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    Clinical Trial Results:
    Open-Label, Single-Arm, Multicenter, Long-Term Study to Evaluate Safety and Efficacy of Brivaracetam Used as Adjunctive Treatment in Pediatric Subjects with Epilepsy

    Summary
    EudraCT number
    2011-000374-60
    Trial protocol
    BE   CZ   ES   PL   Outside EU/EEA   IE   GB   DE   HU   NL   FR   IT  
    Global end of trial date
    03 Feb 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Aug 2022
    First version publication date
    13 Aug 2022
    Other versions
    v2 (removed from public view)

    Trial information

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    Trial identification
    Sponsor protocol code
    N01266
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01364597
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB Pharma SA
    Sponsor organisation address
    Allée de la Recherche 60, Brussels, Belgium, 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)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000332-PIP01-08
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Mar 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Feb 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Document the long-term safety and tolerability of BRV
    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
    N/A
    Actual start date of recruitment
    01 Aug 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    3 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    Czechia: 12
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Hungary: 30
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    Mexico: 61
    Country: Number of subjects enrolled
    Poland: 56
    Country: Number of subjects enrolled
    Spain: 25
    Country: Number of subjects enrolled
    United States: 55
    Worldwide total number of subjects
    257
    EEA total number of subjects
    141
    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)
    36
    Children (2-11 years)
    156
    Adolescents (12-17 years)
    65
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study started to enroll participants in August 2011 and concluded in February 2022.

    Pre-assignment
    Screening details
    The Participant Flow refers to the enrolled set.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Age Cohort: ≥1 month to <2 years
    Arm description
    Participants from core study (LTFU [Long term follow-up] participants from N01263 [NCT00422422], EP0065 [NCT03405714] or N01349 [NCT03325439]) aged greater than or equal to (≥) 1 month to less than (<) 2 years entered evaluation period (EP) and received individualized Brivaracetam (BRV) dose as they were receiving at completion of core study. For all participants, the approximate BRV doses to be administered are 1 to 5 milligrams per kilogram per day (mg/kg/day) (0.5, 1, 2, and 2.5 mg/kg twice daily[bid]), tablet or oral solution and can be up-titrated or down-titrated based on investigator decision with a maximum allowable BRV dose of 5.0 mg/kg/day (2.5 mg/kg bid), not to exceed a dose of 200 mg/day. The duration of the treatment for each participant was planned to be at least 3 years, until BRV received approval for pediatric participants in their age range or until the investigational medicinal product (IMP) development was stopped by the Sponsor.
    Arm type
    Experimental

    Investigational medicinal product name
    Brivaracetam
    Investigational medicinal product code
    UCB 34714
    Other name
    Pharmaceutical forms
    Oral solution, Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received BRV at pre-specified dose and time points.

    Arm title
    Age Cohort: ≥2 to <4 years
    Arm description
    Participants from core study (LTFU participants from N01263 [NCT00422422] and EP0065 [NCT03405714]) aged ≥2 Years to <4 years entered EP and received individualized BRV dose as they were receiving at completion of core study. For all participants, the approximate BRV doses to be administered are 1 to 5 mg/kg/day (0.5, 1, 2, and 2.5mg/kg bid), tablet or oral solution and can be up-titrated or down-titrated based on investigator decision with a maximum allowable BRV dose of 5.0 mg/kg/day (2.5mg/kg bid), not to exceed a dose of 200mg/day. The duration of the treatment for each participant was planned to be at least 3 years, until BRV received approval for pediatric participants in their age range or until the IMP development was stopped by the Sponsor.
    Arm type
    Experimental

    Investigational medicinal product name
    Brivaracetam
    Investigational medicinal product code
    UCB 34714
    Other name
    Pharmaceutical forms
    Oral solution, Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received BRV at pre-specified dose and time points..

    Arm title
    Age Cohort: ≥4 to <12 years
    Arm description
    Participants from core study (LTFU participants from N01263 [NCT00422422] and EP0065 [NCT03405714]) aged ≥4 Years to <12 years entered EP and received individualized BRV dose as they were receiving at completion of core study and Directly Enrolled (DE) participants in this study aged ≥4 years to <12 years of age received BRV dose based on tolerability confirmed during screening period. For all participants, the approximate BRV doses to be administered are 1 to 5 mg/kg/day (0.5, 1, 2, and 2.5mg/kg bid), tablet or oral solution and can be up-titrated or down-titrated based on investigator decision with a maximum allowable BRV dose of 5.0 mg/kg/day (2.5 mg/kg bid), not to exceed a dose of 200 mg/day. The duration of the treatment for each participant was planned to be at least 3 years, until BRV received approval for pediatric participants in their age range or until the IMP development was stopped by the Sponsor.
    Arm type
    Experimental

    Investigational medicinal product name
    Brivaracetam
    Investigational medicinal product code
    UCB 34714
    Other name
    Pharmaceutical forms
    Oral solution, Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received BRV at pre-specified dose and time points.

    Arm title
    Age Cohort: ≥12 to <17 years
    Arm description
    Participants from core study (LTFU participants from N01263 [NCT00422422] and EP0065 [NCT03405714]) aged ≥12 Years to <17 years entered EP and received individualized BRV dose as they were receiving at completion of core study and DE participants in this study aged ≥12 years to <17 years of age received BRV dose based on tolerability confirmed during screening period. For all participants, the approximate BRV doses to be administered are 1 to 5 mg/kg/day (0.5, 1, 2, and 2.5 mg/kg bid), tablet or oral solution and can be up-titrated or down-titrated based on investigator decision with a maximum allowable BRV dose of 5.0 mg/kg/day (2.5 mg/kg bid), not to exceed a dose of 200 mg/day. The duration of the treatment for each participant was planned to be at least 3 years, until BRV received approval for pediatric participants in their age range or until the IMP development was stopped by the Sponsor.
    Arm type
    Experimental

    Investigational medicinal product name
    Brivaracetam
    Investigational medicinal product code
    UCB 34714
    Other name
    Pharmaceutical forms
    Oral solution, Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received BRV at pre-specified dose and time points.

    Number of subjects in period 1
    Age Cohort: ≥1 month to <2 years Age Cohort: ≥2 to <4 years Age Cohort: ≥4 to <12 years Age Cohort: ≥12 to <17 years
    Started
    36
    15
    141
    65
    Directly Enrolled (DE) Participants
    0 [1]
    0 [2]
    85
    35 [3]
    Long-term Follow-up (LTFU) Participants
    36
    15
    56 [4]
    30 [5]
    Completed
    18
    4
    65
    37
    Not completed
    18
    11
    76
    28
         Investigator decision
    -
    -
    1
    -
         Protocol deviation
    -
    -
    2
    -
         Dropout
    -
    -
    3
    1
         Parents went abroad with the patient
    -
    -
    1
    -
         Non compliance
    1
    -
    1
    -
         Sponsor recommended discontinuation
    -
    -
    -
    1
         End of treatment epilepsy
    1
    -
    -
    -
         Unknown
    -
    -
    -
    1
         Lack of efficacy
    4
    4
    23
    8
         Lack of compliance
    1
    -
    -
    -
         Patient was moving
    -
    1
    -
    -
         BRV administration dropout
    -
    -
    1
    -
         Consent withdrawn by subject
    4
    1
    18
    6
         Patient cured from Epilepsy
    -
    -
    1
    -
         BRV discontinued as no seizures during 2 years
    -
    -
    1
    -
         Lack of reliability from the subject's caregiver
    1
    -
    -
    -
         Patient became seizure-free after surgery
    -
    -
    1
    -
         Adverse event, non-fatal
    4
    5
    16
    7
         Cure
    1
    -
    -
    -
         Seizures resolved
    -
    -
    1
    -
         Unreliable subject
    -
    -
    -
    1
         No Seizures
    1
    -
    -
    -
         5 year without seizures. Treatment is finish
    -
    -
    1
    -
         Lost to follow-up
    -
    -
    5
    3
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of participants at this arm is the sum of both the milestones ‘Directly Enrolled (DE) Participants and Long-term Follow-up (LTFU) Participants’ and equals to the started participants only. Hence the number of participants at each of intermediate milestones were lesser.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of participants at this arm is the sum of both the milestones ‘Directly Enrolled (DE) Participants and Long-term Follow-up (LTFU) Participants’ and equals to the started participants only. Hence the number of participants at each of intermediate milestones were lesser.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of participants at this arm is the sum of both the milestones ‘Directly Enrolled (DE) Participants and Long-term Follow-up (LTFU) Participants’ and equals to the started participants only. Hence the number of participants at each of intermediate milestones were lesser.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of participants at this arm is the sum of both the milestones ‘Directly Enrolled (DE) Participants and Long-term Follow-up (LTFU) Participants’ and equals to the started participants only. Hence the number of participants at each of intermediate milestones were lesser.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of participants at this arm is the sum of both the milestones ‘Directly Enrolled (DE) Participants and Long-term Follow-up (LTFU) Participants’ and equals to the started participants only. Hence the number of participants at each of intermediate milestones were lesser.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Age Cohort: ≥1 month to <2 years
    Reporting group description
    Participants from core study (LTFU [Long term follow-up] participants from N01263 [NCT00422422], EP0065 [NCT03405714] or N01349 [NCT03325439]) aged greater than or equal to (≥) 1 month to less than (<) 2 years entered evaluation period (EP) and received individualized Brivaracetam (BRV) dose as they were receiving at completion of core study. For all participants, the approximate BRV doses to be administered are 1 to 5 milligrams per kilogram per day (mg/kg/day) (0.5, 1, 2, and 2.5 mg/kg twice daily[bid]), tablet or oral solution and can be up-titrated or down-titrated based on investigator decision with a maximum allowable BRV dose of 5.0 mg/kg/day (2.5 mg/kg bid), not to exceed a dose of 200 mg/day. The duration of the treatment for each participant was planned to be at least 3 years, until BRV received approval for pediatric participants in their age range or until the investigational medicinal product (IMP) development was stopped by the Sponsor.

    Reporting group title
    Age Cohort: ≥2 to <4 years
    Reporting group description
    Participants from core study (LTFU participants from N01263 [NCT00422422] and EP0065 [NCT03405714]) aged ≥2 Years to <4 years entered EP and received individualized BRV dose as they were receiving at completion of core study. For all participants, the approximate BRV doses to be administered are 1 to 5 mg/kg/day (0.5, 1, 2, and 2.5mg/kg bid), tablet or oral solution and can be up-titrated or down-titrated based on investigator decision with a maximum allowable BRV dose of 5.0 mg/kg/day (2.5mg/kg bid), not to exceed a dose of 200mg/day. The duration of the treatment for each participant was planned to be at least 3 years, until BRV received approval for pediatric participants in their age range or until the IMP development was stopped by the Sponsor.

    Reporting group title
    Age Cohort: ≥4 to <12 years
    Reporting group description
    Participants from core study (LTFU participants from N01263 [NCT00422422] and EP0065 [NCT03405714]) aged ≥4 Years to <12 years entered EP and received individualized BRV dose as they were receiving at completion of core study and Directly Enrolled (DE) participants in this study aged ≥4 years to <12 years of age received BRV dose based on tolerability confirmed during screening period. For all participants, the approximate BRV doses to be administered are 1 to 5 mg/kg/day (0.5, 1, 2, and 2.5mg/kg bid), tablet or oral solution and can be up-titrated or down-titrated based on investigator decision with a maximum allowable BRV dose of 5.0 mg/kg/day (2.5 mg/kg bid), not to exceed a dose of 200 mg/day. The duration of the treatment for each participant was planned to be at least 3 years, until BRV received approval for pediatric participants in their age range or until the IMP development was stopped by the Sponsor.

    Reporting group title
    Age Cohort: ≥12 to <17 years
    Reporting group description
    Participants from core study (LTFU participants from N01263 [NCT00422422] and EP0065 [NCT03405714]) aged ≥12 Years to <17 years entered EP and received individualized BRV dose as they were receiving at completion of core study and DE participants in this study aged ≥12 years to <17 years of age received BRV dose based on tolerability confirmed during screening period. For all participants, the approximate BRV doses to be administered are 1 to 5 mg/kg/day (0.5, 1, 2, and 2.5 mg/kg bid), tablet or oral solution and can be up-titrated or down-titrated based on investigator decision with a maximum allowable BRV dose of 5.0 mg/kg/day (2.5 mg/kg bid), not to exceed a dose of 200 mg/day. The duration of the treatment for each participant was planned to be at least 3 years, until BRV received approval for pediatric participants in their age range or until the IMP development was stopped by the Sponsor.

    Reporting group values
    Age Cohort: ≥1 month to <2 years Age Cohort: ≥2 to <4 years Age Cohort: ≥4 to <12 years Age Cohort: ≥12 to <17 years Total
    Number of subjects
    36 15 141 65 257
    Age Categorical
    Units: Participants
        Infants and toddlers (28 days-23 months)
    36 0 0 0 36
        Children (2-11 years)
    0 15 141 0 156
        Adolescents (12-17 years)
    0 0 0 65 65
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    1.122 ± 0.504 2.761 ± 0.582 7.699 ± 2.394 13.824 ± 1.274 -
    Gender Categorical
    Units: Subjects
        Female
    19 5 62 30 116
        Male
    17 10 79 35 141

    End points

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    End points reporting groups
    Reporting group title
    Age Cohort: ≥1 month to <2 years
    Reporting group description
    Participants from core study (LTFU [Long term follow-up] participants from N01263 [NCT00422422], EP0065 [NCT03405714] or N01349 [NCT03325439]) aged greater than or equal to (≥) 1 month to less than (<) 2 years entered evaluation period (EP) and received individualized Brivaracetam (BRV) dose as they were receiving at completion of core study. For all participants, the approximate BRV doses to be administered are 1 to 5 milligrams per kilogram per day (mg/kg/day) (0.5, 1, 2, and 2.5 mg/kg twice daily[bid]), tablet or oral solution and can be up-titrated or down-titrated based on investigator decision with a maximum allowable BRV dose of 5.0 mg/kg/day (2.5 mg/kg bid), not to exceed a dose of 200 mg/day. The duration of the treatment for each participant was planned to be at least 3 years, until BRV received approval for pediatric participants in their age range or until the investigational medicinal product (IMP) development was stopped by the Sponsor.

    Reporting group title
    Age Cohort: ≥2 to <4 years
    Reporting group description
    Participants from core study (LTFU participants from N01263 [NCT00422422] and EP0065 [NCT03405714]) aged ≥2 Years to <4 years entered EP and received individualized BRV dose as they were receiving at completion of core study. For all participants, the approximate BRV doses to be administered are 1 to 5 mg/kg/day (0.5, 1, 2, and 2.5mg/kg bid), tablet or oral solution and can be up-titrated or down-titrated based on investigator decision with a maximum allowable BRV dose of 5.0 mg/kg/day (2.5mg/kg bid), not to exceed a dose of 200mg/day. The duration of the treatment for each participant was planned to be at least 3 years, until BRV received approval for pediatric participants in their age range or until the IMP development was stopped by the Sponsor.

    Reporting group title
    Age Cohort: ≥4 to <12 years
    Reporting group description
    Participants from core study (LTFU participants from N01263 [NCT00422422] and EP0065 [NCT03405714]) aged ≥4 Years to <12 years entered EP and received individualized BRV dose as they were receiving at completion of core study and Directly Enrolled (DE) participants in this study aged ≥4 years to <12 years of age received BRV dose based on tolerability confirmed during screening period. For all participants, the approximate BRV doses to be administered are 1 to 5 mg/kg/day (0.5, 1, 2, and 2.5mg/kg bid), tablet or oral solution and can be up-titrated or down-titrated based on investigator decision with a maximum allowable BRV dose of 5.0 mg/kg/day (2.5 mg/kg bid), not to exceed a dose of 200 mg/day. The duration of the treatment for each participant was planned to be at least 3 years, until BRV received approval for pediatric participants in their age range or until the IMP development was stopped by the Sponsor.

    Reporting group title
    Age Cohort: ≥12 to <17 years
    Reporting group description
    Participants from core study (LTFU participants from N01263 [NCT00422422] and EP0065 [NCT03405714]) aged ≥12 Years to <17 years entered EP and received individualized BRV dose as they were receiving at completion of core study and DE participants in this study aged ≥12 years to <17 years of age received BRV dose based on tolerability confirmed during screening period. For all participants, the approximate BRV doses to be administered are 1 to 5 mg/kg/day (0.5, 1, 2, and 2.5 mg/kg bid), tablet or oral solution and can be up-titrated or down-titrated based on investigator decision with a maximum allowable BRV dose of 5.0 mg/kg/day (2.5 mg/kg bid), not to exceed a dose of 200 mg/day. The duration of the treatment for each participant was planned to be at least 3 years, until BRV received approval for pediatric participants in their age range or until the IMP development was stopped by the Sponsor.

    Subject analysis set title
    Brivaracetam (BRV): Participants ≥ 2 years to <17 years
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants from core study (LTFU participants from N01263 [NCT00422422]) aged ≥2 Years to <17 years entered EP and received individualized BRV dose as they were receiving at completion of core study and DE participants in this study aged ≥4 years to <17 years of age received BRV dose based on tolerability confirmed during screening period. For all participants, the approximate BRV doses to be administered are 1 to 5 mg/kg/day (0.5, 1, 2, and 2.5 mg/kg bid), tablet or oral solution and can be up-titrated or down-titrated based on investigator decision with a maximum allowable BRV dose of 5.0 mg/kg/day (2.5 mg/kg bid), not to exceed a dose of 200 mg/day. The duration of the treatment for each participant was planned to be at least 3 years, until BRV received approval for pediatric participants in their age range or until the IMP development was stopped by the Sponsor.

    Subject analysis set title
    Brivaracetam (BRV): Participants ≥1 month to <2 years
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants from core study (LTFU [Long term follow-up] participants from N01263 [NCT00422422] or N01349 [NCT03325439]) aged ≥1 month to <2 years entered EP and received individualized BRV dose as they were receiving at completion of core study. For all participants, the approximate BRV doses to be administered are 1 to 5 mg/kg/day (0.5, 1, 2, and 2.5 mg/kg bid), tablet or oral solution and can be up-titrated or down-titrated based on investigator decision with a maximum allowable BRV dose of 5.0 mg/kg/day (2.5 mg/kg bid), not to exceed a dose of 200 mg/day. The duration of the treatment for each participant was planned to be at least 3 years, until BRV received approval for pediatric participants in their age range or until the IMP development was stopped by the Sponsor.

    Primary: Percentage of participants with treatment-emergent adverse events (TEAEs) during the study

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    End point title
    Percentage of participants with treatment-emergent adverse events (TEAEs) during the study [1]
    End point description
    TEAEs are defined as AEs that had onset on or after the day of first BRV dose. The Safety Set (SS) consisted of all enrolled participants who took at least 1 dose of study medication.
    End point type
    Primary
    End point timeframe
    From Baseline to end of study (up to 10 years)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized in tables as descriptive statistics only.
    End point values
    Age Cohort: ≥1 month to <2 years Age Cohort: ≥2 to <4 years Age Cohort: ≥4 to <12 years Age Cohort: ≥12 to <17 years
    Number of subjects analysed
    36
    15
    141
    65
    Units: percentage of participants
        number (not applicable)
    94.4
    93.3
    93.6
    92.3
    No statistical analyses for this end point

    Primary: Percentage of participants with treatment-emergent serious adverse events (SAEs) during the study

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    End point title
    Percentage of participants with treatment-emergent serious adverse events (SAEs) during the study [2]
    End point description
    TEAEs: AEs that had onset on or after day of first BRV dose. SAE: an event that met 1 or more of below criteria: a) Death, b) Life-threatening, (excluding reaction that might caused death had it occurred in more severe form.) c) Significant or persistent disability/incapacity, d) Congenital anomaly/birth defect (including that occurring in fetus), e) Important medical event that, based upon appropriate medical judgment, may have jeopardized participant and required medical or surgical intervention to prevent 1 of other outcomes listed in definition of serious, (Important medical events may have included allergic bronchospasm requiring intensive treatment in an emergency room [ER] or at home) f) Initial inpatient hospitalization or prolongation of hospitalization. (Participant admitted to hospital, even if released on same day, met criteria for initial inpatient hospitalization). Safety Set (SS) consisted of all enrolled participants who took at least 1 dose of study medication.
    End point type
    Primary
    End point timeframe
    From Baseline to end of study (up to 10 years)
    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 in tables as descriptive statistics only.
    End point values
    Age Cohort: ≥1 month to <2 years Age Cohort: ≥2 to <4 years Age Cohort: ≥4 to <12 years Age Cohort: ≥12 to <17 years
    Number of subjects analysed
    36
    15
    141
    65
    Units: percentage of participants
        number (not applicable)
    38.9
    53.3
    29.8
    29.2
    No statistical analyses for this end point

    Secondary: Absolute change in 28-days adjusted partial-onset-seizure (POS) frequency for participants aged ≥2 years from Baseline to the end of the evaluation period in participants with POS only (based on daily record card [DRC])

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    End point title
    Absolute change in 28-days adjusted partial-onset-seizure (POS) frequency for participants aged ≥2 years from Baseline to the end of the evaluation period in participants with POS only (based on daily record card [DRC])
    End point description
    Absolute change in seizure frequency per 28 days based on DRC data, is calculated as baseline seizure frequency per 28 days minus post-Baseline seizure frequency per 28 days. The 28-day adjusted seizure frequency was calculated by dividing number of POS by number of days for which the diary was completed and multiplying resulting value by 28. Full Analysis Set: all enrolled participants who took at least 1 dose of study drug in this Long-term study and had at least 1 completed post-baseline DRC or EEG. Overall number of participants analyzed included all participants evaluable for this OM and it differs in both absolute and percent change because the percent change cannot be calculated for participants with 0 baseline ADF. Per planned analysis, participants were grouped as per cohort linked to source (DRC for ≥2 years /EEG for <2 years) from which their seizure data is recorded. This OM was analyzed in participants ≥2 years (per DRC data) only.
    End point type
    Secondary
    End point timeframe
    From Baseline (LTFU participants: Baseline of previous study N01263 [NCT00422422]; and DE participants: Baseline of current study) to the end of the evaluation period (up to 10 years)
    End point values
    Brivaracetam (BRV): Participants ≥ 2 years to <17 years
    Number of subjects analysed
    134
    Units: seizure frequency per 28-days
        arithmetic mean (standard deviation)
    -37.48 ± 628.34
    No statistical analyses for this end point

    Secondary: Percent change in 28-days adjusted partial-onset-seizure (POS) frequency for participants aged ≥2 years from Baseline to the end of the evaluation period in participants with POS only (based on DRC data)

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    End point title
    Percent change in 28-days adjusted partial-onset-seizure (POS) frequency for participants aged ≥2 years from Baseline to the end of the evaluation period in participants with POS only (based on DRC data)
    End point description
    Percent change is calculated as absolute change in seizure frequency per 28 days divided by baseline seizure frequency per 28 days multiplied to 100. 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. Full Analysis Set: all enrolled participants who took at least 1 dose of study drug in this Long-term study and had at least 1 completed post-baseline DRC or EEG. Overall number of participants analyzed included all participants evaluable for this OM and it differs in both absolute and percent change because the percent change cannot be calculated for participants with 0 baseline ADF. Per planned analysis, participants were grouped as per cohort linked to source (DRC for ≥2 years /EEG for <2 years) from which their seizure data is recorded. This OM was analyzed in participants ≥2 years (per DRC data) only.
    End point type
    Secondary
    End point timeframe
    From Baseline (LTFU participants: Baseline of previous study N01263 [NCT00422422]; and DE participants: Baseline of current study) to the end of the evaluation period (up to 10 years)
    End point values
    Brivaracetam (BRV): Participants ≥ 2 years to <17 years
    Number of subjects analysed
    105
    Units: percent change
        arithmetic mean (standard deviation)
    26.57 ± 123.06
    No statistical analyses for this end point

    Secondary: 50% responder rate for participants ≥2 years of age for total seizures (all types) (based on DRC data)

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    End point title
    50% responder rate for participants ≥2 years of age for total seizures (all types) (based on DRC data)
    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 for LTFU participants or during this study for DE participants. Full Analysis Set: all enrolled participants who took at least 1 dose of study drug in this Long-term study and had at least 1 completed post-baseline DRC or EEG. Overall number of participants analyzed included all participants evaluable for this OM. Per planned analysis, participants were grouped as per cohort linked to source (DRC for ≥2 years /EEG for <2 years) from which their seizure data is recorded. This OM was analyzed in participants ≥2 years (per DRC data) only.
    End point type
    Secondary
    End point timeframe
    From Baseline (LTFU participants: Baseline of previous study N01263 [NCT00422422]; and DE participants: Baseline of current study) to the end of the evaluation period (up to 10 years)
    End point values
    Brivaracetam (BRV): Participants ≥ 2 years to <17 years
    Number of subjects analysed
    167
    Units: percentage of participants
        number (not applicable)
    50.9
    No statistical analyses for this end point

    Secondary: Absolute change in average daily frequency (ADF) of partial-onset-seizures (POS) in participants <2 years of age with POS only (based on EEG data)

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    End point title
    Absolute change in average daily frequency (ADF) of partial-onset-seizures (POS) in participants <2 years of age with POS only (based on EEG data)
    End point description
    Absolute change in ADF is calculated as the baseline ADF minus post-baseline ADF. ADF is calculated as (number of seizures from central reader divided by stop date and time of EEG minus start date and time of EEG) multiplied to 60, multiplied to 24. Full Analysis Set: all enrolled participants who took at least 1 dose of study drug in this Long-term study and had at least 1 completed post-baseline DRC or EEG. Overall number of participants analyzed included all participants evaluable for this OM and it differs in both absolute and percent change because the percent change cannot be calculated for participants with 0 baseline ADF. Per planned analysis, participants were grouped as per cohort linked to source (DRC for ≥2 years /EEG for <2 years) from which their seizure data is recorded. This OM was analyzed in participants <2 years (per EEG data) only.
    End point type
    Secondary
    End point timeframe
    From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422], or N01349 [NCT03325439]) to the end of the evaluation period (up to 10 years)
    End point values
    Brivaracetam (BRV): Participants ≥1 month to <2 years
    Number of subjects analysed
    8
    Units: seizures per day
        arithmetic mean (standard deviation)
    2.56 ± 4.44
    No statistical analyses for this end point

    Secondary: Percent change in average daily frequency (ADF) of partial-onset-seizures (POS) in participants <2 years of age with POS only (based on EEG data)

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    End point title
    Percent change in average daily frequency (ADF) of partial-onset-seizures (POS) in participants <2 years of age with POS only (based on EEG data)
    End point description
    Percent change in average daily frequency (ADF) is calculated as absolute change in ADF divided by baseline ADF multiplied to 100. ADF is calculated as (number of seizures from central reader divided by stop date and time of EEG minus start date and time of EEG) multiplied to 60, multiplied to 24. Full Analysis Set: all enrolled participants who took at least 1 dose of study drug in this Long-term study and had at least 1 completed post-baseline DRC or EEG. Overall number of participants analyzed included all participants evaluable for this OM and it differs in both absolute and percent change because the percent change cannot be calculated for participants with 0 baseline ADF. Per planned analysis, participants were grouped as per cohort linked to source (DRC for ≥2 years /EEG for <2 years) from which their seizure data is recorded. This OM was analyzed in participants <2 years (per EEG data) only.
    End point type
    Secondary
    End point timeframe
    From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422], or N01349 [NCT03325439]) to the end of the evaluation period (up to 10 years)
    End point values
    Brivaracetam (BRV): Participants ≥1 month to <2 years
    Number of subjects analysed
    3
    Units: Percent change
        arithmetic mean (standard deviation)
    98.72 ± 2.22
    No statistical analyses for this end point

    Secondary: 50% responder rate for participants <2 years of age for total seizures (all types) (based on EEG data)

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    End point title
    50% responder rate for participants <2 years of age for total seizures (all types) (based on EEG data)
    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 for LTFU participants. Full Analysis Set: all enrolled participants who took at least 1 dose of study drug in this Long-term study and had at least 1 completed post-baseline DRC or EEG. Overall number of participants analyzed included all participants evaluable for this OM. Per planned analysis, participants were grouped as per cohort linked to source (DRC for ≥2 years /EEG for <2 years) from which their seizure data is recorded. This OM was analyzed in participants <2 years (per EEG data) only.
    End point type
    Secondary
    End point timeframe
    From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422], or N01349 [NCT03325439]) to the end of the evaluation period (up to 10 years)
    End point values
    Brivaracetam (BRV): Participants ≥1 month to <2 years
    Number of subjects analysed
    8
    Units: percentage of participants
        number (not applicable)
    75.0
    No statistical analyses for this end point

    Secondary: Percent change in average daily frequency of POS in participants <2 years of age with Typical Absence Seizures (based on EEG data)

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    End point title
    Percent change in average daily frequency of POS in participants <2 years of age with Typical Absence Seizures (based on EEG data)
    End point description
    Percent change in average daily frequency (ADF) is calculated as absolute change in ADF divided by baseline ADF multiplied to 100. ADF is calculated as (number of seizures from central reader divided by stop date and time of EEG minus start date and time of EEG) multiplied to 60, multiplied to 24. Full Analysis Set: all enrolled participants who took at least 1 dose of study drug in this Long-term study and had at least 1 completed post-baseline DRC or EEG. Overall number of participants analyzed included all participants evaluable for this OM. Per planned analysis, participants were grouped as per cohort linked to source (DRC for ≥2 years /EEG for <2 years) from which their seizure data is recorded.
    End point type
    Secondary
    End point timeframe
    From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422] or N01349 [NCT03325439]) to the end of the evaluation period (up to 10 years)
    End point values
    Brivaracetam (BRV): Participants ≥1 month to <2 years
    Number of subjects analysed
    2 [3]
    Units: Percent change
        arithmetic mean (standard deviation)
    99999 ± 99999
    Notes
    [3] - 99999 indicates that typical absence seizures data was not collected and analyzed.
    No statistical analyses for this end point

    Secondary: Absolute change in average daily frequency of POS in participants <2 years of age with Typical Absence Seizures (based on EEG data)

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    End point title
    Absolute change in average daily frequency of POS in participants <2 years of age with Typical Absence Seizures (based on EEG data)
    End point description
    Absolute change in ADF is calculated as the baseline ADF minus post-baseline ADF. ADF is calculated as (number of seizures from central reader divided by stop date and time of EEG minus start date and time of EEG) multiplied to 60, multiplied to 24. Full Analysis Set: all enrolled participants who took at least 1 dose of study drug in this Long-term study and had at least 1 completed post-baseline DRC or EEG. Overall number of participants analyzed included all participants evaluable for this OM. Per planned analysis, participants were grouped as per cohort linked to source (DRC for ≥2 years /EEG for <2 years) from which their seizure data is recorded.
    End point type
    Secondary
    End point timeframe
    From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422], or N01349 [NCT03325439]) to the end of the evaluation period (up to 10 years)
    End point values
    Brivaracetam (BRV): Participants ≥1 month to <2 years
    Number of subjects analysed
    2 [4]
    Units: Seizure per day
        arithmetic mean (standard deviation)
    99999 ± 99999
    Notes
    [4] - 99999 indicates that typical absence seizures data was not collected and analyzed.
    No statistical analyses for this end point

    Secondary: 50% responder rate for total seizures (all types) in participants <2 years of age with Typical Absence Seizures (based on EEG data)

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    End point title
    50% responder rate for total seizures (all types) in participants <2 years of age with Typical Absence Seizures (based on EEG data)
    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 for LTFU participants. Full Analysis Set: all enrolled participants who took at least 1 dose of study drug in this Long-term study and had at least 1 completed post-baseline DRC or EEG. Overall number of participants analyzed included all participants evaluable for this OM. Per planned analysis, participants were grouped as per cohort linked to source (DRC for ≥2 years /EEG for <2 years) from which their seizure data is recorded.
    End point type
    Secondary
    End point timeframe
    From Baseline (LTFU participants: Baseline of previous studies N01263 [NCT00422422] or N01349 [NCT03325439]) to the end of the evaluation period (up to 10 years)
    End point values
    Brivaracetam (BRV): Participants ≥1 month to <2 years
    Number of subjects analysed
    2 [5]
    Units: Percentage of participants
        number (not applicable)
    99999
    Notes
    [5] - 99999 indicates that typical absence seizures data was not collected and analyzed.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline to end of Study (up to 10 years)
    Adverse event reporting additional description
    TEAEs are defined as AEs that had onset on or after the day of first BRV dose.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Age Cohort: ≥1 month to <2 years
    Reporting group description
    Participants from core study (LTFU [Long term follow-up] participants from N01263 [NCT00422422], EP0065 [NCT03405714] or N01349 [NCT03325439]) aged greater than or equal to (≥) 1 month to less than (<) 2 years entered evaluation period (EP) and received individualized Brivaracetam (BRV) dose as they were receiving at completion of core study. For all participants, the approximate BRV doses to be administered are 1 to 5 milligram per kilogram per day (mg/kg/day) (0.5, 1, 2, and 2.5 mg/kg twice daily[bid]), tablet or oral solution and can be up-titrated or down-titrated based on investigator decision with a maximum allowable BRV dose of 5.0 mg/kg/day (2.5 mg/kg bid), not to exceed a dose of 200 mg/day. The duration of the treatment for each participant was planned to be at least 3 years, until BRV received approval for pediatric participants in their age range or until the investigational medicinal product (IMP) development was stopped by the Sponsor.

    Reporting group title
    Age Cohort: ≥4 to <12 years
    Reporting group description
    Participants from core study (LTFU participants from N01263 [NCT00422422] and EP0065 [NCT03405714]) aged ≥4 Years to <12 years entered EP and received individualized BRV dose as they were receiving at completion of core study and Directly Enrolled (DE) participants in this study aged ≥4 years to <12 years of age received BRV dose based on tolerability confirmed during screening period. For all participants, the approximate BRV doses to be administered are 1 to 5 mg/kg/day (0.5, 1, 2, and 2.5mg/kg bid), tablet or oral solution and can be up-titrated or down-titrated based on investigator decision with a maximum allowable BRV dose of 5.0 mg/kg/day (2.5 mg/kg bid), not to exceed a dose of 200 mg/day. The duration of the treatment for each participant was planned to be at least 3 years, until BRV received approval for pediatric participants in their age range or until the IMP development was stopped by the Sponsor.

    Reporting group title
    Age Cohort: ≥12 to <17 years
    Reporting group description
    Participants from core study (LTFU participants from N01263 [NCT00422422] and EP0065 [NCT03405714]) aged ≥12 Years to <17 years entered EP and received individualized BRV dose as they were receiving at completion of core study and DE participants in this study aged ≥12 years to <17 years of age received BRV dose based on tolerability confirmed during screening period. For all participants, the approximate BRV doses to be administered are 1 to 5 mg/kg/day (0.5, 1, 2, and 2.5 mg/kg bid), tablet or oral solution and can be up-titrated or down-titrated based on investigator decision with a maximum allowable BRV dose of 5.0 mg/kg/day (2.5 mg/kg bid), not to exceed a dose of 200 mg/day. The duration of the treatment for each participant was planned to be at least 3 years, until BRV received approval for pediatric participants in their age range or until the IMP development was stopped by the Sponsor.

    Reporting group title
    Age Cohort: ≥2 to <4 years
    Reporting group description
    Participants from core study (LTFU participants from N01263 [NCT00422422] and EP0065 [NCT03405714]) aged ≥2 Years to <4 years entered EP and received individualized BRV dose as they were receiving at completion of core study. For all participants, the approximate BRV doses to be administered are 1 to 5 mg/kg/day (0.5, 1, 2, and 2.5mg/kg bid), tablet or oral solution and can be up-titrated or down-titrated based on investigator decision with a maximum allowable BRV dose of 5.0 mg/kg/day (2.5mg/kg bid), not to exceed a dose of 200mg/day. The duration of the treatment for each participant was planned to be at least 3 years, until BRV received approval for pediatric participants in their age range or until the IMP development was stopped by the Sponsor.

    Serious adverse events
    Age Cohort: ≥1 month to <2 years Age Cohort: ≥4 to <12 years Age Cohort: ≥12 to <17 years Age Cohort: ≥2 to <4 years
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 36 (38.89%)
    42 / 141 (29.79%)
    19 / 65 (29.23%)
    8 / 15 (53.33%)
         number of deaths (all causes)
    2
    2
    1
    2
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    1 / 65 (1.54%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Haemodynamic instability
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Brain operation
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrostomy
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteotomy
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Astrocytoma, low grade
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    1 / 65 (1.54%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 36 (5.56%)
    3 / 141 (2.13%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypothermia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device extrusion
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    2 / 65 (3.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Affect lability
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aggression
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    1 / 65 (1.54%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anger
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    1 / 65 (1.54%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    1 / 65 (1.54%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Homicidal ideation
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    1 / 65 (1.54%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    1 / 65 (1.54%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Testicular torsion
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    1 / 65 (1.54%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Greenstick fracture
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Iatrogenic injury
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood bicarbonate decreased
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    1 / 65 (1.54%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laparoscopy
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Cryptorchism
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Developmental hip dysplasia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spina bifida
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Phimosis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Respiratory distress
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 141 (1.42%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    1 / 65 (1.54%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Apnoea
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Aspiration
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Asthmatic crisis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune thrombocytopenic purpura
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 36 (2.78%)
    12 / 141 (8.51%)
    2 / 65 (3.08%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 6
    1 / 20
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    2 / 36 (5.56%)
    7 / 141 (4.96%)
    2 / 65 (3.08%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 12
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 36 (2.78%)
    4 / 141 (2.84%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 7
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 141 (1.42%)
    1 / 65 (1.54%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 141 (2.13%)
    1 / 65 (1.54%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Complex partial seizures
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Partial seizures with secondary generalisation
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    1 / 65 (1.54%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Simple partial seizures
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Petit mal epilepsy
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    1 / 65 (1.54%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural hygroma
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness neurosensory
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 141 (2.13%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth deposit
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toothache
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal tubular acidosis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin reaction
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Juvenile idiopathic arthritis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Scoliosis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 36 (2.78%)
    3 / 141 (2.13%)
    1 / 65 (1.54%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperammonaemia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Underweight
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 36 (8.33%)
    4 / 141 (2.84%)
    1 / 65 (1.54%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 11
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 36 (2.78%)
    3 / 141 (2.13%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    1 / 65 (1.54%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 141 (1.42%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 141 (1.42%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Corona virus infection
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neurocysticercosis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    1 / 65 (1.54%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    1 / 65 (1.54%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Age Cohort: ≥1 month to <2 years Age Cohort: ≥4 to <12 years Age Cohort: ≥12 to <17 years Age Cohort: ≥2 to <4 years
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 36 (83.33%)
    120 / 141 (85.11%)
    51 / 65 (78.46%)
    13 / 15 (86.67%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 141 (1.42%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    3
    0
    1
    General disorders and administration site conditions
    Device occlusion
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Fatigue
         subjects affected / exposed
    1 / 36 (2.78%)
    5 / 141 (3.55%)
    6 / 65 (9.23%)
    2 / 15 (13.33%)
         occurrences all number
    1
    6
    10
    3
    Pyrexia
         subjects affected / exposed
    15 / 36 (41.67%)
    37 / 141 (26.24%)
    7 / 65 (10.77%)
    4 / 15 (26.67%)
         occurrences all number
    84
    63
    9
    11
    Gait disturbance
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    5 / 36 (13.89%)
    14 / 141 (9.93%)
    4 / 65 (6.15%)
    0 / 15 (0.00%)
         occurrences all number
    8
    15
    4
    0
    Aggression
         subjects affected / exposed
    0 / 36 (0.00%)
    14 / 141 (9.93%)
    1 / 65 (1.54%)
    2 / 15 (13.33%)
         occurrences all number
    0
    18
    1
    2
    Insomnia
         subjects affected / exposed
    2 / 36 (5.56%)
    11 / 141 (7.80%)
    0 / 65 (0.00%)
    3 / 15 (20.00%)
         occurrences all number
    3
    14
    0
    3
    Anxiety
         subjects affected / exposed
    2 / 36 (5.56%)
    4 / 141 (2.84%)
    2 / 65 (3.08%)
    0 / 15 (0.00%)
         occurrences all number
    2
    5
    2
    0
    Suicidal ideation
         subjects affected / exposed
    0 / 36 (0.00%)
    5 / 141 (3.55%)
    4 / 65 (6.15%)
    0 / 15 (0.00%)
         occurrences all number
    0
    5
    4
    0
    Mental status changes
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    1
    Hallucination, visual
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Laceration
         subjects affected / exposed
    0 / 36 (0.00%)
    4 / 141 (2.84%)
    6 / 65 (9.23%)
    0 / 15 (0.00%)
         occurrences all number
    0
    6
    10
    0
    Fall
         subjects affected / exposed
    1 / 36 (2.78%)
    6 / 141 (4.26%)
    8 / 65 (12.31%)
    0 / 15 (0.00%)
         occurrences all number
    1
    8
    11
    0
    Investigations
    Weight decreased
         subjects affected / exposed
    3 / 36 (8.33%)
    10 / 141 (7.09%)
    2 / 65 (3.08%)
    0 / 15 (0.00%)
         occurrences all number
    3
    13
    2
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 36 (5.56%)
    3 / 141 (2.13%)
    1 / 65 (1.54%)
    0 / 15 (0.00%)
         occurrences all number
    2
    3
    1
    0
    Creatinine renal clearance decreased
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    0
    1
    Cardiac disorders
    Atrioventricular block first degree
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Congenital, familial and genetic disorders
    Arnold-Chiari malformation
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 36 (16.67%)
    19 / 141 (13.48%)
    5 / 65 (7.69%)
    2 / 15 (13.33%)
         occurrences all number
    8
    26
    8
    4
    Oropharyngeal pain
         subjects affected / exposed
    0 / 36 (0.00%)
    6 / 141 (4.26%)
    5 / 65 (7.69%)
    2 / 15 (13.33%)
         occurrences all number
    0
    7
    7
    2
    Rhinitis allergic
         subjects affected / exposed
    2 / 36 (5.56%)
    10 / 141 (7.09%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    5
    11
    0
    0
    Epistaxis
         subjects affected / exposed
    2 / 36 (5.56%)
    6 / 141 (4.26%)
    2 / 65 (3.08%)
    1 / 15 (6.67%)
         occurrences all number
    2
    8
    2
    1
    Rhinorrhoea
         subjects affected / exposed
    4 / 36 (11.11%)
    3 / 141 (2.13%)
    1 / 65 (1.54%)
    0 / 15 (0.00%)
         occurrences all number
    18
    4
    1
    0
    Nasal congestion
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 141 (1.42%)
    1 / 65 (1.54%)
    1 / 15 (6.67%)
         occurrences all number
    1
    3
    1
    1
    Asthma
         subjects affected / exposed
    3 / 36 (8.33%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    5
    0
    0
    2
    Adenoidal hypertrophy
         subjects affected / exposed
    3 / 36 (8.33%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Asthmatic crisis
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Bronchospasm
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    5
    0
    0
    0
    Aspiration
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 36 (8.33%)
    0 / 141 (0.00%)
    1 / 65 (1.54%)
    0 / 15 (0.00%)
         occurrences all number
    5
    0
    2
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 36 (0.00%)
    21 / 141 (14.89%)
    16 / 65 (24.62%)
    1 / 15 (6.67%)
         occurrences all number
    0
    58
    75
    1
    Seizure
         subjects affected / exposed
    3 / 36 (8.33%)
    17 / 141 (12.06%)
    11 / 65 (16.92%)
    2 / 15 (13.33%)
         occurrences all number
    9
    29
    17
    2
    Somnolence
         subjects affected / exposed
    3 / 36 (8.33%)
    15 / 141 (10.64%)
    5 / 65 (7.69%)
    1 / 15 (6.67%)
         occurrences all number
    4
    25
    5
    1
    Dizziness
         subjects affected / exposed
    0 / 36 (0.00%)
    7 / 141 (4.96%)
    8 / 65 (12.31%)
    0 / 15 (0.00%)
         occurrences all number
    0
    13
    16
    0
    Complex partial seizures
         subjects affected / exposed
    3 / 36 (8.33%)
    3 / 141 (2.13%)
    1 / 65 (1.54%)
    0 / 15 (0.00%)
         occurrences all number
    3
    3
    1
    0
    Partial seizures with secondary generalisation
         subjects affected / exposed
    0 / 36 (0.00%)
    2 / 141 (1.42%)
    1 / 65 (1.54%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    1
    1
    Hypotonia
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    2
    Ataxia
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    1
    Muscle spasticity
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Eye disorders
    Strabismus
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Eyelid oedema
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    1
    Hypermetropia
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 36 (0.00%)
    6 / 141 (4.26%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    6
    0
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    11 / 36 (30.56%)
    34 / 141 (24.11%)
    4 / 65 (6.15%)
    5 / 15 (33.33%)
         occurrences all number
    19
    61
    4
    6
    Diarrhoea
         subjects affected / exposed
    7 / 36 (19.44%)
    21 / 141 (14.89%)
    8 / 65 (12.31%)
    0 / 15 (0.00%)
         occurrences all number
    16
    33
    8
    0
    Constipation
         subjects affected / exposed
    7 / 36 (19.44%)
    10 / 141 (7.09%)
    2 / 65 (3.08%)
    0 / 15 (0.00%)
         occurrences all number
    11
    12
    4
    0
    Abdominal pain
         subjects affected / exposed
    4 / 36 (11.11%)
    12 / 141 (8.51%)
    3 / 65 (4.62%)
    0 / 15 (0.00%)
         occurrences all number
    4
    20
    9
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 36 (2.78%)
    9 / 141 (6.38%)
    8 / 65 (12.31%)
    0 / 15 (0.00%)
         occurrences all number
    1
    10
    10
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    5 / 36 (13.89%)
    4 / 141 (2.84%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    6
    5
    0
    1
    Nausea
         subjects affected / exposed
    4 / 36 (11.11%)
    5 / 141 (3.55%)
    3 / 65 (4.62%)
    0 / 15 (0.00%)
         occurrences all number
    4
    5
    3
    0
    Toothache
         subjects affected / exposed
    1 / 36 (2.78%)
    5 / 141 (3.55%)
    1 / 65 (1.54%)
    1 / 15 (6.67%)
         occurrences all number
    21
    5
    1
    1
    Dysphagia
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    0
    3
    Abdominal distension
         subjects affected / exposed
    3 / 36 (8.33%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    5
    1
    0
    0
    Enteritis
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 141 (0.00%)
    1 / 65 (1.54%)
    0 / 15 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Teething
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Hiatus hernia
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    0
    1
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 141 (2.13%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    10
    0
    1
    Neurogenic bladder
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 36 (5.56%)
    10 / 141 (7.09%)
    1 / 65 (1.54%)
    0 / 15 (0.00%)
         occurrences all number
    2
    15
    1
    0
    Dermatitis contact
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 141 (0.71%)
    1 / 65 (1.54%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    1
    1
    Dermatitis diaper
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    0
    1
    Hair growth abnormal
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Alopecia
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Facial asymmetry
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 36 (0.00%)
    6 / 141 (4.26%)
    1 / 65 (1.54%)
    1 / 15 (6.67%)
         occurrences all number
    0
    6
    1
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    6 / 36 (16.67%)
    16 / 141 (11.35%)
    7 / 65 (10.77%)
    1 / 15 (6.67%)
         occurrences all number
    7
    18
    8
    1
    Metabolic acidosis
         subjects affected / exposed
    2 / 36 (5.56%)
    1 / 141 (0.71%)
    1 / 65 (1.54%)
    0 / 15 (0.00%)
         occurrences all number
    2
    1
    1
    0
    Dehydration
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 141 (0.00%)
    1 / 65 (1.54%)
    1 / 15 (6.67%)
         occurrences all number
    2
    0
    1
    1
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Hyperlipidaemia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Hypernatraemia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Hyperuricaemia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Underweight
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Pharyngitis
         subjects affected / exposed
    10 / 36 (27.78%)
    39 / 141 (27.66%)
    8 / 65 (12.31%)
    2 / 15 (13.33%)
         occurrences all number
    21
    60
    8
    9
    Upper respiratory tract infection
         subjects affected / exposed
    10 / 36 (27.78%)
    23 / 141 (16.31%)
    8 / 65 (12.31%)
    5 / 15 (33.33%)
         occurrences all number
    19
    38
    12
    15
    Pharyngotonsillitis
         subjects affected / exposed
    5 / 36 (13.89%)
    21 / 141 (14.89%)
    10 / 65 (15.38%)
    0 / 15 (0.00%)
         occurrences all number
    34
    64
    20
    0
    Influenza
         subjects affected / exposed
    5 / 36 (13.89%)
    16 / 141 (11.35%)
    6 / 65 (9.23%)
    2 / 15 (13.33%)
         occurrences all number
    7
    18
    6
    2
    Gastroenteritis
         subjects affected / exposed
    8 / 36 (22.22%)
    16 / 141 (11.35%)
    5 / 65 (7.69%)
    0 / 15 (0.00%)
         occurrences all number
    14
    30
    6
    0
    Bronchitis
         subjects affected / exposed
    7 / 36 (19.44%)
    16 / 141 (11.35%)
    1 / 65 (1.54%)
    3 / 15 (20.00%)
         occurrences all number
    18
    29
    1
    11
    Rhinitis
         subjects affected / exposed
    5 / 36 (13.89%)
    16 / 141 (11.35%)
    2 / 65 (3.08%)
    2 / 15 (13.33%)
         occurrences all number
    8
    47
    6
    3
    Nasopharyngitis
         subjects affected / exposed
    11 / 36 (30.56%)
    44 / 141 (31.21%)
    16 / 65 (24.62%)
    4 / 15 (26.67%)
         occurrences all number
    44
    114
    41
    6
    Tonsillitis
         subjects affected / exposed
    2 / 36 (5.56%)
    13 / 141 (9.22%)
    2 / 65 (3.08%)
    1 / 15 (6.67%)
         occurrences all number
    2
    21
    3
    1
    Ear infection
         subjects affected / exposed
    2 / 36 (5.56%)
    10 / 141 (7.09%)
    4 / 65 (6.15%)
    1 / 15 (6.67%)
         occurrences all number
    3
    18
    4
    2
    Otitis media
         subjects affected / exposed
    4 / 36 (11.11%)
    10 / 141 (7.09%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    13
    24
    0
    1
    Urinary tract infection
         subjects affected / exposed
    2 / 36 (5.56%)
    6 / 141 (4.26%)
    4 / 65 (6.15%)
    3 / 15 (20.00%)
         occurrences all number
    3
    11
    5
    3
    Varicella
         subjects affected / exposed
    4 / 36 (11.11%)
    9 / 141 (6.38%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    4
    10
    0
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    2 / 36 (5.56%)
    8 / 141 (5.67%)
    2 / 65 (3.08%)
    0 / 15 (0.00%)
         occurrences all number
    3
    9
    3
    0
    Viral infection
         subjects affected / exposed
    3 / 36 (8.33%)
    7 / 141 (4.96%)
    1 / 65 (1.54%)
    1 / 15 (6.67%)
         occurrences all number
    6
    19
    2
    1
    Respiratory tract infection
         subjects affected / exposed
    3 / 36 (8.33%)
    6 / 141 (4.26%)
    1 / 65 (1.54%)
    1 / 15 (6.67%)
         occurrences all number
    3
    11
    1
    37
    Conjunctivitis
         subjects affected / exposed
    5 / 36 (13.89%)
    4 / 141 (2.84%)
    1 / 65 (1.54%)
    1 / 15 (6.67%)
         occurrences all number
    6
    5
    1
    2
    Sinusitis
         subjects affected / exposed
    1 / 36 (2.78%)
    7 / 141 (4.96%)
    1 / 65 (1.54%)
    2 / 15 (13.33%)
         occurrences all number
    3
    12
    1
    2
    Otitis media acute
         subjects affected / exposed
    3 / 36 (8.33%)
    4 / 141 (2.84%)
    2 / 65 (3.08%)
    0 / 15 (0.00%)
         occurrences all number
    4
    5
    2
    0
    Pharyngitis bacterial
         subjects affected / exposed
    2 / 36 (5.56%)
    4 / 141 (2.84%)
    1 / 65 (1.54%)
    0 / 15 (0.00%)
         occurrences all number
    3
    4
    1
    0
    Viral pharyngitis
         subjects affected / exposed
    3 / 36 (8.33%)
    3 / 141 (2.13%)
    1 / 65 (1.54%)
    0 / 15 (0.00%)
         occurrences all number
    3
    3
    1
    0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 141 (2.13%)
    1 / 65 (1.54%)
    1 / 15 (6.67%)
         occurrences all number
    0
    3
    1
    1
    Acute sinusitis
         subjects affected / exposed
    0 / 36 (0.00%)
    3 / 141 (2.13%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    3
    0
    2
    Lice infestation
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 141 (0.71%)
    1 / 65 (1.54%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    1
    1
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 36 (8.33%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Hand-foot-and-mouth disease
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 141 (0.71%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    1
    Bacteraemia
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Oral candidiasis
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Gastroenteritis rotavirus
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Oral fungal infection
         subjects affected / exposed
    0 / 36 (0.00%)
    0 / 141 (0.00%)
    0 / 65 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    Pneumonia
         subjects affected / exposed
    4 / 36 (11.11%)
    9 / 141 (6.38%)
    0 / 65 (0.00%)
    4 / 15 (26.67%)
         occurrences all number
    4
    11
    0
    16

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Aug 2011
    Protocol Amendment 1 was dated 26 Aug 2011 and the rationale was to include the Bayley Scales of Infant Development™, Second Edition (BSID-II™) in order to assess the cognitive development of children <18 months at Baseline in response to the European Pediatric Committee (PDCO) request. Withdrawal criteria were extended to include the consequences of any findings related to the results of liver function tests. 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 request of the FDA that prospective assessments for suicidality are to be included in clinical studies involving all drugs for neurological indications. Some operational updates were also considered. Administrative changes included the update of the SAE reporting and CRO contact details. A few editorial changes were not listed in the specific changes section.
    09 Dec 2011
    Protocol Amendment 2 was dated 09 Dec 2011 and the rationale was to replace the children’s version of the C-SSRS with the version validated in multiple languages for study participants ≥6 years of age. The BSID-II score was replaced by the Bayley-III scales in order to apply the most recent version of the cognition scale. In addition, it was clarified that the cognition scale was to be used only in English-speaking countries, since it is validated only in English. The efficacy variables for study participants <2 years of age and for study participants with absence seizures were updated and amended in response to the PDCO requirements. It was clarified that safety laboratory assessments included hepatic monitoring. Furthermore, an error in the mathematical symbols used for the presentation of the age limits of the EEG assessments was corrected, and the SAE reporting details were updated. Administrative changes included the update of the Clinical Project Manager contact details and typographical corrections. A few editorial changes were additionally listed in the specific changes section.
    26 Sep 2012
    Protocol Amendment 3 was dated 26 Sep 2012 and the rationale was to allow study participants who had not previously participated in a clinical study of BRV to enroll directly into N01266 (ie, DE study participants). Up to 100 study participants who were ≥4 years to <17 years of age with POS and met entry criteria were planned for direct enrollment, and overall planned enrollment increased from up to 500 study participants to up to 600 study participants. The purpose of direct enrollment was to obtain sufficient long-term safety exposure data in study participants ≥4 years to <17 years of age. With this amendment, the BRIEF-P/BRIEF and PedsQL were added to the assessments for study participants ≥2 years of age. These assessments were added to provide an additional means of assessing the effect of BRV on cognition and quality of life, respectively, in pediatric study participants ≥2 years of age.
    10 Dec 2013
    Protocol Amendment 4 was dated 10 Dec 2013. As a result of the PK analyses performed on the plasma samples collected at N01263 completion, the plasma concentrations approximating the concentrations for adults receiving BRV 200mg/day were not achieved by the dosing scheme initially included in N01266. Thus, N01266 was amended to allow a maximum BRV dose of 5.0mg/kg/day (not to exceed a total dose of BRV 200mg/day) for all study participants, irrespective of age. The number of DE study participants was increased from “up to” to “at least” 100 study participants with the planned total enrollment of approximately 600 study participants to allow flexibility in the number of study participants reaching 1 year of exposure. Demographics and childbearing potential were captured at the EV for LTFU study participants, instead of using the data recorded from either the Baseline or the FV of the core study. The handling of protocol deviations was made consistent with the updated statistical analysis process. In addition, it was clarified that although no formal interim analysis was planned, the data may be reported prior to the completion of this study to support ongoing data cleaning, annual reports, regulatory submissions, and publications.
    14 Dec 2016
    Protocol Amendment 5 was dated 14 Dec 2016. The rationale for this amendment was to: • Add an updated list of Anticipated SAEs. • Add a section on adverse events (AEs) of special interest in accordance with the Sponsor template requirement. • Update the schema for down-titration to align with N01263 and provide uniformity across the BRV pediatric development program. • Remove the requirement that study participants <7 years of age receive oral solution and, as appropriate, study participants ≥7 years of age receive tablets in recognition of individual study participant preferences to allow study participants additional flexibility in treatment options. • Provide EV information specific to study participants who enroll from core studies under development. • Provide additional clarity regarding enrolled study participants who participate in EP0065 and then resume participation in N01266. Protocol Amendment 3 had allowed for study participants to participate in what was called a “substudy.” • Clarify the requirement that study participants ≥2 years of age with typical absence seizures have at least a 24-hour EEG, instead of a 1-hour EEG. • Eliminate the EEG at the 3-month visit (Visit 4) and the requirement for study participants to have EEGs after they reach 2 years of age (exception: study participants with typical absence seizures), and allow the EDV EEGs to be done at the Investigator’s discretion. This change was made due to the limited clinical utility of these assessments and to unburden the Investigator, study participant, and study participant’s caregiver/family. • Replace serum pregnancy tests with urine pregnancy tests and include urine pregnancy tests at all MEVs.
    14 Dec 2016
    Protocol Amendment 5 Continued: • Update according to the current Sponsor protocol template. This included: − The addition of text regarding potential drug-induced liver injury (PDILI); these changes were strictly template-driven. They did not reflect a change in the liver safety signal for BRV and were included only for alignment with updated standard Sponsor text across programs. − The streamlining of the Introduction with reference to the availability of additional information in the Investigator’s Brochure. • Update of the Introduction text to include more current literature references and to include information about the marketing authorization of BRV. • Revise the duration of the study for an individual study participant from approximately 3 years to at least 3 years, with the addition of the possibility of study participants entering a managed access program, if available. • Remove the BRV 1.0mg/mL oral solution from the description of the IMP as the BRV 10mg/mL oral solution is adequate for dosing.
    06 Mar 2018
    Protocol Amendment 6 was dated 06 Mar 2018 and the rationale was to: • Update language for Bayley-III scales to include countries where a validated translation was available. • Remove reference to central reading of EEGs to provide flexibility. • Remove EEG assessment for the EV (all study participants). • Update inclusion criteria to align language enhancements provided in country-specific amendment (Czech Republic) (ie, diagnosis of epilepsy and contraceptive language). • Update language in regards to partner pregnancy to align with Sponsor’s Standard Operating Procedure (SOP) and protocol templates. • Add blood draw volumes for study participants <2 years of age. • Clarify PedsQL age range (≥2 years of age) as this assessment is not used in children <2 years of age. • Clarify for all other EEGs (ie, Visit 5 and yearly thereafter) the duration in study participants >2 years of age.
    18 Apr 2019
    Protocol Amendment 7 was dated 18 Apr 2019. This amendment was implemented to update the pregnancy text to clarify that the Pregnancy Report and Outcome form is to be completed for all pregnancies.
    25 Jun 2020
    Protocol Amendment 8 was dated 25 Jun 2020. This amendment was implemented to: • Reorganize the study variables into primary, secondary, other variables in compliance with reporting agencies. This change does not affect the type or processing of data collected and reported in the study report, as they will be assessed as initially planned. • Allow study participants to transition to another BRV study. • Add information regarding down-titration for study participants who do not continue BRV treatment after completing the study. • Clarify the text describing the maximum dose of BRV. • Modify the study conduct to ensure the safety of participants in response to the COVID-19 pandemic.

    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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