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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group 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
    2018-002303-33
    Trial protocol
    EE   DE   BE   GB   HU   NL   DK   SE   AT   GR   BG   FI   ES   CZ   HR   FR   PT   SK   IT   RO  
    Global end of trial date
    28 Sep 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    10 Oct 2021
    First version publication date
    10 Oct 2021
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    EP0092
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03739840
    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
    16 Nov 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Sep 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate the efficacy of the 3 selected dose regimens of padsevonil (PSL) administered concomitantly with up to 3 anti-epileptic drugs (AEDs) compared with placebo for treatment of observable focal-onset seizures in subjects with drug-resistant epilepsy.
    Protection of trial subjects
    During the conduct of the study all participants were closely monitored.
    Background therapy
    Background therapy as permitted in the protocol.
    Evidence for comparator
    -
    Actual start date of recruitment
    06 Mar 2019
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    7 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Japan: 23
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 10
    Country: Number of subjects enrolled
    Bulgaria: 26
    Country: Number of subjects enrolled
    Croatia: 8
    Country: Number of subjects enrolled
    Czechia: 7
    Country: Number of subjects enrolled
    Denmark: 14
    Country: Number of subjects enrolled
    Estonia: 8
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Greece: 5
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Ireland: 4
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    Poland: 19
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    Romania: 5
    Country: Number of subjects enrolled
    Serbia: 4
    Country: Number of subjects enrolled
    Spain: 16
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    Turkey: 17
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    United States: 29
    Country: Number of subjects enrolled
    Belgium: 3
    Worldwide total number of subjects
    232
    EEA total number of subjects
    139
    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)
    218
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study started to enroll participants in March 2019 and concluded in September 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. The 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
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants randomized to the placebo group received 5-6 placebo tablets to maintain the blinding, twice daily (bid) up to Week 19.
    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 100 mg BID
    Arm description
    Participants were randomized to receive a combination of tablets of padsevonil 100 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19.
    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 200 mg BID
    Arm description
    Participants were randomized to receive a combination of tablets of padsevonil 200 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19.
    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 400 mg BID
    Arm description
    Participants were randomized to receive a combination of tablets of padsevonil 400 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19
    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 100 mg BID Padsevonil 200 mg BID Padsevonil 400 mg BID
    Started
    56
    60
    57
    59
    Completed Titration and Stabilization
    54
    58
    51
    54
    Completed Maintenance Period
    46
    44
    44
    36
    Completed
    46
    44
    44
    36
    Not completed
    10
    16
    13
    23
         Protocol deviation
    -
    -
    1
    -
         Lack of efficacy
    -
    1
    -
    3
         Sponsors Decision
    3
    2
    1
    3
         Premature Program Termination
    -
    1
    -
    -
         Sponsor Closed Study- Subject Was Discontinued
    1
    -
    -
    -
         Premature Study Termination By Sponsor
    -
    -
    1
    -
         Program Termination
    3
    -
    1
    1
         Per Sponsor Study Closed
    -
    1
    -
    -
         Promotor Decision
    -
    1
    -
    -
         Consent Withdrawn
    1
    3
    1
    1
         Study Has Been Cancelled By The Sponsor
    -
    -
    -
    1
         Study Early Closure
    -
    -
    1
    -
         Trial Was Closed By Sponsor
    -
    -
    -
    1
         Trial Closed By Sponsor
    -
    1
    -
    -
         Due To Sponsor Instruction
    -
    -
    -
    1
         Premature Closure Of The Study
    -
    -
    1
    -
         Adverse event, non-fatal
    2
    6
    6
    12
    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
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Participants randomized to the placebo group received 5-6 placebo tablets to maintain the blinding, bid up to Week 19.
    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 100 mg BID
    Arm description
    Participants were randomized to receive a combination of tablets of padsevonil 100 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19.
    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 200 mg BID
    Arm description
    Participants were randomized to receive a combination of tablets of padsevonil 200 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19.
    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 400 mg BID
    Arm description
    Participants were randomized to receive a combination of tablets of padsevonil 400 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19
    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 100 mg BID Padsevonil 200 mg BID Padsevonil 400 mg BID
    Started
    46
    44
    44
    36
    Started Conversion Period
    33 [1]
    31 [2]
    29 [3]
    28 [4]
    Completed Conversion Period
    33 [5]
    31 [6]
    29 [7]
    28 [8]
    Started Taper and Safety Follow-up
    19 [9]
    18 [10]
    21 [11]
    13 [12]
    Completed Taper and Safety Follow-up
    15 [13]
    16 [14]
    18 [15]
    12 [16]
    Enrolled in EP0093
    27 [17]
    26 [18]
    23 [19]
    23 [20]
    Completed
    42
    42
    41
    35
    Not completed
    4
    2
    3
    1
         Early Study Closure
    -
    -
    1
    -
         Sponsor's Decision
    -
    1
    -
    -
         Consent Withdrawn
    -
    -
    -
    1
         Sponsor Closed Study- Subject Was Discontinued
    -
    1
    -
    -
         Adverse event, non-fatal
    3
    -
    -
    -
         Trial Closed By Sponsor Decision
    -
    -
    1
    -
         Sponsor Decision + Subject Refusal
    -
    -
    1
    -
         Sponsor Decision To Terminate The Study
    1
    -
    -
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: 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 100 mg BID 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 200 mg BID 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 400 mg BID 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 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.
    [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 100 mg BID 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 200 mg BID 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 400 mg BID 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 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.
    [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 Padsevonil 100 mg BID 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 200 mg BID 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 400 mg BID 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 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.
    [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 100 mg BID 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 Padsevonil 200 mg BID 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 400 mg BID 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 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.
    [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 100 mg BID 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 200 mg BID 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 Padsevonil 400 mg BID 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 5-6 placebo tablets to maintain the blinding, twice daily (bid) up to Week 19.

    Reporting group title
    Padsevonil 100 mg BID
    Reporting group description
    Participants were randomized to receive a combination of tablets of padsevonil 100 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19.

    Reporting group title
    Padsevonil 200 mg BID
    Reporting group description
    Participants were randomized to receive a combination of tablets of padsevonil 200 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19.

    Reporting group title
    Padsevonil 400 mg BID
    Reporting group description
    Participants were randomized to receive a combination of tablets of padsevonil 400 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19

    Reporting group values
    Placebo Padsevonil 100 mg BID Padsevonil 200 mg BID Padsevonil 400 mg BID Total
    Number of subjects
    56 60 57 59 232
    Age Categorical
    Units: Participants
        <=18 years
    1 0 4 0 5
        Between 18 and 65 years
    52 57 48 56 213
        >=65 years
    3 3 5 3 14
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    41.9 ± 13.6 40.7 ± 13.0 39.5 ± 14.3 39.7 ± 13.6 -
    Sex: Female, Male
    Units: Participants
        Female
    34 34 29 34 131
        Male
    22 26 28 25 101
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    1 0 0 0 1
        Asian
    5 5 7 7 24
        Black
    0 1 1 1 3
        Native Hawaiian or Other Pacific Islander
    0 2 0 0 2
        White
    49 50 49 51 199
        Other/mixed
    1 2 0 0 3

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Participants randomized to the placebo group received 5-6 placebo tablets to maintain the blinding, twice daily (bid) up to Week 19.

    Reporting group title
    Padsevonil 100 mg BID
    Reporting group description
    Participants were randomized to receive a combination of tablets of padsevonil 100 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19.

    Reporting group title
    Padsevonil 200 mg BID
    Reporting group description
    Participants were randomized to receive a combination of tablets of padsevonil 200 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19.

    Reporting group title
    Padsevonil 400 mg BID
    Reporting group description
    Participants were randomized to receive a combination of tablets of padsevonil 400 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19
    Reporting group title
    Placebo
    Reporting group description
    Participants randomized to the placebo group received 5-6 placebo tablets to maintain the blinding, bid up to Week 19.

    Reporting group title
    Padsevonil 100 mg BID
    Reporting group description
    Participants were randomized to receive a combination of tablets of padsevonil 100 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19.

    Reporting group title
    Padsevonil 200 mg BID
    Reporting group description
    Participants were randomized to receive a combination of tablets of padsevonil 200 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19.

    Reporting group title
    Padsevonil 400 mg BID
    Reporting group description
    Participants were randomized to receive a combination of tablets of padsevonil 400 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19

    Subject analysis set title
    Placebo (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants randomized to the placebo group received 5-6 placebo tablets to maintain the blinding, bid up to Week 19. Participants formed the Full Analysis Set (FAS).

    Subject analysis set title
    Padsevonil 100 mg BID (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants were randomized to receive a combination of tablets of padsevonil 100 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19. Participants formed the FAS.

    Subject analysis set title
    Padsevonil 200 mg BID (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants were randomized to receive a combination of tablets of padsevonil 200 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19. Participants formed the FAS.

    Subject analysis set title
    Padsevonil 400 mg BID (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Participants were randomized to receive a combination of tablets of padsevonil 400 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19. Participants formed the FAS.

    Subject analysis set title
    Placebo (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants randomized to the placebo group received 5-6 placebo tablets to maintain the blinding, bid up to Week 19. Participants formed the Safety Set (SS).

    Subject analysis set title
    Padsevonil 100 mg BID (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants were randomized to receive a combination of tablets of padsevonil 100 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19. Participants formed the SS.

    Subject analysis set title
    Padsevonil 200 mg BID (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants were randomized to receive a combination of tablets of padsevonil 200 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19. Participants formed the SS.

    Subject analysis set title
    Padsevonil 400 mg BID (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants were randomized to receive a combination of tablets of padsevonil 400 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19. Participants formed the SS.

    Subject analysis set title
    Placebo Treatment Period (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants randomized to the placebo group received 5-6 placebo tablets to maintain the blinding, bid up to Week 19. Participants formed the Safety Set (SS).

    Subject analysis set title
    Padsevonil 100 mg BID Treatment Period (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants were randomized to receive a combination of tablets of padsevonil 100 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19. Participants formed the SS.

    Subject analysis set title
    Padsevonil 200 mg BID Treatment Period (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants were randomized to receive a combination of tablets of padsevonil 200 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19. Participants formed the SS.

    Subject analysis set title
    Padsevonil 400 mg BID Treatment Period (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants were randomized to receive a combination of tablets of padsevonil 400 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19. 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 open-label extension (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 of 400 mg/day for the OLE. Participants formed the Safety Set (SS).

    Subject analysis set title
    Padsevonil 100 mg BID 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 100 mg bid was gradually adapted (increased or decreased) in a blinded way to reach the entry dose of 400 mg/day for the OLE. Participants formed the SS.

    Subject analysis set title
    Padsevonil 200 mg BID 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 200 mg bid was gradually adapted (increased or decreased) in a blinded way to reach the entry dose of 400 mg/day for the OLE. Participants formed the SS.

    Subject analysis set title
    Padsevonil 400 mg BID 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 400 mg bid was gradually adapted (increased or decreased) in a blinded way to reach the entry dose of 400 mg/day 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 discontinued before the end of the 12-Week Maintenance Period. Participants initially randomized to the placebo group received 5-6 placebo tablets to maintain the blinding and have been gradually tapered off the IMP over a 3-Week period followed by 1-week drug-free period. Afterward, 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 100mg BID 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 discontinued before the end of the 12-Week Maintenance Period. Participants initially randomized to padsevonil 100 mg bid have been gradually tapered off the IMP over a 3-Week period followed by 1-week drug-free period. Afterward, participants had a Safety Follow-Up visit 30 days after the last IMP intake. Participants formed the SS.

    Subject analysis set title
    Padsevonil 200mg BID 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 discontinued before the end of the 12-Week Maintenance Period. Participants initially randomized to padsevonil 200 mg bid have been gradually tapered off the IMP over a 3-Week period followed by 1-week drug-free period. Afterward, participants had a Safety Follow-Up visit 30 days after the last IMP intake. Participants formed the SS.

    Subject analysis set title
    Padsevonil 400mg BID 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 discontinued before the end of the 12-Week Maintenance Period. Participants initially randomized to padsevonil 200 mg bid have been gradually tapered off the IMP over a 3-Week period followed by 1-week drug-free period. Afterward, participants had a Safety Follow-Up visit 30 days after the last IMP intake. Participants formed the SS.

    Primary: 75% responder rate from Baseline over the 12-week Maintenance Period

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    End point title
    75% responder rate from Baseline over the 12-week Maintenance Period
    End point description
    The 75 % responder rate, where a responder was 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. Here, number of participants were included who were evaluable for the assessment.
    End point type
    Primary
    End point timeframe
    From Baseline over the 12 Week Maintenance Period (up to Week 16)
    End point values
    Placebo (FAS) Padsevonil 100 mg BID (FAS) Padsevonil 200 mg BID (FAS) Padsevonil 400 mg BID (FAS)
    Number of subjects analysed
    54
    59
    56
    56
    Units: percentage of participants
        number (not applicable)
    13.0
    15.3
    12.5
    14.3
    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 (Yes, No) and log-transformed Baseline seizure frequency as a continuous covariate.
    Comparison groups
    Placebo (FAS) v Padsevonil 100 mg BID (FAS)
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.803 [1]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.39
         upper limit
    3.38
    Notes
    [1] - 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 (Yes, No) and log-transformed Baseline seizure frequency as a continuous covariate.
    Comparison groups
    Placebo (FAS) v Padsevonil 200 mg BID (FAS)
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.772 [2]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.84
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.27
         upper limit
    2.65
    Notes
    [2] - 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 (Yes, No) and log-transformed Baseline seizure frequency as a continuous covariate.
    Comparison groups
    Placebo (FAS) v Padsevonil 400 mg BID (FAS)
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.989 [3]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.33
         upper limit
    3.08
    Notes
    [3] - Nominal p-values were not adjusted for multiplicity.

    Primary: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) [4]
    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. A TEAE was defined as any event not present before the initiation of the first dose of study treatment or any unresolved event already present before initiation of the first dose that worsened in intensity following exposure to the 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
    [4] - 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 100 mg BID (SS) Padsevonil 200 mg BID (SS) Padsevonil 400 mg BID (SS)
    Number of subjects analysed
    55
    60
    57
    59
    Units: percentage of participants
        number (not applicable)
    69.1
    83.3
    78.9
    84.7
    No statistical analyses for this end point

    Primary: Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) leading to study withdrawal

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    End point title
    Percentage of Participants With Treatment-Emergent Adverse Events (TEAEs) leading to study withdrawal [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. A TEAE was defined as any event not present before the initiation of the first dose of study treatment or any unresolved event already present before initiation of the first dose that worsened in intensity following exposure to the 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 100 mg BID (SS) Padsevonil 200 mg BID (SS) Padsevonil 400 mg BID (SS)
    Number of subjects analysed
    55
    60
    57
    59
    Units: percentage of participants
        number (not applicable)
    7.3
    10.0
    10.5
    20.3
    No statistical analyses for this end point

    Primary: Percentage of Participants With Treatment-Emergent Serious Adverse Events (SAEs)

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    End point title
    Percentage of Participants With Treatment-Emergent Serious Adverse Events (SAEs) [6]
    End point description
    A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: Results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, is a congenital anomaly or birth defect, is as infection that requires treatment parenteral antibiotics, other important medical events which based on medical or scientific judgement may jeopardize the patients, or may require medical or surgical intervention to prevent any of the above. A TEAE was defined as any event not present before the initiation of the first dose of study treatment or any unresolved event already present before initiation of the first dose that worsened in intensity following exposure to the 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 100 mg BID (SS) Padsevonil 200 mg BID (SS) Padsevonil 400 mg BID (SS)
    Number of subjects analysed
    55
    60
    57
    59
    Units: percentage of participants
        number (not applicable)
    9.1
    3.3
    1.8
    10.2
    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 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. Here, number of participants were included who were evaluable for the assessment.
    End point type
    Secondary
    End point timeframe
    From Baseline over the 12 Week Maintenance Period (up to Week 16)
    End point values
    Placebo (FAS) Padsevonil 100 mg BID (FAS) Padsevonil 200 mg BID (FAS) Padsevonil 400 mg BID (FAS)
    Number of subjects analysed
    54
    59
    56
    56
    Units: log e seizures per 28 days
        least squares mean (confidence interval 95%)
    -0.41 (-0.6133 to -0.2025)
    -0.35 (-0.54906 to -0.15705)
    -0.47 (-0.67559 to -0.27382)
    -0.47 (-0.67267 to -0.27361)
    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
    Placebo (FAS) v Padsevonil 100 mg BID (FAS)
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.687 [7]
    Method
    ANCOVA
    Parameter type
    Percent reduction
    Point estimate
    -5.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -38.1
         upper limit
    19.2
    Notes
    [7] - Adjusted p-values are 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
    Placebo (FAS) v Padsevonil 400 mg BID (FAS)
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.687 [8]
    Method
    ANCOVA
    Parameter type
    Percent reduction
    Point estimate
    6.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -22.9
         upper limit
    28.6
    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
    Placebo (FAS) v Padsevonil 200 mg BID (FAS)
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.687 [9]
    Method
    ANCOVA
    Parameter type
    Percent reduction
    Point estimate
    6.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -22.7
         upper limit
    28.7
    Notes
    [9] - Adjusted p-values were from the Hochberg step-up procedure within SAS® Proc Multtest to control Type I error.

    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) were 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. Here, number of participants were included who were evaluable for the assessment.
    End point type
    Secondary
    End point timeframe
    From Baseline over the 12 Week Maintenance Period (up to Week 16)
    End point values
    Placebo (FAS) Padsevonil 100 mg BID (FAS) Padsevonil 200 mg BID (FAS) Padsevonil 400 mg BID (FAS)
    Number of subjects analysed
    54
    59
    56
    56
    Units: percent change
        arithmetic mean (standard deviation)
    22.34 ± 44.56
    11.72 ± 81.52
    30.29 ± 39.58
    22.41 ± 62.80
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Dose group comparisons to Placebo p-value are based on the Wilcoxon-Mann-Whitney test. Hodges Lehmann nonparametric effect estimates and corresponding two-sided 95% asymptotic confidence intervals are provided for the effect difference between each PSL dose and placebo.
    Comparison groups
    Placebo (FAS) v Padsevonil 100 mg BID (FAS)
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.737 [10]
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Median difference (final values)
    Point estimate
    3.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.08
         upper limit
    20.36
    Notes
    [10] - Nominal p-values were not adjusted for multiplicity.
    Statistical analysis title
    Statistical analysis 3
    Statistical analysis description
    Dose group comparisons to Placebo p-value are based on the Wilcoxon-Mann-Whitney test. Hodges Lehmann nonparametric effect estimates and corresponding two-sided 95% asymptotic confidence intervals are provided for the effect difference between each PSL dose and placebo.
    Comparison groups
    Placebo (FAS) v Padsevonil 400 mg BID (FAS)
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.341 [11]
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Median difference (net)
    Point estimate
    9.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.92
         upper limit
    28.21
    Notes
    [11] - Nominal p-values were not adjusted for multiplicity.
    Statistical analysis title
    Statistical analysis 2
    Statistical analysis description
    Dose group comparisons to Placebo p-value are based on the Wilcoxon-Mann-Whitney test. Hodges Lehmann nonparametric effect estimates and corresponding two-sided 95% asymptotic confidence intervals are provided for the effect difference between each PSL dose and placebo.
    Comparison groups
    Placebo (FAS) v Padsevonil 200 mg BID (FAS)
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.458 [12]
    Method
    Wilcoxon (Mann-Whitney)
    Parameter type
    Median difference (net)
    Point estimate
    6.17
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10
         upper limit
    21.91
    Notes
    [12] - Nominal p-values were not adjusted for multiplicity.

    Secondary: 50% responder rate from Baseline over the 12-week Maintenance Period

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    End point title
    50% responder rate from Baseline 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. Here, number of participants were included who were evaluable for the assessment.
    End point type
    Secondary
    End point timeframe
    From Baseline over the 12 Week Maintenance Period (up to Week 16)
    End point values
    Placebo (FAS) Padsevonil 100 mg BID (FAS) Padsevonil 200 mg BID (FAS) Padsevonil 400 mg BID (FAS)
    Number of subjects analysed
    54
    59
    56
    56
    Units: percentage of participants
        number (not applicable)
    27.8
    35.6
    33.9
    42.9
    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 (Yes, No) and log-transformed Baseline seizure frequency as a continuous covariate.
    Comparison groups
    Placebo (FAS) v Padsevonil 100 mg BID (FAS)
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.425 [13]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.61
         upper limit
    3.18
    Notes
    [13] - 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 (Yes, No) and log-transformed Baseline seizure frequency as a continuous covariate
    Comparison groups
    Placebo (FAS) v Padsevonil 200 mg BID (FAS)
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.625 [14]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.23
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.53
         upper limit
    2.85
    Notes
    [14] - 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 (Yes, No) and log-transformed Baseline seizure frequency as a continuous covariate
    Comparison groups
    Placebo (FAS) v Padsevonil 400 mg BID (FAS)
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.125 [15]
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.84
         upper limit
    4.34
    Notes
    [15] - Nominal p-values were not adjusted for multiplicity.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    TEAEs were collected from Baseline until Safety Follow-Up (up to Week 23)
    Adverse event reporting additional description
    TEAEs counts are for the number of study participants who entered the respective study period regardless of whether or not they completed the previous period. This is the reason for the difference in number of participants in Taper and SFU period in adverse events section and participant flow.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Padsevonil 100 mg BID Treatment Period (SS)
    Reporting group description
    Participants were randomized to receive a combination of tablets of padsevonil 100 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19. Participants formed the SS.

    Reporting group title
    Placebo Treatment Period (SS)
    Reporting group description
    Participants randomized to the placebo group received 5-6 placebo tablets to maintain the blinding, bid up to Week 19. Participants formed the Safety Set (SS).

    Reporting group title
    Padsevonil 200 mg BID Treatment Period (SS)
    Reporting group description
    Participants were randomized to receive a combination of tablets of padsevonil 200 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19. 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 open-label extension (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 of 400 mg/day for the OLE. Participants formed the Safety Set (SS).

    Reporting group title
    Padsevonil 400 mg BID Treatment Period (SS)
    Reporting group description
    Participants were randomized to receive a combination of tablets of padsevonil 400 mg and placebo (as appropriate) to maintain the blinding, bid up to Week 19. Participants formed the SS.

    Reporting group title
    Padsevonil 100 mg BID 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 100 mg bid was gradually adapted (increased or decreased) in a blinded way to reach the entry dose of 400 mg/day for the OLE. Participants formed the SS.

    Reporting group title
    Padsevonil 200 mg BID 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 200 mg bid was gradually adapted (increased or decreased) in a blinded way to reach the entry dose of 400 mg/day for the OLE. Participants formed the SS.

    Reporting group title
    Padsevonil 400 mg BID 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 400 mg bid was gradually adapted (increased or decreased) in a blinded way to reach the entry dose of 400 mg/day 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 group received 5-6 placebo tablets to maintain the blinding and 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 100 mg BID 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 100 mg bid 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 200 mg BID 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 200 mg bid 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 400 mg BID 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 400 mg bid 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
    Padsevonil 100 mg BID Treatment Period (SS) Placebo Treatment Period (SS) Padsevonil 200 mg BID Treatment Period (SS) Placebo Conversion Period (SS) Padsevonil 400 mg BID Treatment Period (SS) Padsevonil 100 mg BID Conversion Period (SS) Padsevonil 200 mg BID Conversion Period (SS) Padsevonil 400 mg BID Conversion Period (SS) Placebo Taper and SFU Period (SS) Padsevonil 100 mg BID Taper and SFU Period (SS) Padsevonil 200 mg BID Taper and SFU Period (SS) Padsevonil 400 mg BID Taper and SFU Period (SS)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 60 (0.00%)
    3 / 55 (5.45%)
    1 / 57 (1.75%)
    1 / 33 (3.03%)
    5 / 59 (8.47%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 27 (3.70%)
    2 / 30 (6.67%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Radius fracture
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 33 (0.00%)
    1 / 59 (1.69%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    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
    Skin laceration
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 55 (1.82%)
    0 / 57 (0.00%)
    0 / 33 (0.00%)
    0 / 59 (0.00%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (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
         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
    Subdural haematoma
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 55 (1.82%)
    0 / 57 (0.00%)
    0 / 33 (0.00%)
    0 / 59 (0.00%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (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
         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
    Wrist fracture
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 33 (0.00%)
    1 / 59 (1.69%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (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
         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
    Contusion
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    1 / 33 (3.03%)
    0 / 59 (0.00%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (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
         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
    Humerus fracture
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    1 / 33 (3.03%)
    0 / 59 (0.00%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (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
         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
    Rib fracture
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    1 / 33 (3.03%)
    0 / 59 (0.00%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (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
         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
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 55 (1.82%)
    0 / 57 (0.00%)
    0 / 33 (0.00%)
    0 / 59 (0.00%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (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
         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
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 33 (0.00%)
    0 / 59 (0.00%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    0 / 32 (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 / 1
    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
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 55 (0.00%)
    1 / 57 (1.75%)
    0 / 33 (0.00%)
    1 / 59 (1.69%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (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
         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
    Focal dyscognitive seizures
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 55 (1.82%)
    0 / 57 (0.00%)
    0 / 33 (0.00%)
    0 / 59 (0.00%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (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
         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
    Seizure
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 33 (0.00%)
    0 / 59 (0.00%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    0 / 32 (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 / 1
    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
    Status epilepticus
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 33 (0.00%)
    0 / 59 (0.00%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    1 / 32 (3.13%)
         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 / 0
    0 / 1
         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
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 33 (0.00%)
    1 / 59 (1.69%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (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
         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
    Emotional disorder
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 33 (0.00%)
    0 / 59 (0.00%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 27 (3.70%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (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 / 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
    Suicidal ideation
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 33 (0.00%)
    0 / 59 (0.00%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 27 (3.70%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (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 / 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
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 33 (0.00%)
    1 / 59 (1.69%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (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
         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
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    0 / 33 (0.00%)
    1 / 59 (1.69%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (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
         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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Padsevonil 100 mg BID Treatment Period (SS) Placebo Treatment Period (SS) Padsevonil 200 mg BID Treatment Period (SS) Placebo Conversion Period (SS) Padsevonil 400 mg BID Treatment Period (SS) Padsevonil 100 mg BID Conversion Period (SS) Padsevonil 200 mg BID Conversion Period (SS) Padsevonil 400 mg BID Conversion Period (SS) Placebo Taper and SFU Period (SS) Padsevonil 100 mg BID Taper and SFU Period (SS) Padsevonil 200 mg BID Taper and SFU Period (SS) Padsevonil 400 mg BID Taper and SFU Period (SS)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 60 (61.67%)
    25 / 55 (45.45%)
    40 / 57 (70.18%)
    7 / 33 (21.21%)
    41 / 59 (69.49%)
    0 / 31 (0.00%)
    1 / 29 (3.45%)
    1 / 28 (3.57%)
    2 / 27 (7.41%)
    6 / 30 (20.00%)
    4 / 31 (12.90%)
    2 / 32 (6.25%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 55 (0.00%)
    0 / 57 (0.00%)
    2 / 33 (6.06%)
    0 / 59 (0.00%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 55 (0.00%)
    3 / 57 (5.26%)
    0 / 33 (0.00%)
    2 / 59 (3.39%)
    0 / 31 (0.00%)
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    1 / 27 (3.70%)
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    1 / 32 (3.13%)
         occurrences all number
    0
    0
    4
    0
    2
    0
    1
    0
    1
    0
    1
    1
    Contusion
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 55 (5.45%)
    2 / 57 (3.51%)
    1 / 33 (3.03%)
    1 / 59 (1.69%)
    0 / 31 (0.00%)
    1 / 29 (3.45%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    4
    2
    1
    1
    0
    1
    0
    0
    1
    0
    0
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    10 / 60 (16.67%)
    2 / 55 (3.64%)
    19 / 57 (33.33%)
    1 / 33 (3.03%)
    20 / 59 (33.90%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    1 / 30 (3.33%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    11
    2
    22
    1
    23
    0
    0
    0
    0
    1
    0
    0
    Dizziness
         subjects affected / exposed
    14 / 60 (23.33%)
    4 / 55 (7.27%)
    10 / 57 (17.54%)
    0 / 33 (0.00%)
    18 / 59 (30.51%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    1 / 27 (3.70%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    14
    5
    13
    0
    19
    0
    0
    0
    1
    0
    0
    0
    Headache
         subjects affected / exposed
    10 / 60 (16.67%)
    8 / 55 (14.55%)
    9 / 57 (15.79%)
    0 / 33 (0.00%)
    5 / 59 (8.47%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    4 / 30 (13.33%)
    2 / 31 (6.45%)
    1 / 32 (3.13%)
         occurrences all number
    22
    13
    16
    0
    8
    0
    0
    0
    0
    12
    2
    1
    Memory impairment
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 55 (1.82%)
    3 / 57 (5.26%)
    0 / 33 (0.00%)
    6 / 59 (10.17%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    3
    0
    6
    0
    0
    0
    0
    0
    0
    0
    Tremor
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 55 (1.82%)
    0 / 57 (0.00%)
    0 / 33 (0.00%)
    4 / 59 (6.78%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    1 / 28 (3.57%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    5
    1
    0
    0
    4
    0
    0
    1
    0
    0
    0
    0
    Disturbance in attention
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 55 (1.82%)
    5 / 57 (8.77%)
    0 / 33 (0.00%)
    2 / 59 (3.39%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    1
    5
    0
    2
    0
    0
    0
    0
    0
    0
    0
    Balance disorder
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 55 (0.00%)
    3 / 57 (5.26%)
    0 / 33 (0.00%)
    2 / 59 (3.39%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    3
    0
    2
    0
    0
    0
    0
    0
    1
    0
    Dysarthria
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 55 (1.82%)
    0 / 57 (0.00%)
    0 / 33 (0.00%)
    5 / 59 (8.47%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    0
    0
    5
    0
    0
    0
    0
    0
    0
    0
    Seizure
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 55 (1.82%)
    4 / 57 (7.02%)
    0 / 33 (0.00%)
    0 / 59 (0.00%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    5
    0
    0
    0
    0
    0
    0
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 60 (8.33%)
    4 / 55 (7.27%)
    7 / 57 (12.28%)
    1 / 33 (3.03%)
    14 / 59 (23.73%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    5
    4
    7
    1
    15
    0
    0
    0
    0
    0
    0
    0
    Asthenia
         subjects affected / exposed
    6 / 60 (10.00%)
    2 / 55 (3.64%)
    3 / 57 (5.26%)
    0 / 33 (0.00%)
    2 / 59 (3.39%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    1 / 31 (3.23%)
    0 / 32 (0.00%)
         occurrences all number
    6
    2
    4
    0
    2
    0
    0
    0
    0
    0
    1
    0
    Gait disturbance
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 55 (0.00%)
    2 / 57 (3.51%)
    0 / 33 (0.00%)
    4 / 59 (6.78%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    2
    0
    3
    0
    4
    0
    0
    0
    0
    0
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 55 (0.00%)
    5 / 57 (8.77%)
    0 / 33 (0.00%)
    4 / 59 (6.78%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    0
    6
    0
    4
    0
    0
    0
    0
    0
    0
    0
    Irritability
         subjects affected / exposed
    4 / 60 (6.67%)
    3 / 55 (5.45%)
    3 / 57 (5.26%)
    1 / 33 (3.03%)
    3 / 59 (5.08%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    4
    3
    3
    1
    3
    0
    0
    0
    0
    0
    0
    0
    Anxiety
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 55 (1.82%)
    1 / 57 (1.75%)
    0 / 33 (0.00%)
    3 / 59 (5.08%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    2
    0
    3
    0
    0
    0
    0
    0
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 55 (5.45%)
    3 / 57 (5.26%)
    0 / 33 (0.00%)
    1 / 59 (1.69%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    5
    4
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 55 (5.45%)
    0 / 57 (0.00%)
    0 / 33 (0.00%)
    2 / 59 (3.39%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    4
    0
    0
    2
    0
    0
    0
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 55 (1.82%)
    3 / 57 (5.26%)
    0 / 33 (0.00%)
    1 / 59 (1.69%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    1
    3
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 60 (1.67%)
    4 / 55 (7.27%)
    4 / 57 (7.02%)
    1 / 33 (3.03%)
    1 / 59 (1.69%)
    0 / 31 (0.00%)
    0 / 29 (0.00%)
    0 / 28 (0.00%)
    0 / 27 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
    0 / 32 (0.00%)
         occurrences all number
    1
    4
    4
    1
    1
    0
    0
    0
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Jan 2020
    Protocol Amendment 1 was dated 21 Jan 2020; at the time, 143 study participants had received IMP. The primary rationale for the global amendment was to update the name of the legal form of the Sponsor, UCB Biopharma. At the time, Belgium had adopted a new Code of Companies and Associations, resulting in a mandatory change of the name of the legal form of the entity “société privée à responsabilité limitée”, abbreviated “SPRL”, to “société à responsabilité limitée”, abbreviated “SRL”. In addition, the following changes were introduced: • A summary of the known and expected risks and benefits of PSL was included. • The changes introduced by the local Protocol Amendment 0.1 for China were incorporated: - The percentage of Chinese study participants planned to be randomized in the study increased from 10% to 20% in response to a request by the Chinese Center for Drug Evaluation. - It was specified that the exploratory PK analysis would not be done in Chinese study participants. - The blood volumes required for hematology and chemistry were revised to meet the requirements of the central laboratory. • The changes introduced by the local Protocol Amendment 0.2 for Switzerland were incorporated: - The following language regarding expedited reporting of SAEs was added to meet a request by Swissmedic: “Expedited reporting to regulatory authorities will be in line with local laws”.

    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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