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    Clinical Trial Results:
    A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, DOSE FINDING STUDY TO EVALUATE THE EFFICACY AND SAFETY OF PADSEVONIL AS ADJUNCTIVE TREATMENT OF FOCAL-ONSET SEIZURES IN ADULT SUBJECTS WITH DRUG-RESISTANT EPILEPSY

    Summary
    EudraCT number
    2017-003200-48
    Trial protocol
    GB   DE   HU   CZ   BE   ES   FR   BG   LT   SK   PT   IT  
    Global end of trial date
    30 Jan 2020

    Results information
    Results version number
    v1
    This version publication date
    14 Feb 2021
    First version publication date
    14 Feb 2021
    Other versions
    v2

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    EP0091
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03373383
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Feb 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jan 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study are to characterize the dose-response relationship with respect to efficacy of Padsevonil (PSL) administered concomitantly with up to 3 anti-epileptic drugs (AEDs) for treatment of observable focal-onset seizures in subjects with drug-resistant epilepsy and to evaluate the efficacy of the 4 selected dose regimens of PSL compared with placebo.
    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
    12 Feb 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    27 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 13
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    Bulgaria: 42
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Czechia: 27
    Country: Number of subjects enrolled
    France: 27
    Country: Number of subjects enrolled
    Germany: 46
    Country: Number of subjects enrolled
    Hungary: 14
    Country: Number of subjects enrolled
    Italy: 25
    Country: Number of subjects enrolled
    Japan: 27
    Country: Number of subjects enrolled
    Lithuania: 11
    Country: Number of subjects enrolled
    Mexico: 5
    Country: Number of subjects enrolled
    Poland: 28
    Country: Number of subjects enrolled
    Slovakia: 6
    Country: Number of subjects enrolled
    Spain: 62
    Country: Number of subjects enrolled
    Turkey: 5
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    United States: 45
    Worldwide total number of subjects
    411
    EEA total number of subjects
    299
    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)
    0
    Adults (18-64 years)
    401
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    The study started to enroll patients in February 2018 and concluded in January 2020.

    Pre-assignment
    Screening details
    The study included: a 4-week Baseline Period, a 16-week Treatment Period, a 4-week Taper Period (for participants who discontinued or choose not to enroll in the open-label extension study) and a Safety Follow-up Period. Participants continuing to the OLE study had a 3-week Conversion Period. Participant Flow refers to the Randomized Set.

    Period 1
    Period 1 title
    Treatment period: Wk0-16
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Carer, Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants randomized to the placebo group received a combination of several Placebo tablets to maintain the blinding.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PBO
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was provided as tablets of matching size and aspect to Padsevonil tablets allowing a double-blind packaging. All study participants were instructed to take 5 or 6 tablets containing either PSL or placebo bid, approximately 12 hours apart. The IMP was to be dosed within 30 minutes after food when practically feasible.

    Arm title
    Padsevonil dosing regimen 1
    Arm description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 1 and Placebo (as appropriate) to maintain the blinding.
    Arm type
    Experimental

    Investigational medicinal product name
    Padsevonil
    Investigational medicinal product code
    PSL
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Padsevonil was administered as film-coated tablets of different doses, sizes and appearance. All study participants were instructed to take 5 or 6 tablets containing either PSL or placebo bid, approximately 12 hours apart. The IMP was to be dosed within 30 minutes after food when practically feasible.

    Arm title
    Padsevonil dosing regimen 2
    Arm description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 2 and Placebo (as appropriate) to maintain the blinding.
    Arm type
    Experimental

    Investigational medicinal product name
    Padsevonil
    Investigational medicinal product code
    PSL
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Padsevonil was administered as film-coated tablets of different doses, sizes and appearance. All study participants were instructed to take 5 or 6 tablets containing either PSL or placebo bid, approximately 12 hours apart. The IMP was to be dosed within 30 minutes after food when practically feasible.

    Arm title
    Padsevonil dosing regimen 3
    Arm description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 3 and Placebo (as appropriate) to maintain the blinding.
    Arm type
    Experimental

    Investigational medicinal product name
    Padsevonil
    Investigational medicinal product code
    PSL
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Padsevonil was administered as film-coated tablets of different doses, sizes and appearance. All study participants were instructed to take 5 or 6 tablets containing either PSL or placebo bid, approximately 12 hours apart. The IMP was to be dosed within 30 minutes after food when practically feasible.

    Arm title
    Padsevonil dosing regimen 4
    Arm description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 4 and Placebo (as appropriate) to maintain the blinding.
    Arm type
    Experimental

    Investigational medicinal product name
    Padsevonil
    Investigational medicinal product code
    PSL
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Padsevonil was administered as film-coated tablets of different doses, sizes and appearance. All study participants were instructed to take 5 or 6 tablets containing either PSL or placebo bid, approximately 12 hours apart. The IMP was to be dosed within 30 minutes after food when practically feasible.

    Number of subjects in period 1
    Placebo Padsevonil dosing regimen 1 Padsevonil dosing regimen 2 Padsevonil dosing regimen 3 Padsevonil dosing regimen 4
    Started
    83
    81
    83
    82
    82
    Completed Titration and Stabilization
    78
    72
    71
    68
    65
    Completed Maintenance Period
    70
    66
    68
    61
    58
    Had Taper and Safety Follow-up
    6 [1]
    11 [2]
    8 [3]
    18 [4]
    21 [5]
    Completed
    70
    66
    68
    61
    58
    Not completed
    13
    15
    15
    21
    24
         Protocol deviation
    -
    4
    2
    1
    -
         Lack of efficacy
    2
    1
    -
    -
    -
         By opinion of investigator
    -
    -
    -
    1
    -
         As advised by the sponsor
    -
    1
    -
    -
    -
         Adverse event, non-fatal
    7
    6
    11
    15
    21
         Consent withdrawn by subject
    2
    3
    2
    3
    3
         Sponsor decision
    -
    -
    -
    1
    -
         Lost to follow-up
    2
    -
    -
    -
    -
    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: Number of participants at this milestone reflect those who were randomized to Placebo and entered to conversion period, completed conversion period, had taper and safety follow-up or enrolled in EP0093. Participants could enter taper and safety follow-up after period 1.
    [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: Number of participants at this milestone reflect those who were randomized to Padsevonil dosing regimen 1 and entered to conversion period, completed conversion period, had taper and safety follow-up or enrolled in EP0093. Participants could enter taper and safety follow-up after period 1.
    [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: Number of participants at this milestone reflect those who were randomized to Padsevonil dosing regimen 2 and entered to conversion period, completed conversion period, had taper and safety follow-up or enrolled in EP0093. Participants could enter taper and safety follow-up after period 1.
    [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: Number of participants at this milestone reflect those who were randomized to Padsevonil dosing regimen 3 and entered to conversion period, completed conversion period, had taper and safety follow-up or enrolled in EP0093. Participants could enter taper and safety follow-up after period 1.
    [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: Number of participants at this milestone reflect those who were randomized to Padsevonil dosing regimen 4 and entered to conversion period, completed conversion period, had taper and safety follow-up or enrolled in EP0093. Participants could enter taper and safety follow-up after period 1.
    Period 2
    Period 2 title
    Post-Treatment period: Wk16-23
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Carer, Investigator, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants randomized to the placebo group received a combination of several Placebo tablets to maintain the blinding.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PBO
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was provided as tablets of matching size and aspect to Padsevonil tablets allowing a double-blind packaging. All study participants were instructed to take 5 or 6 tablets containing either PSL or placebo bid, approximately 12 hours apart. The IMP was to be dosed within 30 minutes after food when practically feasible.

    Arm title
    Padsevonil dosing regimen 1
    Arm description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 1 and Placebo (as appropriate) to maintain the blinding.
    Arm type
    Experimental

    Investigational medicinal product name
    Padsevonil
    Investigational medicinal product code
    PSL
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Padsevonil was administered as film-coated tablets of different doses, sizes and appearance. All study participants were instructed to take 5 or 6 tablets containing either PSL or placebo bid, approximately 12 hours apart. The IMP was to be dosed within 30 minutes after food when practically feasible.

    Arm title
    Padsevonil dosing regimen 2
    Arm description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 2 and Placebo (as appropriate) to maintain the blinding.
    Arm type
    Experimental

    Investigational medicinal product name
    Padsevonil
    Investigational medicinal product code
    PSL
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Padsevonil was administered as film-coated tablets of different doses, sizes and appearance. All study participants were instructed to take 5 or 6 tablets containing either PSL or placebo bid, approximately 12 hours apart. The IMP was to be dosed within 30 minutes after food when practically feasible.

    Arm title
    Padsevonil dosing regimen 3
    Arm description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 3 and Placebo (as appropriate) to maintain the blinding.
    Arm type
    Experimental

    Investigational medicinal product name
    Padsevonil
    Investigational medicinal product code
    PSL
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Padsevonil was administered as film-coated tablets of different doses, sizes and appearance. All study participants were instructed to take 5 or 6 tablets containing either PSL or placebo bid, approximately 12 hours apart. The IMP was to be dosed within 30 minutes after food when practically feasible.

    Arm title
    Padsevonil dosing regimen 4
    Arm description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 4 and Placebo (as appropriate) to maintain the blinding.
    Arm type
    Experimental

    Investigational medicinal product name
    Padsevonil
    Investigational medicinal product code
    PSL
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Padsevonil was administered as film-coated tablets of different doses, sizes and appearance. All study participants were instructed to take 5 or 6 tablets containing either PSL or placebo bid, approximately 12 hours apart. The IMP was to be dosed within 30 minutes after food when practically feasible.

    Number of subjects in period 2
    Placebo Padsevonil dosing regimen 1 Padsevonil dosing regimen 2 Padsevonil dosing regimen 3 Padsevonil dosing regimen 4
    Started
    70
    66
    68
    61
    58
    Started Conversion Period
    69
    64 [6]
    66 [7]
    55 [8]
    57 [9]
    Completed Conversion Period
    68 [10]
    64 [11]
    66 [12]
    55 [13]
    57 [14]
    Had Taper and Safety Follow-up
    3 [15]
    3 [16]
    3 [17]
    6 [18]
    1 [19]
    Enrolled in EP0093
    67 [20]
    63 [21]
    65 [22]
    55 [23]
    57 [24]
    Completed
    69
    66
    68
    61
    58
    Not completed
    1
    0
    0
    0
    0
         Participant decided not to roll over
    1
    -
    -
    -
    -
    Notes
    [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: Number of participants at this milestone reflect those who were randomized to Padsevonil dosing regimen 1 and entered to conversion period, completed conversion period, had taper and safety follow-up or enrolled in EP0093. Participants could enter taper and safety follow-up after period 1.
    [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: Number of participants at this milestone reflect those who were randomized to Padsevonil dosing regimen 2 and entered to conversion period, completed conversion period, had taper and safety follow-up or enrolled in EP0093. Participants could enter taper and safety follow-up after period 1.
    [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: Number of participants at this milestone reflect those who were randomized to Padsevonil dosing regimen 3 and entered to conversion period, completed conversion period, had taper and safety follow-up or enrolled in EP0093. Participants could enter taper and safety follow-up after period 1.
    [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: Number of participants at this milestone reflect those who were randomized to Padsevonil dosing regimen 4 and entered to conversion period, completed conversion period, had taper and safety follow-up or enrolled in EP0093. Participants could enter taper and safety follow-up after period 1.
    [10] - 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: Number of participants at this milestone reflect those who were randomized to Placebo and entered to conversion period, completed conversion period, had taper and safety follow-up or enrolled in EP0093. Participants could enter taper and safety follow-up after period 1.
    [11] - 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: Number of participants at this milestone reflect those who were randomized to Padsevonil dosing regimen 1 and entered to conversion period, completed conversion period, had taper and safety follow-up or enrolled in EP0093. Participants could enter taper and safety follow-up after period 1.
    [12] - 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: Number of participants at this milestone reflect those who were randomized to Padsevonil dosing regimen 2 and entered to conversion period, completed conversion period, had taper and safety follow-up or enrolled in EP0093. Participants could enter taper and safety follow-up after period 1.
    [13] - 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: Number of participants at this milestone reflect those who were randomized to Padsevonil dosing regimen 3 and entered to conversion period, completed conversion period, had taper and safety follow-up or enrolled in EP0093. Participants could enter taper and safety follow-up after period 1.
    [14] - 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: Number of participants at this milestone reflect those who were randomized to Padsevonil dosing regimen 4 and entered to conversion period, completed conversion period, had taper and safety follow-up or enrolled in EP0093. Participants could enter taper and safety follow-up after period 1.
    [15] - 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: Number of participants at this milestone reflect those who were randomized to Placebo and entered to conversion period, completed conversion period, had taper and safety follow-up or enrolled in EP0093. Participants could enter taper and safety follow-up after period 1.
    [16] - 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: Number of participants at this milestone reflect those who were randomized to Padsevonil dosing regimen 1 and entered to conversion period, completed conversion period, had taper and safety follow-up or enrolled in EP0093. Participants could enter taper and safety follow-up after period 1.
    [17] - 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: Number of participants at this milestone reflect those who were randomized to Padsevonil dosing regimen 2 and entered to conversion period, completed conversion period, had taper and safety follow-up or enrolled in EP0093. Participants could enter taper and safety follow-up after period 1.
    [18] - 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: Number of participants at this milestone reflect those who were randomized to Padsevonil dosing regimen 3 and entered to conversion period, completed conversion period, had taper and safety follow-up or enrolled in EP0093. Participants could enter taper and safety follow-up after period 1.
    [19] - 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: Number of participants at this milestone reflect those who were randomized to Padsevonil dosing regimen 4 and entered to conversion period, completed conversion period, had taper and safety follow-up or enrolled in EP0093. Participants could enter taper and safety follow-up after period 1.
    [20] - 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: Number of participants at this milestone reflect those who were randomized to Placebo and entered to conversion period, completed conversion period, had taper and safety follow-up or enrolled in EP0093. Participants could enter taper and safety follow-up after period 1.
    [21] - 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: Number of participants at this milestone reflect those who were randomized to Padsevonil dosing regimen 1 and entered to conversion period, completed conversion period, had taper and safety follow-up or enrolled in EP0093. Participants could enter taper and safety follow-up after period 1.
    [22] - 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: Number of participants at this milestone reflect those who were randomized to Padsevonil dosing regimen 2 and entered to conversion period, completed conversion period, had taper and safety follow-up or enrolled in EP0093. Participants could enter taper and safety follow-up after period 1.
    [23] - 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: Number of participants at this milestone reflect those who were randomized to Padsevonil dosing regimen 3 and entered to conversion period, completed conversion period, had taper and safety follow-up or enrolled in EP0093. Participants could enter taper and safety follow-up after period 1.
    [24] - 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: Number of participants at this milestone reflect those who were randomized to Padsevonil dosing regimen 4 and entered to conversion period, completed conversion period, had taper and safety follow-up or enrolled in EP0093. Participants could enter taper and safety follow-up after period 1.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants randomized to the placebo group received a combination of several Placebo tablets to maintain the blinding.

    Reporting group title
    Padsevonil dosing regimen 1
    Reporting group description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 1 and Placebo (as appropriate) to maintain the blinding.

    Reporting group title
    Padsevonil dosing regimen 2
    Reporting group description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 2 and Placebo (as appropriate) to maintain the blinding.

    Reporting group title
    Padsevonil dosing regimen 3
    Reporting group description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 3 and Placebo (as appropriate) to maintain the blinding.

    Reporting group title
    Padsevonil dosing regimen 4
    Reporting group description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 4 and Placebo (as appropriate) to maintain the blinding.

    Reporting group values
    Placebo Padsevonil dosing regimen 1 Padsevonil dosing regimen 2 Padsevonil dosing regimen 3 Padsevonil dosing regimen 4 Total
    Number of subjects
    83 81 83 82 82 411
    Age categorical
    Units: Subjects
        <=18 years
    0 0 2 1 1 4
        Between 18 and 65 years
    82 76 80 79 80 397
        >=65 years
    1 5 1 2 1 10
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    40.0 ± 12.9 42.5 ± 11.6 36.9 ± 13.1 40.9 ± 12.0 38.8 ± 12.1 -
    Gender categorical
    Units: Subjects
        Female
    48 46 47 51 43 235
        Male
    35 35 36 31 39 176

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants randomized to the placebo group received a combination of several Placebo tablets to maintain the blinding.

    Reporting group title
    Padsevonil dosing regimen 1
    Reporting group description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 1 and Placebo (as appropriate) to maintain the blinding.

    Reporting group title
    Padsevonil dosing regimen 2
    Reporting group description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 2 and Placebo (as appropriate) to maintain the blinding.

    Reporting group title
    Padsevonil dosing regimen 3
    Reporting group description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 3 and Placebo (as appropriate) to maintain the blinding.

    Reporting group title
    Padsevonil dosing regimen 4
    Reporting group description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 4 and Placebo (as appropriate) to maintain the blinding.
    Reporting group title
    Placebo
    Reporting group description
    Participants randomized to the placebo group received a combination of several Placebo tablets to maintain the blinding.

    Reporting group title
    Padsevonil dosing regimen 1
    Reporting group description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 1 and Placebo (as appropriate) to maintain the blinding.

    Reporting group title
    Padsevonil dosing regimen 2
    Reporting group description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 2 and Placebo (as appropriate) to maintain the blinding.

    Reporting group title
    Padsevonil dosing regimen 3
    Reporting group description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 3 and Placebo (as appropriate) to maintain the blinding.

    Reporting group title
    Padsevonil dosing regimen 4
    Reporting group description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 4 and Placebo (as appropriate) to maintain the blinding.

    Subject analysis set title
    Placebo (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants randomized to the placebo group received a combination of several Placebo tablets to maintain the blinding. Participants formed the Full Analysis Set (FAS).

    Subject analysis set title
    Padsevonil dosing regimen 1 (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 1 and Placebo (as appropriate) to maintain the blinding. Participants formed the FAS.

    Subject analysis set title
    Padsevonil dosing regimen 2 (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 2 and Placebo (as appropriate) to maintain the blinding. Participants formed the FAS.

    Subject analysis set title
    Padsevonil dosing regimen 3 (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 3 and Placebo (as appropriate) to maintain the blinding. Participants formed the FAS.

    Subject analysis set title
    Padsevonil dosing regimen 4 (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 4 and Placebo (as appropriate) to maintain the blinding. Participants formed the FAS.

    Subject analysis set title
    Placebo Treatment period (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    During the Treatment period, participants randomized to the placebo group received a combination of several Placebo tablets to maintain the blinding. Participants formed the Safety Set (SS).

    Subject analysis set title
    Padsevonil dosing regimen 1 Treatment period (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    During the Treatment period, participants were randomized to receive a combination of tablets of Padsevonil dose 1 and Placebo (as appropriate) to maintain the blinding. Participants formed the SS.

    Subject analysis set title
    Padsevonil dosing regimen 2 Treatment period (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    During the Treatment period, participants were randomized to receive a combination of tablets of Padsevonil dose 2 and Placebo (as appropriate) to maintain the blinding. Participants formed the SS.

    Subject analysis set title
    Padsevonil dosing regimen 3 Treatment period (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    During the Treatment period, participants were randomized to receive a combination of tablets of Padsevonil dose 3 and Placebo (as appropriate) to maintain the blinding. Participants formed the SS.

    Subject analysis set title
    Padsevonil dosing regimen 4 Treatment period (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    During the Treatment period, participants were randomized to receive a combination of tablets of Padsevonil dose 4 and Placebo (as appropriate) to maintain the blinding. Participants formed the SS.

    Subject analysis set title
    Placebo Conversion period (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    A 3-week Conversion Period was required for study participants who chose to enroll in the OLE study at the end of the 12-week Maintenance Period. Participants initially randomized to Placebo progressively received Padsevonil in a blinded way to reach the entry dose for the OLE. Participants formed the Safety Set (SS).

    Subject analysis set title
    Padsevonil dosing regimen 1 Conversion period (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    A 3-week Conversion Period was required for study participants who chose to enroll in the OLE study at the end of the 12-week Maintenance Period. The dose for participants initially randomized to Padsevonil dose 1 was gradually adapted (increased or decreased) in a blinded way to reach the entry dose for the OLE. Participants formed the SS.

    Subject analysis set title
    Padsevonil dosing regimen 2 Conversion period (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    A 3-week Conversion Period was required for study participants who chose to enroll in the OLE study at the end of the 12-week Maintenance Period. The dose for participants initially randomized to Padsevonil dose 2 was gradually adapted (increased or decreased) in a blinded way to reach the entry dose for the OLE. Participants formed the SS.

    Subject analysis set title
    Padsevonil dosing regimen 3 Conversion period (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    A 3-week Conversion Period was required for study participants who chose to enroll in the OLE study at the end of the 12-week Maintenance Period. The dose for participants initially randomized to Padsevonil dose 3 was gradually adapted (increased or decreased) in a blinded way to reach the entry dose for the OLE. Participants formed the SS.

    Subject analysis set title
    Padsevonil dosing regimen 4 Conversion period (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    A 3-week Conversion Period was required for study participants who chose to enroll in the OLE study at the end of the 12-week Maintenance Period. The dose for participants initially randomized to Padsevonil dose 4 was gradually adapted (increased or decreased) in a blinded way to reach the entry dose for the OLE. Participants formed the SS.

    Subject analysis set title
    Placebo Taper and SFU period (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    A 4-week Taper Period was required for participants who chose not to enroll in the OLE study or who discontinued prior to the end of the 12-week Maintenance Period. Participants initially randomized to Placebo have been gradually tapered off the IMP over a 3-week period followed by 1-week drug-free period. Afterwards, participants had a Safety Follow-Up visit 30 days after the last IMP intake. Participants formed the Safety Set (SS).

    Subject analysis set title
    Padsevonil dosing regimen 1 Taper and SFU period (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    A 4-week Taper Period was required for participants who chose not to enroll in the OLE study or who discontinued prior to the end of the 12-week Maintenance Period. Participants initially randomized to Padsevonil dose 1 have been gradually tapered off the IMP over a 3-week period followed by 1-week drug-free period. Afterwards, participants had a Safety Follow-Up visit 30 days after the last IMP intake. Participants formed the SS.

    Subject analysis set title
    Padsevonil dosing regimen 2 Taper and SFU period (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    A 4-week Taper Period was required for participants who chose not to enroll in the OLE study or who discontinued prior to the end of the 12-week Maintenance Period. Participants initially randomized to Padsevonil dose 2 have been gradually tapered off the IMP over a 3-week period followed by 1-week drug-free period. Afterwards, participants had a Safety Follow-Up visit 30 days after the last IMP intake. Participants formed the SS.

    Subject analysis set title
    Padsevonil dosing regimen 3 Taper and SFU period (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    A 4-week Taper Period was required for participants who chose not to enroll in the OLE study or who discontinued prior to the end of the 12-week Maintenance Period. Participants initially randomized to Padsevonil dose 3 have been gradually tapered off the IMP over a 3-week period followed by 1-week drug-free period. Afterwards, participants had a Safety Follow-Up visit 30 days after the last IMP intake. Participants formed the SS.

    Subject analysis set title
    Padsevonil dosing regimen 4 Taper and SFU period (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    A 4-week Taper Period was required for participants who chose not to enroll in the OLE study or who discontinued prior to the end of the 12-week Maintenance Period. Participants initially randomized to Padsevonil dose 4 have been gradually tapered off the IMP over a 3-week period followed by 1-week drug-free period. Afterwards, participants had a Safety Follow-Up visit 30 days after the last IMP intake. Participants formed the SS.

    Subject analysis set title
    Placebo (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants randomized to the placebo group received a combination of several Placebo tablets to maintain the blinding. Participants formed the Safety Set (SS).

    Subject analysis set title
    Padsevonil dosing regimen 1 (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 1 and Placebo (as appropriate) to maintain the blinding. Participants formed the SS.

    Subject analysis set title
    Padsevonil dosing regimen 2 (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 2 and Placebo (as appropriate) to maintain the blinding. Participants formed the SS.

    Subject analysis set title
    Padsevonil dosing regimen 3 (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 3 and Placebo (as appropriate) to maintain the blinding. Participants formed the SS.

    Subject analysis set title
    Padsevonil dosing regimen 4 (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants were randomized to receive a combination of tablets of Padsevonil dose 4 and Placebo (as appropriate) to maintain the blinding. Participants formed the SS.

    Primary: 75 % responder rate over the 12 Week Maintenance Period

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    End point title
    75 % responder rate over the 12 Week Maintenance Period
    End point description
    The 75% responder rate, where a responder is a participant experiencing a ≥75% reduction in observable focal-onset seizure frequency from Baseline, over the 12-Week Maintenance Period. The Full Analysis Set (FAS) consisted of all study participants in the RS who were administered at least 1 dose or a partial dose of IMP and had Baseline and at least 1 post-Baseline seizure frequency data during the 16-week Treatment Period.
    End point type
    Primary
    End point timeframe
    End of Maintenance Period (Week 16) following 3 Weeks of titration and 1 Week stabilization
    End point values
    Placebo (FAS) Padsevonil dosing regimen 1 (FAS) Padsevonil dosing regimen 2 (FAS) Padsevonil dosing regimen 3 (FAS) Padsevonil dosing regimen 4 (FAS)
    Number of subjects analysed
    81
    80
    82
    81
    81
    Units: percentage of participants
        number (not applicable)
    6.2
    13.8
    12.2
    11.1
    16.0
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    PSL dose/Placebo was calculated using logistic regression with categorical factors for treatment group, Region (Europe, Non-Europe), Baseline SV2A use (0, 1) and log-transformed Baseline seizure frequency as a continuous covariate.
    Comparison groups
    Padsevonil dosing regimen 1 (FAS) v Placebo (FAS)
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.081 [1]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.88
         upper limit
    8.39
    Notes
    [1] - Nominal p-values were not adjusted for multiplicity.
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    PSL dose/Placebo was calculated using logistic regression with categorical factors for treatment group, Region (Europe, Non-Europe), Baseline SV2A use (0, 1) and log-transformed Baseline seizure frequency as a continuous covariate.
    Comparison groups
    Padsevonil dosing regimen 2 (FAS) v Placebo (FAS)
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.137 [2]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.37
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.76
         upper limit
    7.41
    Notes
    [2] - Nominal p-values were not adjusted for multiplicity.
    Statistical analysis title
    Statistical analysis 3
    Statistical analysis description
    PSL dose/Placebo was calculated using logistic regression with categorical factors for treatment group, Region (Europe, Non-Europe), Baseline SV2A use (0, 1) and log-transformed Baseline seizure frequency as a continuous covariate.
    Comparison groups
    Padsevonil dosing regimen 3 (FAS) v Placebo (FAS)
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.192 [3]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.68
         upper limit
    6.89
    Notes
    [3] - Nominal p-values were not adjusted for multiplicity.
    Statistical analysis title
    Statistical analysis 4
    Statistical analysis description
    PSL dose/Placebo was calculated using logistic regression with categorical factors for treatment group, Region (Europe, Non-Europe), Baseline SV2A use (0, 1) and log-transformed Baseline seizure frequency as a continuous covariate.
    Comparison groups
    Padsevonil dosing regimen 4 (FAS) v Placebo (FAS)
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.041 [4]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    3.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.05
         upper limit
    9.42
    Notes
    [4] - Nominal p-values were not adjusted for multiplicity.

    Primary: Incidence of Treatment-Emergent Adverse Events (TEAEs) reported by the subject and/or caregiver or observed by the investigator during the entire study

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    End point title
    Incidence of Treatment-Emergent Adverse Events (TEAEs) reported by the subject and/or caregiver or observed by the investigator during the entire study [5]
    End point description
    An Adverse Event 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. The Safety Set consisted of all study participants who were administered at least 1 dose or a partial dose of IMP.
    End point type
    Primary
    End point timeframe
    From Baseline until Safety Follow-Up (up to Week 23)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypothesis testing was planned for this endpoint. Results were summarized as descriptive statistics only.
    End point values
    Placebo (SS) Padsevonil dosing regimen 1 (SS) Padsevonil dosing regimen 2 (SS) Padsevonil dosing regimen 3 (SS) Padsevonil dosing regimen 4 (SS)
    Number of subjects analysed
    83
    81
    83
    82
    81
    Units: percentage of participants
        number (not applicable)
    78.3
    84.0
    80.7
    75.6
    92.6
    No statistical analyses for this end point

    Primary: Incidence of Treatment-Emergent Adverse Events (TEAEs) leading to study withdrawal

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    End point title
    Incidence of Treatment-Emergent Adverse Events (TEAEs) leading to study withdrawal [6]
    End point description
    An Adverse Event 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. The Safety Set consisted of all study participants who were administered at least 1 dose or a partial dose of IMP.
    End point type
    Primary
    End point timeframe
    From Baseline until Safety Follow-Up (up to Week 23)
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypothesis testing was planned for this endpoint. Results were summarized as descriptive statistics only.
    End point values
    Placebo (SS) Padsevonil dosing regimen 1 (SS) Padsevonil dosing regimen 2 (SS) Padsevonil dosing regimen 3 (SS) Padsevonil dosing regimen 4 (SS)
    Number of subjects analysed
    83
    81
    83
    82
    81
    Units: percentage of participants
        number (not applicable)
    8.4
    7.4
    12.0
    18.3
    25.9
    No statistical analyses for this end point

    Primary: Incidence of Treatment-Emergent Serious Adverse Events (SAEs) during the entire study

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    End point title
    Incidence of Treatment-Emergent Serious Adverse Events (SAEs) during the entire study [7]
    End point description
    A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: - Results in death - Is life-threatening - Requires in patient hospitalization or prolongation of existing hospitalization - Is a congenital anomaly or birth defect - Is an infection that requires treatment parenteral antibiotics - Other important medical events which based on medical or scientific judgement may jeopardize the patients, or may require medical or surgical intervention to prevent any of the above. The Safety Set consisted of all study participants who were administered at least 1 dose or a partial dose of IMP.
    End point type
    Primary
    End point timeframe
    From Baseline until Safety Follow-Up (up to Week 23)
    Notes
    [7] - 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 endpoint. Results were summarized as descriptive statistics only.
    End point values
    Placebo (SS) Padsevonil dosing regimen 1 (SS) Padsevonil dosing regimen 2 (SS) Padsevonil dosing regimen 3 (SS) Padsevonil dosing regimen 4 (SS)
    Number of subjects analysed
    83
    81
    83
    82
    81
    Units: percentage of participants
        number (not applicable)
    4.8
    7.4
    4.8
    6.1
    6.2
    No statistical analyses for this end point

    Secondary: Change in log-transformed observable focal onset seizure frequency from Baseline over the 12 week Maintenance Period

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    End point title
    Change in log-transformed observable focal onset seizure frequency from Baseline over the 12 week Maintenance Period
    End point description
    During the study, participants kept diaries to record daily seizure activity. Seizure frequency refers to 28-day adjusted frequency. Seizure frequency was based on investigator assessment of participants' reports of daily seizure type and frequency. Observable focal-onset seizures refer to Type IA1, IB, and IC (ILAE Classification of Epileptic Seizures, 1981). Based on ANCOVA on change in log-transformed, 28-day adjusted seizure frequency from Baseline with treatment group as the main factor, Baseline log-transformed seizure frequency as a continuous covariate, Baseline SV2A use (yes or no) and Region (Europe, Non-Europe) as categorical factors. The Full Analysis Set (FAS) consisted of all study participants in the RS who were administered at least 1 dose or a partial dose of IMP and had Baseline and at least 1 post-Baseline seizure frequency data during the 16-week Treatment Period.
    End point type
    Secondary
    End point timeframe
    From Baseline over the 12 week Maintenance Period
    End point values
    Placebo (FAS) Padsevonil dosing regimen 1 (FAS) Padsevonil dosing regimen 2 (FAS) Padsevonil dosing regimen 3 (FAS) Padsevonil dosing regimen 4 (FAS)
    Number of subjects analysed
    81
    80
    82
    81
    81
    Units: seizures per 28 days
        least squares mean (confidence interval 95%)
    -0.27585 (-0.44311 to -0.10858)
    -0.46424 (-0.63276 to -0.29573)
    -0.48804 (-0.65436 to -0.32172)
    -0.48960 (-0.65734 to -0.32187)
    -0.40831 (-0.57485 to -0.24177)
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Percent reduction over placebo was calculated as 100*(1-exp[diff]), where diff was the model estimate of the log ratio between each PSL group and placebo group.
    Comparison groups
    Padsevonil dosing regimen 1 (FAS) v Placebo (FAS)
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.102 [8]
    Method
    ANCOVA
    Parameter type
    Percent reduction
    Point estimate
    17.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.8
         upper limit
    33.9
    Notes
    [8] - Adjusted p-values were from the Hochberg step-up procedure within SAS® Proc Multtest to control Type I error.
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    Percent reduction over placebo was calculated as 100*(1-exp[diff]), where diff was the model estimate of the log ratio between each PSL group and placebo group.
    Comparison groups
    Padsevonil dosing regimen 2 (FAS) v Placebo (FAS)
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.064 [9]
    Method
    ANCOVA
    Parameter type
    Percent reduction
    Point estimate
    19.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    35.4
    Notes
    [9] - Adjusted p-values were from the Hochberg step-up procedure within SAS® Proc Multtest to control Type I error.
    Statistical analysis title
    Statistical analysis 3
    Statistical analysis description
    Percent reduction over placebo was calculated as 100*(1-exp[diff]), where diff was the model estimate of the log ratio between each PSL group and placebo group.
    Comparison groups
    Padsevonil dosing regimen 3 (FAS) v Placebo (FAS)
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.063 [10]
    Method
    ANCOVA
    Parameter type
    Percent reduction
    Point estimate
    19.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.2
         upper limit
    35.5
    Notes
    [10] - Adjusted p-values were from the Hochberg step-up procedure within SAS® Proc Multtest to control Type I error.
    Statistical analysis title
    Statistical analysis 4
    Statistical analysis description
    Percent reduction over placebo was calculated as 100*(1-exp[diff]), where diff was the model estimate of the log ratio between each PSL group and placebo group.
    Comparison groups
    Padsevonil dosing regimen 4 (FAS) v Placebo (FAS)
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.248 [11]
    Method
    ANCOVA
    Parameter type
    Percent reduction
    Point estimate
    12.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.7
         upper limit
    30.1
    Notes
    [11] - Adjusted p-values were from the Hochberg step-up procedure within SAS® Proc Multtest to control Type I error.

    Secondary: 50 % responder rate over the 12 Week Maintenance Period

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    End point title
    50 % responder rate over the 12 Week Maintenance Period
    End point description
    The 50% responder rate, where a responder was a participant experiencing a ≥50% reduction in observable focal-onset seizure frequency from Baseline, over the 12-Week Maintenance Period. The Full Analysis Set (FAS) consisted of all study participants in the RS who were administered at least 1 dose or a partial dose of IMP and had Baseline and at least 1 post-Baseline seizure frequency data during the 16-week Treatment Period.
    End point type
    Secondary
    End point timeframe
    End of Maintenance Period (Week 16) following 3 Weeks of titration and 1 Week stabilization
    End point values
    Placebo (FAS) Padsevonil dosing regimen 1 (FAS) Padsevonil dosing regimen 2 (FAS) Padsevonil dosing regimen 3 (FAS) Padsevonil dosing regimen 4 (FAS)
    Number of subjects analysed
    81
    80
    82
    81
    81
    Units: percentage of participants
        number (not applicable)
    21.0
    33.8
    31.7
    25.9
    32.1
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    PSL dose/placebo calculated using logistic regression with categorical factors for treatment group (each PSL dose group referenced to the placebo group), region (Europe, Non-Europe), Baseline SV2A use (0, 1) and log-transformed Baseline seizure frequency as a continuous covariate.
    Comparison groups
    Padsevonil dosing regimen 1 (FAS) v Placebo (FAS)
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.045 [12]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    2.09
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.02
         upper limit
    4.3
    Notes
    [12] - Nominal p-values were not adjusted for multiplicity.
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    PSL dose/placebo calculated using logistic regression with categorical factors for treatment group (each PSL dose group referenced to the placebo group), region (Europe, Non-Europe), Baseline SV2A use (0, 1) and log-transformed Baseline seizure frequency as a continuous covariate.
    Comparison groups
    Padsevonil dosing regimen 2 (FAS) v Placebo (FAS)
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.079 [13]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.91
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.93
         upper limit
    3.93
    Notes
    [13] - Nominal p-values were not adjusted for multiplicity.
    Statistical analysis title
    Statistical analysis 3
    Statistical analysis description
    PSL dose/placebo calculated using logistic regression with categorical factors for treatment group (each PSL dose group referenced to the placebo group), region (Europe, Non-Europe), Baseline SV2A use (0, 1) and log-transformed Baseline seizure frequency as a continuous covariate.
    Comparison groups
    Padsevonil dosing regimen 3 (FAS) v Placebo (FAS)
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.338 [14]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.44
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.68
         upper limit
    3.02
    Notes
    [14] - Nominal p-values were not adjusted for multiplicity.
    Statistical analysis title
    Statistical analysis 4
    Statistical analysis description
    PSL dose/Placebo calculated using logistic regression with categorical factors for treatment group, Region (Europe, Non-Europe), Baseline SV2A use (0, 1) and log-transformed Baseline seizure frequency as a continuous covariate.
    Comparison groups
    Padsevonil dosing regimen 4 (FAS) v Placebo (FAS)
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.087 [15]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.88
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.91
         upper limit
    3.87
    Notes
    [15] - Nominal p-values were not adjusted for multiplicity.

    Secondary: Percent change in observable focal-onset seizure frequency from Baseline over the 12 Week Maintenance Period

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    End point title
    Percent change in observable focal-onset seizure frequency from Baseline over the 12 Week Maintenance Period
    End point description
    During the study, participants kept diaries to record daily seizure activity. The percentage of participants who experienced a 50 % or greater reduction in seizure frequency per 28 days relative to Baseline (responders) was assessed. The Full Analysis Set (FAS) consisted of all study participants in the RS who were administered at least 1 dose or a partial dose of IMP and had Baseline and at least 1 post-Baseline seizure frequency data during the 16-week Treatment Period.
    End point type
    Secondary
    End point timeframe
    End of Maintenance Period (Week 16) following 3 Weeks of titration and 1 Week stabilization
    End point values
    Placebo (FAS) Padsevonil dosing regimen 1 (FAS) Padsevonil dosing regimen 2 (FAS) Padsevonil dosing regimen 3 (FAS) Padsevonil dosing regimen 4 (FAS)
    Number of subjects analysed
    81
    80
    82
    81
    81
    Units: percent change
        arithmetic mean (standard deviation)
    12.49 ± 58.26
    24.70 ± 46.62
    25.25 ± 51.73
    20.79 ± 66.54
    15.79 ± 67.55
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Dose group comparisons to Placebo p-value were based on the Wilcoxon-Mann-Whitney test. The Hodges-Lehmann nonparametric estimator was used to estimate the median difference between each PSL dose group versus placebo, along with the corresponding 95% CI of the estimate.
    Comparison groups
    Padsevonil dosing regimen 1 (FAS) v Placebo (FAS)
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.316 [16]
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Median difference (net)
    Point estimate
    7.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.59
         upper limit
    21.89
    Notes
    [16] - Nominal p-values were not adjusted for multiplicity.
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    Dose group comparisons to Placebo p-value were based on the Wilcoxon-Mann-Whitney test. The Hodges-Lehmann nonparametric estimator was used to estimate the median difference between each PSL dose group versus placebo, along with the corresponding 95% CI of the estimate.
    Comparison groups
    Padsevonil dosing regimen 2 (FAS) v Placebo (FAS)
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.133 [17]
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Median difference (net)
    Point estimate
    9.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.15
         upper limit
    23.26
    Notes
    [17] - Nominal p-values were not adjusted for multiplicity.
    Statistical analysis title
    Statistical analysis 3
    Statistical analysis description
    Dose group comparisons to Placebo p-value were based on the Wilcoxon-Mann-Whitney test. The Hodges-Lehmann nonparametric estimator was used to estimate the median difference between each PSL dose group versus placebo, along with the corresponding 95% CI of the estimate.
    Comparison groups
    Padsevonil dosing regimen 3 (FAS) v Placebo (FAS)
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.203 [18]
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Median difference (net)
    Point estimate
    8.19
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.95
         upper limit
    21.37
    Notes
    [18] - Nominal p-values were not adjusted for multiplicity.
    Statistical analysis title
    Statistical analysis 4
    Statistical analysis description
    Dose group comparisons to Placebo p-value were based on the Wilcoxon-Mann-Whitney test. The Hodges-Lehmann nonparametric estimator was used to estimate the median difference between each PSL dose group versus placebo, along with the corresponding 95% CI of the estimate.
    Comparison groups
    Padsevonil dosing regimen 4 (FAS) v Placebo (FAS)
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.784 [19]
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Median difference (net)
    Point estimate
    2.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -13.65
         upper limit
    17.79
    Notes
    [19] - Nominal p-values were not adjusted for multiplicity.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent AEs were collected from Baseline to Safety Follow-Up (up to Week 23)
    Adverse event reporting additional description
    Adverse events refer to the SS which consisted of all participants who were administered at least 1 dose or a partial dose of IMP. TEAEs counts are for each study period: Treatment Period, Conversion Period for participants who entered the OLE study and Taper Period followed by SFU for participants not entering OLE study.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Placebo Treatment period (SS)
    Reporting group description
    During the Treatment period, participants randomized to the placebo group received a combination of several Placebo tablets to maintain the blinding. Participants formed the Safety Set (SS).

    Reporting group title
    Padsevonil dosing regimen 1 Treatment period (SS)
    Reporting group description
    During the Treatment period, participants were randomized to receive a combination of tablets of Padsevonil dose 1 and Placebo (as appropriate) to maintain the blinding. Participants formed the SS.

    Reporting group title
    Padsevonil dosing regimen 2 Treatment period (SS)
    Reporting group description
    During the Treatment period, participants were randomized to receive a combination of tablets of Padsevonil dose 2 and Placebo (as appropriate) to maintain the blinding. Participants formed the SS.

    Reporting group title
    Padsevonil dosing regimen 3 Treatment period (SS)
    Reporting group description
    During the Treatment period, participants were randomized to receive a combination of tablets of Padsevonil dose 3 and Placebo (as appropriate) to maintain the blinding. Participants formed the SS.

    Reporting group title
    Padsevonil dosing regimen 4 Treatment period (SS)
    Reporting group description
    During the Treatment period, participants were randomized to receive a combination of tablets of Padsevonil dose 4 and Placebo (as appropriate) to maintain the blinding. Participants formed the SS.

    Reporting group title
    Padsevonil dosing regimen 1 Conversion period (SS)
    Reporting group description
    A 3-week Conversion Period was required for study participants who chose to enroll in the OLE study at the end of the 12-week Maintenance Period. The dose for participants initially randomized to Padsevonil dose 1 was gradually adapted (increased or decreased) in a blinded way to reach the entry dose for the OLE. Participants formed the SS.

    Reporting group title
    Placebo Conversion period (SS)
    Reporting group description
    A 3-week Conversion Period was required for study participants who chose to enroll in the OLE study at the end of the 12-week Maintenance Period. Participants initially randomized to Placebo progressively received Padsevonil in a blinded way to reach the entry dose for the OLE. Participants formed the Safety Set (SS).

    Reporting group title
    Padsevonil dosing regimen 2 Conversion period (SS)
    Reporting group description
    A 3-week Conversion Period was required for study participants who chose to enroll in the OLE study at the end of the 12-week Maintenance Period. The dose for participants initially randomized to Padsevonil dose 2 was gradually adapted (increased or decreased) in a blinded way to reach the entry dose for the OLE. Participants formed the SS.

    Reporting group title
    Padsevonil dosing regimen 3 Conversion period (SS)
    Reporting group description
    A 3-week Conversion Period was required for study participants who chose to enroll in the OLE study at the end of the 12-week Maintenance Period. The dose for participants initially randomized to Padsevonil dose 3 was gradually adapted (increased or decreased) in a blinded way to reach the entry dose for the OLE. Participants formed the SS.

    Reporting group title
    Padsevonil dosing regimen 4 Conversion period (SS)
    Reporting group description
    A 3-week Conversion Period was required for study participants who chose to enroll in the OLE study at the end of the 12-week Maintenance Period. The dose for participants initially randomized to Padsevonil dose 4 was gradually adapted (increased or decreased) in a blinded way to reach the entry dose for the OLE. Participants formed the SS.

    Reporting group title
    Placebo Taper and SFU period (SS)
    Reporting group description
    A 4-week Taper Period was required for participants who chose not to enroll in the OLE study or who discontinued prior to the end of the 12-week Maintenance Period. Participants initially randomized to Placebo have been gradually tapered off the IMP over a 3-week period followed by 1-week drug-free period. Afterwards, participants had a Safety Follow-Up visit 30 days after the last IMP intake. Participants formed the Safety Set (SS).

    Reporting group title
    Padsevonil dosing regimen 1 Taper and SFU period (SS)
    Reporting group description
    A 4-week Taper Period was required for participants who chose not to enroll in the OLE study or who discontinued prior to the end of the 12-week Maintenance Period. Participants initially randomized to Padsevonil dose 1 have been gradually tapered off the IMP over a 3-week period followed by 1-week drug-free period. Afterwards, participants had a Safety Follow-Up visit 30 days after the last IMP intake. Participants formed the SS.

    Reporting group title
    Padsevonil dosing regimen 2 Taper and SFU period (SS)
    Reporting group description
    A 4-week Taper Period was required for participants who chose not to enroll in the OLE study or who discontinued prior to the end of the 12-week Maintenance Period. Participants initially randomized to Padsevonil dose 2 have been gradually tapered off the IMP over a 3-week period followed by 1-week drug-free period. Afterwards, participants had a Safety Follow-Up visit 30 days after the last IMP intake. Participants formed the SS.

    Reporting group title
    Padsevonil dosing regimen 3 Taper and SFU period (SS)
    Reporting group description
    A 4-week Taper Period was required for participants who chose not to enroll in the OLE study or who discontinued prior to the end of the 12-week Maintenance Period. Participants initially randomized to Padsevonil dose 3 have been gradually tapered off the IMP over a 3-week period followed by 1-week drug-free period. Afterwards, participants had a Safety Follow-Up visit 30 days after the last IMP intake. Participants formed the SS.

    Reporting group title
    Padsevonil dosing regimen 4 Taper and SFU period (SS)
    Reporting group description
    A 4-week Taper Period was required for participants who chose not to enroll in the OLE study or who discontinued prior to the end of the 12-week Maintenance Period. Participants initially randomized to Padsevonil dose 4 have been gradually tapered off the IMP over a 3-week period followed by 1-week drug-free period. Afterwards, participants had a Safety Follow-Up visit 30 days after the last IMP intake. Participants formed the SS.

    Serious adverse events
    Placebo Treatment period (SS) Padsevonil dosing regimen 1 Treatment period (SS) Padsevonil dosing regimen 2 Treatment period (SS) Padsevonil dosing regimen 3 Treatment period (SS) Padsevonil dosing regimen 4 Treatment period (SS) Padsevonil dosing regimen 1 Conversion period (SS) Placebo Conversion period (SS) Padsevonil dosing regimen 2 Conversion period (SS) Padsevonil dosing regimen 3 Conversion period (SS) Padsevonil dosing regimen 4 Conversion period (SS) Placebo Taper and SFU period (SS) Padsevonil dosing regimen 1 Taper and SFU period (SS) Padsevonil dosing regimen 2 Taper and SFU period (SS) Padsevonil dosing regimen 3 Taper and SFU period (SS) Padsevonil dosing regimen 4 Taper and SFU period (SS)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 83 (3.61%)
    5 / 81 (6.17%)
    4 / 83 (4.82%)
    3 / 82 (3.66%)
    5 / 81 (6.17%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    2 / 55 (3.64%)
    0 / 57 (0.00%)
    1 / 9 (11.11%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 81 (0.00%)
    1 / 83 (1.20%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 81 (0.00%)
    0 / 83 (0.00%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 81 (0.00%)
    1 / 83 (1.20%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 81 (0.00%)
    0 / 83 (0.00%)
    1 / 82 (1.22%)
    0 / 81 (0.00%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic haemothorax
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 81 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Medical device battery replacement
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 81 (0.00%)
    1 / 83 (1.20%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 81 (1.23%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia aspiration
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 81 (0.00%)
    1 / 83 (1.20%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 81 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 81 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Focal dyscognitive seizures
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 81 (1.23%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 81 (1.23%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure cluster
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 81 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 83 (1.20%)
    1 / 81 (1.23%)
    1 / 83 (1.20%)
    1 / 82 (1.22%)
    1 / 81 (1.23%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    1 / 55 (1.82%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 81 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    1 / 81 (1.23%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 81 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    1 / 55 (1.82%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute psychosis
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 81 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    1 / 9 (11.11%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal disorder
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 81 (0.00%)
    1 / 83 (1.20%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 81 (0.00%)
    1 / 83 (1.20%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 81 (1.23%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    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 Treatment period (SS) Padsevonil dosing regimen 1 Treatment period (SS) Padsevonil dosing regimen 2 Treatment period (SS) Padsevonil dosing regimen 3 Treatment period (SS) Padsevonil dosing regimen 4 Treatment period (SS) Padsevonil dosing regimen 1 Conversion period (SS) Placebo Conversion period (SS) Padsevonil dosing regimen 2 Conversion period (SS) Padsevonil dosing regimen 3 Conversion period (SS) Padsevonil dosing regimen 4 Conversion period (SS) Placebo Taper and SFU period (SS) Padsevonil dosing regimen 1 Taper and SFU period (SS) Padsevonil dosing regimen 2 Taper and SFU period (SS) Padsevonil dosing regimen 3 Taper and SFU period (SS) Padsevonil dosing regimen 4 Taper and SFU period (SS)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    45 / 83 (54.22%)
    54 / 81 (66.67%)
    60 / 83 (72.29%)
    53 / 82 (64.63%)
    65 / 81 (80.25%)
    18 / 64 (28.13%)
    11 / 69 (15.94%)
    10 / 66 (15.15%)
    5 / 55 (9.09%)
    5 / 57 (8.77%)
    3 / 9 (33.33%)
    3 / 14 (21.43%)
    0 / 11 (0.00%)
    3 / 24 (12.50%)
    4 / 22 (18.18%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    4 / 83 (4.82%)
    2 / 81 (2.47%)
    1 / 83 (1.20%)
    1 / 82 (1.22%)
    7 / 81 (8.64%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    1 / 66 (1.52%)
    1 / 55 (1.82%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    4
    2
    1
    2
    7
    0
    0
    2
    1
    0
    0
    0
    0
    0
    0
    Ligament sprain
         subjects affected / exposed
    0 / 83 (0.00%)
    2 / 81 (2.47%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    2 / 64 (3.13%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    1 / 9 (11.11%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    2
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Burns second degree
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 81 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 81 (0.00%)
    1 / 83 (1.20%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    1 / 9 (11.11%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Anticonvulsant drug level increased
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 81 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    1 / 9 (11.11%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    9 / 83 (10.84%)
    18 / 81 (22.22%)
    23 / 83 (27.71%)
    19 / 82 (23.17%)
    28 / 81 (34.57%)
    2 / 64 (3.13%)
    3 / 69 (4.35%)
    1 / 66 (1.52%)
    2 / 55 (3.64%)
    2 / 57 (3.51%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 24 (4.17%)
    1 / 22 (4.55%)
         occurrences all number
    9
    19
    31
    25
    55
    2
    3
    1
    2
    6
    0
    0
    0
    1
    1
    Somnolence
         subjects affected / exposed
    10 / 83 (12.05%)
    19 / 81 (23.46%)
    24 / 83 (28.92%)
    25 / 82 (30.49%)
    30 / 81 (37.04%)
    4 / 64 (6.25%)
    1 / 69 (1.45%)
    1 / 66 (1.52%)
    1 / 55 (1.82%)
    2 / 57 (3.51%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    11
    24
    29
    26
    35
    5
    1
    1
    1
    2
    0
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    10 / 83 (12.05%)
    17 / 81 (20.99%)
    9 / 83 (10.84%)
    15 / 82 (18.29%)
    9 / 81 (11.11%)
    3 / 64 (4.69%)
    0 / 69 (0.00%)
    2 / 66 (3.03%)
    0 / 55 (0.00%)
    1 / 57 (1.75%)
    1 / 9 (11.11%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    2 / 24 (8.33%)
    1 / 22 (4.55%)
         occurrences all number
    14
    29
    16
    21
    31
    3
    0
    3
    0
    5
    1
    0
    0
    2
    1
    Memory impairment
         subjects affected / exposed
    1 / 83 (1.20%)
    3 / 81 (3.70%)
    1 / 83 (1.20%)
    8 / 82 (9.76%)
    14 / 81 (17.28%)
    0 / 64 (0.00%)
    1 / 69 (1.45%)
    1 / 66 (1.52%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    1
    3
    1
    9
    14
    0
    1
    1
    0
    0
    0
    0
    0
    0
    1
    Tremor
         subjects affected / exposed
    0 / 83 (0.00%)
    5 / 81 (6.17%)
    2 / 83 (2.41%)
    6 / 82 (7.32%)
    5 / 81 (6.17%)
    0 / 64 (0.00%)
    1 / 69 (1.45%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    5
    2
    6
    5
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Balance disorder
         subjects affected / exposed
    1 / 83 (1.20%)
    3 / 81 (3.70%)
    3 / 83 (3.61%)
    5 / 82 (6.10%)
    3 / 81 (3.70%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    2
    3
    3
    5
    3
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Nystagmus
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 81 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 64 (0.00%)
    1 / 69 (1.45%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    10 / 83 (12.05%)
    20 / 81 (24.69%)
    12 / 83 (14.46%)
    14 / 82 (17.07%)
    20 / 81 (24.69%)
    5 / 64 (7.81%)
    3 / 69 (4.35%)
    2 / 66 (3.03%)
    1 / 55 (1.82%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
         occurrences all number
    10
    27
    17
    22
    21
    5
    3
    2
    1
    0
    0
    0
    0
    2
    0
    Gait disturbance
         subjects affected / exposed
    1 / 83 (1.20%)
    2 / 81 (2.47%)
    0 / 83 (0.00%)
    1 / 82 (1.22%)
    5 / 81 (6.17%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    2
    0
    1
    5
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    7 / 83 (8.43%)
    3 / 81 (3.70%)
    2 / 83 (2.41%)
    3 / 82 (3.66%)
    4 / 81 (4.94%)
    0 / 64 (0.00%)
    1 / 69 (1.45%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    7
    3
    2
    3
    5
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    8 / 83 (9.64%)
    4 / 81 (4.94%)
    7 / 83 (8.43%)
    1 / 82 (1.22%)
    5 / 81 (6.17%)
    1 / 64 (1.56%)
    0 / 69 (0.00%)
    1 / 66 (1.52%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    8
    4
    7
    1
    6
    1
    0
    1
    0
    0
    0
    0
    0
    0
    1
    Anxiety
         subjects affected / exposed
    3 / 83 (3.61%)
    1 / 81 (1.23%)
    1 / 83 (1.20%)
    7 / 82 (8.54%)
    0 / 81 (0.00%)
    0 / 64 (0.00%)
    1 / 69 (1.45%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    3
    1
    2
    9
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Paranoia
         subjects affected / exposed
    0 / 83 (0.00%)
    0 / 81 (0.00%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    0 / 81 (0.00%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    7 / 83 (8.43%)
    4 / 81 (4.94%)
    7 / 83 (8.43%)
    2 / 82 (2.44%)
    7 / 81 (8.64%)
    0 / 64 (0.00%)
    1 / 69 (1.45%)
    1 / 66 (1.52%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    7
    4
    7
    3
    13
    0
    1
    1
    0
    0
    0
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    3 / 83 (3.61%)
    6 / 81 (7.41%)
    3 / 83 (3.61%)
    5 / 82 (6.10%)
    4 / 81 (4.94%)
    1 / 64 (1.56%)
    1 / 69 (1.45%)
    1 / 66 (1.52%)
    0 / 55 (0.00%)
    1 / 57 (1.75%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    1 / 24 (4.17%)
    0 / 22 (0.00%)
         occurrences all number
    3
    8
    4
    7
    5
    1
    1
    1
    0
    1
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 81 (1.23%)
    2 / 83 (2.41%)
    2 / 82 (2.44%)
    5 / 81 (6.17%)
    0 / 64 (0.00%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    1 / 9 (11.11%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    2
    2
    5
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 83 (6.02%)
    5 / 81 (6.17%)
    9 / 83 (10.84%)
    7 / 82 (8.54%)
    5 / 81 (6.17%)
    1 / 64 (1.56%)
    1 / 69 (1.45%)
    0 / 66 (0.00%)
    1 / 55 (1.82%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    5
    5
    13
    11
    5
    1
    1
    0
    1
    0
    0
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 83 (1.20%)
    5 / 81 (6.17%)
    0 / 83 (0.00%)
    0 / 82 (0.00%)
    2 / 81 (2.47%)
    1 / 64 (1.56%)
    0 / 69 (0.00%)
    0 / 66 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 9 (0.00%)
    1 / 14 (7.14%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    3
    5
    0
    0
    3
    1
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 83 (2.41%)
    1 / 81 (1.23%)
    1 / 83 (1.20%)
    0 / 82 (0.00%)
    2 / 81 (2.47%)
    0 / 64 (0.00%)
    1 / 69 (1.45%)
    1 / 66 (1.52%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    1 / 9 (11.11%)
    0 / 14 (0.00%)
    0 / 11 (0.00%)
    0 / 24 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    2
    1
    1
    0
    2
    0
    1
    1
    0
    0
    1
    0
    0
    0
    1

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Mar 2018
    Protocol Amendment 1, dated 09 Mar 2018, provided the following key changes: The purpose of this substantial amendment was primarily to increase the potential for the study to be 1 of 2 adequate and well-controlled studies that supported registration. This required an increase in the sample size to allow for pairwise comparisons and the use of the 75% responder rate status as the primary variable for the European Medicines Agency (EMA) (CHMP/EWP/566/98 Rev.2/Corr, 2010). Per EMA guidance, the primary variable in add-on epilepsy studies should have dichotomized the data into responders/nonresponders, where responders were participants who obtained at least a certain predefined percentage reduction of seizure frequency. An improvement of >75% was regarded as clinically more meaningful than >50% and seemed feasible given the premise of greater efficacy of Padsevonil based upon nonclinical animal data and EP0069 results. Therefore, the 75% responder rate was selected as the primary variable, rather than the more commonly used 50% responder rate. Another important addition to the protocol was that the Data Monitoring Committee (DMC) could stop enrollment into a Padsevonil dose arm for safety and tolerability reasons and allocate remaining patients to remaining Padsevonil dose or placebo arms. This addition did not reflect a change in intent. Rather, the plan had been to describe this possibility in the Data Monitoring Committee (DMC) Charter, but it was included in the protocol to avoid disruption to the study via a subsequent amendment in the unlikely event that a dose arm was dropped from the study for safety/tolerability reasons.
    12 Oct 2018
    Protocol Amendment 2, dated 12 Oct 2018, provided the following key changes: The purpose of this substantial amendment was to clarify that the primary efficacy analysis was comparing each Padsevonil dose to placebo with Type I error controlled for all comparisons. Multiple Comparison Procedure-Modelling (MCP-Mod) analysis was removed since it would no longer contribute to the overall study conclusion and dose selection for future studies. Other changes included the following: • Updates to study contact information. • Minor refinements to the wording describing responder rate variables. • Correction of the maximum duration of exposure to PSL from 20 to 19 weeks. • Clarification of the rationale for the study to state that dose-response relationship was evaluated with respect to safety as well as efficacy. • Revised other efficacy variable, number of seizure-free days to percentage of seizure-free days. • Revised other efficacy variable, time to return to baseline observable (Type IA1+IB+IC) focal-onset seizure frequency to time to return to baseline 28-day observable seizure count. • Revision of designation of treatment-emergent adverse events (TEAEs), TEAEs leading to withdrawal, and SAEs from “safety variables” to “primary safety variables.” A heading was added for these primary variables. • Clarification of a Schedule of Assessments footnote that questionnaires should have been completed prior to other study procedures, when possible. Previously it was mandated that these be completed prior to other procedures. • Removal of efficiencies of the MCP-Mod model based design and analysis as 1 of the drivers for EP0091 dose selection. In addition, the rationale for selection of intermediate doses was revised due to the elimination of MCP-Mod analysis. •Revision of Inclusion Criterion 2 to account for the fact that use of legal representative/caregiver may not have been legally permitted in some countries.
    12 Oct 2018
    Continuation of Protocol Amendment 2 (2) • Other modifications to the Statistics section (in addition to those related to the removal of MCP-Mod analysis), such as inclusion of information on handling of dropouts and missing data and further details about the determination of sample size.
    12 Oct 2018
    Continuation of Protocol Amendment 2 (1) • Modification of Inclusion Criterion 5 to facilitate the acceptance of ambulatory electroencephalograms (EEGs), which were used more frequently in some regions, to require (must versus should) consultation with the UCB Study Physician or representative when determining study participant eligibility based on eye-witness seizure report, home video documentation, or other proof, and to allow substitution of head computed tomography (CT) scan for magnetic resonance imaging (MRI) if MRI was contraindicated. • Modification of Exclusion Criterion 1 to allow rescreening of study participants under certain circumstances. • Clarification of the description of the interpretation of echocardiograms − The original description stated that the echocardiograms would be interpreted at the sites by local cardiologists and then provided to a central reader where they would be interpreted. Given that all echocardiograms were to be centrally read and a report provided within 7 business days of receipt, in the absence of queries, there was no need for a local cardiologist. Therefore, the protocol was modified to say that it was only necessary that the local physician examine the echocardiograms for suitability for central reading and for determination if an expedited review by the central reader was required. It was also made explicit that the central reader was a cardiologist. • Clarification of the Titration Period Dosing Table 7-1 in the protocol, to indicate that this period consisted of Week 1, Week 2, and Week 3 (versus previous unclear designations of Day 1, Week 1 and Week 2). • Clarifications regarding administration of the Seizure Severity Global Item (SSG), Quality of Life Inventory in Epilepsy-31-P (QOLIE-31-P), and Hospital Anxiety and Depression Scale (HADS).

    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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