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    Clinical Trial Results:
    A multi-center, open-label, four-arm, randomized trial evaluating the safety and tolerability of Brivaracetam intravenous infusion and bolus, administered in BID regimen as an adjunctive antiepileptic treatment in subjects from 16 to 70 years suffering from epilepsy

    Summary
    EudraCT number
    2008-004714-27
    Trial protocol
    CZ   DE  
    Global end of trial date
    20 Jul 2012

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Apr 2016
    First version publication date
    02 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    N01258
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01405508
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB Biosciences Inc.
    Sponsor organisation address
    8010 Arco Corporate Drive, Raleigh, United States, NC 27617
    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
    26 Sep 2012
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jul 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the safety and tolerability of Brivaracetam (BRV) 200 mg/day administered intravenous (iv) as an infusion or a bolus, according to an initiation or a conversion scheme, during repeated dosing (100 mg/Administration twice a day (bid) for 4.5 days) as an adjunctive treatment in adult subjects suffering from localization-related or generalized epilepsy.
    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
    09 Aug 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    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
    United States: 74
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Poland: 16
    Country: Number of subjects enrolled
    Czech Republic: 8
    Worldwide total number of subjects
    105
    EEA total number of subjects
    31
    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)
    103
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study started to recruit patients in August 2011 and concluded in July 2012. 105 subjects were randomized to 4 different treatment groups.

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

    Period 1
    Period 1 title
    Study Overall (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo tablets / Brivaracetam bolus
    Arm description
    Subjects will receive Placebo (PBO) tablets for one week followed by Brivaracetam (BRV) bolus for 4.5 days. Down-Titration: - If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In - If subject discontinues during the Evaluation Period or after Day 12, the subject will receive Placebo tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week
    Arm type
    Experimental

    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
    100 mg twice daily (BID) for 7 days during Run-In Period.

    Investigational medicinal product name
    Brivaracetam bolus
    Investigational medicinal product code
    BRV bolus
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    10 mL (= 100 mg) of Brivaracetam administered intravenously over 2 minutes twice daily (BID) during Evaluation Period.

    Arm title
    Placebo tablets / Brivaracetam infusion
    Arm description
    Subjects will receive Placebo (PBO) tablets for one week followed by Brivaracetam (BRV) intravenous infusion for 4.5 days. Down-Titration: - If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In - If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week
    Arm type
    Experimental

    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
    100 mg twice daily (BID) for 7 days during Run-In Period.

    Investigational medicinal product name
    Brivaracetam infusion
    Investigational medicinal product code
    BRV infusion
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 mL (= 100 mg) of Brivaracetam diluted in 90 mL 0.9 % isotonic saline sterile solution for intravenous administration infused over 15 minutes twice daily (BID) during Evaluation Period.

    Arm title
    Brivaracetam (BRV) tablets / BRV bolus
    Arm description
    Subjects will receive Brivaracetam (BRV) tablets for one week followed by BRV bolus for 4.5 days. Down-Titration: - If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In - If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake bid for the fourth week
    Arm type
    Experimental

    Investigational medicinal product name
    Brivaracetam tablets
    Investigational medicinal product code
    BRV tablets
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg, intake twice daily (BID) for 7 days during Run-In Period.

    Investigational medicinal product name
    Brivaracetam bolus
    Investigational medicinal product code
    BRV bolus
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    10 mL (= 100 mg) of Brivaracetam administered intravenously over 2 minutes twice daily (BID) during Evaluation Period.

    Arm title
    Brivaracetam (BRV) tablets / BRV infusion
    Arm description
    Subjects will receive Brivaracetam (BRV) tablets for one week followed by Brivaracetam intravenous infusion for 4.5 days. Down-Titration: - If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In - If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week
    Arm type
    Experimental

    Investigational medicinal product name
    Brivaracetam tablets
    Investigational medicinal product code
    BRV tablets
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg, intake twice daily (BID) for 7 days during Run-In Period.

    Investigational medicinal product name
    Brivaracetam infusion
    Investigational medicinal product code
    BRV infusion
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 mL (= 100 mg) of Brivaracetam diluted in 90 mL 0.9 % isotonic saline sterile solution for intravenous administration infused over 15 minutes twice daily (BID) during Evaluation Period.

    Number of subjects in period 1
    Placebo tablets / Brivaracetam bolus Placebo tablets / Brivaracetam infusion Brivaracetam (BRV) tablets / BRV bolus Brivaracetam (BRV) tablets / BRV infusion
    Started
    26
    26
    27
    26
    Completed
    25
    25
    27
    26
    Not completed
    1
    1
    0
    0
         AE, non-serious non-fatal
    1
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo tablets / Brivaracetam bolus
    Reporting group description
    Subjects will receive Placebo (PBO) tablets for one week followed by Brivaracetam (BRV) bolus for 4.5 days. Down-Titration: - If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In - If subject discontinues during the Evaluation Period or after Day 12, the subject will receive Placebo tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week

    Reporting group title
    Placebo tablets / Brivaracetam infusion
    Reporting group description
    Subjects will receive Placebo (PBO) tablets for one week followed by Brivaracetam (BRV) intravenous infusion for 4.5 days. Down-Titration: - If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In - If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week

    Reporting group title
    Brivaracetam (BRV) tablets / BRV bolus
    Reporting group description
    Subjects will receive Brivaracetam (BRV) tablets for one week followed by BRV bolus for 4.5 days. Down-Titration: - If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In - If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake bid for the fourth week

    Reporting group title
    Brivaracetam (BRV) tablets / BRV infusion
    Reporting group description
    Subjects will receive Brivaracetam (BRV) tablets for one week followed by Brivaracetam intravenous infusion for 4.5 days. Down-Titration: - If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In - If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week

    Reporting group values
    Placebo tablets / Brivaracetam bolus Placebo tablets / Brivaracetam infusion Brivaracetam (BRV) tablets / BRV bolus Brivaracetam (BRV) tablets / BRV infusion Total
    Number of subjects
    26 26 27 26 105
    Age Categorical
    Units: Subjects
        <=18 years
    0 0 0 0 0
        Between 18 and 65 years
    26 25 27 25 103
        >=65 years
    0 1 0 1 2
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    40.6 ± 12.2 39.5 ± 14.4 42 ± 9.2 44.4 ± 12.6 -
    Gender Categorical
    Units: Subjects
        Male
    14 16 10 9 49
        Female
    12 10 17 17 56

    End points

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    End points reporting groups
    Reporting group title
    Placebo tablets / Brivaracetam bolus
    Reporting group description
    Subjects will receive Placebo (PBO) tablets for one week followed by Brivaracetam (BRV) bolus for 4.5 days. Down-Titration: - If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In - If subject discontinues during the Evaluation Period or after Day 12, the subject will receive Placebo tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week

    Reporting group title
    Placebo tablets / Brivaracetam infusion
    Reporting group description
    Subjects will receive Placebo (PBO) tablets for one week followed by Brivaracetam (BRV) intravenous infusion for 4.5 days. Down-Titration: - If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In - If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week

    Reporting group title
    Brivaracetam (BRV) tablets / BRV bolus
    Reporting group description
    Subjects will receive Brivaracetam (BRV) tablets for one week followed by BRV bolus for 4.5 days. Down-Titration: - If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In - If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake bid for the fourth week

    Reporting group title
    Brivaracetam (BRV) tablets / BRV infusion
    Reporting group description
    Subjects will receive Brivaracetam (BRV) tablets for one week followed by Brivaracetam intravenous infusion for 4.5 days. Down-Titration: - If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In - If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week

    Primary: Number of subjects with at least one treatment-emergent adverse event during the study (maximum 40 days)

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    End point title
    Number of subjects with at least one treatment-emergent adverse event during the study (maximum 40 days) [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 could therefore be any unfavorable and unintended sign, 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
    40 days
    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 tablets / Brivaracetam bolus Placebo tablets / Brivaracetam infusion Brivaracetam (BRV) tablets / BRV bolus Brivaracetam (BRV) tablets / BRV infusion
    Number of subjects analysed
    26
    26
    27
    26
    Units: Participants
        Number of subjects
    20
    19
    21
    20
    No statistical analyses for this end point

    Secondary: Number of subjects who withdrew due to a treatment-emergent adverse event during the study (maximum 40 days)

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    End point title
    Number of subjects who withdrew due to a treatment-emergent adverse event during the study (maximum 40 days)
    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 could therefore be any unfavorable and unintended sign, 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
    Secondary
    End point timeframe
    40 days
    End point values
    Placebo tablets / Brivaracetam bolus Placebo tablets / Brivaracetam infusion Brivaracetam (BRV) tablets / BRV bolus Brivaracetam (BRV) tablets / BRV infusion
    Number of subjects analysed
    26
    26
    27
    26
    Units: Participants
        Number of subjects
    1
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with at least one injection-related treatment-emergent adverse event (TEAE) during the Evaluation Period.

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    End point title
    Number of subjects with at least one injection-related treatment-emergent adverse event (TEAE) during the Evaluation Period.
    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 could therefore be any unfavorable and unintended sign, 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
    Secondary
    End point timeframe
    4.5-day Evaluation Period
    End point values
    Placebo tablets / Brivaracetam bolus Placebo tablets / Brivaracetam infusion Brivaracetam (BRV) tablets / BRV bolus Brivaracetam (BRV) tablets / BRV infusion
    Number of subjects analysed
    26
    26
    27
    26
    Units: Participants
        Number of subjects
    1
    3
    4
    3
    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 Baseline over Run-In (Day 1) and Evaluation Period (Day 8 to Day 12) to the Safety Visit or Early Discontinuation Visit (up to 54 days).
    Adverse event reporting additional description
    Adverse Events refer to the Safety Population consisting of all subjects who took at least 1 dose of study drug.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Placebo tablets / Brivaracetam bolus
    Reporting group description
    Subjects will receive Placebo (PBO) tablets for one week followed by Brivaracetam (BRV) bolus for 4.5 days. Down-Titration: o If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In o If subject discontinues during the Evaluation Period or after Day 12, the subject will receive Placebo tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week

    Reporting group title
    Brivaracetam (BRV) tablets / BRV bolus
    Reporting group description
    Subjects will receive Brivaracetam (BRV) tablets for one week followed by BRV bolus for 4.5 days. Down-Titration: o If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In o If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake bid for the fourth week

    Reporting group title
    Brivaracetam (BRV) tablets / BRV infusion
    Reporting group description
    Subjects will receive Brivaracetam (BRV) tablets for one week followed by Brivaracetam intravenous infusion for 4.5 days. Down-Titration: o If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In o If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week

    Reporting group title
    Placebo tablets / Brivaracetam infusion
    Reporting group description
    Subjects will receive Placebo (PBO) tablets for one week followed by Brivaracetam (BRV) intravenous infusion for 4.5 days. Down-Titration: o If subject discontinues the study during the Run-In Period, then the subject will receive the treatment that he/she was assigned during Run-In o If subject discontinues during the Evaluation Period or after Day 12, the subject will receive BRV tablets during Down-Titration: Tablets will be provided for 4 weeks; 75 mg / intake BID for the first week, 50 mg / intake BID for the second week, 25 mg / intake BID for the third week, 10 mg / intake BID for the fourth week

    Serious adverse events
    Placebo tablets / Brivaracetam bolus Brivaracetam (BRV) tablets / BRV bolus Brivaracetam (BRV) tablets / BRV infusion Placebo tablets / Brivaracetam infusion
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo tablets / Brivaracetam bolus Brivaracetam (BRV) tablets / BRV bolus Brivaracetam (BRV) tablets / BRV infusion Placebo tablets / Brivaracetam infusion
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 26 (65.38%)
    15 / 27 (55.56%)
    14 / 26 (53.85%)
    15 / 26 (57.69%)
    Cardiac disorders
    Postural orthostatic tachycardia syndrome
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    0
    2
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    8 / 26 (30.77%)
    7 / 27 (25.93%)
    9 / 26 (34.62%)
    7 / 26 (26.92%)
         occurrences all number
    8
    9
    10
    7
    Dizziness
         subjects affected / exposed
    4 / 26 (15.38%)
    3 / 27 (11.11%)
    4 / 26 (15.38%)
    4 / 26 (15.38%)
         occurrences all number
    4
    3
    4
    4
    Headache
         subjects affected / exposed
    2 / 26 (7.69%)
    2 / 27 (7.41%)
    2 / 26 (7.69%)
    1 / 26 (3.85%)
         occurrences all number
    2
    3
    2
    1
    Dysgeusia
         subjects affected / exposed
    2 / 26 (7.69%)
    2 / 27 (7.41%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    2
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 26 (3.85%)
    3 / 27 (11.11%)
    0 / 26 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    1
    4
    0
    4
    Infusion site pain
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 27 (7.41%)
    0 / 26 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    2
    0
    3
    Injection site erythema
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 27 (7.41%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Injection site pain
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 27 (7.41%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 26 (3.85%)
    2 / 27 (7.41%)
    1 / 26 (3.85%)
    1 / 26 (3.85%)
         occurrences all number
    1
    2
    1
    1
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    1 / 26 (3.85%)
    2 / 27 (7.41%)
    0 / 26 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 26 (11.54%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
    1 / 26 (3.85%)
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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Dec 2008
    Protocol Amendment 1 was approved and effective prior to the date of first patient first visit (FPFV). The rationale for this amendment was to integrate the USA Food and Drug Administration (FDA) recommendations regarding cardiac monitoring, received on 20 Nov 2008: - At V2, an ECG was added - Immediately after each BRV iv administration, ECGs were added - A central reader was organized for the ECG tracings - The section describing the adverse events (AEs) was updated to be consistent with the new CRF AE module - The recently defined IND number for BRV iv development was implemented
    05 Mar 2009
    Protocol Amendment 2 was approved and effective prior to the date of FPFV. The rationale for this amendment was to integrate the USA FDA recommendations regarding cardiac monitoring, as expressed in their letter received on 19 Feb 2009, in response to the Investigational New Drug (IND) submission for BRV iv solution: - 12-lead ECGs were to be recorded; predose and at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, and 12 hours immediately after the initiation of BRV iv administration - During the BRV iv administration, continuous live monitoring of ECG was included - There was a change in the statistical analysis of the ECG data, with only the central readings of the ECG data to be used in the descriptive and shift tables
    01 Apr 2011
    Protocol Amendment 3 was approved and effective prior to the date of FPFV. The rationale for this amendment was to increase the total daily dose of BRV to 200 mg/day (100 mg/intake bid) from the original dose of 100 mg/day (50 mg/intake bid) in line with the recommendation of the regulatory authorities and in accordance with the oral dose that UCB had selected for Evaluation in the new Phase 3 study (N01358). The following changes were made throughout the protocol: - The dose in the LTFU study (N01379) was increased from 100 mg/day to 200 mg/day - The Down-Titration Period was increased from 2 weeks to 4 weeks with a 4-step down-titration instead of the previous 2-step down-titration - The dosing schedule for the Down-Titration Period was clarified - The duration of the iv bolus was increased from 60 seconds to 2 minutes - The maximum study and treatment durations for each subject were increased - The number of sites expected to participate in the study was increased to approximately 35 - Information on blinding during the Run-In Period and the Down-Titration Period was added - Information on the description of the study drug, packaging, and supply was updated - The timing of serum and urine pregnancy tests was revised - The randomization and IVRS processes was updated
    01 Apr 2011
    The following changes were made throughout the protocol: - The patient-reported outcomes (PRO) questionnaires (Patient Weighted Quality of Life in Epilepsy Inventory-Form 31 [QOLIE-31-P] and Hospital Anxiety and Depression Scale [HADS]) were removed from the exploratory objectives and variables. Only baseline data were collected at V2 to allow for evaluation later in the LTFU study, N01379 - The EuroQoL-5 Dimensions questionnaire was removed - Socio-professional data were added at V2 to provide baseline data to allow for eEvaluation later in the LTFU study, N01379 - The collection and analysis of deoxyribonucleic acid (DNA) samples were removed, as this analysis will be conducted in another study - The exploratory objective for healthcare resource utilization was corrected to include this assessment at other visits as well as baseline data - The number of the LTFU study was added - The timing of the BRV and AED sampling during the iv administration was revised, and the sampling of concomitant AED levels at the SV (V8) was removed - Healthcare provider consultations not foreseen by the protocol was added as a component of the healthcare resource utilization variable - The Sponsor contact information was updated - The contract research organization (CRO) information was added - The protocol summary and introduction sections were updated - Other minor editorial changes were made to ensure consistency within the protocol and across the BRV program
    12 Sep 2011
    Protocol Amendment 4 was approved and effective after subjects had been enrolled in the study. The rationale for this amendment was to implement the USA FDA Final Rule requirements with regard to procedures for reporting serious adverse events (SAEs) and to address the requirement of the FDA that prospective assessments for suicidality should be included in clinical studies involving all drugs for neurological indications. The following changes were made throughout the protocol: - A suicidality assessment using the Columbia-Suicide Severity Rating Scale (C-SSRS) in response to the USA FDA requirement was included - The prospective assessment for suicidality using the C-SSRS was added to the exclusion criteria, withdrawal criteria, and safety assessments - The list of Anticipated SAEs in response to the USA FDA Final Rule was added - A few minor changes were made to the protocol to update the name of the Clinical Project Manager (CPM), to clarify some study conduct details, and to correct grammatical errors

    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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