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    Clinical Trial Results:
    An international, double-blind, randomized, multi-center, parallel group, historical-control conversion to monotherapy study to evaluate the efficacy and safety of brivaracetam in subjects (≥ 16 to 75 years old) with partial onset seizures with or without secondary generalization

    Summary
    EudraCT number
    2008-000145-58
    Trial protocol
    DE   ES   HU   FI   FR   IT  
    Global end of trial date
    09 Mar 2010

    Results information
    Results version number
    v1(current)
    This version publication date
    07 Dec 2016
    First version publication date
    07 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    N01306
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00699283
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB Pharma S.A.
    Sponsor organisation address
    Chemin du Foriest, Braine-l’Alleud, Belgium, B-1420
    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
    15 Oct 2010
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Mar 2010
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the efficacy of Brivaracetam (BRV) in the conversion to monotherapy at the doses of 50 and 100 mg/day (administered in two equal doses per day) in subjects with partial onset seizures when compared to a historical pseudo-placebo control group.
    Protection of trial subjects
    Standard measures to minimize pain and distress.
    Background therapy
    Not applicable
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    06 Aug 2008
    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
    France: 2
    Country: Number of subjects enrolled
    Germany: 18
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    United States: 25
    Worldwide total number of subjects
    62
    EEA total number of subjects
    37
    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)
    0
    Adults (18-64 years)
    59
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This multi-Center study started to enroll subjects in August 2008 and concluded in March 2010.

    Pre-assignment
    Screening details
    The Participant Flow refers to the Randomized Set (RS). Subjects withdrawn due to meeting an exit criterion are included in the count of early discontinuations with a reason of "Adverse Event" or "Lack of efficacy" as reported by the Investigator.

    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, Carer, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Brivaracetam (BRV) 50 mg
    Arm description
    50 mg daily for 17 weeks (or 21 weeks if down-titrated (50 mg > 20 mg) for subjects not participating in the follow-up study).
    Arm type
    Experimental

    Investigational medicinal product name
    Brivaracetam
    Investigational medicinal product code
    BRV
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg tablet - 50 mg or 100 mg daily for 17 weeks (or 21 weeks if down-titrated for subjects not participating in the follow-up study).

    Arm title
    Brivaracetam (BRV) 100 mg
    Arm description
    100 mg daily for 17 weeks (or 21 weeks if down-titrated (100 mg > 50 mg > 20 mg) for subjects not participating in the follow-up study).
    Arm type
    Experimental

    Investigational medicinal product name
    Brivaracetam
    Investigational medicinal product code
    BRV
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg tablet - 50 mg or 100 mg daily for 17 weeks (or 21 weeks if down-titrated for subjects not participating in the follow-up study).

    Number of subjects in period 1
    Brivaracetam (BRV) 50 mg Brivaracetam (BRV) 100 mg
    Started
    47
    15
    Completed
    14
    7
    Not completed
    33
    8
         Other Reason
    5
    1
         Lack of efficacy
    15
    5
         SAE, non-fatal
    1
    1
         AE of unknown type
    1
    -
         AE, non-serious non-fatal
    8
    1
         Consent withdrawn by subject
    1
    -
         Lost to follow-up
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brivaracetam (BRV) 50 mg
    Reporting group description
    50 mg daily for 17 weeks (or 21 weeks if down-titrated (50 mg > 20 mg) for subjects not participating in the follow-up study).

    Reporting group title
    Brivaracetam (BRV) 100 mg
    Reporting group description
    100 mg daily for 17 weeks (or 21 weeks if down-titrated (100 mg > 50 mg > 20 mg) for subjects not participating in the follow-up study).

    Reporting group values
    Brivaracetam (BRV) 50 mg Brivaracetam (BRV) 100 mg Total
    Number of subjects
    47 15 62
    Age Categorical
    Units: Subjects
        <18 Years
    0 0 0
        Between 18 and 65 Years
    45 14 59
        >= 65 Years
    2 1 3
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    39 ± 13.8 44.3 ± 15.9 -
    Gender Categorical
    Units: Subjects
        Male
    20 4 24
        Female
    27 11 38

    End points

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    End points reporting groups
    Reporting group title
    Brivaracetam (BRV) 50 mg
    Reporting group description
    50 mg daily for 17 weeks (or 21 weeks if down-titrated (50 mg > 20 mg) for subjects not participating in the follow-up study).

    Reporting group title
    Brivaracetam (BRV) 100 mg
    Reporting group description
    100 mg daily for 17 weeks (or 21 weeks if down-titrated (100 mg > 50 mg > 20 mg) for subjects not participating in the follow-up study).

    Subject analysis set title
    Efficacy Set (Brivaracetam 50 mg treated subjects)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    50 mg daily for 17 weeks (or 21 weeks if down-titrated (50 mg > 20 mg) for subjects not participating in the follow-up study). The Efficacy Analysis Set (EFF) consisted of all randomized subjects with at least 1 intake of study medication who also entered into the Baseline antiepileptic drug (AED) Tapering Phase (during the Evaluation Period) and started with the withdrawal of Baseline AEDs.

    Primary: The Cumulative Exit Rate at 112 days after the beginning of the Baseline Antiepileptic Drug (AED) tapering phase

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    End point title
    The Cumulative Exit Rate at 112 days after the beginning of the Baseline Antiepileptic Drug (AED) tapering phase [1]
    End point description
    The cumulative exit rate was estimated using Kaplan-Meier methods and was based on the duration between start of the Evaluation Period (EP) and the earliest date the first exit criterion was met for each subject. Subjects completing the EP without meeting an exit criterion were censored on Day 112. The primary comparison was BRV 50 mg/day vs a historical control. The upper limit of the 2-sided 95 % Confidence Interval for the estimate was compared to the historical lower bound estimate of 0.722.
    End point type
    Primary
    End point timeframe
    From Visit 4 (week 1) to the end of the Evaluation Period (week 17) (approximately 16 weeks)
    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: Values presented below are from the statistical analysis of this Primary Endpoint. The upper limit of the two-sided 95% CI for the estimate of the exit rate at Day 112 for the BRV 50 mg/day arm, 0.638, was lower than the historical control exit rate of 0.722. Therefore the BRV 50 mg/day arm was considered statistically superior to historical control.
    End point values
    Efficacy Set (Brivaracetam 50 mg treated subjects)
    Number of subjects analysed
    45
    Units: percentage of subjects
        number (confidence interval 95%)
    0.474 (0.31 to 0.638)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events were collected from Week 0 over the 1-week BRV Add-On Period and the 15-week Evaluation Period until the end fo Follow-Up Period (Week 23) or Early Discontinuation Visit.
    Adverse event reporting additional description
    Adverse Events refer to the Intent-to-Treat (ITT) Set, consisting of all randomized subjects with at least 1 intake of study medication.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Brivaracetam (BRV) 50 mg
    Reporting group description
    50 mg daily for 17 weeks (or 21 weeks if down-titrated (50 mg > 20 mg) for subjects not participating in the follow-up study).

    Reporting group title
    Brivaracetam (BRV) 100 mg
    Reporting group description
    100 mg daily for 17 weeks (or 21 weeks if down-titrated (100 mg > 50 mg > 20 mg) for subjects not participating in the follow-up study).

    Serious adverse events
    Brivaracetam (BRV) 50 mg Brivaracetam (BRV) 100 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 47 (6.38%)
    1 / 15 (6.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Intentional overdose
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 15 (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
    Convulsion
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    1 / 47 (2.13%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Brivaracetam (BRV) 50 mg Brivaracetam (BRV) 100 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 47 (65.96%)
    10 / 15 (66.67%)
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 47 (8.51%)
    2 / 15 (13.33%)
         occurrences all number
    4
    2
    Irritability
         subjects affected / exposed
    5 / 47 (10.64%)
    0 / 15 (0.00%)
         occurrences all number
    6
    0
    Asthenia
         subjects affected / exposed
    4 / 47 (8.51%)
    0 / 15 (0.00%)
         occurrences all number
    4
    0
    Chest pain
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    3 / 47 (6.38%)
    2 / 15 (13.33%)
         occurrences all number
    3
    2
    Insomnia
         subjects affected / exposed
    4 / 47 (8.51%)
    0 / 15 (0.00%)
         occurrences all number
    4
    0
    Anxiety
         subjects affected / exposed
    4 / 47 (8.51%)
    0 / 15 (0.00%)
         occurrences all number
    5
    0
    Suicidal ideation
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Skin laceration
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Muscle strain
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    Investigations
    Electrocardiogram ST segment depression
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    White blood cells urine positive
         subjects affected / exposed
    1 / 47 (2.13%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    7 / 47 (14.89%)
    2 / 15 (13.33%)
         occurrences all number
    8
    2
    Convulsion
         subjects affected / exposed
    5 / 47 (10.64%)
    2 / 15 (13.33%)
         occurrences all number
    11
    2
    Headache
         subjects affected / exposed
    4 / 47 (8.51%)
    1 / 15 (6.67%)
         occurrences all number
    5
    1
    Grand mal convulsion
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 15 (0.00%)
         occurrences all number
    4
    0
    Lethargy
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Memory impairment
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 47 (4.26%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    Vomiting
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 15 (0.00%)
         occurrences all number
    3
    0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    3 / 47 (6.38%)
    0 / 15 (0.00%)
         occurrences all number
    3
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Hypophosphataemia
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Decreased appetite
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 15 (13.33%)
         occurrences all number
    1
    2
    Infections and infestations
    Asymptomatic bacteriuria
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Bronchitis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 47 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Apr 2008
    Protocol Amendment 1 was finalized on 04 Apr 2008, before any subjects were enrolled, and resulted in the following: • Replacement of the option for enrollment in N01199 and N01125 with the option of enrollment in N01315. This change was based on feedback received from ethics committees and regulatory authorities in some European countries. Addition of text describing randomization stratification by region to provide clarity with regard to the percentage of the subjects anticipated for enrollment in the US • Clarification that the total duration of the Baseline Period was 8 weeks ±1 week • Replacement of exclusion criteria referring to “clusters” of seizures with “seizure patterns being too frequent or indistinctively separated to reliably be counted.” in order to more clearly define the term “clusters” • Addition of a recommendation for the sites to call subjects weekly to promote good completion of the subject diary. Text referring to this recommendation was added to the Informed Consent
    04 Apr 2008
    Protocol Amendment 1 was finalized on 04 Apr 2008, before any subjects were enrolled, and resulted in the following: • Replacement of the interactive voice response system (IVRS) with EDC for screening subjects. This change was made in accordance with recommendations of the IVRS and Seizure Frequency EDC system provider • Replacement of the subject’s daily record card (DRC) with the CRF as the location for recording the “Investigator Seizure Assessment” • Addition of requirement that Investigator confirm AEs next to subject’s entry of seizure data on DRC itself • Correction of typographical errors • Revision of the methods for handling missing data in acknowledgement of the fact that no details were known regarding the way missing data were handled, if at all, in the historical-control studies. Thus the application of any imputation rule for the assessment of Exit Criterion 2 during the study (and implemented in the study EDC system) leading to subjects being prematurely or incorrectly exited from the study was avoided. Final sensitivity analyses were to include these revised methods. The possibility for the Investigator exiting subjects on the basis of Exit Criterion 4 was considered an adequate safeguard against subjects remaining too long in the study if missing data interfered with the assessment of Exit Criteria 1 or 2.
    02 Nov 2009
    Protocol Amendment 2 was finalized on 02 Nov 2009 and resulted in the following: • Addition of a recruitment hold and interim analysis. This change was motivated by ongoing monitoring that suggested a higher than expected number of subjects discontinuing either for predefined exit criteria or other reasons. The interim analysis was to include efficacy information for all subjects who had an opportunity to complete 112 days of treatment after initiation of concomitant AED tapering by the time of the defined clinical cut-off date • Establishment of an IDMC to review primary efficacy, sensitivity, and safety data for the purpose of making a recommendation to the Sponsor regarding study continuation • Elimination of the requirement for restricted database access of the study team before approval of the final Statistical Analysis Plan (SAP) in accordance UCB Standard Operating Procedures (SOPs) revised subsequent to study initiation. Due to this change and because the primary efficacy analysis was fully specified in the original and amended protocols, this requirement was eliminated from this protocol • Updates of UCB study personnel and the List of Abbreviations Following the recruitment hold a decision was made to require subjects who were in the Baseline Period, the BRV Add-On Period, and the AED Tapering Phase to terminate the study. Subjects who had already progressed to the Monotherapy Phase were permitted to remain in the study.
    16 Nov 2009
    Protocol Amendment 3 was finalized on 16 Nov 2009 (after the recruitment hold) and resulted in the following: • Provision for enrollment in N01315 for subjects discontinued from the BRV Add-On Period or the Baseline AED Tapering Phase due to recruitment hold and interim analysis. This enrollment option was made available to provide continued treatment with BRV to these subjects as deemed beneficial by both subjects and Investigators • Correction of an error in Amendment 2 that placed information pertaining to database access and SAP finalization in an incorrect section of the protocol

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    02 Nov 2009
    Concerning high discontinuation rate and subsequent determination of low probabilty of success (eg, criteria for futility were met).
    -

    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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