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    Clinical Trial Results:
    An International, Randomized, Double-blind, Parallel-group, Placebo-controlled, Flexible Dose Study: Evaluation of the Safety and Efficacy of Brivaracetam in Subjects (≥ 16 to 70 Years Old) Suffering From Localization-related or Generalized Epilepsy

    Summary
    EudraCT number
    		 2006-006346-34
    Trial protocol
    		 BE   CZ   SE   DE   AT   IT  
    Global end of trial date
    15 Dec 2008

    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
    N01254
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00504881
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UCB Pharma S.A.
    Sponsor organisation address
    Allée de la Recherche 70, Brussels, Belgium, 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
    31 Mar 2009
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Dec 2008
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to assess the safety and tolerability of brivaracetam (BRV) at the dose range from 20 to 150 mg/day in twice daily administration in subjects suffering from localization-related or generalized epilepsy not fully controlled despite optimal treatment with 1 to 3 concomitant antiepileptic drug(s) (AED[s]), compared to placebo (PBO).
    Protection of trial subjects
    Standard measure to minimize pain and distress.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    15 Oct 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
    Austria: 29
    Country: Number of subjects enrolled
    Belgium: 21
    Country: Number of subjects enrolled
    Czech Republic: 35
    Country: Number of subjects enrolled
    Germany: 33
    Country: Number of subjects enrolled
    Hong Kong: 11
    Country: Number of subjects enrolled
    India: 65
    Country: Number of subjects enrolled
    Italy: 23
    Country: Number of subjects enrolled
    Korea, Republic of: 88
    Country: Number of subjects enrolled
    Norway: 15
    Country: Number of subjects enrolled
    Russian Federation: 51
    Country: Number of subjects enrolled
    Singapore: 9
    Country: Number of subjects enrolled
    South Africa: 2
    Country: Number of subjects enrolled
    Sweden: 19
    Country: Number of subjects enrolled
    Taiwan: 27
    Country: Number of subjects enrolled
    Ukraine: 52
    Worldwide total number of subjects
    480
    EEA total number of subjects
    175
    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)
    8
    Adults (18-64 years)
    468
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This multicenter study was conducted in 15 countries. It started in October 2007 and concluded in December 2008.

    Pre-assignment
    Screening details
    		 The Participant Flow refers to the Randomized Set (RS).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 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
    Arm description
    		 A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/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
    Brivaracetam - Pharmaceutical form: Film-coated tablet - Route of Administration: Oral use - Concentration: 10 mg and 25 mg tablets

    Number of subjects in period 1
    		Placebo Brivaracetam
    Started
    121
    359
    Completed
    111
    323
    Not completed
    10
    36
         AE, serious fatal
    -
    1
         Consent withdrawn by subject
    1
    4
         Non-Compliance
    1
    -
         No Birth Control
    -
    1
         AE, non-serious non-fatal
    4
    14
         AE of unknown type
    1
    -
         Safety Visit not performed
    -
    1
         Lost to follow-up
    -
    2
         SAE, non-fatal
    2
    6
         Lack of efficacy
    1
    5
         SAE, non-fatal + AE, non-serious non-fatal
    -
    2

    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
    Reporting group description
    		 A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day

    Reporting group values
    		 Placebo Brivaracetam Total
    Number of subjects
    		 121 359 480
    Age categorical
    Units: Subjects
        < 18 years
    		 3 5 8
        18 - < 65 years
    		 116 352 468
        65 - < 85 years
    		 2 2 4
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 36.5 ( 11.5 ) 35.6 ( 11.5 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 52 178 230
        Male
    		 69 181 250

    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
    Reporting group description
    		 A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day

    Primary: Percentage of subjects with at least one Adverse Event during the 16-week Treatment Period

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    End point title
    		 Percentage of subjects with at least one Adverse Event during the 16-week Treatment Period [1]
    End point description
    An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product.
    End point type
    Primary
    End point timeframe
    Week 2 to the end of the Treatment Period (Week 16)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized in tables as descriptive statistics only.
    End point values
    		 Placebo Brivaracetam
    Number of subjects analysed
    121
    359
    Units: percentage of participants
    number (not applicable)
        Percentage of participants
    66.1
    66.6
    No statistical analyses for this end point

    Primary: Partial Onset Seizure (Type I) frequency per week over the 16-week Treatment Period

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    End point title
    		 Partial Onset Seizure (Type I) frequency per week over the 16-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 generalized tonic-clonic convulsions. Partial Onset Seizure (POS) frequency per week over the Treatment Period (TP) was calculated as: (Total Type I seizures over the TP)*7/(Total number of days with no missing seizure count in the TP)
    End point type
    Primary
    End point timeframe
    Baseline (Week 0) to the end of the Treatment Period (Week 16)
    End point values
    		 Placebo Brivaracetam
    Number of subjects analysed
    108
    323
    Units: seizures per week
    median (inter-quartile range (Q1-Q3))
        Median (Q1 - Q3)
    1.86 (1 to 3.98)
    1.74 (0.86 to 4.04)
    Statistical analysis title
    		 Statistical Analysis
    Statistical analysis description
    ANCOVA on log-transformed partial seizure frequency per week over the treatment period, with log-transformed baseline seizure frequency per week as covariate, and including terms for treatment and stratification factors.
    Comparison groups
    Placebo v Brivaracetam
    Number of subjects included in analysis
    431
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.125
    Method
    		 ANCOVA
    Parameter type
    		 Percent Reduction over Placebo
    Point estimate
    7.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.2
         upper limit
    		 15.9

    Secondary: Responder rate for partial onset seizures (Type I) frequency per week over the 16-week Treatment Period

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    End point title
    		 Responder rate for partial onset seizures (Type I) frequency per week over the 16-week Treatment Period
    End point description
    The responder rate was presented as the percentage of responders and non-responders. A subject is a responder, if the subject has at least 50 % reduction in Partial Onset Seizure frequency per week from Baseline to Treatment Period. Subjects with zero seizure frequency per week at Baseline were considered as non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to the end of Treatment Period (Week 16)
    End point values
    		 Placebo Brivaracetam
    Number of subjects analysed
    108
    323
    Units: percentage of participants
    number (not applicable)
        Responders
    16.7
    30.3
        Non-Responders
    83.3
    69.7
    No statistical analyses for this end point

    Secondary: Seizure frequency (all seizure types) per week over the 16-week Treatment Period

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    End point title
    		 Seizure frequency (all seizure types) per week over the 16-week Treatment Period
    End point description
    There are three different types of seizures: - Type I: Partial seizures - Type II: Generalized seizures - Type III: Unclassified epileptic seizures. All seizure frequency per week over Treatment Period (TP) was calculated as: (Total number of seizures over the TP)*7/(Total number of days with no missing seizure count in the TP)
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to the end of Treatment Period (Week 16)
    End point values
    		 Placebo Brivaracetam
    Number of subjects analysed
    108
    323
    Units: seizure frequency per week
    median (inter-quartile range (Q1-Q3))
        Median (Q1 - Q3)
    1.87 (1 to 4.59)
    1.74 (0.86 to 4.04)
    No statistical analyses for this end point

    Secondary: Percent change from Baseline to the 16-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 16-week Treatment Period in Partial Onset Seizure (Type I) frequency per week
    End point description
    Percent change from Baseline was calculated as percent reduction by: (weekly seizure frequency Baseline - weekly seizure frequency Treatment)*100/(weekly seizure frequency Baseline). A negative value in percent Change from Baseline indicates an improvement from Baseline. The higher the negative values for percent change in Partial Onset Seizure (POS) frequency, the higher the improvement from Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to end of Treatment Period (Week 16)
    End point values
    		 Placebo Brivaracetam
    Number of subjects analysed
    108
    323
    Units: seizure frequency per week
    median (inter-quartile range (Q1-Q3))
        Median (Q1 - Q3)
    -18.93 (-39.05 to -7.83)
    -26.92 (-55.98 to 11.44)
    No statistical analyses for this end point

    Secondary: Categorized response from Baseline in seizure frequency for Partial Onset Seizure (Type I) over the 16-week Treatment Period

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    End point title
    		 Categorized response from Baseline in seizure frequency for Partial Onset Seizure (Type I) over the 16-week Treatment Period
    End point description
    Subjects were classified in 1 of the following categories based on their percent reduction from Baseline to Treatment Period in Partial Onset Seizure (POS) frequency per week: <-25 %, -25 % to <25 %, 25 % to <50 %, 50 % to <75 %, 75 % to <100 %, and 100 %. Subjects having zero for Baseline seizure frequency per week were classified in the <-25 % category.
    End point type
    Secondary
    End point timeframe
    Baseline to 16-week Treatment Period
    End point values
    		 Placebo Brivaracetam
    Number of subjects analysed
    108
    323
    Units: percentage of participants
    number (not applicable)
        <- 25 %
    14.8
    18.3
        -25 % to < 25 %
    44.4
    29.1
        25 % to < 50 %
    24.1
    22.3
        50 % to < 75 %
    13.9
    17
        75 % to < 100 %
    2.8
    11.8
        100 %
    0
    1.5
    No statistical analyses for this end point

    Secondary: Seizure freedom rate (all seizure types) over the 16-week Treatment Period

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    End point title
    		 Seizure freedom rate (all seizure types) over the 16-week Treatment Period
    End point description
    Subjects were considered seizure free if their seizure counts for every day over the Treatment Period (TP) was zero and if they did not discontinue before the end of the TP. Seizure freedom rate was calculated as: (total number of seizure - free subjects in treatment group during TP)/(total number of evaluable Intent-To-Treat (ITT) subjects in treatment group)
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to the end of Treatment Period (Week 16)
    End point values
    		 Placebo Brivaracetam
    Number of subjects analysed
    108
    323
    Units: percentage of participants
    number (not applicable)
        Seizure-free
    0
    1.5
        No Seizure but non-completer
    0
    0
        Not Seizure free
    100
    98.5
    No statistical analyses for this end point

    Secondary: Reduction of Type IC/Type I seizure frequency ratio from Baseline to the 16-week Treatment Period

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    End point title
    		 Reduction of Type IC/Type I seizure frequency ratio from Baseline to the 16-week Treatment Period
    End point description
    This variable was not analyzed and no results are available.
    End point type
    Secondary
    End point timeframe
    Baseline to 16-week Treatment Period
    End point values
    		 Placebo Brivaracetam
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Not applicable
    ( )
    ( )
    Notes
    [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.
    No statistical analyses for this end point

    Secondary: Time to first Type I seizure during the 16-week Treatment Period

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    End point title
    		 Time to first Type I seizure during the 16-week Treatment Period
    End point description
    Time to first Type I seizure during the 16-week Treatment Period was measured in days.
    End point type
    Secondary
    End point timeframe
    Baseline to 16-week Treatment Period
    End point values
    		 Placebo Brivaracetam
    Number of subjects analysed
    108
    323
    Units: days
    median (confidence interval 95%)
        Median (95 % CI)
    3 (2 to 4)
    4 (4 to 5)
    No statistical analyses for this end point

    Secondary: Time to fifth Type I seizure during the 16-week Treatment Period

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    End point title
    		 Time to fifth Type I seizure during the 16-week Treatment Period
    End point description
    Time to fifth Type I seizure during the 16-week Treatment Period was measured in days.
    End point type
    Secondary
    End point timeframe
    Baseline to 16-week Treatment Period
    End point values
    		 Placebo Brivaracetam
    Number of subjects analysed
    108
    323
    Units: days
    median (confidence interval 95%)
        Median (95 % CI)
    14 (11 to 19)
    18 (16 to 21)
    No statistical analyses for this end point

    Secondary: Time to tenth Type I seizure during Treatment Period

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    End point title
    		 Time to tenth Type I seizure during Treatment Period
    End point description
    Time to tenth Type I seizure during the 16-week Treatment Period was measured in days.
    End point type
    Secondary
    End point timeframe
    Baseline to 16-week Treatment Period
    End point values
    		 Placebo Brivaracetam
    Number of subjects analysed
    108
    323
    Units: days
    median (confidence interval 95%)
        Median (95 % CI)
    36 (23 to 44)
    38 (31 to 43)
    No statistical analyses for this end point

    Secondary: Change from Baseline to the 16-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 16-week Treatment Period in Total Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score
    End point description
    The Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into 7 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. In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items asking the subjects to rate the degree of 'distress' related to the topic of each subscale (ie, distress items). The QOLIE-31-P also contains an item asking about the relative importance of each subscale topic (ie, prioritization item). The subscale scores, the total score and the Health Status item score were calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function.
    End point type
    Secondary
    End point timeframe
    Baseline to 16-week Treatment Period
    End point values
    		 Placebo Brivaracetam
    Number of subjects analysed
    98
    284
    Units: units on a scale
    arithmetic mean (standard deviation)
        Arithmetic Mean (Standard Deviation)
    3.04 ( 12.58 )
    4.22 ( 13.73 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to the 16-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 16-week Treatment Period in Seizure Worry Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score
    End point description
    The Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into 7 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. In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items asking the subjects to rate the degree of 'distress' related to the topic of each subscale (ie, distress items). The QOLIE-31-P also contains an item asking about the relative importance of each subscale topic (ie, prioritization item). The subscale scores, the total score and the Health Status item score were calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function.
    End point type
    Secondary
    End point timeframe
    Baseline to 16-week Treatment Period
    End point values
    		 Placebo Brivaracetam
    Number of subjects analysed
    99
    291
    Units: units on a scale
    arithmetic mean (standard deviation)
        Arithmetic Mean (Standard Deviation)
    4.66 ( 23.23 )
    10.29 ( 21.99 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to the 16-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 16-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 Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into 7 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. In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items asking the subjects to rate the degree of 'distress' related to the topic of each subscale (ie, distress items). The QOLIE-31-P also contains an item asking about the relative importance of each subscale topic (ie, prioritization item). The subscale scores, the total score and the Health Status item score were calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function.
    End point type
    Secondary
    End point timeframe
    Baseline to 16-week Treatment Period
    End point values
    		 Placebo Brivaracetam
    Number of subjects analysed
    99
    290
    Units: units on a scale
    arithmetic mean (standard deviation)
        Arithmetic Mean (Standard Deviation)
    5.61 ( 21.87 )
    2.66 ( 23.48 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to the 16-week Treatment Period in Hospital Anxiety score

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    End point title
    		 Change from Baseline to the 16-week Treatment Period in Hospital Anxiety score
    End point description
    The Hospital Anxiety and Depression Scale (HADS) was used to evaluate Anxiety and Depression. The HADS was developed as a self-administered scale to assess the presence and severity of 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 (higher scores indicating greater problems). A negative value in change from Baseline indicates an improvement from Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline to 16-week Treatment Period
    End point values
    		 Placebo Brivaracetam
    Number of subjects analysed
    97
    286
    Units: units on a scale
    arithmetic mean (standard deviation)
        Arithmetic Mean (Standard Deviation)
    -0.57 ( 3.35 )
    -0.85 ( 3.62 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to the 16-week Treatment Period in Hospital Depression score

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    End point title
    		 Change from Baseline to the 16-week Treatment Period in Hospital Depression score
    End point description
    The Hospital Anxiety and Depression Scale (HADS) was used to eveluate Anxiety and Depression.The HADS was developed as a self-administered scale to assess the presence and severity of 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 (higher scores indicating greater problems). A negative value in change from Baseline indicates an improvement from Baseline.
    End point type
    Secondary
    End point timeframe
    Baseline to 16-week Treatment Period
    End point values
    		 Placebo Brivaracetam
    Number of subjects analysed
    97
    285
    Units: units on a scale
    arithmetic mean (standard deviation)
        Arithmetic Mean (Standard Deviation)
    0.3 ( 3.08 )
    -0.41 ( 3.54 )
    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 completed it by answering to the following: 'Overall, has there been a change in your seizures since the start of the study medication?'
    End point type
    Secondary
    End point timeframe
    Baseline to last visit or early discontinuation visit in the 16-week Treatment Period
    End point values
    		 Placebo Brivaracetam
    Number of subjects analysed
    99
    282
    Units: units on a scale
    arithmetic mean (standard deviation)
        Arithmetic Mean (Standard Deviation)
    4.73 ( 1.37 )
    5.07 ( 1.36 )
    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 the reference time point. The Investigator completed it by answering to the following: 'Assess the overall change in the severity of patient's illness, compared to start of study medication.'
    End point type
    Secondary
    End point timeframe
    Baseline to Last Visit or Early Discontinuation Visit in the 16-week Treatment Period
    End point values
    		 Placebo Brivaracetam
    Number of subjects analysed
    108
    319
    Units: units on a scale
    arithmetic mean (standard deviation)
        Arithmetic Mean (Standard Deviation)
    4.79 ( 1.14 )
    5 ( 1.22 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to the 16-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 16-week Treatment Period in Energy/Fatigue Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score
    End point description
    The Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into 7 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. In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items asking the subjects to rate the degree of 'distress' related to the topic of each subscale (ie, distress items). The QOLIE-31-P also contains an item asking about the relative importance of each subscale topic (ie, prioritization item). The subscale scores, the total score and the Health Status item score were calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function.
    End point type
    Secondary
    End point timeframe
    Baseline to 16-week Treatment Period
    End point values
    		 Placebo Brivaracetam
    Number of subjects analysed
    99
    286
    Units: units on a scale
    arithmetic mean (standard deviation)
        Arithmetic Mean (Standard Deviation)
    2.98 ( 18 )
    3.34 ( 19.06 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to the 16-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 16-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 Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into 7 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. In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items asking the subjects to rate the degree of 'distress' related to the topic of each subscale (ie, distress items). The QOLIE-31-P also contains an item asking about the relative importance of each subscale topic (ie, prioritization item). The subscale scores, the total score and the Health Status item score were calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function.
    End point type
    Secondary
    End point timeframe
    Baseline to 16-week Treatment Period
    End point values
    		 Placebo Brivaracetam
    Number of subjects analysed
    99
    287
    Units: units on a scale
    arithmetic mean (standard deviation)
        Arithmetic Mean (Standard Deviation)
    1.97 ( 19.29 )
    2.84 ( 18.07 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to the 16-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 16-week Treatment Period in Cognitive Functioning Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score
    End point description
    The Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into 7 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. In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items asking the subjects to rate the degree of 'distress' related to the topic of each subscale (ie, distress items). The QOLIE-31-P also contains an item asking about the relative importance of each subscale topic (ie, prioritization item). The subscale scores, the total score and the Health Status item score were calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function.
    End point type
    Secondary
    End point timeframe
    Baseline to 16-week Treatment Period
    End point values
    		 Placebo Brivaracetam
    Number of subjects analysed
    99
    290
    Units: units on a scale
    arithmetic mean (standard deviation)
        Arithmetic Mean (Standard Deviation)
    2.28 ( 19.88 )
    5.51 ( 18.55 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to the 16-week Treatment Period in overall 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 16-week Treatment Period in overall Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score
    End point description
    The Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into 7 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. In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items asking the subjects to rate the degree of 'distress' related to the topic of each subscale (ie, distress items). The QOLIE-31-P also contains an item asking about the relative importance of each subscale topic (ie, prioritization item). The subscale scores, the total score and the Health Status item score were calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function.
    End point type
    Secondary
    End point timeframe
    Baseline to 16-week Treatment Period
    End point values
    		 Placebo Brivaracetam
    Number of subjects analysed
    98
    291
    Units: units on a scale
    arithmetic mean (standard deviation)
        Arithmetic Mean (Standard Deviation)
    -0.48 ( 17.4 )
    4.08 ( 19.23 )
    No statistical analyses for this end point

    Secondary: Change from Baseline to the 16-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 16-week Treatment Period in Medication effects Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) score
    End point description
    The Quality of Life in Epilepsy Inventory-Form 31 (QOLIE-31-P) is an adaptation of the original QOLIE-31 instrument that includes 30 items grouped into 7 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. In addition to the 31 items of the QOLIE-31, the QOLIE-31-P contains 7 items asking the subjects to rate the degree of 'distress' related to the topic of each subscale (ie, distress items). The QOLIE-31-P also contains an item asking about the relative importance of each subscale topic (ie, prioritization item). The subscale scores, the total score and the Health Status item score were calculated according to the scoring algorithm defined by the author with scores ranging from 0 to 100 and higher scores indicating better function.
    End point type
    Secondary
    End point timeframe
    Baseline to 16-week Treatment Period
    End point values
    		 Placebo Brivaracetam
    Number of subjects analysed
    99
    290
    Units: units on a scale
    arithmetic mean (standard deviation)
        Arithmetic Mean (Standard Deviation)
    2.83 ( 27.21 )
    -0.24 ( 25.84 )
    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 24 weeks from Visit 1 (Week -4) to the Safety Visit (Week 20).
    Adverse event reporting additional description
    Adverse Events (AEs) refer to the Safety Population, including all randomized subjects who received at least 1 dose of study medication.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    9.0
    Reporting groups
    Reporting group title
    Brivaracetam
    Reporting group description
    		 A flexible dose of Brivaracetam tablets, administered twice a day, starting with a dose of 20 mg/day and could increase to 50 mg/day, 100 mg/day or 150 mg/day

    Reporting group title
    Placebo
    Reporting group description
    		 Matching Placebo tablets administered twice a day

    Serious adverse events
    		 Brivaracetam Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 359 (5.57%)
    9 / 121 (7.44%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Drug toxity
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Burns second degree
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Face injury
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial ischaemia
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postictal state
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    7 / 359 (1.95%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    5 / 9
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    2 / 359 (0.56%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drowning
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 359 (0.28%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Hepatitis B
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 359 (0.00%)
    1 / 121 (0.83%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetis mellitus inadequate control
         subjects affected / exposed
    1 / 359 (0.28%)
    0 / 121 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Brivaracetam Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    139 / 359 (38.72%)
    40 / 121 (33.06%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    31 / 359 (8.64%)
    7 / 121 (5.79%)
         occurrences all number
    36
    9
    Headache
         subjects affected / exposed
    52 / 359 (14.48%)
    24 / 121 (19.83%)
         occurrences all number
    79
    45
    Somnolence
         subjects affected / exposed
    40 / 359 (11.14%)
    5 / 121 (4.13%)
         occurrences all number
    47
    7
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    27 / 359 (7.52%)
    5 / 121 (4.13%)
         occurrences all number
    31
    5
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    20 / 359 (5.57%)
    11 / 121 (9.09%)
         occurrences all number
    26
    14
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    11 / 359 (3.06%)
    8 / 121 (6.61%)
         occurrences all number
    11
    9
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    14 / 359 (3.90%)
    8 / 121 (6.61%)
         occurrences all number
    16
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 May 2007
    A global protocol amendment was issued on 08 May 2007 in response to Food and Drug Administration (FDA) feedback on the N01253 final protocol. The following changes were implemented; no subjects were enrolled at the time: • One step was added in the Down-Titration Scheme to reduce subjects from BRV 50 mg/day to BRV 20 mg/day before entering the Study Drug-Free Period. For subjects not entering the LTFU study and taking doses of BRV 50 mg/day, 100 mg/day, or 150 mg/day (or corresponding matching PBO) a down-titration of 1, 2, or 3 weeks, respectively, was required prior to entering the Study Drug-Free Period. • Addition of a clinic visit requiring a complete safety evaluation, including laboratory safety assessments and electrocardiogram (ECG), at 2-weeks after randomization. • Addition of microscopy evaluations for all urinalysis assessments.
    08 May 2007
    In order to harmonize the 3 studies for the BRV POS Phase 3 program, the following changes were applied for N01254: • One step was added in the Down-Titration Scheme to reduce subjects from BRV 50 mg/day to BRV 20 mg/day before entering the Study Drug-Free Period. • An ECG was added at Visit (V) 3 (2 weeks after randomization). • Laboratory safety assessments, pregnancy test (if applicable), AED plasma level, and BRV plasma level were added at V3 (2 weeks after randomization). • Weight was also measured at V3. Other changes implemented in this amendment include: • 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 (V8), did not have any Early Discontinuation Visit (EDV), and entered the LTFU study; or was randomized, underwent the V8 and Safety Visit (SV), did not have any EDV, and did not enter the LTFU study. Otherwise, the subject was considered discontinued. • Specifications for the handling of missing data for primary efficacy analysis on the Intent-to-Treat (ITT) Population 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/24116853
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