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    Clinical Trial Results:
    A Multi-center, Double-blind, Parallel-group, Placebo-Controlled, Randomized Study: Evaluation of the Efficacy and Safety of Brivaracetam in Subjects (>= 16 to 70 Years Old) With Partial Onset Seizures

    Summary
    EudraCT number
    2006-006344-59
    Trial protocol
    BE   NL   FR   GB   HU   FI   IT   DE   ES  
    Global end of trial date
    09 Feb 2009

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Oct 2016
    First version publication date
    22 Oct 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    N01252
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00490035
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB Pharma SA
    Sponsor organisation address
    Allée de la Recherche 60, Brussels, Belgium, B-1070
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Apr 2009
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Feb 2009
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate the efficacy of Brivaracetam (BRV) at doses of 20, 50, and 100 mg/day in reducing seizure frequency in subjects with partial onset seizures not fully controlled despite optimal treatment with 1 to 2 concomitant antiepileptic drug(s) (AED(s)), compared with Placebo (PBO).
    Protection of trial subjects
    Standard measures to minimize pain and distress.
    Background therapy
    Not applicable
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    10 Sep 2007
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    8 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Finland: 11
    Country: Number of subjects enrolled
    France: 60
    Country: Number of subjects enrolled
    Germany: 41
    Country: Number of subjects enrolled
    Hungary: 12
    Country: Number of subjects enrolled
    India: 91
    Country: Number of subjects enrolled
    Italy: 20
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Poland: 108
    Country: Number of subjects enrolled
    Spain: 22
    Country: Number of subjects enrolled
    Switzerland: 15
    Country: Number of subjects enrolled
    United Kingdom: 6
    Worldwide total number of subjects
    399
    EEA total number of subjects
    293
    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)
    5
    Adults (18-64 years)
    383
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study started to enroll subjects in September 2007 and concluded in February 2009.

    Pre-assignment
    Screening details
    Participant Flow refers to the Randomized Set.

    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, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Matching Placebo tablets administered twice a day
    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 to Brivaracetam tablets.

    Arm title
    Brivaracetam 20 mg/day
    Arm description
    Brivaracetam 20 mg/day, 10 mg administered twice a day
    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
    10 mg and 25 mg tablets. Two equal intakes, morning and evening, in a double-blinded way for the 12-week Treatment Period.

    Arm title
    Brivaracetam 50 mg/day
    Arm description
    Brivaracetam 50 mg/day, 25 mg administered twice a day
    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
    10 mg and 25 mg tablets. Two equal intakes, morning and evening, in a double-blinded way for the 12-week Treatment Period.

    Arm title
    Brivaracetam 100 mg/day
    Arm description
    Brivaracetam 100 mg/day, 50 mg administered twice a day
    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
    10 mg and 25 mg tablets. Two equal intakes, morning and evening, in a double-blinded way for the 12-week Treatment Period.

    Number of subjects in period 1
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day
    Started
    100
    99
    100
    100
    Completed
    92
    93
    88
    94
    Not completed
    8
    6
    12
    6
         SAE, non-fatal
    -
    -
    1
    -
         Other reason
    -
    1
    3
    1
         AE, serious fatal
    1
    -
    -
    -
         AE of unknown type
    -
    -
    2
    -
         Consent withdrawn by subject
    2
    1
    1
    -
         AE, non-serious non-fatal
    3
    4
    4
    5
         Lost to follow-up
    2
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Matching Placebo tablets administered twice a day

    Reporting group title
    Brivaracetam 20 mg/day
    Reporting group description
    Brivaracetam 20 mg/day, 10 mg administered twice a day

    Reporting group title
    Brivaracetam 50 mg/day
    Reporting group description
    Brivaracetam 50 mg/day, 25 mg administered twice a day

    Reporting group title
    Brivaracetam 100 mg/day
    Reporting group description
    Brivaracetam 100 mg/day, 50 mg administered twice a day

    Reporting group values
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day Total
    Number of subjects
    100 99 100 100 399
    Age Categorical
    Units: Subjects
        <18 years
    2 2 0 1 5
        Between 18 and 65 years
    96 94 97 96 383
        >=65 years
    2 3 3 3 11
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    36.4 ± 13 35.7 ± 12.5 39 ± 13.5 38 ± 13.1 -
    Gender Categorical
    Units: Subjects
        Female
    46 38 45 42 171
        Male
    54 61 55 58 228
    Region of Enrollment
    Units: Subjects
        Hungary
    4 2 3 3 12
        Poland
    26 28 27 27 108
        India
    23 22 23 23 91
        Belgium
    3 0 3 0 6
        Finland
    3 3 1 4 11
        France
    17 17 11 15 60
        Germany
    8 10 14 9 41
        Italy
    4 8 3 5 20
        Netherlands
    3 0 1 3 7
        Spain
    8 4 6 4 22
        Switzerland
    1 3 6 5 15
        United Kingdom
    0 2 2 2 6

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Matching Placebo tablets administered twice a day

    Reporting group title
    Brivaracetam 20 mg/day
    Reporting group description
    Brivaracetam 20 mg/day, 10 mg administered twice a day

    Reporting group title
    Brivaracetam 50 mg/day
    Reporting group description
    Brivaracetam 50 mg/day, 25 mg administered twice a day

    Reporting group title
    Brivaracetam 100 mg/day
    Reporting group description
    Brivaracetam 100 mg/day, 50 mg administered twice a day

    Primary: Partial Onset Seizure (Type I) frequency per week over the 12-week Treatment Period

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    End point title
    Partial Onset Seizure (Type I) frequency per week over the 12-week Treatment Period
    End point description
    Partial (Type I) Seizures can be classified into one of the following three groups: Simple Partial Seizures, Complex Partial Seizures, Partial Seizures evolving to Secondarily Generalized Seizures.
    End point type
    Primary
    End point timeframe
    From Baseline to 12-week Treatment Period
    End point values
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day
    Number of subjects analysed
    100
    99
    99
    100
    Units: Seizure Frequency per Week
    median (inter-quartile range (Q1-Q3))
        Median (Q1-Q3)
    1.75 (0.76 to 5.12)
    1.34 (0.7 to 3.12)
    1.49 (0.69 to 2.78)
    1.26 (0.52 to 2.93)
    Statistical analysis title
    BRV 50 mg/day versus PBO
    Statistical analysis description
    In order to control the Type I error testing was performed in sequence starting with 50 mg, then 100 mg and finally 20 mg Brivaracetam per day versus Placebo, only moving to the next test if the previous one was significant at the 5 % level.
    Comparison groups
    Placebo v Brivaracetam 50 mg/day
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.261
    Method
    ANCOVA
    Parameter type
    Percentage Reduction over Placebo
    Point estimate
    6.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.2
         upper limit
    16.9

    Secondary: Responder rate for partial onset seizures (Type I) frequency per week over the 12-week Treatment Period

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    End point title
    Responder rate for partial onset seizures (Type I) frequency per week over the 12-week Treatment Period
    End point description
    Responders are those subjects with at least 50 % reduction from Baseline to Treatment Period in Partial Onset Seizure frequency per week. The Responder Rate for Partial Onset Seizures (Type I) is the proportion of subjects who have a >= 50 % reduction in seizure frequency per week from Baseline.
    End point type
    Secondary
    End point timeframe
    From Baseline to 12-week Treatment Period
    End point values
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day
    Number of subjects analysed
    100
    99
    99
    100
    Units: Percentage of Participants
    number (not applicable)
        Non-responders
    80
    72.7
    72.7
    64
        Responders
    20
    27.3
    27.3
    36
    No statistical analyses for this end point

    Secondary: All seizure frequency (Type I+II+III) per week over the 12-week Treatment Period

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    End point title
    All seizure frequency (Type I+II+III) per week over the 12-week Treatment Period
    End point description
    There are three types of Epilepsy: Partial Epilepsies (Type I), Generalized Epilepsies (Type II) and uncertain classification of Epilepsies (Type III).
    End point type
    Secondary
    End point timeframe
    From Baseline to 12-week Treatment Period
    End point values
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day
    Number of subjects analysed
    100
    99
    99
    100
    Units: Times per week
    median (inter-quartile range (Q1-Q3))
        Median (Q1-Q3)
    1.75 (0.76 to 5.61)
    1.34 (0.7 to 3.12)
    1.49 (0.69 to 2.78)
    1.26 (0.52 to 2.93)
    No statistical analyses for this end point

    Secondary: Percent change from Baseline to the 12-week Treatment Period in Partial Onset Seizure (Type I) Frequency per week

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    End point title
    Percent change from Baseline to the 12-week Treatment Period in Partial Onset Seizure (Type I) Frequency per week
    End point description
    The percent change from Baseline was computed as: Weekly Seizure Frequency (Treatment) - Weekly Seizure Frequency (Baseline) / Weekly Seizure Frequency (Baseline) * 100. Negative values indicate a reduction from Baseline with higher negative values showing higher reduction.
    End point type
    Secondary
    End point timeframe
    From Baseline to 12-week Treatment Period
    End point values
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day
    Number of subjects analysed
    100
    99
    99
    100
    Units: Percent change in seizures per week
    median (inter-quartile range (Q1-Q3))
        Median (Q1-Q3)
    -17.03 (-40.27 to 17.59)
    -30.03 (-55.99 to -2.11)
    -26.83 (-60.05 to 6.32)
    -32.45 (-72.51 to 0.04)
    No statistical analyses for this end point

    Secondary: Categorized percentage change from Baseline in seizure frequency for Partial Onset Seizure (Type I) over the 12-week Treatment Period

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    End point title
    Categorized percentage change from Baseline in seizure frequency for Partial Onset Seizure (Type I) over the 12-week Treatment Period
    End point description
    The categories are: - <= 25 % - - 25 % to < 25 % - 25 % to < 50 % - 50 % to < 75 % - 75 % to < 100 % - 100 %
    End point type
    Secondary
    End point timeframe
    From Baseline to 12-week Treatment Period
    End point values
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day
    Number of subjects analysed
    100
    99
    99
    100
    Units: Percentage of Participants
    number (not applicable)
        <= 25 %
    19
    10.1
    15.2
    10
        - 25 % to < 25 %
    41
    35.4
    33.3
    33
        25 % to < 50 %
    20
    27.3
    24.2
    21
        50 % to < 75 %
    12
    18.2
    17.2
    14
        75 % to < 100 %
    8
    7.1
    9.1
    18
        100 %
    0
    2
    1
    4
    No statistical analyses for this end point

    Secondary: Seizure Freedom Rate (all seizure types) over the 12-week Treatment Period

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    End point title
    Seizure Freedom Rate (all seizure types) over the 12-week Treatment Period
    End point description
    Subjects were considered seizure free if their seizure counts for every day over the entire Treatment Period was zero and if they completed the Treatment Period.
    End point type
    Secondary
    End point timeframe
    From Baseline to 12-week Treatment Period
    End point values
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day
    Number of subjects analysed
    100
    99
    99
    100
    Units: Percentage of Participants
    number (not applicable)
        Seizure free
    0
    2
    0
    4
        No Seizures but non-completer
    0
    0
    1
    0
        Not Seizure-free
    100
    98
    99
    96
    No statistical analyses for this end point

    Secondary: Time to first Type I Seizure during the 12-week Treatment Period

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    End point title
    Time to first Type I Seizure during the 12-week Treatment Period
    End point description
    The time to first Type I Seizure during the 12-week Treatment Period was measured in days.
    End point type
    Secondary
    End point timeframe
    From Baseline to 12-week Treatment Period
    End point values
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day
    Number of subjects analysed
    100
    99
    99
    100
    Units: Days
    median (confidence interval 95%)
        Median (95 % CI)
    4 (3 to 5)
    6 (3 to 8)
    6 (4 to 10)
    4 (3 to 5)
    No statistical analyses for this end point

    Secondary: Time to Fifth Type I Seizure during the 12-week Treatment Period

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    End point title
    Time to Fifth Type I Seizure during the 12-week Treatment Period
    End point description
    The time to Fifth Type I Seizure during the 12-week Treatment Period was measured in days.
    End point type
    Secondary
    End point timeframe
    From Baseline to 12-week Treatment Period
    End point values
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day
    Number of subjects analysed
    100
    99
    99
    100
    Units: Days
    median (confidence interval 95%)
        Median (95 % CI)
    19 (14 to 25)
    25 (20 to 34)
    24 (20 to 32)
    24 (18 to 34)
    No statistical analyses for this end point

    Secondary: Time to tenth Type I seizure during the 12-week Treatment Period

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    End point title
    Time to tenth Type I seizure during the 12-week Treatment Period
    End point description
    The time to tenth Type I Seizure during the 12-week Treatment Period was measured in days.
    End point type
    Secondary
    End point timeframe
    From Baseline to 12-week Treatment Period
    End point values
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day
    Number of subjects analysed
    100
    99
    99
    100
    Units: Days
    median (confidence interval 95%)
        Median (95 % CI)
    39 (24 to 50)
    49 (36 to 64)
    40 (33 to 49)
    46 (34 to 66)
    No statistical analyses for this end point

    Secondary: Reduction of Type IC/Type I Seizure frequency ratio from Baseline to the 12- week Treatment Period.

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    End point title
    Reduction of Type IC/Type I Seizure frequency ratio from Baseline to the 12- week Treatment Period.
    End point description
    Reduction of Type IC/Type I Seizure frequency ratio from Baseline to the 12- week Treatment Period. This variable was not analyzed and no results are available.
    End point type
    Secondary
    End point timeframe
    From Baseline to 12-week Treatment Period
    End point values
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day
    Number of subjects analysed
    0 [1]
    0 [2]
    0 [3]
    0 [4]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Not applicable
    ±
    ±
    ±
    ±
    Notes
    [1] - This analysis was not performed as it was not needed for labeling purposes.
    [2] - This analysis was not performed as it was not needed for labeling purposes.
    [3] - This analysis was not performed as it was not needed for labeling purposes.
    [4] - This analysis was not performed as it was not needed for labeling purposes.
    No statistical analyses for this end point

    Secondary: Change from Baseline to the 12-week Treatment Period in Total Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score

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    End point title
    Change from Baseline to the 12-week Treatment Period in Total Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score
    End point description
    The QOLIE-31-P is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into seven multi-item subscales - Seizure Worry (5 items), Overall Quality of Life (2 items), Emotional Well-Being (5 items), Energy/Fatigue (4 items), Cognitive Functioning (6 items), Medication Effects (3 items) and Daily Activities/Social Functioning (5 items) - and a Health Status item. The subscale scores, the Total score and the Health Status item score are calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function. A positive value in Change from Baseline indicates an improvement from Baseline.
    End point type
    Secondary
    End point timeframe
    From Baseline to 12-week Treatment Period
    End point values
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day
    Number of subjects analysed
    86
    91
    94
    80
    Units: units on a scale
    arithmetic mean (standard deviation)
        Arithmetic Mean (Standard Deviation)
    2.29 ± 14.03
    4.5 ± 12.71
    3.09 ± 14.43
    1.78 ± 13.95
    No statistical analyses for this end point

    Secondary: Change from Baseline to the 12-week Treatment Period in Seizure Worry Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score

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    End point title
    Change from Baseline to the 12-week Treatment Period in Seizure Worry Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score
    End point description
    The QOLIE-31-P is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into seven multi-item subscales - Seizure Worry (5 items), Overall Quality of Life (2 items), Emotional Well-Being (5 items), Energy/Fatigue (4 items), Cognitive Functioning (6 items), Medication Effects (3 items) and Daily Activities/Social Functioning (5 items) - and a Health Status item. The subscale scores, the Total score and the Health Status item score are calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function. A positive value in Change from Baseline indicates an improvement from Baseline.
    End point type
    Secondary
    End point timeframe
    From Baseline to 12-week Treatment Period
    End point values
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day
    Number of subjects analysed
    88
    93
    96
    86
    Units: units on a scale
    arithmetic mean (standard deviation)
        Arithmetic Mean (Standard Deviation)
    8.25 ± 22.01
    6.23 ± 17.97
    5.34 ± 23.81
    8.04 ± 26.26
    No statistical analyses for this end point

    Secondary: Change from Baseline to the 12-week Treatment Period in Daily Activities/Social Functioning Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score

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    End point title
    Change from Baseline to the 12-week Treatment Period in Daily Activities/Social Functioning Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score
    End point description
    The QOLIE-31-P is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into seven multi-item subscales - Seizure Worry (5 items), Overall Quality of Life (2 items), Emotional Well-Being (5 items), Energy/Fatigue (4 items), Cognitive Functioning (6 items), Medication Effects (3 items) and Daily Activities/Social Functioning (5 items) - and a Health Status item. The subscale scores, the Total score and the Health Status item score are calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function. A positive value in Change from Baseline indicates an improvement from Baseline.
    End point type
    Secondary
    End point timeframe
    From Baseline to 12-week Treatment Period
    End point values
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day
    Number of subjects analysed
    88
    93
    96
    85
    Units: units on a scale
    arithmetic mean (standard deviation)
        Arithmetic Mean (Standard Deviation)
    -2.09 ± 20.26
    3.35 ± 19.72
    3.09 ± 20.79
    3.5 ± 22.52
    No statistical analyses for this end point

    Secondary: Change from Baseline to the 12-week Treatment Period in Hospital Anxiety Score

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    End point title
    Change from Baseline to the 12-week Treatment Period in Hospital Anxiety Score
    End point description
    The Hospital Anxiety and Depression Scale (HADS) was used to evaluate anxiety and depression simultaneously. The HADS was developed as a self-administered scale that has been designed to assess the presence and severity of both anxiety and depression. It consists of 14 items that are scored on a 4-point severity scale ranging from 0 to 3. A score per dimension was calculated with each score ranging from 0 to 21 and higher scores indicating higher depression / anxiety. Negative values in Change from Baseline indicate a decrease of HADS from Baseline to Treatment Period.
    End point type
    Secondary
    End point timeframe
    From Baseline to 12-week Treatment Period
    End point values
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day
    Number of subjects analysed
    86
    91
    95
    83
    Units: units on a scale
    arithmetic mean (standard deviation)
        Anxiety
    -1.54 ± 3.89
    -0.59 ± 3.89
    -0.41 ± 3.82
    0.08 ± 3.6
    No statistical analyses for this end point

    Secondary: Change from Baseline to the 12-week Treatment Period in Hospital Depression Score

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    End point title
    Change from Baseline to the 12-week Treatment Period in Hospital Depression Score
    End point description
    The Hospital Anxiety and Depression Scale (HADS) was used to evaluate anxiety and depression simultaneously. The HADS was developed as a self-administered scale that has been designed to assess the presence and severity of both anxiety and depression. It consists of 14 items that are scored on a 4-point severity scale ranging from 0 to 3. A score per dimension was calculated with each score ranging from 0 to 21 and higher scores indicating higher depression / anxiety. Negative values in Change from Baseline indicate a decrease of HADS from Baseline to Treatment Period.
    End point type
    Secondary
    End point timeframe
    From Baseline to 12-week Treatment Period
    End point values
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day
    Number of subjects analysed
    86
    91
    95
    83
    Units: units on a scale
    arithmetic mean (standard deviation)
        Depression
    -0.65 ± 3.58
    -0.1 ± 3.67
    0.26 ± 3.84
    -0.24 ± 3.69
    No statistical analyses for this end point

    Secondary: Patient's Global Evaluation Scale (P-GES) evaluated at Last Visit or Early Discontinuation Visit

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    End point title
    Patient's Global Evaluation Scale (P-GES) evaluated at Last Visit or Early Discontinuation Visit
    End point description
    The Patient's Global Evaluation Scale (P-GES) is a global assessment of the disease evolution which was performed using a seven-point scale (1 = Marked worsening to 7 = Marked improvement) with the start of the study medication as the reference time point. The subject not mentally impaired had to complete it by answering the following question: “Overall, has there been a change in your seizures since the start of the study medication?”
    End point type
    Secondary
    End point timeframe
    Last Visit or Early Discontinuation Visit in the 12-week Treatment Period
    End point values
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day
    Number of subjects analysed
    81
    90
    90
    85
    Units: units on a scale
    arithmetic mean (standard deviation)
        Arithmetic Mean (Standard Deviation)
    4.93 ± 1.39
    5.17 ± 1.27
    5.04 ± 1.29
    5.47 ± 1.16
    No statistical analyses for this end point

    Secondary: Investigator's Global Evaluation Scale (I-GES) evaluated at last visit or early discontinuation visit

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    End point title
    Investigator's Global Evaluation Scale (I-GES) evaluated at last visit or early discontinuation visit
    End point description
    The Investigator's Global Evaluation Scale (I-GES) is a global assessment of the disease evolution which was performed using a seven-point scale (1 = Marked worsening to 7 = Marked improvement), with the start of the study medication as reference time point. The Investigator was to complete it by answering the following question: “Assess the Overall change in the severity of patient’s illness, compared to start of study medication.”
    End point type
    Secondary
    End point timeframe
    Last Visit or Early Discontinuation Visit in the 12-week Treatment Period
    End point values
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day
    Number of subjects analysed
    96
    99
    98
    100
    Units: units on a scale
    arithmetic mean (standard deviation)
        Arithmetic Mean (Standard Deviation)
    4.78 ± 1.2
    4.99 ± 1.15
    4.99 ± 1.1
    5.34 ± 1.12
    No statistical analyses for this end point

    Secondary: Change from Baseline to the 12-week Treatment Period in Energy/Fatigue Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score

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    End point title
    Change from Baseline to the 12-week Treatment Period in Energy/Fatigue Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score
    End point description
    The QOLIE-31-P is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into seven multi-item subscales - Seizure Worry (5 items), Overall Quality of Life (2 items), Emotional Well-Being (5 items), Energy/Fatigue (4 items), Cognitive Functioning (6 items), Medication Effects (3 items) and Daily Activities/Social Functioning (5 items) - and a Health Status item. The subscale scores, the Total score and the Health Status item score are calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function. A positive value in Change from Baseline indicates an improvement from Baseline.
    End point type
    Secondary
    End point timeframe
    From Baseline to 12-week Treatment Period
    End point values
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day
    Number of subjects analysed
    86
    92
    95
    83
    Units: units on a scale
    arithmetic mean (standard deviation)
        Arithmetic Mean (Standard Deviation)
    3.49 ± 19.22
    3.53 ± 17.04
    1.95 ± 20.74
    1.99 ± 20.42
    No statistical analyses for this end point

    Secondary: Change from Baseline to the 12-week Treatment Period in Emotional Well-Being Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score

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    End point title
    Change from Baseline to the 12-week Treatment Period in Emotional Well-Being Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score
    End point description
    The QOLIE-31-P is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into seven multi-item subscales - Seizure Worry (5 items), Overall Quality of Life (2 items), Emotional Well-Being (5 items), Energy/Fatigue (4 items), Cognitive Functioning (6 items), Medication Effects (3 items) and Daily Activities/Social Functioning (5 items) - and a Health Status item. The subscale scores, the Total score and the Health Status item score are calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function. A positive value in Change from Baseline indicates an improvement from Baseline.
    End point type
    Secondary
    End point timeframe
    From Baseline to 12-week Treatment Period
    End point values
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day
    Number of subjects analysed
    88
    93
    96
    84
    Units: units on a scale
    arithmetic mean (standard deviation)
        Arithmetic Mean (Standard Deviation)
    3.8 ± 18.71
    3.75 ± 15.94
    3.13 ± 19.35
    -2.45 ± 18.55
    No statistical analyses for this end point

    Secondary: Change from Baseline to the 12-week Treatment Period in Cognitive Functioning Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score

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    End point title
    Change from Baseline to the 12-week Treatment Period in Cognitive Functioning Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score
    End point description
    The QOLIE-31-P is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into seven multi-item subscales - Seizure Worry (5 items), Overall Quality of Life (2 items), Emotional Well-Being (5 items), Energy/Fatigue (4 items), Cognitive Functioning (6 items), Medication Effects (3 items) and Daily Activities/Social Functioning (5 items) - and a Health Status item. The subscale scores, the Total score and the Health Status item score are calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function. A positive value in Change from Baseline indicates an improvement from Baseline.
    End point type
    Secondary
    End point timeframe
    From Baseline to 12-week Treatment Period
    End point values
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day
    Number of subjects analysed
    88
    93
    96
    85
    Units: units on a scale
    arithmetic mean (standard deviation)
        Arithmetic Mean (Standard Deviation)
    1.8 ± 19.16
    5.36 ± 20.69
    1.02 ± 19.95
    0.69 ± 16.66
    No statistical analyses for this end point

    Secondary: Change from Baseline to the 12-week Treatment Period in Medication Effects Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score

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    End point title
    Change from Baseline to the 12-week Treatment Period in Medication Effects Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score
    End point description
    The QOLIE-31-P is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into seven multi-item subscales - Seizure Worry (5 items), Overall Quality of Life (2 items), Emotional Well-Being (5 items), Energy/Fatigue (4 items), Cognitive Functioning (6 items), Medication Effects (3 items) and Daily Activities/Social Functioning (5 items) - and a Health Status item. The subscale scores, the Total score and the Health Status item score are calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function. A positive value in Change from Baseline indicates an improvement from Baseline.
    End point type
    Secondary
    End point timeframe
    From Baseline to 12-week Treatment Period
    End point values
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day
    Number of subjects analysed
    88
    92
    96
    86
    Units: units on a scale
    arithmetic mean (standard deviation)
        Arithmetic Mean (Standard Deviation)
    0.92 ± 28.93
    3.64 ± 29.24
    -0.85 ± 24.36
    3 ± 28.22
    No statistical analyses for this end point

    Secondary: Change from Baseline to the 12-week Treatment Period in Overall Quality of Life Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score

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    End point title
    Change from Baseline to the 12-week Treatment Period in Overall Quality of Life Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score
    End point description
    The QOLIE-31-P is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into seven multi-item subscales - Seizure Worry (5 items), Overall Quality of Life (2 items), Emotional Well-Being (5 items), Energy/Fatigue (4 items), Cognitive Functioning (6 items), Medication Effects (3 items) and Daily Activities/Social Functioning (5 items) - and a Health Status item. The subscale scores, the Total score and the Health Status item score are calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function. A positive value in Change from Baseline indicates an improvement from Baseline.
    End point type
    Secondary
    End point timeframe
    From Baseline to 12-week Treatment Period
    End point values
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day
    Number of subjects analysed
    88
    93
    95
    86
    Units: units on a scale
    arithmetic mean (standard deviation)
        Arithmetic Mean (Standard Deviation)
    5.11 ± 18.48
    4.52 ± 16.73
    4.55 ± 18.93
    2.24 ± 18.45
    No statistical analyses for this end point

    Secondary: Change from Baseline to the 12-week Treatment Period in Health Status of Life Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score

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    End point title
    Change from Baseline to the 12-week Treatment Period in Health Status of Life Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score
    End point description
    The QOLIE-31-P is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into seven multi-item subscales - Seizure Worry (5 items), Overall Quality of Life (2 items), Emotional Well-Being (5 items), Energy/Fatigue (4 items), Cognitive Functioning (6 items), Medication Effects (3 items) and Daily Activities/Social Functioning (5 items) - and a Health Status item. The subscale scores, the Total score and the Health Status item score are calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function. A positive value in Change from Baseline indicates an improvement from Baseline.
    End point type
    Secondary
    End point timeframe
    From Baseline to 12-week Treatment Period
    End point values
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day
    Number of subjects analysed
    88
    93
    95
    84
    Units: units on a scale
    arithmetic mean (standard deviation)
        Arithmetic Mean (Standard Deviation)
    6.6 ± 16.3
    6.9 ± 20.1
    9.7 ± 19.8
    4.9 ± 18.1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) were collected up to 23 weeks from Visit 1 (Week -8) to the Safety Visit (Week 15).
    Adverse event reporting additional description
    Adverse Events (AEs) refer to the Safety Set (SS) population wich contains the same set of subjects as the Itention-To-Treat (ITT) population.
    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
    Matching Placebo tablets administered twice a day

    Reporting group title
    Brivaracetam 20 mg/day
    Reporting group description
    Brivaracetam 20 mg/day, 10 mg administered twice a day

    Reporting group title
    Brivaracetam 50 mg/day
    Reporting group description
    Brivaracetam 50 mg/day, 25 mg administered twice a day

    Reporting group title
    Brivaracetam 100 mg/day
    Reporting group description
    Brivaracetam 100 mg/day, 50 mg administered twice a day

    Serious adverse events
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 100 (6.00%)
    2 / 99 (2.02%)
    4 / 99 (4.04%)
    2 / 100 (2.00%)
         number of deaths (all causes)
    1
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    0 / 99 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 99 (1.01%)
    0 / 99 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 99 (0.00%)
    0 / 99 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    3 / 100 (3.00%)
    0 / 99 (0.00%)
    1 / 99 (1.01%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    1 / 99 (1.01%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    0 / 99 (0.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion spontaneous
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 99 (1.01%)
    0 / 99 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 99 (0.00%)
    0 / 99 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis erosive
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    1 / 99 (1.01%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Amnesia
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    1 / 99 (1.01%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic Disorder
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    1 / 99 (1.01%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vaginal hemorrhage
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 99 (1.01%)
    0 / 99 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 99 (0.00%)
    0 / 99 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Brivaracetam 20 mg/day Brivaracetam 50 mg/day Brivaracetam 100 mg/day
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 100 (22.00%)
    31 / 99 (31.31%)
    35 / 99 (35.35%)
    37 / 100 (37.00%)
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 100 (1.00%)
    5 / 99 (5.05%)
    1 / 99 (1.01%)
    2 / 100 (2.00%)
         occurrences all number
    1
    7
    1
    2
    Dizziness
         subjects affected / exposed
    5 / 100 (5.00%)
    5 / 99 (5.05%)
    7 / 99 (7.07%)
    5 / 100 (5.00%)
         occurrences all number
    11
    8
    12
    5
    Headache
         subjects affected / exposed
    10 / 100 (10.00%)
    14 / 99 (14.14%)
    18 / 99 (18.18%)
    9 / 100 (9.00%)
         occurrences all number
    14
    19
    31
    15
    Somnolence
         subjects affected / exposed
    6 / 100 (6.00%)
    8 / 99 (8.08%)
    6 / 99 (6.06%)
    8 / 100 (8.00%)
         occurrences all number
    6
    10
    7
    8
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    3 / 100 (3.00%)
    1 / 99 (1.01%)
    2 / 99 (2.02%)
    8 / 100 (8.00%)
         occurrences all number
    5
    2
    2
    26
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 100 (2.00%)
    3 / 99 (3.03%)
    4 / 99 (4.04%)
    8 / 100 (8.00%)
         occurrences all number
    2
    4
    5
    9
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    4 / 100 (4.00%)
    0 / 99 (0.00%)
    1 / 99 (1.01%)
    6 / 100 (6.00%)
         occurrences all number
    4
    0
    1
    7
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 99 (0.00%)
    5 / 99 (5.05%)
    1 / 100 (1.00%)
         occurrences all number
    0
    0
    5
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 100 (1.00%)
    8 / 99 (8.08%)
    1 / 99 (1.01%)
    2 / 100 (2.00%)
         occurrences all number
    1
    8
    1
    2

    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
    Protocol amendment 1 was issued on 02 Feb 2007. The following changes were implemented; no subjects were enrolled at the time: • A storage period of up to 20 years was proposed for the DNA samples in order to have the possibility to re-evaluate a possible correlation between SV2 (A, B, and C) gene variations and treatment response if, and when, new mutations are found to be relevant to SV2 pharmacogenomics. The initial genotyping will occur during the conduct of the study, but there is high likelihood that new mutations in SV2A, B or C will be found over the subsequent years as this is a rapidly evolving area. In addition, it will be of interest to examine the genetic variability in other disease-related genes of possible relevance for epileptic disorders and in genes related to SV2 biology. • The rationale for collecting the race has been added according to legal requirement in some countries. • Clarification of the electrocardiogram (ECG) tracings retrieval has been added to include the following text: Copies of all ECG tracings will be retrieved for all subjects presenting treatment-emergent, clinically significant abnormalities during the study.
    08 May 2007
    A protocol amendment was issued on 08 May 2007 in response to Food and Drug Administration (FDA) feedback on the N01253 final protocol, which was identical in design to N01252. The following changes were implemented; no subjects were enrolled at the time: • An additional 1 week step at 20 mg/day was added to the Down-Titration Period for subjects on 50 mg/day or on 100 mg/day. • A clinic visit was added 2 weeks after randomization which included a complete safety evaluation (including laboratory analysis and ECGs). • Microscopy evaluations for all urinalysis assessments were added at clinic visits when urinalysis samples were taken. Other changes implemented in this amendment included: • Details of the statistical methods used to analyze the Type IC/Type I seizure frequency ratio were removed from the protocol. A reference to the Statistical Analysis Plan (SAP) was added. • The definition of a completed subject was clarified. A subject completed the study if either he/she was randomized, underwent the Evaluation Visit (V) (V7), did not have any Early Discontinuation Visit (EDV), and entered the LTFU; or was randomized, underwent the Evaluation Visit (V7) and Safety Visit (SV), did not have any EDV, and did not enter the LTFU. Otherwise the subject was to be considered discontinued. • Specifications for the handling of missing data for primary efficacy analysis on the Intent-to- Treat (ITT) Population analyses were added. The primary efficacy analysis assumes that subjects who prematurely withdrew from the Treatment Period had the same seizure frequency for the remaining unobserved period. In addition, a sensitivity analysis was further described in the SAP. • Additional instructions for blood sampling volumes for laboratory assessments and genotyping 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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/24256083
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