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    Clinical Trial Results:
    An open-label, multicenter, follow-up trial to evaluate long-term safety and efficacy of brivaracetam used as adjunctive treatment at a flexible dose up to a maximum of 200 mg/day in subjects aged 16 years or older suffering from Epilepsy

    Summary
    EudraCT number
    2004-002140-10
    Trial protocol
    BE   CZ   DE   GB   FI   ES   IT   SE   HU   AT  
    Global end of trial date
    28 May 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Dec 2019
    First version publication date
    18 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    N01125
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00175916
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB Pharma S.A.
    Sponsor organisation address
    Allée de la Recherche 60, Brussels, Belgium, B-1070
    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
    15 Jul 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 May 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    28 May 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 with a maximum of 200mg/day in subjects suffering from epilepsy
    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
    08 Sep 2005
    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: 24
    Country: Number of subjects enrolled
    Belgium: 28
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Hong Kong: 10
    Country: Number of subjects enrolled
    Czech Republic: 52
    Country: Number of subjects enrolled
    Finland: 30
    Country: Number of subjects enrolled
    France: 99
    Country: Number of subjects enrolled
    Germany: 86
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Italy: 49
    Country: Number of subjects enrolled
    Netherlands: 19
    Country: Number of subjects enrolled
    Norway: 10
    Country: Number of subjects enrolled
    Poland: 141
    Country: Number of subjects enrolled
    Russian Federation: 47
    Country: Number of subjects enrolled
    Serbia: 5
    Country: Number of subjects enrolled
    Singapore: 6
    Country: Number of subjects enrolled
    South Africa: 1
    Country: Number of subjects enrolled
    Korea, Republic of: 79
    Country: Number of subjects enrolled
    Spain: 23
    Country: Number of subjects enrolled
    Sweden: 19
    Country: Number of subjects enrolled
    Switzerland: 12
    Country: Number of subjects enrolled
    Taiwan: 24
    Country: Number of subjects enrolled
    Tunisia: 10
    Country: Number of subjects enrolled
    Ukraine: 48
    Country: Number of subjects enrolled
    United States: 9
    Worldwide total number of subjects
    853
    EEA total number of subjects
    591
    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)
    7
    Adults (18-64 years)
    834
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study started to enroll patients in September 2005 and concluded in May 2019.

    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
    10 mg and 25 mg tablets. Flexible dosing up to 200 mg/day, twice daily.

    Number of subjects in period 1
    Brivaracetam
    Started
    853
    Completed
    234
    Not completed
    619
         Administrative reason
    1
         Lack of efficacy
    354
         Adverse event, serious fatal
    19
         Subject Choice
    98
         Lack of compliance
    8
         Patient went to prison
    1
         Patient cannot record seizures
    1
         Loss of job and economic burden
    1
         Site was closed
    9
         Consent withdrawn by subject
    1
         Treating physiciant's choice
    1
         Patient's request
    2
         Vigabatrin intake
    1
         Moved overseas
    1
         Pregnancy
    1
         Adverse event, non-fatal
    81
         Lost to follow-up
    17
         Sponsor decision
    17
         Suicidal behaviour
    1
         Seizure - free
    4

    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
    853 853
    Age categorical
    Units: Subjects
        <=18 years
    14 14
        Between 18 and 65 years
    827 827
        >=65 years
    12 12
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    37.5 ± 11.8 -
    Gender categorical
    Units: Subjects
        Male
    435 435
        Female
    418 418

    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 1 through End of Treatment (up to a maximum of 13 and a half years - 162 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
    853
    Units: Percentage of participants
        number (not applicable)
    84.4
    No statistical analyses for this end point

    Primary: Percentage of participants who withdrew due to an adverse event (AE)

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    End point title
    Percentage of participants who withdrew due to an adverse event (AE) [2]
    End point description
    An AE is any untoward medical occurrence in a participant or trial participant 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 1 through End of Treatment (up to a maximum of 13 and a half years - 162 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
    853
    Units: Percentage of participants
        number (not applicable)
    11.6
    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 an 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 1 through End of Treatment (up to a maximum of 13 and a half years - 162 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
    853
    Units: Percentage of participants
        number (not applicable)
    29.4
    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 to the Evaluation Period (up to a maximum of 13 and a half years - 162 months)
    End point values
    Brivaracetam (POS Efficacy)
    Number of subjects analysed
    729
    Units: Seizures per 28 days
    median (inter-quartile range (Q1-Q3))
        Baseline
    8.4 (5.0 to 16.1)
        On Treatment
    4.9 (2.1 to 10.8)
    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.
    End point type
    Secondary
    End point timeframe
    From Baseline of the previous study to the Evaluation Period (up to a maximum of 13 and a half years - 162 months)
    End point values
    Brivaracetam (POS Efficacy)
    Number of subjects analysed
    729
    Units: Percent change
        median (inter-quartile range (Q1-Q3))
    43.1 (9.9 to 71.5)
    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 participant with a ≥ 50% reduction in seizure frequency from the Baseline Period of the previous study.
    End point type
    Secondary
    End point timeframe
    From Baseline of the previous study to the Evaluation Period (up to a maximum of 13 and a half years - 162 months)
    End point values
    Brivaracetam (POS Efficacy)
    Number of subjects analysed
    729
    Units: Percentage of participants
        number (not applicable)
    43.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the Entry Visit, at Month 0 and up to the Last Visit at Year 11.
    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
    248 / 853 (29.07%)
         number of deaths (all causes)
    19
         number of deaths resulting from adverse events
    2
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    10 / 853 (1.17%)
         occurrences causally related to treatment / all
    3 / 11
         deaths causally related to treatment / all
    0 / 0
    Contusion
         subjects affected / exposed
    5 / 853 (0.59%)
         occurrences causally related to treatment / all
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    5 / 853 (0.59%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Ankle fracture
         subjects affected / exposed
    4 / 853 (0.47%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Fall
         subjects affected / exposed
    4 / 853 (0.47%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 1
    Femur fracture
         subjects affected / exposed
    4 / 853 (0.47%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Laceration
         subjects affected / exposed
    4 / 853 (0.47%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Concussion
         subjects affected / exposed
    3 / 853 (0.35%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Extradural haematoma
         subjects affected / exposed
    3 / 853 (0.35%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    3 / 853 (0.35%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Hand fracture
         subjects affected / exposed
    3 / 853 (0.35%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Spinal fracture
         subjects affected / exposed
    3 / 853 (0.35%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    3 / 853 (0.35%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hip fracture
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Jaw fracture
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ligament rupture
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Meniscus lesion
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Poisoning
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Skull fracture
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Skull fractured base
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Thermal burn
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Tibia fracture
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Accident
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Accidental exposure
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Accidental overdose
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bursa injury
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cartilage injury
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chest injury
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Face injury
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Forearm fracture
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Incorrect dose administered
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscle rupture
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Near drowning
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Open wound
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Postoperative hernia
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal column injury
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Traumatic haematoma
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Thyroid function test abnormal
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigation
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Supraventricular tachycardia
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorder
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Congenital, familial and genetic disorders
    Baltic myoclonic epilepsy
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    Blood and lymphatic system disorders
    Anaemia macrocytic
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    36 / 853 (4.22%)
         occurrences causally related to treatment / all
    10 / 54
         deaths causally related to treatment / all
    0 / 0
    Epilepsy
         subjects affected / exposed
    11 / 853 (1.29%)
         occurrences causally related to treatment / all
    2 / 13
         deaths causally related to treatment / all
    0 / 0
    Status epilepticus
         subjects affected / exposed
    10 / 853 (1.17%)
         occurrences causally related to treatment / all
    2 / 12
         deaths causally related to treatment / all
    0 / 1
    Grand mal convulsion
         subjects affected / exposed
    8 / 853 (0.94%)
         occurrences causally related to treatment / all
    4 / 12
         deaths causally related to treatment / all
    0 / 1
    Myoclonus
         subjects affected / exposed
    9 / 853 (1.06%)
         occurrences causally related to treatment / all
    1 / 20
         deaths causally related to treatment / all
    0 / 0
    Seizure cluster
         subjects affected / exposed
    4 / 853 (0.47%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Myoclonic epilepsy
         subjects affected / exposed
    4 / 853 (0.47%)
         occurrences causally related to treatment / all
    3 / 11
         deaths causally related to treatment / all
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Somnolence
         subjects affected / exposed
    3 / 853 (0.35%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Complex partial seizures
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    2 / 853 (0.23%)
         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 / 853 (0.23%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Altered state of consciousness
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Ataxia
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Balance disorder
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Aura
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Brachial plexopathy
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cerebral haematoma
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Coordination abnormal
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dysarthria
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Hemiplegia
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Migraine
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychomotor hyperactivity
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Radiculitis lumbosacral
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Status migrainosus
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Corneal erosion
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vision blurred
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Opsoclonus myoclonus
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Visual impairment
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    4 / 853 (0.47%)
         occurrences causally related to treatment / all
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    Hypoacusis
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Tinnitus
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vertigo positional
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    3 / 853 (0.35%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain
         subjects affected / exposed
    5 / 853 (0.59%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Dysphagia
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    Nausea
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anal fissure
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Duodenitis
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric polyps
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Proctocolitis
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    3 / 853 (0.35%)
         occurrences causally related to treatment / all
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    Calculus bladder
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bladder pain
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Calculus ureteric
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Calculus urinary
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal failure acute
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dysuria
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract disorder
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatomyositis
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Angioedema
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hidradenitis
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Swelling face
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    7 / 853 (0.82%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Back pain
         subjects affected / exposed
    4 / 853 (0.47%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Intervertebral disc disorder
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Arthralgia
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Bursitis
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femoroacetabular impingement
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Groin pain
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Systemic lupus erythematosus
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thyroiditis
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    6 / 853 (0.70%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Histamine intolerance
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    6 / 853 (0.70%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    Pneumonia
         subjects affected / exposed
    9 / 853 (1.06%)
         occurrences causally related to treatment / all
    2 / 14
         deaths causally related to treatment / all
    0 / 1
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 853 (0.47%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 853 (0.47%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Appendicitis
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Skin infection
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Septic shock
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Bronchitis
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ear infection
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Incision site infection
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infected bites
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia mycoplasmal
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tooth infection
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Hypertension
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Artificial urinary sphincter implant
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholecystectomy
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cataract operation
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gallbladder operation
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hernia repair
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Shoulder operation
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Radiotherapy
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tonsillectomy
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tracheostomy
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Urethral repair
         subjects affected / exposed
    1 / 853 (0.12%)
         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)
    Prostate cancer
         subjects affected / exposed
    4 / 853 (0.47%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Astrocytoma
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast cancer metastatic
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic lymphocytic leukaemia
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ependymoma
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fibroma
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mixed oligo-astrocytoma
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mesothelioma
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Ovarian neoplasm
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasm prostate
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Testicular neoplasm
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Prostate cancer recurrent
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immunodeficiency
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    4 / 853 (0.47%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Abortion
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Foetal growth restriction
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Abortion complete
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pregnancy on contraceptive
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pregnancy on oral contraceptive
         subjects affected / exposed
    1 / 853 (0.12%)
         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
    5 / 853 (0.59%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Fatigue
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Death
         subjects affected / exposed
    4 / 853 (0.47%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    1 / 4
    Unevaluable event
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Device failure
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Drowning
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Gait disturbance
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhagic cyst
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Irritability
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Implant site haematoma
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    7 / 853 (0.82%)
         occurrences causally related to treatment / all
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    Depression
         subjects affected / exposed
    6 / 853 (0.70%)
         occurrences causally related to treatment / all
    1 / 7
         deaths causally related to treatment / all
    0 / 1
    Aggression
         subjects affected / exposed
    3 / 853 (0.35%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    1 / 1
    Psychotic disorder
         subjects affected / exposed
    3 / 853 (0.35%)
         occurrences causally related to treatment / all
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    Suicide attempt
         subjects affected / exposed
    3 / 853 (0.35%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Abnormal behaviour
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Acute psychosis
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Anxiety
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Confusional state
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    Depressed mood
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Dysthymic disorder
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Suicidal behaviour
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Agitation
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Conversion disorder
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Decreased interest
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Delirium tremens
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dissociative disorder
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mental disorder
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Insomnia
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Panic attack
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Panic disorder
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Polydipsia psychogenic
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Restlessness
         subjects affected / exposed
    1 / 853 (0.12%)
         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
    4 / 853 (0.47%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Menometrorrhagia
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Epididymitis
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Menorrhagia
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Menstrual disorder
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pelvic fluid collection
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Uterine polyp
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Postmenopausal haemorrhage
         subjects affected / exposed
    1 / 853 (0.12%)
         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 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Asthma
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Vocal cord polyp
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    2 / 853 (0.23%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    3 / 853 (0.35%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 853 (0.12%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 853 (0.12%)
         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
    569 / 853 (66.71%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    43 / 853 (5.04%)
         occurrences all number
    53
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    45 / 853 (5.28%)
         occurrences all number
    68
    Fall
         subjects affected / exposed
    47 / 853 (5.51%)
         occurrences all number
    62
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Somnolence
         subjects affected / exposed
    73 / 853 (8.56%)
         occurrences all number
    104
    Nervous system disorders
    Headache
         subjects affected / exposed
    186 / 853 (21.81%)
         occurrences all number
    419
    Dizziness
         subjects affected / exposed
    123 / 853 (14.42%)
         occurrences all number
    191
    Convulsion
         subjects affected / exposed
    112 / 853 (13.13%)
         occurrences all number
    158
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    84 / 853 (9.85%)
         occurrences all number
    106
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    58 / 853 (6.80%)
         occurrences all number
    114
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    71 / 853 (8.32%)
         occurrences all number
    95
    Depression
         subjects affected / exposed
    65 / 853 (7.62%)
         occurrences all number
    80
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    55 / 853 (6.45%)
         occurrences all number
    78
    Diarrhoea
         subjects affected / exposed
    78 / 853 (9.14%)
         occurrences all number
    112
    Vomiting
         subjects affected / exposed
    53 / 853 (6.21%)
         occurrences all number
    89
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    77 / 853 (9.03%)
         occurrences all number
    99
    Arthralgia
         subjects affected / exposed
    52 / 853 (6.10%)
         occurrences all number
    73
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    75 / 853 (8.79%)
         occurrences all number
    125
    Nasopharyngitis
         subjects affected / exposed
    157 / 853 (18.41%)
         occurrences all number
    332
    Upper respiratory tract infection
         subjects affected / exposed
    50 / 853 (5.86%)
         occurrences all number
    127
    Influenza
         subjects affected / exposed
    66 / 853 (7.74%)
         occurrences all number
    104
    Bronchitis
         subjects affected / exposed
    47 / 853 (5.51%)
         occurrences all number
    68

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Apr 2005
    Limitation of the maximal dose to 150 mg/day.
    07 Apr 2006
    Issued to fulfill requirements by the German Central Ethics Committee; however, the amendment was not country-specific, but applied to all study sites. Updates made to several sections of the protocol to clarify wording used and study procedures.
    05 May 2006
    Allowed the inclusion of study participants with genetically ascertained Unverricht-Lundborg Disease (ULD) who might have benefited from BRV as adjunctive treatment in a previous confirmatory study. Furthermore, specific sections related to treatment of study participants with ULD were added.
    02 Feb 2007
    • Updated the exclusion criteria (suppression of exclusion criteria linked to laboratory values on the basis of favorable Phase 2 data). • Updated BRV background information. • Expanded study by including study participants with POS and study participants with generalized epilepsy coming from BRV Phase 3 studies (N01252, N01254, and possibly N01253), as well as collection and analysis of their data. • Allowed the Investigator to adjust dosage of concomitant antiepileptic drug(s) (AED(s)). Withdrawal of concomitant AED(s) resulting in monotherapy with BRV was permitted. • Addition of long-term exploratory data, namely Hospital Anxiety and Depression Scale (HADS) for study participants coming from N01114, and HADS, EuroQol 5 Dimensions (EQ-5D) and socioprofessional data for study participants coming from N01252, N01254, and possibly N01253.
    01 Jun 2007
    Issued as a follow up to the Food and Drug Administration (FDA) feedback received on N01253, where the FDA specifically requested to add an additional down-titration step for study participants with POS taking BRV 50 mg/day or more—a last down-titration step at 20 mg/day for 1 week was recommended prior to the Study Post-Treatment Period.
    01 Jun 2007
    Update to Amendment 6; was issued as a follow up to the FDA feedback received on N01253 requesting that an additional down-titration step for study participants taking 50 mg/day or more be added. The amendment also did the following: • Harmonized the duration of N01125 with the BRV program for study participants with ULD. The program was to continue until an FDA approval for the indication of ULD was obtained, or until the development program for the indication was stopped by the sponsor. • Clarified the use of 10 and 50 mg oral tablets. • Modified the instructions on the study drug storage conditions. • Clarified study procedures.
    26 Oct 2007
    Update to Amendment 6 and Amendment 9; was issued to remove some restrictions imposed on study participants switching from their previous study to this long-term follow-up (LTFU) study. The amendment also did the following: • Clarified the inclusion criterion for birth control methods. • Clarified end of study conditions. • Modified study drug discontinuation procedures as described in Amendment 9.
    04 Apr 2008
    Amendment to Amendment 8. Updates made to several sections of the protocol to clarify study procedures and FDA warning for suicidality and suicidal thoughts for study participants taking AEDs. The amendment also did the following: • Clarified the study objective. • Clarified the inclusion criterion regarding contraceptive methods (female study participants with childbearing potential were allowed to enter the study if their sexual inactivity was judged to be reliable by the Investigator). • Specified that doses beyond 40 mg/day increments were only to be made using 10 or 25 mg tablets.
    03 Jan 2011
    Amendments reduced the number of assessments for the study participants in view of the quantity of data already collected, the good safety profile of the drug, the extension of the study and the focus on safety aspects. Amendment 24 is the amendment to Protocol Amendment 18 for study participants with POS/PGS. Amendment 25 is the amendment to Protocol Amendment 10 for study participants with ULD. Integrated Amendment 25 combined Amendment 24 and 25, as well as specified the following: • Study participants were not allowed to convert to BRV monotherapy. • The maximum allowable daily dose of BRV was increased from 150 mg/day to 200 mg/day to align with more recent LTFU studies. The maximum dose was chosen following consultation with regulatory authorities. • Removed 2.5 mg BRV tablets and all capsules. • Introduced the Partner Pregnancy Consent form.
    25 Oct 2011
    • Addition of the suicidality assessment and the requirements per the Food and Drug Administration (FDA) Final Rule and update of the study variables. • Updated procedures for reporting serious adverse events (SAEs). • Specified that BRV packaging was updated (80 tablet containers no longer supplied).
    12 Mar 2015
    • Updated contact information. • Addition of procedures for study participants enrolling from another study (N01315). • Deletion of outdated exposure numbers. • Addition of language allowing all participants to enroll into a managed access program (or similar). • Updated protocol adherence language. • Added Sponsor declaration page.

    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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