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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, multicenter, parallel-group study to evaluate the efficacy and safety of Brivaracetam in subjects (≥16 to 80 years old) with partial onset seizures

    Summary
    EudraCT number
    		 2010-019361-28
    Trial protocol
    		 BE   DE   CZ   ES   IT   GB   SE   FR   FI   AT   NL   EE   LT   LV   HU   BG   RO  
    Global end of trial date
    22 May 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    N01358
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01261325
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UCB BIOSCIENCES Inc.
    Sponsor organisation address
    8010 Arco Corporate Drive, Raleigh, United States, 27617
    Public contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, 0049 2173 48 15 15, clinicaltrials@ucb.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, 0049 2173 48 15 15, clinicaltrials@ucb.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Jun 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 May 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the efficacy of brivaracetam (BRV) at doses of 100 and 200mg/day compared with placebo (PBO) as adjunctive treatment in adult focal epilepsy subjects with partial-onset seizures (POS) not fully controlled despite current treatment with 1 or 2 concomitant antiepileptic drugs (AEDs).
    Protection of trial subjects
    Subject’s informed consent must be obtained and documented in accordance with local regulations, ICH-GCP requirements, and the ethical principles that have their origin in the principles of the Declaration of Helsinki. Prior to obtaining informed consent, information should be given in a language and at a level of complexity understandable to the subject in both oral and written form by the Investigator (or designee). Each subject will have the opportunity to discuss the study and its alternatives with the Investigator.
    Background therapy
    		 N/A
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    10 Dec 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 49
    Country: Number of subjects enrolled
    Sweden: 15
    Country: Number of subjects enrolled
    Taiwan: 18
    Country: Number of subjects enrolled
    United Kingdom: 19
    Country: Number of subjects enrolled
    United States: 165
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Brazil: 20
    Country: Number of subjects enrolled
    Bulgaria: 8
    Country: Number of subjects enrolled
    Canada: 22
    Country: Number of subjects enrolled
    Czech Republic: 36
    Country: Number of subjects enrolled
    Estonia: 23
    Country: Number of subjects enrolled
    Finland: 7
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Germany: 26
    Country: Number of subjects enrolled
    Hong Kong: 4
    Country: Number of subjects enrolled
    Hungary: 20
    Country: Number of subjects enrolled
    India: 36
    Country: Number of subjects enrolled
    Italy: 52
    Country: Number of subjects enrolled
    Japan: 7
    Country: Number of subjects enrolled
    Korea, Republic of: 26
    Country: Number of subjects enrolled
    Latvia: 9
    Country: Number of subjects enrolled
    Lithuania: 11
    Country: Number of subjects enrolled
    Mexico: 66
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Poland: 65
    Country: Number of subjects enrolled
    Puerto Rico: 1
    Country: Number of subjects enrolled
    Russian Federation: 28
    Worldwide total number of subjects
    768
    EEA total number of subjects
    375
    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)
    20
    Adults (18-64 years)
    725
    From 65 to 84 years
    23
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment for the N01358 study began in December 2010. The study concluded in May 2014.

    Pre-assignment
    Screening details
    		 The Participant Flow and Baseline Demographics data is taken from the Randomized Set (RS). The RS consists of all subjects who were randomized.

    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 daily
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PBO
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral film-coated tablets taken twice a day.

    Arm title
    		 Brivaracetam 100 mg/day
    Arm description
    		 Brivaracetam 50 mg administered twice daily.
    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
    Oral film-coated tablets of BRV 10mg, BRV 25mg, or BRV 50mg taken orally twice a day.

    Arm title
    		 Brivaracetam 200 mg/day
    Arm description
    		 Brivaracetam 100 mg administered twice daily
    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
    Oral film-coated tablets of BRV 10mg, BRV 25mg, or BRV 50mg taken orally twice a day.

    Number of subjects in period 1
    		Placebo Brivaracetam 100 mg/day Brivaracetam 200 mg/day
    Started
    263
    254
    251
    Completed
    246
    225
    225
    Not completed
    17
    29
    26
         Randomized in error
    -
    -
    1
         AE, serious fatal
    -
    -
    2
         Non Compliance
    2
    -
    -
         Screen Failure
    1
    -
    -
         AE, non-serious non-fatal
    9
    15
    13
         Randomized by mistake
    -
    1
    -
         SAE, non-fatal + AE, non-serious non-fatal
    -
    1
    1
         Consent withdrawn by subject
    2
    2
    4
         Erroneously Randomized
    1
    -
    -
         Lost to follow-up
    -
    1
    3
         SAE, non-fatal
    1
    5
    1
         Lack of efficacy
    1
    1
    -
         Protocol deviation
    -
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo tablets administered twice daily

    Reporting group title
    Brivaracetam 100 mg/day
    Reporting group description
    		 Brivaracetam 50 mg administered twice daily.

    Reporting group title
    Brivaracetam 200 mg/day
    Reporting group description
    		 Brivaracetam 100 mg administered twice daily

    Reporting group values
    		 Placebo Brivaracetam 100 mg/day Brivaracetam 200 mg/day Total
    Number of subjects
    		 263 254 251 768
    Age Categorical
    This analysis set consists of the Randomized Subjects (RS), which is all subjects randomized into the study.
    Units: Subjects
        12-<18
    		 7 6 7 20
        18-<65
    		 250 237 238 725
        65-<85
    		 6 11 6 23
    Age Continuous
    This analysis set consists of the Randomized Subjects (RS), which is all subjects randomized into the study.
    Units: years
        arithmetic mean (standard deviation)
    		 39.8 ± 12.8 39 ± 13.4 39.7 ± 12.8 -
    Gender Categorical
    This analysis set consists of the Randomized Subjects (RS), which is all subjects randomized into the study.
    Units: Subjects
        Male
    		 135 102 134 371
        Female
    		 128 152 117 397
    Racial Group
    This analysis set consists of the Randomized Subjects (RS), which is all subjects randomized into the study.
    Units: Subjects
        American Indian or Alaska Native
    		 10 8 11 29
        Asian
    		 32 32 29 93
        Black or African American
    		 11 8 7 26
        White
    		 190 183 183 556
        Other
    		 17 21 18 56
        Missing
    		 3 2 3 8
    Weight
    This analysis set consists of the Randomized Subjects (RS), which is all subjects randomized into the study.
    Units: kilograms
        median (standard deviation)
    		 76.1 ± 19.9 74.1 ± 16.8 75.5 ± 19 -
    Height
    This analysis set consists of the Randomized Subjects (RS), which is all subjects randomized into the study.
    Units: centimeters
        arithmetic mean (standard deviation)
    		 168.4 ± 10 166.6 ± 9.8 168.7 ± 9.9 -
    BMI
    This analysis set consists of the Randomized Subjects (RS), which is all subjects randomized into the study.
    Units: kg/m^2
        arithmetic mean (standard deviation)
    		 26.6 ± 5.7 26.7 ± 5.6 26.4 ± 6 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo tablets administered twice daily

    Reporting group title
    Brivaracetam 100 mg/day
    Reporting group description
    		 Brivaracetam 50 mg administered twice daily.

    Reporting group title
    Brivaracetam 200 mg/day
    Reporting group description
    		 Brivaracetam 100 mg administered twice daily

    Primary: Percent reduction over placebo for partial onset seizure (Type I) frequency over the Treatment Period standardized to a 28-day duration

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    End point title
    		 Percent reduction over placebo for partial onset seizure (Type I) frequency over the Treatment Period standardized to a 28-day duration
    End point description
    Primary endpoint: United States of America (FDA)
    End point type
    Primary
    End point timeframe
    12 week Treatment Period
    End point values
    		 Placebo Brivaracetam 100 mg/day Brivaracetam 200 mg/day
    Number of subjects analysed
    259 [1]
    252 [2]
    249 [3]
    Units: Percentage of reduction
    number (not applicable)
        percentage
    0
    22.8
    23.2
    Notes
    [1] - Intent-to-Treat (ITT) Population
    [2] - Intent-to-Treat (ITT) Population
    [3] - Intent-to-Treat (ITT) Population
    Statistical analysis title
    		 Statistical Analysis - BRV 100 mg/ day v Placebo
    Statistical analysis description
    Statistically significant with control of Type I error rate based on a Hochberg multiple comparison procedure.
    Comparison groups
    Brivaracetam 100 mg/day v Placebo
    Number of subjects included in analysis
    511
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 < 0.001 [5]
    Method
    		 ANCOVA
    Parameter type
    		 Percent reduction over PBO
    Point estimate
    22.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 13.3
         upper limit
    		 31.2
    Notes
    [4] - ANCOVA (analysis of covariance), with Log-transformed Treatment Period 28-day adjusted POS frequency as the outcome, and effects of treatment, country, and the four possible combinations of LEV status (never used or prior use) with number of previous AEDs (≤2 or >2), and log-transformed baseline seizure frequency as a continuous covariate.
    [5] - Multiplicity-adjusted p-values based on a Hochberg multiple comparison procedure.
    Statistical analysis title
    		 Statistical Analysis - BRV 200 mg/ day v Placebo
    Statistical analysis description
    Statistically significant with control of Type I error rate based on a Hochberg multiple comparison procedure.
    Comparison groups
    Placebo v Brivaracetam 200 mg/day
    Number of subjects included in analysis
    508
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 < 0.001 [7]
    Method
    		 ANCOVA
    Parameter type
    		 Percent reduction over PBO
    Point estimate
    23.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 13.8
         upper limit
    		 31.6
    Notes
    [6] - ANCOVA (analysis of covariance), with Log-transformed Treatment Period 28-day adjusted POS frequency as the outcome, and effects of treatment, country, and the four possible combinations of LEV status (never used or prior use) with number of previous AEDs (≤2 or >2), and log-transformed baseline seizure frequency as a continuous covariate.
    [7] - Multiplicity-adjusted p-values based on a Hochberg multiple comparison procedure.

    Primary: 50% responder rate for partial onset seizure (Type I) frequency over the Treatment Period standardized to a 28-day duration

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    End point title
    		 50% responder rate for partial onset seizure (Type I) frequency over the Treatment Period standardized to a 28-day duration
    End point description
    Primary Endpoint: European Regulatory Authorities
    End point type
    Primary
    End point timeframe
    Baseline to 12 week Treatment Period
    End point values
    		 Placebo Brivaracetam 100 mg/day Brivaracetam 200 mg/day
    Number of subjects analysed
    259 [8]
    252 [9]
    249 [10]
    Units: Percentage of responders
    number (not applicable)
        Responders
    21.6
    38.9
    37.8
        Non-Responders
    78.4
    61.1
    62.2
    Notes
    [8] - Intent-to-Treat (ITT) Population
    [9] - Intent-to-Treat (ITT) Population
    [10] - Intent-to-Treat (ITT) Population
    Statistical analysis title
    		 Statistical Analysis - BRV 100 mg/ day v Placebo
    Statistical analysis description
    Statistically significant with control of Type I error rate based on a Hochberg multiple comparison procedure.
    Comparison groups
    Brivaracetam 100 mg/day v Placebo
    Number of subjects included in analysis
    511
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 < 0.001 [12]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (BRV versus PBO)
    Point estimate
    2.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.6
         upper limit
    		 3.6
    Notes
    [11] - Logistic regression model, with effects of treatment, country, and the four possible combinations of LEV status (never used or prior use) with number of previous AEDs (≤2 or >2), and log-transformed baseline seizure frequency as a continuous covariate.
    [12] - Multiplicity-adjusted p-values based on a Hochberg multiple comparison procedure.
    Statistical analysis title
    		 Statistical Analysis - BRV 200 mg/ day v Placebo
    Statistical analysis description
    Statistically significant with control of Type I error rate based on a Hochberg multiple comparison procedure.
    Comparison groups
    Brivaracetam 200 mg/day v Placebo
    Number of subjects included in analysis
    508
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 < 0.001 [14]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (BRV versus PBO)
    Point estimate
    2.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.5
         upper limit
    		 3.3
    Notes
    [13] - Logistic regression model, with effects of treatment, country, and the four possible combinations of LEV status (never used or prior use) with number of previous AEDs (≤2 or >2), and log-transformed baseline seizure frequency as a continuous covariate.
    [14] - Multiplicity-adjusted p-values based on a Hochberg multiple comparison procedure.

    Secondary: Percent reduction in partial onset seizure (Type I) frequency from the Baseline to the Treatment Period

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    End point title
    		 Percent reduction in partial onset seizure (Type I) frequency from the Baseline to the Treatment Period
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 week Treatment Period
    End point values
    		 Placebo Brivaracetam 100 mg/day Brivaracetam 200 mg/day
    Number of subjects analysed
    259 [15]
    252 [16]
    249 [17]
    Units: percentage of reduction
    median (inter-quartile range (Q1-Q3))
        median (Q1 - Q3)
    17.6 (-8.3 to 46)
    37.2 (0.1 to 69.4)
    35.6 (4.8 to 66.2)
    Notes
    [15] - Intent-to-Treat (ITT) Population
    [16] - Intent-to-Treat (ITT) Population
    [17] - Intent-to-Treat (ITT) Population
    Statistical analysis title
    		 Statistical Analysis - BRV 100 mg/ day v Placebo
    Statistical analysis description
    Treatment group comparisons are based on the Wilcoxon-Mann-Whitney test. Hodges-Lehmann non-parametric effect estimates and corresponding two-sided 95% confidence intervals are provided for the effect difference between each BRV treatment group and placebo.
    Comparison groups
    Brivaracetam 100 mg/day v Placebo
    Number of subjects included in analysis
    511
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    P-value
    		 < 0.001 [19]
    Method
    		 Hodges-Lehmann non-parametric analysis
    Parameter type
    		 Median difference vs placebo
    Point estimate
    15.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 7.6
         upper limit
    		 24.2
    Notes
    [18] - Treatment group comparisons are based on the Wilcoxon-Mann-Whitney test.
    [19] - p-values not adjusted for multiplicity.
    Statistical analysis title
    		 Statistical Analysis - BRV 200 mg/ day v Placebo
    Statistical analysis description
    Treatment group comparisons are based on the Wilcoxon-Mann-Whitney test. Hodges-Lehmann non-parametric effect estimates and corresponding two-sided 95% confidence intervals are provided for the effect difference between each BRV treatment group and placebo.
    Comparison groups
    Placebo v Brivaracetam 200 mg/day
    Number of subjects included in analysis
    508
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    P-value
    		 < 0.001 [21]
    Method
    		 Hodges-Lehmann non-parametric analysis
    Parameter type
    		 Median difference vs placebo
    Point estimate
    18.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 10.4
         upper limit
    		 26.4
    Notes
    [20] - Treatment group comparisons are based on the Wilcoxon-Mann-Whitney test.
    [21] - p-values not adjusted for multiplicity.

    Secondary: Categorized percent reduction form Baseline in seizure frequency for partial onset seizure (Type I) over the Treatment Period

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    End point title
    		 Categorized percent reduction form Baseline in seizure frequency for partial onset seizure (Type I) over the Treatment Period
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 week Treatment Period
    End point values
    		 Placebo Brivaracetam 100 mg/day Brivaracetam 200 mg/day
    Number of subjects analysed
    259 [22]
    252 [23]
    249 [24]
    Units: percentage of subjects
    number (not applicable)
        <-25 %
    16.6
    14.3
    10.8
        -25 % to <25 %
    40.5
    28.6
    29.3
        25 % to <50 %
    21.2
    18.3
    22.1
        50 % to <75 %
    13.9
    19
    18.1
        75 % to <100 %
    6.9
    13.9
    13.7
        100 %
    0.8
    6
    6
    Notes
    [22] - Intent-to-Treat (ITT) Population
    [23] - Intent-to-Treat (ITT) Population
    [24] - Intent-to-Treat (ITT) Population
    No statistical analyses for this end point

    Secondary: Seizure freedom rate (all seizure types) during the 12-week Treatment Period

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    End point title
    		 Seizure freedom rate (all seizure types) during the 12-week Treatment Period
    End point description
    End point type
    Secondary
    End point timeframe
    12 week Treatment Period
    End point values
    		 Placebo Brivaracetam 100 mg/day Brivaracetam 200 mg/day
    Number of subjects analysed
    259 [25]
    252 [26]
    249 [27]
    Units: percentage of subjects
    number (not applicable)
        Seizure free
    0.8
    5.2
    4
        No seizures but discontinued
    0.4
    1.2
    1.2
        Not seizure free
    98.8
    93.7
    94.8
    Notes
    [25] - Intent-to-Treat (ITT) Population
    [26] - Intent-to-Treat (ITT) Population
    [27] - Intent-to-Treat (ITT) Population
    No statistical analyses for this end point

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

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    End point title
    		 All seizure frequency (Type I + II + III) during the 12-week Treatment Period
    End point description
    End point type
    Secondary
    End point timeframe
    12 week Treatment Period
    End point values
    		 Placebo Brivaracetam 100 mg/day Brivaracetam 200 mg/day
    Number of subjects analysed
    259 [28]
    252 [29]
    249 [30]
    Units: seizure frequency
    median (inter-quartile range (Q1-Q3))
        median (Q1 - Q3)
    8.7 (4.3 to 23.6)
    6.3 (2.7 to 17.8)
    5.8 (2.3 to 14.2)
    Notes
    [28] - Intent-to-Treat Population
    [29] - Intent-to-Treat Population
    [30] - Intent-to-Treat Population
    No statistical analyses for this end point

    Secondary: Time to the first Type I seizure during the Treatment Period

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    End point title
    		 Time to the first Type I seizure during the Treatment Period
    End point description
    End point type
    Secondary
    End point timeframe
    12 week Treatment Period
    End point values
    		 Placebo Brivaracetam 100 mg/day Brivaracetam 200 mg/day
    Number of subjects analysed
    259 [31]
    252 [32]
    249 [33]
    Units: days
    median (confidence interval 95%)
        median days (CI)
    3 (2 to 3)
    5 (3 to 7)
    6 (4 to 7)
    Notes
    [31] - Intent-to-Treat (ITT) Population
    [32] - Intent-to-Treat (ITT) Population
    [33] - Intent-to-Treat (ITT) Population
    Statistical analysis title
    		 Statistical Analysis - Brivaracetam 100 mg/ day
    Statistical analysis description
    Hazard ratios and treatment group comparisons are based on a semi-parametric hazards regression model with number of days to nth seizure as the outcome and an effect for treatment, an effect for pooled country, and an effect for the four combinations of stratification levels for number of previous AEDs and LEV Status, and log-transformed Baseline POS frequency as a continuous covariate.
    Comparison groups
    Brivaracetam 100 mg/day v Placebo
    Number of subjects included in analysis
    511
    Analysis specification
    Pre-specified
    Analysis type
    		 other [34]
    P-value
    		 < 0.001
    Method
    		 Semi-parametric hazards regression model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.56
         upper limit
    		 0.82
    Notes
    [34] - N/A
    Statistical analysis title
    		 Statistical Analysis - Brivaracetam 200 mg/ day
    Statistical analysis description
    Hazard ratios and treatment group comparisons are based on a semi-parametric hazards regression model with number of days to nth seizure as the outcome and an effect for treatment, an effect for pooled country, and an effect for the four combinations of stratification levels for number of previous AEDs and LEV Status, and log-transformed Baseline POS frequency as a continuous covariate.
    Comparison groups
    Brivaracetam 200 mg/day v Placebo
    Number of subjects included in analysis
    508
    Analysis specification
    Pre-specified
    Analysis type
    		 other [35]
    P-value
    		 < 0.001
    Method
    		 Semi-parametric hazards regression model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 0.79
    Notes
    [35] - N/A

    Secondary: Time to the fifth Type I seizure during the Treatment Period

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    End point title
    		 Time to the fifth Type I seizure during the Treatment Period
    End point description
    End point type
    Secondary
    End point timeframe
    12 week Treatment Period
    End point values
    		 Placebo Brivaracetam 100 mg/day Brivaracetam 200 mg/day
    Number of subjects analysed
    259 [36]
    252 [37]
    249 [38]
    Units: days
    median (confidence interval 95%)
        median days (CI)
    16 (12 to 19)
    21 (17 to 25)
    23 (20 to 26)
    Notes
    [36] - Intent-to-Treat (ITT) Population
    [37] - Intent-to-Treat (ITT) Population
    [38] - Intent-to-Treat (ITT) Population
    Statistical analysis title
    		 Statistical Analysis - Brivaracetam 200 mg/ day
    Statistical analysis description
    Hazard ratios and treatment group comparisons are based on a semi-parametric hazards regression model with number of days to nth seizure as the outcome and an effect for treatment, an effect for pooled country, and an effect for the four combinations of stratification levels for number of previous AEDs and LEV Status, and log-transformed Baseline POS frequency as a continuous covariate.
    Comparison groups
    Brivaracetam 200 mg/day v Placebo
    Number of subjects included in analysis
    508
    Analysis specification
    Pre-specified
    Analysis type
    		 other [39]
    P-value
    		 < 0.001
    Method
    		 Semi-parametric hazards regression model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 0.71
    Notes
    [39] - N/A
    Statistical analysis title
    		 Statistical Analysis - Brivaracetam 100 mg/ day
    Statistical analysis description
    Hazard ratios and treatment group comparisons are based on a semi-parametric hazards regression model with number of days to nth seizure as the outcome and an effect for treatment, an effect for pooled country, and an effect for the four combinations of stratification levels for number of previous AEDs and LEV Status, and log-transformed Baseline POS frequency as a continuous covariate.
    Comparison groups
    Brivaracetam 100 mg/day v Placebo
    Number of subjects included in analysis
    511
    Analysis specification
    Pre-specified
    Analysis type
    		 other [40]
    P-value
    		 < 0.001
    Method
    		 Semi-parametric hazards regression model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 0.8
    Notes
    [40] - N/A

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

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    End point title
    		 Time to the tenth Type I seizure during the Treatment Period
    End point description
    End point type
    Secondary
    End point timeframe
    12 week Treatment Period
    End point values
    		 Placebo Brivaracetam 100 mg/day Brivaracetam 200 mg/day
    Number of subjects analysed
    259 [41]
    252 [42]
    249 [43]
    Units: days
    median (confidence interval 95%)
        median days (CI)
    32 (24 to 36)
    37 (29 to 46)
    43 (36 to 49)
    Notes
    [41] - Intent-to-Treat (ITT) Population
    [42] - Intent-to-Treat (ITT) Population
    [43] - Intent-to-Treat (ITT) Population
    Statistical analysis title
    		 Statistical Analysis - Brivaracetam 100 mg/ day
    Comparison groups
    Placebo v Brivaracetam 100 mg/day
    Number of subjects included in analysis
    511
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.009
    Method
    		 Semi-parametric hazards regression model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 0.93
    Statistical analysis title
    		 Statistical Analysis - Brivaracetam 200 mg/ day
    Comparison groups
    Placebo v Brivaracetam 200 mg/day
    Number of subjects included in analysis
    508
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Semi-parametric hazards regression model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 0.85

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent Adverse Events (TEAE) were collected during the study, which began in Dec 2010 and concluded in May 2014.
    Adverse event reporting additional description
    TEAEs are comprised of the Safety Population, which consists of all randomized subjects who receive at least 1 dose of study medication. The Non-serious Adverse Events section represents a >= 5% threshold of subjects experiencing Non-serious TEAEs in any treatment group and not the total population.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo tablets administered twice daily

    Reporting group title
    Brivaracetam 100 mg/day
    Reporting group description
    		 Brivaracetam 50 mg administered twice daily.

    Reporting group title
    Brivaracetam 200 mg/day
    Reporting group description
    		 Brivaracetam 100 mg administered twice daily

    Serious adverse events
    		 Placebo Brivaracetam 100 mg/day Brivaracetam 200 mg/day
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 261 (3.45%)
    8 / 253 (3.16%)
    8 / 250 (3.20%)
         number of deaths (all causes)
    0
    0
    2
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Thymoma
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 253 (0.00%)
    0 / 250 (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
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 253 (0.40%)
    2 / 250 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 253 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 253 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 253 (0.40%)
    0 / 250 (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
    Traumatic renal injury
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 253 (0.40%)
    0 / 250 (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
    Clavicle fracture
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 253 (0.00%)
    0 / 250 (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
    Joint dislocation
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 253 (0.00%)
    0 / 250 (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
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 253 (0.40%)
    0 / 250 (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
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 253 (0.40%)
    0 / 250 (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
    Coronary artery stenosis
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 253 (0.00%)
    0 / 250 (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
    Nervous system disorders
    Grand mal convulsion
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 253 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure cluster
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 253 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 253 (0.40%)
    0 / 250 (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
    Epilepsy
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 253 (0.00%)
    0 / 250 (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
    Postictal state
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 253 (0.00%)
    0 / 250 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 253 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Sudden unexplained death in epilepsy
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 253 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Psychiatric disorders
    Adjustment disorder
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 253 (0.40%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 253 (0.40%)
    0 / 250 (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
    Conversion disorder
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 253 (0.40%)
    0 / 250 (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
    Epileptic psychosis
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 253 (0.40%)
    0 / 250 (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
    Psychotic disorder
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 253 (0.40%)
    0 / 250 (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
    Infections and infestations
    Localised infection
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 253 (0.00%)
    1 / 250 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 253 (0.00%)
    0 / 250 (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
    Pneumonia
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 253 (0.00%)
    0 / 250 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Brivaracetam 100 mg/day Brivaracetam 200 mg/day
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    61 / 261 (23.37%)
    96 / 253 (37.94%)
    97 / 250 (38.80%)
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    20 / 261 (7.66%)
    49 / 253 (19.37%)
    42 / 250 (16.80%)
         occurrences all number
    20
    53
    43
    Dizziness
         subjects affected / exposed
    13 / 261 (4.98%)
    26 / 253 (10.28%)
    36 / 250 (14.40%)
         occurrences all number
    14
    27
    38
    Headache
         subjects affected / exposed
    22 / 261 (8.43%)
    17 / 253 (6.72%)
    20 / 250 (8.00%)
         occurrences all number
    30
    18
    21
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    10 / 261 (3.83%)
    19 / 253 (7.51%)
    29 / 250 (11.60%)
         occurrences all number
    10
    19
    32
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    8 / 261 (3.07%)
    13 / 253 (5.14%)
    2 / 250 (0.80%)
         occurrences all number
    8
    13
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Sep 2011
    The protocol was amended for the following reasons: •Procedures for reporting SAEs were updated to implement the Food and Drug Administration (FDA) Final Rule requirements (Investigational new drug safety reporting requirements for human drug and biological products and safety reporting requirements for bioavailability and bioequivalence studies in humans, 21 Code of Federal Regulations Parts 312 and 320, 2010). •The Columbia-Suicide Severity Rating Scale (C-SSRS) was added to address the requirement of the FDA that prospective assessments for suicidality be included in clinical studies involving all drugs for neurological indications. There were also a few minor changes made to the protocol to update the name of the company, name and address of Study Physician, and SAE reporting contact numbers, and to clarify some study conduct details.

    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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