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    Clinical Trial Results:
    AN OPEN-LABEL, MULTICENTER, FOLLOW-UP STUDY TO EVALUATE THE LONG-TERM SAFETY AND EFFICACY OF BRIVARACETAM USED AS ADJUNCTIVE TREATMENT IN SUBJECTS AGED 16 YEARS OR OLDER WITH EPILEPSY

    Summary
    EudraCT number
    2010-020345-27
    Trial protocol
    BE   DE   CZ   ES   GB   SE   FR   AT   FI   NL   IT   EE   LT   LV   HU   BG  
    Global end of trial date
    18 Apr 2019

    Results information
    Results version number
    v2(current)
    This version publication date
    01 Jul 2020
    First version publication date
    01 Nov 2019
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Alignment with final posting on ClinicalTrials.gov after NIH review.

    Trial information

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    Trial identification
    Sponsor protocol code
    N01379
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01339559
    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
    Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
    Scientific contact
    Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, 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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Jun 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Apr 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the long-term safety and tolerability of brivaracetam (BRV) at individualized doses up to a maximum of 200 mg/day in epilepsy subjects.
    Protection of trial subjects
    During the conduct of the study all participants were closely monitored.
    Background therapy
    Background therapy as permitted in the protocol.
    Evidence for comparator
    Not Applicable
    Actual start date of recruitment
    10 May 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 6
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    Brazil: 14
    Country: Number of subjects enrolled
    Bulgaria: 7
    Country: Number of subjects enrolled
    Canada: 16
    Country: Number of subjects enrolled
    Czech Republic: 42
    Country: Number of subjects enrolled
    Estonia: 22
    Country: Number of subjects enrolled
    Finland: 5
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Germany: 22
    Country: Number of subjects enrolled
    Hong Kong: 2
    Country: Number of subjects enrolled
    Hungary: 19
    Country: Number of subjects enrolled
    India: 33
    Country: Number of subjects enrolled
    Italy: 45
    Country: Number of subjects enrolled
    Japan: 7
    Country: Number of subjects enrolled
    Latvia: 8
    Country: Number of subjects enrolled
    Lithuania: 11
    Country: Number of subjects enrolled
    Mexico: 59
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Poland: 74
    Country: Number of subjects enrolled
    Russian Federation: 24
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 22
    Country: Number of subjects enrolled
    Spain: 44
    Country: Number of subjects enrolled
    Sweden: 15
    Country: Number of subjects enrolled
    Taiwan: 17
    Country: Number of subjects enrolled
    United Kingdom: 17
    Country: Number of subjects enrolled
    United States: 212
    Worldwide total number of subjects
    766
    EEA total number of subjects
    360
    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)
    13
    Adults (18-64 years)
    728
    From 65 to 84 years
    25
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study started to enroll patients in May 2011 and concluded in April 2019. 767 participants were included in the Enrolled Set but 1 participant from the United States of America was lost to follow-up and was excluded from the Safety Analysis Set.

    Pre-assignment
    Screening details
    Participants Flow refers to the Safety Set (SS).

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

    Arms
    Arm title
    Brivaracetam
    Arm description
    Brivaracetam (BRV) was administered with a maximum of 200 mg/day, twice, daily, incremented by 50 mg/day on a weekly basis, during the Up-Titration. During the Down-Titration Period, the BRV dose was decreased in steps of a maximum of 50 mg/day on a weekly basis. A last down-titration step at 20 mg/day for 1 week was included prior to the Post-Treatment Period.
    Arm type
    Experimental

    Investigational medicinal product name
    BRIVARACETAM
    Investigational medicinal product code
    BRV
    Other name
    UCB34714
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral film-coated tablets of BRV 10mg, 25mg, and 50mg were used in this study. The BRV 10mg dose (20 mg/day) was used only for down-titration.

    Number of subjects in period 1
    Brivaracetam
    Started
    766
    Completed
    368
    Not completed
    398
         Investigator decision
    2
         PI decision
    1
         Protocol deviation
    15
         Study closure at site
    1
         Pregnancy planned
    2
         Patient didn't wish to continue
    1
         Lack of efficacy
    164
         Adverse event, serious fatal
    5
         Epilepsy surgery
    1
         Subject choice
    89
         Incarcerated
    2
         Adverse event, non-fatal
    92
         Left the country
    1
         Lost to follow-up
    22

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Brivaracetam
    Reporting group description
    Brivaracetam (BRV) was administered with a maximum of 200 mg/day, twice, daily, incremented by 50 mg/day on a weekly basis, during the Up-Titration. During the Down-Titration Period, the BRV dose was decreased in steps of a maximum of 50 mg/day on a weekly basis. A last down-titration step at 20 mg/day for 1 week was included prior to the Post-Treatment Period.

    Reporting group values
    Brivaracetam Total
    Number of subjects
    766 766
    Age categorical
    Units: Subjects
        <=18 years
    19 19
        Between 18 and 65 years
    722 722
        >=65 years
    25 25
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    40.0 ± 12.9 -
    Gender categorical
    Units: Subjects
        Male
    370 370
        Female
    396 396

    End points

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    End points reporting groups
    Reporting group title
    Brivaracetam
    Reporting group description
    Brivaracetam (BRV) was administered with a maximum of 200 mg/day, twice, daily, incremented by 50 mg/day on a weekly basis, during the Up-Titration. During the Down-Titration Period, the BRV dose was decreased in steps of a maximum of 50 mg/day on a weekly basis. A last down-titration step at 20 mg/day for 1 week was included prior to the Post-Treatment Period.

    Subject analysis set title
    Brivaracetam (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Brivaracetam (BRV) was administered with a maximum of 200 mg/day, twice, daily, incremented by 50 mg/day on a weekly basis, during the Up-Titration. During the Down-Titration Period, the BRV dose was decreased in steps of a maximum of 50 mg/day on a weekly basis. A last down-titration step at 20 mg/day for 1 week was included prior to the Post-Treatment Period. Participants formed the Safety Set (SS).

    Subject analysis set title
    Brivaracetam (POS Efficacy)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Brivaracetam (BRV) was administered with a maximum of 200 mg/day, twice, daily, incremented by 50 mg/day on a weekly basis, during the Up-Titration. During the Down-Titration Period, the BRV dose was decreased in steps of a maximum of 50 mg/day on a weekly basis. A last down-titration step at 20 mg/day for 1 week was included prior to the Post-Treatment Period. Participants formed the Partial Onset Seizure Efficacy Set (POS Efficacy).

    Primary: Percentage of participants with at least one Treatment-Emergent Adverse Event (TEAE)

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    End point title
    Percentage of participants with at least one Treatment-Emergent Adverse Event (TEAE) [1]
    End point description
    Treatment-emergent Adverse Events (TEAEs) were defined as those events which started on or after the date of first dose of investigational medicinal product (IMP), or events in which severity worsened on or after the date of first dose of study medication. The event does not necessarily have a causal relationship with that treatment or usage.
    End point type
    Primary
    End point timeframe
    From Entry Visit (Month 0) until the Last Visit (up to 84 months)
    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 as descriptive statistics only.
    End point values
    Brivaracetam (SS)
    Number of subjects analysed
    766
    Units: Percentage of participants
        number (not applicable)
    83.9
    No statistical analyses for this end point

    Primary: Percentage of participants who withdrew due to Adverse Events (AEs)

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    End point title
    Percentage of participants who withdrew due to Adverse Events (AEs) [2]
    End point description
    An AE is any untoward medical occurrence in a participant or trial subject that is administered a drug or biologic (medicinal product) or that is using a medical device. The event does not necessarily have a causal relationship with that treatment or usage.
    End point type
    Primary
    End point timeframe
    From Entry Visit (Month 0) until the Last Visit (up to 84 months)
    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: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.
    End point values
    Brivaracetam (SS)
    Number of subjects analysed
    766
    Units: Percentage of participants
        number (not applicable)
    11.9
    No statistical analyses for this end point

    Primary: Percentage of participants with at least one Serious Adverse Event (SAE)

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    End point title
    Percentage of participants with at least one Serious Adverse Event (SAE) [3]
    End point description
    A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: - Results in death - Is life-threatening - Requires in patient hospitalization or prolongation of existing hospitalization - Is a congenital anomaly or birth defect - Is as infection that requires treatment parenteral antibiotics - Other important medical events which based on medical or scientific judgement may jeopardize the patients or may require medical or surgical intervention to prevent any of the above.
    End point type
    Primary
    End point timeframe
    From Entry Visit (Month 0) until the Last Visit (up to 84 months)
    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: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.
    End point values
    Brivaracetam (SS)
    Number of subjects analysed
    766
    Units: Percentage of participants
        number (not applicable)
    18.4
    No statistical analyses for this end point

    Secondary: Partial onset seizure (POS) (type I) frequency per 28 days during the Evaluation Period

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    End point title
    Partial onset seizure (POS) (type I) frequency per 28 days during the Evaluation Period
    End point description
    The 28 day adjusted seizure frequency was calculated by dividing the number of partial seizures by the number of days for which the diary was completed, and multiplying the resulting value by 28.
    End point type
    Secondary
    End point timeframe
    From Baseline of the previous study until the Last Visit (up to 84 months)
    End point values
    Brivaracetam (POS Efficacy)
    Number of subjects analysed
    749
    Units: Seizures per 28 days
    median (inter-quartile range (Q1-Q3))
        Baseline
    9.7 (5.5 to 23.7)
        On Treatment
    4.2 (1.4 to 12.7)
    No statistical analyses for this end point

    Secondary: Percent change in Partial Onset Seizure (POS) (Type I) frequency per 28 days from Baseline of the previous study to the Evaluation Period

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    End point title
    Percent change in Partial Onset Seizure (POS) (Type I) frequency per 28 days from Baseline of the previous study to the Evaluation Period
    End point description
    The percent change from the previous study baselines, in Partial Onset Seizure (POS) (Type I) frequency per 28 days is defined as: (the value at the previous study baselines) minus (the value at each time-points during the evaluation period) divided by the value at the previous study baselines. Note: Since N01258 was a safety study, participants were not required to meet seizure frequency requirements during the Baseline Period, and the Baseline Period was short (ie, 7 days). Therefore, participants from N01258 were excluded from efficacy summaries in the variable of percent change in POS frequency.
    End point type
    Secondary
    End point timeframe
    From Baseline of the previous study until the Last Visit (up to 84 months)
    End point values
    Brivaracetam (POS Efficacy)
    Number of subjects analysed
    675
    Units: Percent change
        median (inter-quartile range (Q1-Q3))
    52.0 (16.8 to 81.5)
    No statistical analyses for this end point

    Secondary: Responder rate in POS (type I) frequency over the Evaluation Period

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    End point title
    Responder rate in POS (type I) frequency over the Evaluation Period
    End point description
    A responder is defined as a subject with a ≥ 50% reduction in seizure frequency from the Baseline Period of the previous study. Note: Since N01258 was a safety study, participants were not required to meet seizure frequency requirements during the Baseline Period, and the Baseline Period was short (ie, 7 days). Therefore, participants from N01258 were excluded from efficacy summaries in the variable of responder rates in POS frequency.
    End point type
    Secondary
    End point timeframe
    From Baseline of the previous study until the Last Visit (up to 84 months)
    End point values
    Brivaracetam (POS Efficacy)
    Number of subjects analysed
    675
    Units: Percentage of participants
        number (not applicable)
    51.7
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Entry Visit (Month 0) until the Last Visit (up to 84 months)
    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
    Brivaracetam (BRV) was administered with a maximum of 200 mg/day, twice, daily, incremented by 50 mg/day on a weekly basis, during the Up-Titration. During the Down-Titration Period, the BRV dose was decreased in steps of a maximum of 50 mg/day on a weekly basis. A last down-titration step at 20 mg/day for 1 week was included prior to the Post-Treatment Period. Participants formed the Safety Set (SS).

    Serious adverse events
    Brivaracetam (SS)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    140 / 766 (18.28%)
         number of deaths (all causes)
    5
         number of deaths resulting from adverse events
    1
    Surgical and medical procedures
    Intervertebral disc operation
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tenodesis
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gliomatosis cerebri
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thymoma
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Imminent abortion
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 766 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device malfunction
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    7 / 766 (0.91%)
         occurrences causally related to treatment / all
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    5 / 766 (0.65%)
         occurrences causally related to treatment / all
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    Acute psychosis
         subjects affected / exposed
    2 / 766 (0.26%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Depression
         subjects affected / exposed
    2 / 766 (0.26%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Aggression
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anxiety disorder
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Delirium febrile
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Emotional disorder
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    2 / 766 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Menometrorrhagia
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spermatic cord haemorrhage
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Uterine polyp
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Toxicity to various agents
         subjects affected / exposed
    3 / 766 (0.39%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Accidental overdose
         subjects affected / exposed
    2 / 766 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Brain contusion
         subjects affected / exposed
    2 / 766 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Contusion
         subjects affected / exposed
    2 / 766 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Fall
         subjects affected / exposed
    2 / 766 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Head injury
         subjects affected / exposed
    2 / 766 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Joint dislocation
         subjects affected / exposed
    2 / 766 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Road traffic accident
         subjects affected / exposed
    2 / 766 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye injury
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intentional overdose
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Jaw fracture
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nail injury
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post procedural complication
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pubis fracture
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skeletal injury
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skull fracture
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal cord injury cervical
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thermal burn
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Diagnostic procedure
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Troponin increased
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    2 / 766 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 766 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 766 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Angina pectoris
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Coronary artery stenosis
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Congenital, familial and genetic disorders
    Sickle cell anaemia
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hiccups
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Haemorrhagic anaemia
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoplastic anaemia
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Microcytic anaemia
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    15 / 766 (1.96%)
         occurrences causally related to treatment / all
    3 / 16
         deaths causally related to treatment / all
    0 / 0
    Status epilepticus
         subjects affected / exposed
    11 / 766 (1.44%)
         occurrences causally related to treatment / all
    1 / 11
         deaths causally related to treatment / all
    0 / 0
    Epilepsy
         subjects affected / exposed
    7 / 766 (0.91%)
         occurrences causally related to treatment / all
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    Seizure cluster
         subjects affected / exposed
    4 / 766 (0.52%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    2 / 766 (0.26%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    2 / 766 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Partial seizures with secondary generalisation
         subjects affected / exposed
    2 / 766 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 766 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ataxia
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Balance disorder
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebellar syndrome
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cervical cord compression
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Complex partial seizures
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dementia Alzheimer's type
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myelopathy
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Radiculopathy
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Simple partial seizures
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    Somnolence
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 766 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    2 / 766 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 766 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophageal perforation
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal colic
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    3 / 766 (0.39%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Cervical spinal stenosis
         subjects affected / exposed
    2 / 766 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    3 / 766 (0.39%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    5 / 766 (0.65%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    Sepsis
         subjects affected / exposed
    2 / 766 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis escherichia coli
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infected cyst
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Otitis media chronic
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Perineal abscess
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pharyngitis bacterial
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Typhoid fever
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 766 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 766 (0.13%)
         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
    421 / 766 (54.96%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    44 / 766 (5.74%)
         occurrences all number
    71
    Fall
         subjects affected / exposed
    43 / 766 (5.61%)
         occurrences all number
    60
    Nervous system disorders
    Headache
         subjects affected / exposed
    102 / 766 (13.32%)
         occurrences all number
    187
    Dizziness
         subjects affected / exposed
    100 / 766 (13.05%)
         occurrences all number
    123
    Somnolence
         subjects affected / exposed
    73 / 766 (9.53%)
         occurrences all number
    88
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    59 / 766 (7.70%)
         occurrences all number
    67
    Psychiatric disorders
    Depression
         subjects affected / exposed
    45 / 766 (5.87%)
         occurrences all number
    53
    Anxiety
         subjects affected / exposed
    42 / 766 (5.48%)
         occurrences all number
    48
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    46 / 766 (6.01%)
         occurrences all number
    59
    Arthralgia
         subjects affected / exposed
    41 / 766 (5.35%)
         occurrences all number
    56
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    65 / 766 (8.49%)
         occurrences all number
    102
    Upper respiratory tract infection
         subjects affected / exposed
    59 / 766 (7.70%)
         occurrences all number
    101
    Urinary tract infection
         subjects affected / exposed
    57 / 766 (7.44%)
         occurrences all number
    86
    Influenza
         subjects affected / exposed
    40 / 766 (5.22%)
         occurrences all number
    47

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jan 2011
    Addition of deoxyribonucleic acid (DNA) analysis to assess the role of gene variants of synaptic vesicle protein 2A (SV2) in affecting response to BRV. Allowed study participants coming from N01258. Addition of laboratory assessments of liver function at 3-month intervals during the first year and a yearly thyroid-stimulating hormone (TSH) measurement in response to a regulatory agency request.
    14 Sep 2011
    Procedures for reporting serious adverse events (SAEs) were updated to implement the Food and Drug Administration (FDA) Final Rule requirements. The Columbia-Suicide Severity Rating Scale (C-SSRS) was added 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 study variables were rearranged to more appropriately show that the main purpose of N01379 was to evaluate long-term safety of BRV in this patient population.
    15 May 2015
    Aligned existing language with updated UCB Standard Operating Procedures (SOPs) and/or best practices as well as to allow for a named patient or compassionate use program (or similar) or for participants to switch to another BRV study or to commercial BRV, if, when, and where available. The following changes were made where applicable in these protocols: • In accordance with a new UCB SOP, the sponsor signature block was removed and replaced with a Sponsor Declaration and electronic signature. • Outdated safety information was deleted from Section 2.4 of the protocol. • The protocol contact information was updated. • The study duration language was revised to include the possibility of a named patient or compassionate use program (or similar) as a reason for ending the study. • Language regarding Investigator deviation from the protocol in the event of a medical emergency was revised to align with current UCB standard language.

    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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