3 2 3 8
        United States
    2 3 4 9
        Canada
    4 3 2 9
        Finland
    3 4 2 9
        Russian Federation
    2 3 3 8
        Israel
    0 0 2 2
        Tunisia
    2 3 0 5

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo twice a day (bid), 14 weeks (2 week Up-Titration Period + 12 week Maintenance Period)

    Reporting group title
    Brivaracetam 5 mg/day
    Reporting group description
    Brivaracetam (BRV) 5 mg/day 2.5 mg twice a day (bid) using 2.5 mg tablets for 12 weeks (after 2 week Up- Titration Period)

    Reporting group title
    Brivaracetam 150 mg/day
    Reporting group description
    Brivaracetam (BRV) 150 mg/day 75 mg twice a day (bid) using 25 mg and 50 mg tablets for 12 weeks (after 2 week Up-Titration Period)

    Primary: Percent change from Baseline to the End of Treatment Period on the Action Myoclonus Score (Unified Myoclonus Rating Scale (UMRS) Section 4)

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    End point title
    Percent change from Baseline to the End of Treatment Period on the Action Myoclonus Score (Unified Myoclonus Rating Scale (UMRS) Section 4)
    End point description
    The range for Action Myoclonus Score (centrally read) is 0 (best) - 160 (worst). Percent change from Baseline = 100 X ((Baseline UMRS4 - Treatment UMRS4) / Baseline UMRS4). Baseline is defined as the last non-missing value prior to or on Randomization Visit.
    End point type
    Primary
    End point timeframe
    From Baseline to End of Treatment Period (Week 14 or Early Discontinuation Visit)
    End point values
    Placebo Brivaracetam 5 mg/day Brivaracetam 150 mg/day
    Number of subjects analysed
    18
    20
    18
    Units: Percent Reduction
    median (full range (min-max))
        median (full range)
    17.45 (-170 to 61.5)
    -4.6 (-430 to 81.8)
    12.34 (-58.3 to 96.9)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The first hypothesis for the primary efficacy variable compares placebo versus Brivaracetam (BRV) 150 mg/day. The second hypothesis for the primary efficacy variable compares placebo versus BRV 5 mg/day. However, this second hypothesis will only be tested when all the hypotheses for placebo versus BRV 150 mg/day are significant for the primary three UMRS related secondary endpoints. The hypotheses will be tested using nonparametric analysis. The study was designed to have 80 % power.
    Comparison groups
    Placebo v Brivaracetam 150 mg/day
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.942
    Method
    stratified Wilcoxon Test
    Parameter type
    Hodges-Lehmann-estimator of difference
    Point estimate
    0.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -26.12
         upper limit
    24.96
    Notes
    [1] - All hypotheses are tested at the 5 % level. The multiplicity scheme (hierarchical testing procedure) assures strong control of the type I error at the 5 % level.
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Brivaracetam 5 mg/day
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    = 0.105
    Method
    stratified Wilcoxon Test
    Parameter type
    Hodges-Lehmann-estimator of difference
    Point estimate
    -18.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -39.31
         upper limit
    4.86
    Notes
    [2] - Tested at the 5 % level - given the primary endpoint and the three UMRS related secondary endpoints comparing placebo versus Brivaracetam (BRV) 150 mg/day are significant at the 5 % level (hierarchical testing procedure).

    Secondary: Percent change from Baseline to the end of Treatment Period on the Functional Disability Score (Unified Myoclonus Rating Scale (UMRS) Section 5)

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    End point title
    Percent change from Baseline to the end of Treatment Period on the Functional Disability Score (Unified Myoclonus Rating Scale (UMRS) Section 5)
    End point description
    The range for Functional Disability Score is 0 (best) to 28 (worst). Percent change from Baseline = 100 X ((Baseline UMRS5 - Treatment UMRS5) / Baseline UMRS5). Baseline is defined as the last non-missing value prior to or on Randomization Visit.
    End point type
    Secondary
    End point timeframe
    Baseline to End of Treatment Period (Week 14 or Early Discontinuation Visit)
    End point values
    Placebo Brivaracetam 5 mg/day Brivaracetam 150 mg/day
    Number of subjects analysed
    18
    20
    18
    Units: Percent Reduction
    median (full range (min-max))
        median (full range)
    0 (-380 to 53.8)
    0 (-380 to 60)
    0 (-85.7 to 75)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    If primary efficacy is proven for Brivaracetam (BRV) 150 mg/day, the following secondary endpoints will be tested for Placebo versus BRV 150 mg/day. The testing scheme will be hierarchical, thus statistical significance at 5 % on BRV 150 mg/day on a secondary endpoint is needed to continue testing BRV 150 mg/day at 5 % significance level for the next secondary endpoint.
    Comparison groups
    Placebo v Brivaracetam 150 mg/day
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.672
    Method
    stratified Wilcoxon Test
    Parameter type
    Hodges-Lehmann-estimator of difference
    Point estimate
    1.24
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -21.9
         upper limit
    31.06
    Notes
    [3] - Tested at the 5 % level - given the Primary Outcome testing Placebo versus BRV 150 mg/day is significant at the 5 % level (hierarchical testing procedure).
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    In case the three endpoints are significant for placebo versus Brivaracetam (BRV) 150 mg/day, the primary endpoint will be tested for Placebo versus BRV 5 mg/day. In case of significance, the three UMRS related secondary endpoints will be tested for Placebo versus BRV 5 mg/day, provided the previous is significant at 5 %. Secondary endpoints are tested in the following order: - Functional Disability - Stimulus Sensitivity - Myoclonus Patient Questionnaire
    Comparison groups
    Placebo v Brivaracetam 5 mg/day
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    = 0.806
    Method
    stratified Wilcoxon Test
    Parameter type
    Hodges-Lehmann-estimator of difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -33.33
         upper limit
    18.75
    Notes
    [4] - Tested at the 5 % level - given the primary endpoint testing Placebo versus Brivaracetam (BRV) 5 mg/day is significant at the 5 % level (hierarchical testing procedure).

    Secondary: Percent change from Baseline to the end of Treatment Period on the Stimulus Sensitivity Score (Unified Myoclonus Rating Scale (UMRS) Section 3)

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    End point title
    Percent change from Baseline to the end of Treatment Period on the Stimulus Sensitivity Score (Unified Myoclonus Rating Scale (UMRS) Section 3)
    End point description
    The range for Stimulus Sensitivity Score is 0 (best) to 17 (worst). Percent change from Baseline = 100 X ((Baseline UMRS3 - Treatment UMRS3) / Baseline UMRS3). Baseline is defined as the last non-missing value prior to or on Randomization Visit.
    End point type
    Secondary
    End point timeframe
    Baseline to End of Treatment Period (Week 14 or Early Discontinuation Visit)
    End point values
    Placebo Brivaracetam 5 mg/day Brivaracetam 150 mg/day
    Number of subjects analysed
    18
    20
    18
    Units: Percent Reduction
    median (full range (min-max))
        median (full range)
    0 (-300 to 100)
    43.44 (-300 to 100)
    0 (-300 to 100)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Brivaracetam 150 mg/day
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    = 0.549
    Method
    stratified Willcoxon Test
    Parameter type
    Hodges-Lehmann-estimator of difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -25
         upper limit
    100
    Notes
    [5] - Tested at the 5 % level - given the Functional Disability Score comparing Placebo versus Brivaracetam (BRV) 5 mg/day is significant at the 5 % level (hierarchical testing procedure).
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Brivaracetam 5 mg/day
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    = 0.654
    Method
    stratified Wilcoxon Test
    Parameter type
    Hodges-Lehmann-estimator of difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -50
         upper limit
    66.67
    Notes
    [6] - Tested at the 5 % level - given the Functional Disability Score comparing Placebo versus Brivaracetam (BRV) 5 mg/day is significant at the 5 % level (hierarchical testing procedure).

    Secondary: Percent change from Baseline to the end of Treatment Period on the Myoclonus Patient Questionnaire (Unified Myoclonus Rating Scale (UMRS) Section 1)

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    End point title
    Percent change from Baseline to the end of Treatment Period on the Myoclonus Patient Questionnaire (Unified Myoclonus Rating Scale (UMRS) Section 1)
    End point description
    The range for Myoclonus Patient Questionnaire is 0 (best) to 44 (worst). Percent change from Baseline = 100 X ((Baseline UMRS1 - Treatment UMRS1) / Baseline UMRS1). Baseline is defined as the last non-missing value prior to or on Randomization Visit.
    End point type
    Secondary
    End point timeframe
    Baseline to End of Treatment Period (Week 14 or Early Discontinuation Visit)
    End point values
    Placebo Brivaracetam 5 mg/day Brivaracetam 150 mg/day
    Number of subjects analysed
    17
    20
    18
    Units: Percent Reduction
    median (full range (min-max))
        median (full range)
    -9.68 (-125 to 63)
    0 (-95 to 55.6)
    5.41 (-24 to 100)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Brivaracetam 150 mg/day
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.037
    Method
    stratified Wilcoxon Test
    Parameter type
    Hodges-Lehmann-estimator of difference
    Point estimate
    14.29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.76
         upper limit
    39.39
    Notes
    [7] - Tested at the 5 % level - given the Functional Disability Score comparing Placebo versus Brivaracetam (BRV) 150 mg/day is significant at the 5 % level (hierarchical testing procedure).
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Brivaracetam 5 mg/day
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    superiority [8]
    P-value
    = 0.111
    Method
    stratified Wilcoxon Test
    Parameter type
    Hodges-Lehmann-estimator of difference
    Point estimate
    10
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.56
         upper limit
    30
    Notes
    [8] - Tested at the 5 % level - given the Functional Disability Score comparing Placebo versus Brivaracetam (BRV) 5 mg/day is significant at the 5 % level (hierarchical testing procedure).

    Secondary: Global Evaluation Score (Investigator) at the end of Treatment Period

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    End point title
    Global Evaluation Score (Investigator) at the end of Treatment Period
    End point description
    The Global Evaluation Scale Score (Investigator) ranges from 1 (Marked worsening) to 7 (Marked improvement).
    End point type
    Secondary
    End point timeframe
    End of Treatment Period (Week 14 or Early Discontinuation Visit)
    End point values
    Placebo Brivaracetam 5 mg/day Brivaracetam 150 mg/day
    Number of subjects analysed
    18
    20
    18
    Units: percentage of participants
    number (not applicable)
        Marked improvement
    0
    10
    11.1
        Moderate improvement
    11.1
    0
    11.1
        Slight improvement
    33.3
    30
    33.3
        No change
    50
    50
    33.3
        Slight worsening
    0
    10
    5.6
        Moderate worsening
    0
    0
    5.6
        Marked worsening
    5.6
    0
    0
    Statistical analysis title
    Statistical Analysis 2
    Comparison groups
    Placebo v Brivaracetam 150 mg/day
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.253 [10]
    Method
    Stratified Wilcoxon test
    Confidence interval
    Notes
    [9] - P-value for pairwise comparison of each Brivaracetam dose versus Placebo.
    [10] - The Global Evaluation Scale by Investigator (I-GES) was compared between placebo and each dose at 5 % significance level independently from the previous secondary endpoints.
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Placebo v Brivaracetam 5 mg/day
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    = 0.931
    Method
    Stratified Wilcoxon test
    Confidence interval
    Notes
    [11] - The Global Evaluation Scale by Investigator (I-GES) was compared between placebo and each dose at 5 % significance level independently from the previous secondary endpoints

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) were collected from Visit 1 (Week -2) until final Visit 10 (Week 18).
    Adverse event reporting additional description
    The Intent-To-Treat (ITT) population consists of all randomized subjects who took at least one dose of study medication.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    9.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo twice a day (bid), 14 weeks (2 week Up-Titration Period + 12 week Maintenance Period)

    Reporting group title
    Brivaracetam 150 mg/day
    Reporting group description
    Brivaracetam (BRV) 150 mg/day 75 mg twice a day (bid) using 25 mg and 50 mg tablets for 12 weeks (after 2 week Up-Titration Period)

    Reporting group title
    Brivaracetam 5 mg/day
    Reporting group description
    Brivaracetam (BRV) 5 mg/day 2.5 mg twice a day (bid) using 2.5 mg tablets for 12 weeks (after 2 week Up- Titration Period)

    Serious adverse events
    Placebo Brivaracetam 150 mg/day Brivaracetam 5 mg/day
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 18 (11.11%)
    2 / 18 (11.11%)
    3 / 20 (15.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myoclonic epilepsy
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Attention-seeking behavior
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 20 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Placebo Brivaracetam 150 mg/day Brivaracetam 5 mg/day
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 18 (72.22%)
    15 / 18 (83.33%)
    13 / 20 (65.00%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 18 (11.11%)
    3 / 18 (16.67%)
    1 / 20 (5.00%)
         occurrences all number
    2
    6
    1
    Oedema peripheral
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    0
    Pyrexia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    1
    0
    2
    Insomnia
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    2
    0
    2
    Anxiety
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    1
    1
    0
    Depression
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    1
    Bradyphrenia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Depressed mood
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Disorientation
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Memory impairment
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Reproductive system and breast disorders
    Genital pruritus female
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Injury, poisoning and procedural complications
    Excoriation
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Joint injury
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Limb injury
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Joint sprain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Electrocardiogram QT corrected interval prolonged
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Sinus congestion
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Upper respiratory tract congestion
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Granulocytopenia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Lymphadenopathy
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    0
    2
    0
    Nervous system disorders
    Myoclonus
         subjects affected / exposed
    1 / 18 (5.56%)
    3 / 18 (16.67%)
    4 / 20 (20.00%)
         occurrences all number
    2
    4
    4
    Somnolence
         subjects affected / exposed
    2 / 18 (11.11%)
    4 / 18 (22.22%)
    3 / 20 (15.00%)
         occurrences all number
    2
    7
    3
    Headache
         subjects affected / exposed
    7 / 18 (38.89%)
    2 / 18 (11.11%)
    3 / 20 (15.00%)
         occurrences all number
    8
    2
    4
    Balance disorder
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 18 (11.11%)
    1 / 20 (5.00%)
         occurrences all number
    0
    4
    1
    Dizziness
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    1
    Grand mal convulsion
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    0
    2
    Hyporeflexia
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 18 (11.11%)
    0 / 20 (0.00%)
         occurrences all number
    0
    2
    0
    Complex partial seizures
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Coordination abnormal
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Migraine
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    0
    3
    0
    Dysarthria
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    1
    2
    0
    Nystagmus
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Tremor
         subjects affected / exposed
    3 / 18 (16.67%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    4
    1
    0
    Convulsion
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Myoclonic epilepsy
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Sciatica
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    1
    Middle ear inflammation
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    2 / 20 (10.00%)
         occurrences all number
    1
    1
    2
    Abdominal pain upper
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    2
    0
    2
    Diarrhoea
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    3
    1
    1
    Abdominal pain
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    3
    1
    0
    Constipation
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    2
    1
    0
    Gingival bleeding
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Toothache
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    Enuresis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Pollakiuria
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Ecchymosis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Ingrowing nail
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Dry skin
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Night sweats
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Skin ulcer
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    1
    1
    1
    Arthralgia
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    1
    2
    0
    Arthritis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Back pain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    0
    2
    0
    Shoulder pain
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    1
    1
    0
    Metabolism and nutrition disorders
    Weight decreased
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    1
    Anorexia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Increased appetite
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Weight increased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    0
    3
    1
    Nasopharyngitis
         subjects affected / exposed
    3 / 18 (16.67%)
    1 / 18 (5.56%)
    1 / 20 (5.00%)
         occurrences all number
    4
    1
    1
    Gastrointestinal infection
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    1
    0
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Otitis externa
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    3
    0
    0
    Pharyngitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Sinusitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Feb 2007
    Allowed two study visits (Visit 3 and Visit 8) to be performed by telephone, where appropriate.
    20 Mar 2007
    Adaptation of the hypothesis testing strategy for dealing with multiple endpoints and multiple doses. The sample size calculations assumptions were corrected. It was specified that the primary efficacy analysis will be performed adding in a covariate for the stratification factor used in the randomization process, and some adjustments and additions to the sensitivity analyses for the primary efficacy analysis were provided. Stimulus sensitivity was added to the secondary objectives. Inconsistency between secondary objectives and secondary endpoints was corrected.

    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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