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    Clinical Trial Results:
    Open-label, single-arm, multicenter, pharmacokinetic, safety, and efficacy study of adjunctive administration of brivaracetam in subjects from ≥1 month to <16 years old with epilepsy

    Due to a system error, the data reported in v1 is not correct and has been removed from public view.
    Summary
    EudraCT number
    2006-006536-22
    Trial protocol
    BE   CZ   ES   PL   Outside EU/EEA  
    Global end of trial date
    13 Mar 2013

    Results information
    Results version number
    v2(current)
    This version publication date
    09 Nov 2017
    First version publication date
    30 Jul 2015
    Other versions
    v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    Correction of full data set: outcome measure titles correction.

    Trial information

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    Trial identification
    Sponsor protocol code
    N01263
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00422422
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB Pharma SA
    Sponsor organisation address
    Allée de la Recherche 60, Brussels, Belgium, B-1070
    Public contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, 0049 2173 48 15 15, clinicaltrials@ucb.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, 0049 2173 48 15 15, clinicaltrials@ucb.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000332-PIP01-08
    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
    08 May 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Mar 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives were to characterize the steady-state pharmacokinetics (PK) of brivaracetam (BRV) and its metabolites in subjects from ≥1 month to <16 years of age, evaluate their relationship with physiological developmental variables, and develop dosing adaptations.
    Protection of trial subjects
    Informed consent was obtained and documented in accordance with local regulations, ICH-GCP requirements, and the ethical principles that have their origin in the principles of the Declaration of Helsinki. Prior to obtaining informed consent, information was given in a language and at a level of complexity understandable in both oral and written form by the Investigator (or designee). Parent(s), legal representative(s), and subject if applicable had the opportunity to discuss the study and its alternatives with the Investigator.
    Background therapy
    N/A
    Evidence for comparator
    N/A
    Actual start date of recruitment
    05 Jul 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Czech Republic: 5
    Country: Number of subjects enrolled
    Mexico: 19
    Country: Number of subjects enrolled
    Poland: 30
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    United States: 29
    Worldwide total number of subjects
    100
    EEA total number of subjects
    52
    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)
    30
    Children (2-11 years)
    52
    Adolescents (12-17 years)
    18
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The N01263 study began recruitment in July 2011, with subjects enrolled in the European Union, Mexico, and the United States. The study concluded in March 2013.

    Pre-assignment
    Screening details
    Participant Flow data is taken from the Enrolled Set, which is all subjects enrolled into the study.

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

    Arms
    Arm title
    Brivaracetam (ES)
    Arm description
    Enrolled Subjects, which is all subjects enrolled into the study.
    Arm type
    Experimental

    Investigational medicinal product name
    Brivaracetam
    Investigational medicinal product code
    BRV
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    For subjects ≥8 years: • 0.4 mg/kg bid for Week 1 • 0.8 mg/kg bid for Week 2 • 1.6 mg/kg bid for Week 3 For subjects <8 years: • 0.5 mg/kg bid for Week 1 • 1.0 mg/kg bid for Week 2 • 2.0 mg/kg bid for Week 3 Down-titration period (up to 2 weeks): For subjects ≥8 years: • 0.8 mg/kg bid for Week 4 • 0.4 mg/kg bid for Week 5 For subjects <8 years: • 1.0 mg/kg bid for Week 4 • 0.5 mg/kg bid for Week 5

    Number of subjects in period 1
    Brivaracetam (ES)
    Started
    100
    Completed
    90
    Not completed
    10
         Protocol deviation
    1
         Lack of efficacy
    1
         SAE, non-fatal
    1
         AE, non-serious non-fatal
    5
         Consent withdrawn by subject
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brivaracetam (ES)
    Reporting group description
    Enrolled Subjects, which is all subjects enrolled into the study.

    Reporting group values
    Brivaracetam (ES) Total
    Number of subjects
    100
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    6.3 ± 4.8 -
    Gender Categorical
    Units: Subjects
        Male
    49 49
        Female
    51 51
    Racial Group
    Units: Subjects
        Black or African American
    4 4
        White
    80 80
        Other
    16 16
    Weight
    Units: kilograms
        arithmetic mean (standard deviation)
    24.2 ± 16.2 -
    Height
    Units: centimeters
        arithmetic mean (standard deviation)
    111.8 ± 32.9 -
    BMI
    Units: kg/m^2
        median (standard deviation)
    17.1 ± 3.4 -

    End points

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    End points reporting groups
    Reporting group title
    Brivaracetam (ES)
    Reporting group description
    Enrolled Subjects, which is all subjects enrolled into the study.

    Subject analysis set title
    Brivaracetam (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Full Analysis Set, which is all subjects in the Safety Set, who have at least 1 completed post-Baseline Daily Record Card (DRC) or electroencephalogram (EEG).

    Subject analysis set title
    Brivaracetam (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Safety Set, which is all enrolled subjects who took at least 1 dose of study medication. All safety analyses will be performed on the Safety Set.

    Subject analysis set title
    Brivaracetam (PPS)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Pharmacokinetic Per Protocol Set consists of all subjects who provided at least 1 measurable plasma sample on at least 1 visit with documented drug intake times.

    Primary: Mean Trough Plasma Concentration at 3rd Level for age range greater or equals to 1 month to less than 2 years

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    End point title
    Mean Trough Plasma Concentration at 3rd Level for age range greater or equals to 1 month to less than 2 years [1]
    End point description
    End point type
    Primary
    End point timeframe
    Day 21
    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: The primary objectives of study N01263 were to characterize the steady-state pharmacokinetics (PK) of brivaracetam (BRV) and its metabolites in subjects from ≥1 month to <16 years of age, evaluate their relationship with physiological developmental variables, and develop dosing adaptations. Descriptive statistics were used for the description of the PK profile of BRV across several variables. Therefore, no statistical analysis is entered.
    End point values
    Brivaracetam (PPS)
    Number of subjects analysed
    12
    Units: ug/mL
    arithmetic mean (standard deviation)
        mean (standard deviation)
    0.825 ± 0.826
    No statistical analyses for this end point

    Primary: Mean Trough Plasma Concentration at 3rd Level for age range greater or equals to 2 to less than 12 years

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    End point title
    Mean Trough Plasma Concentration at 3rd Level for age range greater or equals to 2 to less than 12 years [2]
    End point description
    End point type
    Primary
    End point timeframe
    Day 21
    Notes
    [2] - 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: The primary objectives of study N01263 were to characterize the steady-state pharmacokinetics (PK) of brivaracetam (BRV) and its metabolites in subjects from ≥1 month to <16 years of age, evaluate their relationship with physiological developmental variables, and develop dosing adaptations. Descriptive statistics were used for the description of the PK profile of BRV across several variables. Therefore, no statistical analysis is entered.
    End point values
    Brivaracetam (PPS)
    Number of subjects analysed
    22
    Units: ug/mL
    arithmetic mean (standard deviation)
        mean (standard deviation)
    0.967 ± 0.536
    No statistical analyses for this end point

    Primary: Mean Trough Plasma Concentration at 3rd Level for age range greater or equals to 12 to less than 16 years

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    End point title
    Mean Trough Plasma Concentration at 3rd Level for age range greater or equals to 12 to less than 16 years [3]
    End point description
    End point type
    Primary
    End point timeframe
    Day 21
    Notes
    [3] - 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: The primary objectives of study N01263 were to characterize the steady-state pharmacokinetics (PK) of brivaracetam (BRV) and its metabolites in subjects from ≥1 month to <16 years of age, evaluate their relationship with physiological developmental variables, and develop dosing adaptations. Descriptive statistics were used for the description of the PK profile of BRV across several variables. Therefore, no statistical analysis is entered.
    End point values
    Brivaracetam (PPS)
    Number of subjects analysed
    4
    Units: ug/mL
    arithmetic mean (standard deviation)
        mean (standard deviation)
    1.117 ± 0.4
    No statistical analyses for this end point

    Primary: Mean Max Plasma Concentration for age range greater or equals to 1 month to less than 2 years

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    End point title
    Mean Max Plasma Concentration for age range greater or equals to 1 month to less than 2 years [4]
    End point description
    End point type
    Primary
    End point timeframe
    Day 7 - 21
    Notes
    [4] - 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: The primary objectives of study N01263 were to characterize the steady-state pharmacokinetics (PK) of brivaracetam (BRV) and its metabolites in subjects from ≥1 month to <16 years of age, evaluate their relationship with physiological developmental variables, and develop dosing adaptations. Descriptive statistics were used for the description of the PK profile of BRV across several variables. Therefore, no statistical analysis is entered.
    End point values
    Brivaracetam (PPS)
    Number of subjects analysed
    12
    Units: ug/mL
    arithmetic mean (full range (min-max))
        mean (full range)
    2.071 (0.32 to 4.305)
    No statistical analyses for this end point

    Primary: Mean Max Plasma Concentration for age range greater or equals to 2 to less than 12 years

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    End point title
    Mean Max Plasma Concentration for age range greater or equals to 2 to less than 12 years [5]
    End point description
    End point type
    Primary
    End point timeframe
    Day 7 - 21
    Notes
    [5] - 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: The primary objectives of study N01263 were to characterize the steady-state pharmacokinetics (PK) of brivaracetam (BRV) and its metabolites in subjects from ≥1 month to <16 years of age, evaluate their relationship with physiological developmental variables, and develop dosing adaptations. Descriptive statistics were used for the description of the PK profile of BRV across several variables. Therefore, no statistical analysis is entered.
    End point values
    Brivaracetam (PPS)
    Number of subjects analysed
    22
    Units: ug/mL
    arithmetic mean (full range (min-max))
        mean (full range)
    2.673 (0.561 to 5.418)
    No statistical analyses for this end point

    Primary: Mean Max Plasma Concentration for age range greater or equals to 12 to less than 16 years

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    End point title
    Mean Max Plasma Concentration for age range greater or equals to 12 to less than 16 years [6]
    End point description
    End point type
    Primary
    End point timeframe
    Day 7 - 21
    Notes
    [6] - 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: The primary objectives of study N01263 were to characterize the steady-state pharmacokinetics (PK) of brivaracetam (BRV) and its metabolites in subjects from ≥1 month to <16 years of age, evaluate their relationship with physiological developmental variables, and develop dosing adaptations. Descriptive statistics were used for the description of the PK profile of BRV across several variables. Therefore, no statistical analysis is entered.
    End point values
    Brivaracetam (PPS)
    Number of subjects analysed
    4
    Units: ug/mL
    arithmetic mean (full range (min-max))
        mean (full range)
    2.861 (2.627 to 3.371)
    No statistical analyses for this end point

    Secondary: Number of subjects with at least one treatment-emergent adverse event reported during the 3-week evaluation period

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    End point title
    Number of subjects with at least one treatment-emergent adverse event reported during the 3-week evaluation period
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to end of the 3-week evaluation period
    End point values
    Brivaracetam (SS)
    Number of subjects analysed
    99
    Units: participants
        number
    66
    No statistical analyses for this end point

    Secondary: Percent compliance with brivaracetam oral solution during the 3-week evaluation period

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    End point title
    Percent compliance with brivaracetam oral solution during the 3-week evaluation period
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to the end of the 3-week evaluation period
    End point values
    Brivaracetam (SS)
    Number of subjects analysed
    97
    Units: participants
    number (not applicable)
        <80 %
    5
        80 % to 120 %
    90
        >120 %
    2
    No statistical analyses for this end point

    Secondary: Number of subjects with a 50 % reduction in seizures based on seizure diary data from baseline to end of the 3-week evaluation period

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    End point title
    Number of subjects with a 50 % reduction in seizures based on seizure diary data from baseline to end of the 3-week evaluation period
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to end of the 3-week evaluation period
    End point values
    Brivaracetam (FAS)
    Number of subjects analysed
    80
    Units: participants
        number
    17
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent Adverse Events (TEAEs) were collected during the course of the study, which started July 2011 and concluded March 2013. The Safety Set will be utilized for TEAE reporting.
    Adverse event reporting additional description
    The Safety Set is all enrolled subjects who took at least 1 dose of study drug. Subjects had the ability to report more than one event. The Serious Adverse Events and Non-serious Adverse Events sections are reported in this manner.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Brivaracetam (SS)
    Reporting group description
    Safety Set, which is all enrolled subjects who took at least 1 dose of study medication. All safety analyses will be performed on the SS.

    Serious adverse events
    Brivaracetam (SS)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 99 (8.08%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Investigations
    Cytomegalovirus test positive
         subjects affected / exposed
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    4 / 99 (4.04%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 99 (2.02%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Respiratory tract infection
         subjects affected / exposed
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Toxoplasmosis
         subjects affected / exposed
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 99 (1.01%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Brivaracetam (SS)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 99 (33.33%)
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    8 / 99 (8.08%)
         occurrences all number
    9
    Convulsion
         subjects affected / exposed
    6 / 99 (6.06%)
         occurrences all number
    7
    General disorders and administration site conditions
    Irritability
         subjects affected / exposed
    8 / 99 (8.08%)
         occurrences all number
    9
    Pyrexia
         subjects affected / exposed
    7 / 99 (7.07%)
         occurrences all number
    8
    Fatigue
         subjects affected / exposed
    5 / 99 (5.05%)
         occurrences all number
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    7 / 99 (7.07%)
         occurrences all number
    7
    Infections and infestations
    Pharyngotonsillitis
         subjects affected / exposed
    5 / 99 (5.05%)
         occurrences all number
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Feb 2011
    Protocol Amendment 1 (dated 24 Feb 2011) was implemented prior to the date of first patient first visit (FPFV on 05 Jul 2011). The rationale for this amendment was to update the Sponsor’s name and to add the Investigational New Drug number. Also, the Food and Drug Administration (FDA) recommendation that a PK blood sample should be taken whenever the subject reports a Serious Adverse Event (SAE) was added.
    26 Aug 2011
    Protocol Amendment 2 (dated 26 Aug 2011) was implemented after the date of FPFV. The rationale for this amendment was to include the Bayley Scales of Infant Development™, Second Edition (BSID-II™) in order to assess the cognitive development of pediatric subjects <18 months at Baseline in response to the European Medicines Agency’s (EMA) Paediatric Committee’s (PDCO) request. Exclusion and withdrawal criteria were extended to include the consequences of any findings related to the results of the liver function tests (LFTs). Procedures for reporting SAEs were updated to implement the FDA Final Rule requirements (Investigational new drug safety reporting requirements for human drug and biological products and safety reporting requirements for bioavailability and bioequivalence studies in humans, 21 Code of Federal Regulations [CFR] Parts 312 and 320, 2010). The Columbia-Suicide Severity Rating Scale (C-SSRS) was added to address the request of the FDA that prospective assessments for suicidality should be included in clinical studies involving all drugs for neurological indications. Some operational updates (eg, the replacement of the paper-based Case Report form [CRF] with an eCRF) were also considered.
    15 Dec 2011
    Protocol Amendment 3 (dated 15 Dec 2011) was implemented after the date of FPFV. The rationale for this amendment was to replace the pediatric subjects’ version of the C-SSRS with the version validated in multiple languages for subjects 6 years of age and older. The BSID-II score was replaced by the Bayley Scales of Infant and Toddler Development®, Third Edition (Bayley-III®) scales in order to apply the most recent version of the cognition scale; no data were collected using the BSID-II before this change was implemented. In addition, it was clarified that the cognition scale would be used only in English-speaking countries, since it was validated only in English. The requirements for blood sampling (volumes and frequencies of the blood samples) were updated based on the subject’s body weight and all sections referring to biochemistry assessments were amended in order to clarify that tests for hepatic monitoring were to be included in all safety laboratory assessments. Furthermore, an error in the mathematical symbols used for the presentation of the age limits of the EEG assessments was corrected, and the SAE reporting details were updated. Administrative changes included the update of the Clinical Project Manager contact details and typographical corrections.

    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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