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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-controlled, Multicenter, Parallel-group Study to Evaluate the Efficacy and Safety of Adjunctive Brivaracetam in Subjects (>=16 to 80 Years of Age) With Partial Seizures With or Without Secondary Generalization

    Summary
    EudraCT number
    		 2019-001203-21
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    30 Jun 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Dec 2022
    First version publication date
    31 Dec 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EP0083
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03083665
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UCB Biopharma SRL
    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)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Aug 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jun 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Evaluate the efficacy of brivaracetam (BRV) compared to placebo (PBO) as adjunctive treatment in subjects (>=16 to 80 years of age) with partial seizures with or without secondary generalization despite current treatment with 1 or 2 concomitant antiepileptic drugs (AEDs)
    Protection of trial subjects
    During the conduct of the study all participants were closely monitored.
    Background therapy
    		 Background therapy as permitted in the protocol.
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    22 Aug 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    China: 86
    Country: Number of subjects enrolled
    Japan: 98
    Country: Number of subjects enrolled
    Malaysia: 47
    Country: Number of subjects enrolled
    Philippines: 62
    Country: Number of subjects enrolled
    Singapore: 6
    Country: Number of subjects enrolled
    Taiwan: 5
    Country: Number of subjects enrolled
    Thailand: 145
    Worldwide total number of subjects
    449
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    20
    Adults (18-64 years)
    421
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study started to enroll participants in August 2017 and concluded in June 2022.

    Pre-assignment
    Screening details
    		 The Participant Flow refers to the Randomized Set. Double-Blind Period included Treatment Period and the Down-Titration Period plus Study Drug-Free Period or the Transition Period.

    Period 1
    Period 1 title
    Double-Blind Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received matching Placebo as film-coated tablets, administered orally, twice daily (bid), during 12 weeks of Treatment Period. At the end of the Treatment Period, participants who entered long-term follow-up (LTFU) study (EP0085 (NCT03250377)) or managed access program (MAP), the same matching Placebo dose was kept during 2 weeks of Transition Period and brivaracetam (BRV) 100 milligrams/day (mg/day) in LTFU study or MAP. Participants who did not enter the LTFU study or MAP had 4 weeks Down-Titration Period followed by a Study Drug-Free Period (no drug for 2 weeks). During Down-Titration Period, participants received the same Placebo dose for 4 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received matching placebo at pre-defined timepoints.

    Arm title
    		 BRV 50 mg/day
    Arm description
    		 Participants received BRV 50 mg/day as film-coated tablets, administered orally, bid, during 12 weeks of Treatment Period. At the end of the Treatment Period, participants who entered the LTFU study or MAP received BRV 50 mg/day during 2 weeks of Transition Period and BRV 100 mg/day in LTFU study or MAP. Participants who did not enter the LTFU study or MAP had 4 weeks Down-Titration Period followed by a Study Drug-Free Period (no drug for 2 weeks). During Down-Titration Period, participants received BRV 25 mg/day for 1 week followed by Placebo for 3 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brivaracetam
    Investigational medicinal product code
    BRV
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received Brivaracetam 50 mg/day at pre-defined timepoints.

    Arm title
    		 BRV 200 mg/day
    Arm description
    		 Participants received BRV 200 mg/day as film-coated tablets, administered orally, bid, during 12 weeks of Treatment Period. At the end of the Treatment Period, participants who entered LTFU study or MAP received BRV 150 mg/day during 2 weeks of Transition Period and BRV 100 mg/day in LTFU study or MAP. Participants who did not enter the LTFU study or MAP had 4 weeks Down-Titration Period followed by a Study Drug-Free Period (no drug for 2 weeks). During Down-Titration Period, participants received BRV 150 mg/day for 1 week followed by BRV 100 mg/day for 1 week, followed by BRV 50 mg/day for 1 week, followed by BRV 25 mg/day for 1 week.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brivaracetam
    Investigational medicinal product code
    BRV
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received Brivaracetam 200 mg/day at pre-defined timepoints.

    Number of subjects in period 1
    		Placebo BRV 50 mg/day BRV 200 mg/day
    Started
    149
    152
    148
    Started Treatment Period (12 weeks)
    149
    152
    148
    Started Down-Titration Period (4 weeks)
    7 [1]
    9 [2]
    7 [3]
    Started Study Drug-Free Period (2 weeks)
    7 [4]
    9 [5]
    7 [6]
    Started Transition Period (2 weeks)
    133 [7]
    139 [8]
    137 [9]
    Completed
    138
    147
    140
    Not completed
    11
    5
    8
         Adverse event, serious fatal
    -
    1
    -
         Consent withdrawn by subject
    3
    -
    -
         Consent withdrawn by subject due to concern on AE
    1
    -
    -
         Subjects were able to never take a study drug
    -
    1
    -
         Adverse event, non-fatal
    5
    3
    5
         Lost to follow-up
    1
    -
    1
         Protocol deviation
    1
    -
    1
         Lack of efficacy
    -
    -
    1
    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 milestones were created based on the the fact if Participants were conveyed to LTFU and MAP or not and hence whether they took BRV through Transition or Down-Titration Periods.
    [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 milestones were created based on the the fact if Participants were conveyed to LTFU and MAP or not and hence whether they took BRV through Transition or Down-Titration Periods.
    [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 milestones were created based on the the fact if Participants were conveyed to LTFU and MAP or not and hence whether they took BRV through Transition or Down-Titration Periods.
    [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 milestones were created based on the the fact if Participants were conveyed to LTFU and MAP or not and hence whether they took BRV through Transition or Down-Titration Periods.
    [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 milestones were created based on the the fact if Participants were conveyed to LTFU and MAP or not and hence whether they took BRV through Transition or Down-Titration Periods.
    [6] - 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 milestones were created based on the the fact if Participants were conveyed to LTFU and MAP or not and hence whether they took BRV through Transition or Down-Titration Periods.
    [7] - 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 milestones were created based on the the fact if Participants were conveyed to LTFU and MAP or not and hence whether they took BRV through Transition or Down-Titration Periods.
    [8] - 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 milestones were created based on the the fact if Participants were conveyed to LTFU and MAP or not and hence whether they took BRV through Transition or Down-Titration Periods.
    [9] - 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 milestones were created based on the the fact if Participants were conveyed to LTFU and MAP or not and hence whether they took BRV through Transition or Down-Titration Periods.
    Period 2
    Period 2 title
    Open-Label Temporary Period (OLTP)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo to OLTP BRV
    Arm description
    		 Participants who received Placebo during Treatment Period and were eligible to enter MAP received BRV 100 mg/day due to delayed importation of medication during OLTP. BRV dose might be adjusted for an individual participant (between 50 mg/day to 200 mg/day) during the OLTP. The period was defined from immediately after the last visit of the Transition Period (Week 14) and until a visit when the participant could convert to MAP.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brivaracetam
    Investigational medicinal product code
    BRV
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received Brivaracetam at pre-defined timepoints.

    Arm title
    		 BRV 50 mg/day to OLTP BRV
    Arm description
    		 Participants who received BRV 50 mg/day during Treatment Period and were eligible to enter MAP received BRV 100 mg/day due to delayed importation of medication during Open-Label Temporary Period (OLTP). BRV dose might be adjusted for an individual participant (between 50 mg/day to 200 mg/day) during the OLTP. The period was defined from immediately after the last visit of the Transition Period (Week 14) and until a visit when the participant could convert to MAP.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brivaracetam
    Investigational medicinal product code
    BRV
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received Brivaracetam at pre-defined timepoints.

    Arm title
    		 BRV 200 mg/day to OLTP BRV
    Arm description
    		 Participants who received BRV 200 mg/day during Treatment Period and were eligible to enter MAP received BRV 100 mg/day due to delayed importation of medication during Open-Label Temporary Period (OLTP). BRV dose might be adjusted for an individual participant (between 50 mg/day to 200 mg/day) during the OLTP. The period was defined from immediately after the last visit of the Transition Period (Week 14) and until a visit when the participant could convert to MAP.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brivaracetam
    Investigational medicinal product code
    BRV
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received Brivaracetam at pre-defined timepoints.

    Number of subjects in period 2 [10]
    		Placebo to OLTP BRV BRV 50 mg/day to OLTP BRV BRV 200 mg/day to OLTP BRV
    Started
    64
    68
    74
    Completed
    60
    67
    68
    Not completed
    4
    1
    6
         Consent withdrawn by subject
    1
    1
    1
         Patient not keen to continue open label
    1
    -
    -
         Adverse event, non-fatal
    2
    -
    -
         Subject enrolled to compassionate use program
    -
    -
    1
         Patient non compliant to open label study drug
    -
    -
    1
         Withdrawal by parent/guardian
    -
    -
    1
         Lack of efficacy
    -
    -
    2
    Notes
    [10] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: These are the participants who were assigned to enter MAP but who could not directly convert to MAP; started after the end date of the Transition Period and continued until date when participant could convert to MAP, BRV was commercially available or until UCB decides to close the study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching Placebo as film-coated tablets, administered orally, twice daily (bid), during 12 weeks of Treatment Period. At the end of the Treatment Period, participants who entered long-term follow-up (LTFU) study (EP0085 (NCT03250377)) or managed access program (MAP), the same matching Placebo dose was kept during 2 weeks of Transition Period and brivaracetam (BRV) 100 milligrams/day (mg/day) in LTFU study or MAP. Participants who did not enter the LTFU study or MAP had 4 weeks Down-Titration Period followed by a Study Drug-Free Period (no drug for 2 weeks). During Down-Titration Period, participants received the same Placebo dose for 4 weeks.

    Reporting group title
    BRV 50 mg/day
    Reporting group description
    		 Participants received BRV 50 mg/day as film-coated tablets, administered orally, bid, during 12 weeks of Treatment Period. At the end of the Treatment Period, participants who entered the LTFU study or MAP received BRV 50 mg/day during 2 weeks of Transition Period and BRV 100 mg/day in LTFU study or MAP. Participants who did not enter the LTFU study or MAP had 4 weeks Down-Titration Period followed by a Study Drug-Free Period (no drug for 2 weeks). During Down-Titration Period, participants received BRV 25 mg/day for 1 week followed by Placebo for 3 weeks.

    Reporting group title
    BRV 200 mg/day
    Reporting group description
    		 Participants received BRV 200 mg/day as film-coated tablets, administered orally, bid, during 12 weeks of Treatment Period. At the end of the Treatment Period, participants who entered LTFU study or MAP received BRV 150 mg/day during 2 weeks of Transition Period and BRV 100 mg/day in LTFU study or MAP. Participants who did not enter the LTFU study or MAP had 4 weeks Down-Titration Period followed by a Study Drug-Free Period (no drug for 2 weeks). During Down-Titration Period, participants received BRV 150 mg/day for 1 week followed by BRV 100 mg/day for 1 week, followed by BRV 50 mg/day for 1 week, followed by BRV 25 mg/day for 1 week.

    Reporting group values
    		 Placebo BRV 50 mg/day BRV 200 mg/day Total
    Number of subjects
    		 149 152 148 449
    Age Categorical
    Units: participants
        <=18 years
    		 9 14 8 31
        Between 18 and 65 years
    		 137 135 138 410
        >=65 years
    		 3 3 2 8
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 34.5 ± 13.2 33.7 ± 12.6 35.2 ± 13.2 -
    Sex: Female, Male
    Units: participants
        Female
    		 82 77 83 242
        Male
    		 67 75 65 207

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching Placebo as film-coated tablets, administered orally, twice daily (bid), during 12 weeks of Treatment Period. At the end of the Treatment Period, participants who entered long-term follow-up (LTFU) study (EP0085 (NCT03250377)) or managed access program (MAP), the same matching Placebo dose was kept during 2 weeks of Transition Period and brivaracetam (BRV) 100 milligrams/day (mg/day) in LTFU study or MAP. Participants who did not enter the LTFU study or MAP had 4 weeks Down-Titration Period followed by a Study Drug-Free Period (no drug for 2 weeks). During Down-Titration Period, participants received the same Placebo dose for 4 weeks.

    Reporting group title
    BRV 50 mg/day
    Reporting group description
    		 Participants received BRV 50 mg/day as film-coated tablets, administered orally, bid, during 12 weeks of Treatment Period. At the end of the Treatment Period, participants who entered the LTFU study or MAP received BRV 50 mg/day during 2 weeks of Transition Period and BRV 100 mg/day in LTFU study or MAP. Participants who did not enter the LTFU study or MAP had 4 weeks Down-Titration Period followed by a Study Drug-Free Period (no drug for 2 weeks). During Down-Titration Period, participants received BRV 25 mg/day for 1 week followed by Placebo for 3 weeks.

    Reporting group title
    BRV 200 mg/day
    Reporting group description
    		 Participants received BRV 200 mg/day as film-coated tablets, administered orally, bid, during 12 weeks of Treatment Period. At the end of the Treatment Period, participants who entered LTFU study or MAP received BRV 150 mg/day during 2 weeks of Transition Period and BRV 100 mg/day in LTFU study or MAP. Participants who did not enter the LTFU study or MAP had 4 weeks Down-Titration Period followed by a Study Drug-Free Period (no drug for 2 weeks). During Down-Titration Period, participants received BRV 150 mg/day for 1 week followed by BRV 100 mg/day for 1 week, followed by BRV 50 mg/day for 1 week, followed by BRV 25 mg/day for 1 week.
    Reporting group title
    Placebo to OLTP BRV
    Reporting group description
    		 Participants who received Placebo during Treatment Period and were eligible to enter MAP received BRV 100 mg/day due to delayed importation of medication during OLTP. BRV dose might be adjusted for an individual participant (between 50 mg/day to 200 mg/day) during the OLTP. The period was defined from immediately after the last visit of the Transition Period (Week 14) and until a visit when the participant could convert to MAP.

    Reporting group title
    BRV 50 mg/day to OLTP BRV
    Reporting group description
    		 Participants who received BRV 50 mg/day during Treatment Period and were eligible to enter MAP received BRV 100 mg/day due to delayed importation of medication during Open-Label Temporary Period (OLTP). BRV dose might be adjusted for an individual participant (between 50 mg/day to 200 mg/day) during the OLTP. The period was defined from immediately after the last visit of the Transition Period (Week 14) and until a visit when the participant could convert to MAP.

    Reporting group title
    BRV 200 mg/day to OLTP BRV
    Reporting group description
    		 Participants who received BRV 200 mg/day during Treatment Period and were eligible to enter MAP received BRV 100 mg/day due to delayed importation of medication during Open-Label Temporary Period (OLTP). BRV dose might be adjusted for an individual participant (between 50 mg/day to 200 mg/day) during the OLTP. The period was defined from immediately after the last visit of the Transition Period (Week 14) and until a visit when the participant could convert to MAP.

    Subject analysis set title
    BRV 150 mg/day
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    At the end of the Treatment Period, participants of arm BRV 200 mg/day who entered LTFU study or MAP received BRV 150 mg/day during 2 weeks of Transition Period. The number of participants for BRV 150 mg/day group are those who had BRV 200 mg/day and valid PK data in Transition Period.

    Primary: Percentage of participants with Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    		 Percentage of participants with Treatment-Emergent Adverse Events (TEAEs) [1]
    End point description
    An AE is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. Treatment-Emergent AEs were defined as AEs which had onset on or after the first dose of IMP. As per planned analysis, safety data for all study periods was combined excluding Open-Label Temporary period. The Safety Set (SS) included all randomized study participants who received at least 1 dose of IMP.
    End point type
    Primary
    End point timeframe
    From start of the Treatment Period (Week 0) until Safety Visit (up to Week 18); only for OLTP- From last visit of Transition Period to beginning of MAP (up to 4 Years 10 Months)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized in tables as descriptive statistics only.
    End point values
    		 Placebo Placebo to OLTP BRV BRV 50 mg/day BRV 50 mg/day to OLTP BRV BRV 200 mg/day BRV 200 mg/day to OLTP BRV
    Number of subjects analysed
    149
    64
    151
    68
    148
    74
    Units: percentage of participants
        number (not applicable)
    58.4
    21.9
    57.0
    19.1
    60.1
    21.6
    No statistical analyses for this end point

    Primary: Percentage of participants with Treatment-Emergent AEs (TEAEs) leading to study withdrawal

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    End point title
    		 Percentage of participants with Treatment-Emergent AEs (TEAEs) leading to study withdrawal [2]
    End point description
    An AE is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. Treatment-Emergent AEs were defined as AEs which had onset on or after the first dose of IMP. As per planned analysis, safety data for all study periods was combined excluding Open-Label Temporary period. The SS included all randomized study participants who received at least 1 dose of IMP.
    End point type
    Primary
    End point timeframe
    From start of the Treatment Period (Week 0) until Safety Visit (up to Week 18); only for OLTP- From last visit of Transition Period to beginning of MAP (up to 4 Years 10 Months)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized in tables as descriptive statistics only.
    End point values
    		 Placebo Placebo to OLTP BRV BRV 50 mg/day BRV 50 mg/day to OLTP BRV BRV 200 mg/day BRV 200 mg/day to OLTP BRV
    Number of subjects analysed
    149
    64
    151
    68
    148
    74
    Units: percentage of participants
        number (not applicable)
    4.7
    0
    2.6
    0
    3.4
    0
    No statistical analyses for this end point

    Primary: Percentage of participants with Treatment-Emergent Serious Adverse Events (SAEs)

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    End point title
    		 Percentage of participants with Treatment-Emergent Serious Adverse Events (SAEs) [3]
    End point description
    Serious Adverse event (SAE) was defined as any events which: • results in death, • is life-threatening threatening (note that this did not include a reaction that might have caused death had it occurred in a more severe form.), •results in significant or persistent disability/incapacity, • results in a congenital anomaly/birth defect (including that occurring in a fetus), • results in Important medical event that, based upon appropriate medical judgment, may jeopardize the participant and might require medical or surgical intervention to prevent 1 of the other outcomes listed here, and • results in initial inpatient hospitalization or prolongation of hospitalization. As per planned analysis, safety data for all study periods was combined excluding Open-Label Temporary period. The SS included all randomized study participants who received at least 1 dose of IMP.
    End point type
    Primary
    End point timeframe
    From start of the Treatment Period (Week 0) until Safety Visit (up to Week 18); only for OLTP- From last visit of Transition Period to beginning of MAP (up to 4 Years 10 Months)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypothesis testing was planned for this study. Results were summarized in tables as descriptive statistics only.
    End point values
    		 Placebo Placebo to OLTP BRV BRV 50 mg/day BRV 50 mg/day to OLTP BRV BRV 200 mg/day BRV 200 mg/day to OLTP BRV
    Number of subjects analysed
    149
    64
    151
    68
    148
    74
    Units: percentage of participants
        number (not applicable)
    0.7
    3.1
    1.3
    0
    2.7
    1.4
    No statistical analyses for this end point

    Primary: Partial seizure frequency per 28 days during the 12-week Treatment Period

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    End point title
    		 Partial seizure frequency per 28 days during the 12-week Treatment Period
    End point description
    According to International League Against Epilepsy (ILAE) classification (1981), seizures were classified as type IA (IA1, IA2, IA3, and IA4), IB, IC, II (IIA, IIB, IIC, IID, IIE, and IIF) or III. 28 day adjusted seizure frequency for partial seizures (seizure types IA+IB+IC) was calculated for treatment period by dividing the number of partial seizures by the number of days for which the DRC was completed for treatment period and multiplying the resulting value by 28. The Full Analysis Set (FAS) consisted of all randomized study participants who received at least 1 dose of IMP and had at least 1 post Baseline seizure daily record card (DRC) data during the Treatment Period.
    End point type
    Primary
    End point timeframe
    From Baseline to 12-week Treatment Period
    End point values
    		 Placebo BRV 50 mg/day BRV 200 mg/day
    Number of subjects analysed
    147
    151
    148
    Units: seizure frequency per 28 days
        median (full range (min-max))
    7.17 (1.0 to 317.0)
    5.93 (0.0 to 123.7)
    4.19 (0.0 to 269.4)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v BRV 50 mg/day
    Number of subjects included in analysis
    298
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.0004 [5]
    Method
    		 ANCOVA
    Parameter type
    		 Percent reduction over Placebo
    Point estimate
    24.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11.8
         upper limit
    		 35.6
    Notes
    [4] - Based on ANCOVA with log-transformed [log(x+1)] Treatment Period 28-day adjusted partial seizure frequency.
    [5] - Statistical testing with control of Type I error rate were based on a Hochberg multiple comparison procedure.
    Statistical analysis title
    		 Statistical Analysis 2
    Comparison groups
    Placebo v BRV 200 mg/day
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 < 0.0001 [7]
    Method
    		 ANCOVA
    Parameter type
    		 Percent reduction over Placebo
    Point estimate
    33.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 21.9
         upper limit
    		 43.1
    Notes
    [6] - Based on ANCOVA with log-transformed [log(x+1)] Treatment Period 28-day adjusted partial seizure frequency.
    [7] - Statistical testing with control of Type I error rate were based on a Hochberg multiple comparison procedure.

    Secondary: 50% responder rate based on percent change in partial seizure frequency per 28 days from Baseline to the 12-week Treatment Period 

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    End point title
    		 50% responder rate based on percent change in partial seizure frequency per 28 days from Baseline to the 12-week Treatment Period 
    End point description
    Responders were those participants with at least 50% reduction from Baseline to the 12-week Treatment Period in partial seizure frequency per 28 days. 50% Responder rate was calculated for treatment period by dividing the number of 50% responders by the number of participants in the analysis set and multiplying the resulting value by 100. The FAS consisted of all randomized study participants who received at least 1 dose of IMP and had at least 1 post Baseline seizure DRC data during the Treatment Period.
    End point type
    Secondary
    End point timeframe
    From Baseline to 12-week Treatment Period
    End point values
    		 Placebo BRV 50 mg/day BRV 200 mg/day
    Number of subjects analysed
    147
    151
    148
    Units: percentage of responders
        number (confidence interval 95%)
    19.0 (13.0 to 26.3)
    41.1 (33.1 to 49.3)
    49.3 (41.0 to 57.7)
    No statistical analyses for this end point

    Secondary: Percent change in partial seizure frequency per 28 days from Baseline to the 12-week Treatment Period

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    End point title
    		 Percent change in partial seizure frequency per 28 days from Baseline to the 12-week Treatment Period
    End point description
    Percent change from Baseline to the Treatment Period in partial seizure frequency was calculated by subtracting 28-day adjusted Treatment Period partial seizure frequency from 28-day adjusted Baseline Period partial seizure frequency, and multiplying the resulting quantity by 100 and dividing by the Baseline Period 28-day adjusted partial seizure frequency. A negative value in percent change from Baseline indicates a decrease in partial seizure frequency from Baseline to the Treatment Period. The FAS consisted of all randomized study participants who received at least 1 dose of IMP and had at least 1 post Baseline seizure DRC data during the Treatment Period.
    End point type
    Secondary
    End point timeframe
    From Baseline to 12-week Treatment Period
    End point values
    		 Placebo BRV 50 mg/day BRV 200 mg/day
    Number of subjects analysed
    147
    151
    148
    Units: percent change
        median (full range (min-max))
    21.3 (-123 to 87)
    38.9 (-233 to 100)
    46.7 (-1097 to 100)
    No statistical analyses for this end point

    Secondary: Percentage of participants with categorized percent change in partial seizure frequency per 28 days from Baseline to the 12-week Treatment Period

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    End point title
    		 Percentage of participants with categorized percent change in partial seizure frequency per 28 days from Baseline to the 12-week Treatment Period
    End point description
    The percentage of participants within each of the following categories of percent change in partial seizure frequency from Baseline to the Treatment Period were summarized for each treatment group: 100%, 75% to less than 100%, 50% to less than 75%, 25% to less than 50%, -25% to less than 25%, and less than -25%. Percent change from Baseline to the Treatment Period in partial seizure frequency was calculated by subtracting 28-day adjusted Treatment Period partial seizure frequency from 28-day adjusted Baseline Period partial seizure frequency and multiplying the resulting quantity by 100 and dividing by the Baseline Period 28-day adjusted partial seizure frequency. The FAS consisted of all randomized study participants who received at least 1 dose of IMP and had at least 1 post Baseline seizure DRC data during the Treatment Period.
    End point type
    Secondary
    End point timeframe
    From Baseline to 12-week Treatment Period
    End point values
    		 Placebo BRV 50 mg/day BRV 200 mg/day
    Number of subjects analysed
    147
    151
    148
    Units: percentage of participants
    number (not applicable)
        100%
    0
    5.3
    7.4
        75% to less than 100%
    3.4
    14.6
    17.6
        50% to less than 75%
    15.6
    21.2
    24.3
        25% to less than 50%
    27.2
    16.6
    20.9
        -25% to less than 25%
    42.9
    31.1
    18.2
        less than -25%
    10.9
    11.3
    11.5
    No statistical analyses for this end point

    Secondary: All seizure frequency (partial, generalized, and unclassified epileptic seizures) per 28 days during the 12-week Treatment Period

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    End point title
    		 All seizure frequency (partial, generalized, and unclassified epileptic seizures) per 28 days during the 12-week Treatment Period
    End point description
    There were three types of epileptic seizures: Partial epileptic seizures (Type I), Generalized epileptic seizures (Type II) and unclassified epileptic seizures (Type III). 28 day adjusted seizure frequency for all seizure types was calculated for treatment period by dividing the number of targeted seizures by the number of days for which the DRC was completed for treatment period and multiplying the resulting value by 28. The FAS consisted of all randomized study participants who received at least 1 dose of IMP and had at least 1 post Baseline seizure DRC data during the Treatment Period.
    End point type
    Secondary
    End point timeframe
    During the 12-week Treatment Period
    End point values
    		 Placebo BRV 50 mg/day BRV 200 mg/day
    Number of subjects analysed
    147
    151
    148
    Units: seizure frequency per 28 days
        median (full range (min-max))
    7.17 (1.0 to 317.0)
    5.93 (0.0 to 123.7)
    4.19 (0.0 to 269.4)
    No statistical analyses for this end point

    Secondary: Percentage of participants who are seizure free (partial, all epileptic seizures) during the 12-week Treatment Period

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    End point title
    		 Percentage of participants who are seizure free (partial, all epileptic seizures) during the 12-week Treatment Period
    End point description
    Participants were defined as seizure free, if they did not have missing diary days and no reported seizures during the Treatment Period. The FAS consisted of all randomized study participants who received at least 1 dose of IMP and had at least 1 post Baseline seizure DRC data during the Treatment Period.
    End point type
    Secondary
    End point timeframe
    During the 12-week Treatment Period
    End point values
    		 Placebo BRV 50 mg/day BRV 200 mg/day
    Number of subjects analysed
    147
    151
    148
    Units: percentage of participants
    number (not applicable)
        All epileptic seizures
    0
    4.6
    6.8
        Partial onset seizures
    0
    4.6
    6.8
    No statistical analyses for this end point

    Secondary: Time to 1st partial seizure during the 12-week Treatment Period

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    End point title
    		 Time to 1st partial seizure during the 12-week Treatment Period
    End point description
    The evaluation of time to 1st partial seizure was based on the relative day of occurrence of the 1st partial seizure during the Treatment Period. The FAS consisted of all randomized study participants who received at least 1 dose of IMP and had at least 1 post Baseline seizure DRC data during the Treatment Period.
    End point type
    Secondary
    End point timeframe
    During the 12-week Treatment Period
    End point values
    		 Placebo BRV 50 mg/day BRV 200 mg/day
    Number of subjects analysed
    147
    151
    148
    Units: days
        median (confidence interval 95%)
    3 (2 to 3)
    5 (3 to 6)
    6 (5 to 8)
    No statistical analyses for this end point

    Secondary: Time to 5th partial seizure during the 12-week Treatment Period

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    End point title
    		 Time to 5th partial seizure during the 12-week Treatment Period
    End point description
    The evaluation of time to 5th partial seizure was based on the relative day of occurrence of the 5th partial seizure during the Treatment Period. The FAS consisted of all randomized study participants who received at least 1 dose of IMP and had at least 1 post Baseline seizure DRC data during the Treatment Period.
    End point type
    Secondary
    End point timeframe
    During the 12-week Treatment Period
    End point values
    		 Placebo BRV 50 mg/day BRV 200 mg/day
    Number of subjects analysed
    147
    151
    148
    Units: days
        median (confidence interval 95%)
    17 (15 to 21)
    28 (23 to 36)
    32 (29 to 38)
    No statistical analyses for this end point

    Secondary: Time to 10th partial seizure during the 12-week Treatment Period

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    End point title
    		 Time to 10th partial seizure during the 12-week Treatment Period
    End point description
    The evaluation of time to 10th partial seizure was based on the relative day of occurrence of the 10th partial seizure during the Treatment Period. The FAS consisted of all randomized study participants who received at least 1 dose of IMP and had at least 1 post Baseline seizure DRC data during the Treatment Period. Here, ‘99999’ signifies that Upper limit of 95% Confidence interval (CI) was not calculated due to less number of participants with events.
    End point type
    Secondary
    End point timeframe
    During the 12-week Treatment Period
    End point values
    		 Placebo BRV 50 mg/day BRV 200 mg/day
    Number of subjects analysed
    147
    151
    148
    Units: days
        median (confidence interval 95%)
    43 (32 to 52)
    59 (48 to 76)
    69 (59 to 99999)
    No statistical analyses for this end point

    Secondary: Brivaracetam plasma concentration

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    End point title
    		 Brivaracetam plasma concentration [8]
    End point description
    Blood samples were collected at indicated time points to determine the brivaracetam plasma concentration. Participants of arm ‘BRV 200 mg/day’ received BRV 200 mg/day until Week 12 only and 150 mg/day during the Transition Period at Week 14. Therefore, the data is reported according to the dosage information at specified time point. As per planned analysis, one blood sample was collected for BRV plasma levels during each dosing interval between 0 to 4 hours, 4 to 8 hours, and 8 to 12 hours postdose. The Pharmacokinetic Per-Protocol Set (PK-PPS) consisted of all study participants who took at least 1 dose of BRV and for whom at least 1 valid BRV plasma concentration time and dosing information were available. Here, 'n' signifies participants who were evaluable at specified time points. Here, 99999 signifies that 0 participants were analyzed at specified time point.
    End point type
    Secondary
    End point timeframe
    Plasma samples were collected at >0-4hours, >4-8hours, >8hours in weeks 2, 4, 8, 12, and 14
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be reported for Brivaracetam arms only.
    End point values
    		 BRV 50 mg/day BRV 200 mg/day BRV 150 mg/day
    Number of subjects analysed
    150
    146
    128
    Units: microgram/ millilitre (ug/mL)
    geometric mean (geometric coefficient of variation)
        Week 2: > 0 - 4 hours (n= 120, 99, 0)
    0.68556 ± 95.6
    3.4340 ± 42.5
    99999 ± 99999
        Week 2: > 4 - 8 hours (n= 18, 27, 0)
    0.66523 ± 38.6
    2.0615 ± 334.4
    99999 ± 99999
        Week 2: > 8 hours (n= 8, 15, 0)
    0.18427 ± 979.4
    1.2144 ± 100.1
    99999 ± 99999
        Week 4: > 0 - 4 hours (n= 118,101, 0)
    0.75902 ± 88.8
    3.0038 ± 120.2
    99999 ± 99999
        Week 4: > 4 - 8 hours (n= 18, 31, 0)
    0.64781 ± 39.2
    2.8516 ± 43.2
    99999 ± 99999
        Week 4: > 8 hours (n= 7, 7, 0)
    0.39652 ± 54.7
    1.1054 ± 74.4
    99999 ± 99999
        Week 8: > 0 - 4 hours (n= 115, 102, 0)
    0.76942 ± 87.3
    2.9983 ± 127.7
    99999 ± 99999
        Week 8: > 4 - 8 hours (n= 19, 24, 0)
    0.76172 ± 34.0
    2.7030 ± 54.9
    99999 ± 99999
        Week 8: > 8 hours (n= 7, 9, 0)
    0.27840 ± 10.9
    1.5590 ± 67.7
    99999 ± 99999
        Week 12: > 0 - 4 hours (n= 98, 97, 0)
    0.77400 ± 89.5
    3.2508 ± 121.1
    99999 ± 99999
        Week 12: > 4 - 8 hours (n=28, 29, 0)
    0.65274 ± 39.4
    1.6017 ± 838.9
    99999 ± 99999
        Week 12: > 8 hours (n= 10, 9, 0)
    0.18229 ± 579.5
    1.5001 ± 45.4
    99999 ± 99999
        Week 14 (Transition):> 0 - 4 hours (n= 106, 0, 95)
    0.75949 ± 85.3
    99999 ± 99999
    2.4989 ± 54.8
        Week 14 (Transition):> 4 - 8 hours (n= 15, 0, 28)
    0.75692 ± 34.6
    99999 ± 99999
    1.4383 ± 309.5
        Week 14 (Transition):> 8 hours (n= 7, 0, 5)
    0.41286 ± 66.4
    99999 ± 99999
    0.82681 ± 30.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of the Treatment Period (Week 0) until Safety Visit (up to Week 18); only for OLTP- From last visit of Transition Period to beginning of MAP (up to 4 Years 10 Months)
    Adverse event reporting additional description
    TEAEs were defined as AEs which had onset on or after the first dose of investigational medicinal product (IMP). The Safety Set (SS) included all randomized participants who took at least 1 dose of study medication. As per planned analysis, safety data for all study periods was combined excluding Open-Label Temporary period.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching Placebo as film-coated tablets, administered orally, twice daily (bid), during 12 weeks of Treatment Period. At the end of the Treatment Period, participants who entered long-term follow-up (LTFU) study (EP0085 (NCT03250377)) or managed access program (MAP), the same matching Placebo dose was kept during 2 weeks of Transition Period and brivaracetam (BRV) 100 milligrams/day (mg/day) in LTFU study or MAP. Participants who did not enter the LTFU study or MAP had 4 weeks Down-Titration Period followed by a Study Drug-Free Period (no drug for 2 weeks). During Down-Titration Period, participants received the same Placebo dose for 4 weeks.

    Reporting group title
    BRV 50 mg/day
    Reporting group description
    		 Participants received BRV 50 mg/day as film-coated tablets, administered orally, bid, during 12 weeks of Treatment Period. At the end of the Treatment Period, participants who entered the LTFU study or MAP received BRV 50 mg/day during 2 weeks of Transition Period and BRV 100 mg/day in LTFU study or MAP. Participants who did not enter the LTFU study or MAP had 4 weeks Down-Titration Period followed by a Study Drug-Free Period (no drug for 2 weeks). During Down-Titration Period, participants received BRV 25 mg/day for 1 week followed by Placebo for 3 weeks.

    Reporting group title
    BRV 200 mg/day
    Reporting group description
    		 Participants received BRV 200 mg/day as film-coated tablets, administered orally, bid, during 12 weeks of Treatment Period. At the end of the Treatment Period, participants who entered LTFU study or MAP received BRV 150 mg/day during 2 weeks of Transition Period and BRV 100 mg/day in LTFU study or MAP. Participants who did not enter the LTFU study or MAP had 4 weeks Down-Titration Period followed by a Study Drug-Free Period (no drug for 2 weeks). During Down-Titration Period, participants received BRV 150 mg/day for 1 week followed by BRV 100 mg/day for 1 week, followed by BRV 50 mg/day for 1 week, followed by BRV 25 mg/day for 1 week.

    Reporting group title
    Placebo to OLTP BRV
    Reporting group description
    		 Participants who received Placebo during Treatment Period and were eligible to enter MAP received BRV 100 mg/day due to delayed importation of medication during OLTP. BRV dose might be adjusted for an individual participant (between 50 mg/day to 200 mg/day) during the OLTP. The period was defined from immediately after the last visit of the Transition Period (Week 14) and until a visit when the participant could convert to MAP.

    Reporting group title
    BRV 50 mg/day to OLTP BRV
    Reporting group description
    		 Participants who received BRV 50 mg/day during Treatment Period and were eligible to enter MAP received BRV 100 mg/day due to delayed importation of medication during Open-Label Temporary Period (OLTP). BRV dose might be adjusted for an individual participant (between 50 mg/day to 200 mg/day) during the OLTP. The period was defined from immediately after the last visit of the Transition Period (Week 14) and until a visit when the participant could convert to MAP.

    Reporting group title
    BRV 200 mg/day to OLTP BRV
    Reporting group description
    		 Participants who received BRV 200 mg/day during Treatment Period and were eligible to enter MAP received BRV 100 mg/day due to delayed importation of medication during Open-Label Temporary Period (OLTP). BRV dose might be adjusted for an individual participant (between 50 mg/day to 200 mg/day) during the OLTP. The period was defined from immediately after the last visit of the Transition Period (Week 14) and until a visit when the participant could convert to MAP.

    Serious adverse events
    		 Placebo BRV 50 mg/day BRV 200 mg/day Placebo to OLTP BRV BRV 50 mg/day to OLTP BRV BRV 200 mg/day to OLTP BRV
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 149 (0.67%)
    2 / 151 (1.32%)
    4 / 148 (2.70%)
    2 / 64 (3.13%)
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         number of deaths (all causes)
    0
    1
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Near drowning
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 151 (0.00%)
    0 / 148 (0.00%)
    1 / 64 (1.56%)
    0 / 68 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 151 (0.00%)
    0 / 148 (0.00%)
    2 / 64 (3.13%)
    0 / 68 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervicogenic headache
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 151 (0.00%)
    0 / 148 (0.00%)
    0 / 64 (0.00%)
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 151 (0.00%)
    0 / 148 (0.00%)
    0 / 64 (0.00%)
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Drowning
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
    0 / 148 (0.00%)
    0 / 64 (0.00%)
    0 / 68 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 151 (0.00%)
    1 / 148 (0.68%)
    0 / 64 (0.00%)
    0 / 68 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Miscarriage of partner
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 151 (0.00%)
    1 / 148 (0.68%)
    0 / 64 (0.00%)
    0 / 68 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Large intestine polyp
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 151 (0.00%)
    1 / 148 (0.68%)
    0 / 64 (0.00%)
    0 / 68 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia aspiration
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 151 (0.00%)
    0 / 148 (0.00%)
    1 / 64 (1.56%)
    0 / 68 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 151 (0.00%)
    0 / 148 (0.00%)
    1 / 64 (1.56%)
    0 / 68 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Postictal psychosis
         subjects affected / exposed
    0 / 149 (0.00%)
    1 / 151 (0.66%)
    0 / 148 (0.00%)
    0 / 64 (0.00%)
    0 / 68 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus ureteric
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 151 (0.00%)
    1 / 148 (0.68%)
    0 / 64 (0.00%)
    0 / 68 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Corona virus infection
         subjects affected / exposed
    1 / 149 (0.67%)
    0 / 151 (0.00%)
    0 / 148 (0.00%)
    0 / 64 (0.00%)
    0 / 68 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 149 (0.00%)
    0 / 151 (0.00%)
    0 / 148 (0.00%)
    0 / 64 (0.00%)
    0 / 68 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo BRV 50 mg/day BRV 200 mg/day Placebo to OLTP BRV BRV 50 mg/day to OLTP BRV BRV 200 mg/day to OLTP BRV
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 149 (26.17%)
    42 / 151 (27.81%)
    54 / 148 (36.49%)
    3 / 64 (4.69%)
    4 / 68 (5.88%)
    4 / 74 (5.41%)
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    12 / 149 (8.05%)
    15 / 151 (9.93%)
    28 / 148 (18.92%)
    0 / 64 (0.00%)
    0 / 68 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    14
    15
    29
    0
    0
    0
    Dizziness
         subjects affected / exposed
    6 / 149 (4.03%)
    17 / 151 (11.26%)
    21 / 148 (14.19%)
    0 / 64 (0.00%)
    0 / 68 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    6
    19
    24
    0
    0
    0
    Headache
         subjects affected / exposed
    11 / 149 (7.38%)
    11 / 151 (7.28%)
    7 / 148 (4.73%)
    0 / 64 (0.00%)
    0 / 68 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    15
    16
    8
    0
    0
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 149 (4.70%)
    10 / 151 (6.62%)
    8 / 148 (5.41%)
    0 / 64 (0.00%)
    0 / 68 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    8
    14
    9
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    10 / 149 (6.71%)
    7 / 151 (4.64%)
    10 / 148 (6.76%)
    3 / 64 (4.69%)
    4 / 68 (5.88%)
    4 / 74 (5.41%)
         occurrences all number
    11
    10
    10
    3
    5
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Feb 2019
    Protocol amendment 3 (dated 01 Feb 2019) was a substantial amendment. A total of 158 participants were enrolled at the time of this amendment. The following changes were made: • Included non-Asian study participants • Included EU countries • An increase of levetiracetam (LEV) limitation from 20% to 30%, and the establishment of consistency between the protocol and Case Report Form (CRF) Completion Guidelines. Global changes to the protocol during this amendment included the inclusion of non-Asian study participants and an increase of prior LEV limitation from 20% to 30%.
    10 Jan 2020
    Protocol amendment 4 (dated 10 Jan 2020) was a substantial amendment. A total of 272 participants were enrolled at the time of this amendment. The following changes were made: • Reduced the total sample size from 504 to 444 study participants • Reduced the minimum required number of Japanese study participants • Added China Mainland to the list of participating countries and regions • Updated exclusion criteria 20 and 27 • Provided clarifications around the LEV use and LEV cap • Updated the study contact information • Updated the company designation from SPRL to SRL Additionally, minor administrative edits including typographical changes for formatting and/or spelling errors have been made Global changes to the protocol during this amendment included a change of “exploratory safety variable” language to “other safety variable” throughout the protocol. The pharmacodynamic variables were also removed.

    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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