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    Clinical Trial Results:
    A Multicenter, Double-Blind, Randomized, Placebo-Controlled, Dose- Response Trial of YKP3089 as Adjunctive Therapy in Subjects with Partial Onset Seizures, with Optional Open-Label Extension

    Summary
    EudraCT number
    		 2013-001858-10
    Trial protocol
    		 ES   DE   CZ   GB   HU   PL   BG  
    Global end of trial date
    05 Apr 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Apr 2022
    First version publication date
    21 Apr 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    YKP3089C017
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01866111
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    SK Life Science, Inc.
    Sponsor organisation address
    461 From Road, Paramus, United States, NJ 07652
    Public contact
    Laurie Orlinski, SK Life Science, Inc., 1 201-421-3816, lorlinski@sklsi.com
    Scientific contact
    Marc Kamin, SK Life Science, Inc., 1 201-421-3830, mkamin@sklsi.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
    31 Oct 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Apr 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Apr 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to determine the effective dose range of YKP3089 as adjunctive therapy for the treatment of partial seizures. The study also evaluated the safety and tolerability of YKP3089 in the partial epilepsy population.
    Protection of trial subjects
    This study was conducted according to United States and international standards of Good Clinical Practice (GCP; FDA Title 21 parts 50 and 312 and ICH guidelines), applicable government regulations, and institutional research policies and procedures. Written consent of a subject, using the IEC/IRB-approved consent form, was obtained before the subject underwent any study procedure. All subjects were given adequate time to ask questions and were provided with a signed copy of the consent for his/her records. The consenting process was clearly documented in the subject’s chart. The investigator was responsible for ensuring that valid consent was obtained and documented for all subjects.
    Background therapy
    		 The subjects received standard of treatment. They must have been taken 1 to 3 concomitant AEDs at a stable dose for at least 12 weeks before Randomization. They continued these prescribed AED regimens throughout the double-blind phase of the study. During the open-label extension phase of the study, the Investigators were allowed to change the dosage of concomitant AEDs but the subject couldn't be treated with YKP3089 monotherapy. Intermittent benzodiazepines (other than diaszepam) were allowed as rescue medication once during the baseline period, twice during the treatment phase, and intermittently in the open-label extension.
    Evidence for comparator
    		 This was a placebo-controlled study and placebo was considered as comparator.
    Actual start date of recruitment
    30 Jul 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 48
    Country: Number of subjects enrolled
    Spain: 27
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Bulgaria: 37
    Country: Number of subjects enrolled
    Czechia: 24
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Germany: 33
    Country: Number of subjects enrolled
    Hungary: 15
    Country: Number of subjects enrolled
    Korea, Republic of: 31
    Country: Number of subjects enrolled
    Romania: 4
    Country: Number of subjects enrolled
    Serbia: 28
    Country: Number of subjects enrolled
    Thailand: 8
    Country: Number of subjects enrolled
    Ukraine: 23
    Country: Number of subjects enrolled
    United States: 111
    Country: Number of subjects enrolled
    Australia: 24
    Country: Number of subjects enrolled
    Israel: 12
    Worldwide total number of subjects
    437
    EEA total number of subjects
    192
    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)
    427
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 437 patients were randomly assigned in a 1:1:1:1 ratio to placebo or YKP3089 at 100 mg/day, 200 mg/day, or 400 mg/day. Qualifying subjects entered a 6-week titration phase. According to the original protocol all subjects began with a daily dose of 100 mg, followed by weekly increments of 100 mg in the daily dose, to the target dose.

    Pre-assignment
    Screening details
    		 At screening, each subject or their legally authorized representative signed an informed consent form (ICF). Assessments were performed to determine a subject’s eligibility for the study. Subjects who met all inclusion criteria and none of the exclusion criteria were assigned to one of the treatment arms or placebo.

    Period 1
    Period 1 title
    Double-Blind Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer
    Blinding implementation details
    This was a double-blind study. Treatment assignments remained blinded to the subject and all study personnel until the database lock of the double-blind treatment period. Selected individuals from the sponsor and/or designee could be unblinded to the study treatments on a need-to-know basis, if they felt it was medically necessary and that knowledge of the treatment assignment was essential for the patient’s care.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 YKP3089 (100 mg qd)
    Arm description
    		 100 mg YKP3089 was administrated daily during 18-week double-blind treatment period (including a 6-week titration phase and 12-week maintenance phase), followed by a 3-week blinded study drug taper period (for subjects leaving the study) or a 2-week blinded conversion period (for subjects participating in the open-label extension), with a final follow-up visit 2 weeks after the last dose of study drug.
    Arm type
    		 Experimental

    Investigational medicinal product name
    YKP3089 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg were administrated once daily. Subjects were supplied with YKP3089 50 mg and 100 mg tablets to be taken orally in the morning. Study drug could have been taken with or without food.

    Arm title
    		 YKP3089 (200 mg qd)
    Arm description
    		 200 mg YKP3089 was administrated daily during 18-week double-blind treatment period (including a 6-week titration phase and 12-week maintenance phase), followed by a 3-week blinded study drug taper period (for subjects leaving the study) or a 2-week blinded conversion period (for subjects participating in the open-label extension), with a final follow-up visit 2 weeks after the last dose of study drug.
    Arm type
    		 Experimental

    Investigational medicinal product name
    YKP3089 200 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg were administrated once daily. Subjects were supplied with YKP3089 50 mg and 100 mg tablets to be taken orally in the morning. Study drug could have been taken with or without food.

    Arm title
    		 YKP3089 (400 mg qd)
    Arm description
    		 400 mg YKP3089 was administrated daily during 18-week double-blind treatment period (including a 6-week titration phase and 12-week maintenance phase), followed by a 3-week blinded study drug taper period (for subjects leaving the study) or a 2-week blinded conversion period (for subjects participating in the open-label extension), with a final follow-up visit 2 weeks after the last dose of study drug.
    Arm type
    		 Experimental

    Investigational medicinal product name
    YKP3089 400 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg were administrated once daily. Subjects were supplied with YKP3089 50 mg and 100 mg tablets to be taken orally in the morning. Study drug could have been taken with or without food.

    Arm title
    		 Placebo
    Arm description
    		 Placebo was administrated daily during 18-week double-blind treatment period (including a 6-week titration phase and 12-week maintenance phase), followed by a 3-week blinded study drug taper period (for subjects leaving the study) or a 2-week blinded conversion period (for subjects participating in the open-label extension), with a final follow-up visit 2 weeks after the last dose of study drug.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo were administrated once daily. Subjects were supplied with Placebo, identical in appearance to the study drug, to be taken orally in the morning. Placebo could have been taken with or without food.

    Number of subjects in period 1
    		YKP3089 (100 mg qd) YKP3089 (200 mg qd) YKP3089 (400 mg qd) Placebo
    Started
    108
    110
    111
    108
    Completed
    95
    90
    81
    94
    Not completed
    13
    20
    30
    14
         Consent withdrawn by subject
    -
    4
    3
    5
         Other
    -
    -
    1
    3
         Pregnancy
    -
    -
    -
    1
         Adverse event
    12
    15
    23
    5
         Lost to follow-up
    -
    -
    1
    -
         Lack of efficacy
    1
    -
    1
    -
         Protocol deviation
    -
    1
    1
    -
    Period 2
    Period 2 title
    Open-Label Extension Phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    A total of 356 subjects entered the open-label extension phase from the double-blind treatment period.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DB YKP3089 100 mg to YKP3089 OLE
    Arm description
    		 95 subjects from YKP3089 100 mg/day group entered the open-label extension phase from the double-blind treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    YKP3089
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were supplied with YKP3089 50 mg and 100 mg tablets to be taken orally in the morning. Study drug could have been taken with or without food. The initial target dose for the open-label extension phase was 300 mg/day. However, if a subject was not able to tolerate the 300 mg/day dose, YKP3089 dose was reduced to a minimum of 50 mg/day. If the investigator felt that a subject required a dose that was higher than 300 mg/day, the dose was increased to a maximum of 400 mg/day once the target dose of 300 mg/day was reached. If 50 mg/day of YKP3089 was not tolerated, the subject was withdrawn from the study. The dose adjustments occurred in weekly increments of 100 mg/day or 50 mg/day.

    Arm title
    		 DB YKP3089 200 mg to YKP3089 OLE
    Arm description
    		 90 subjects from YKP3089 200 mg/day group entered the open-label extension phase from the double-blind treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    YKP3089
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were supplied with YKP3089 50 mg and 100 mg tablets to be taken orally in the morning. Study drug could have been taken with or without food. The initial target dose for the open-label extension phase was 300 mg/day. However, if a subject was not able to tolerate the 300 mg/day dose, YKP3089 dose was reduced to a minimum of 50 mg/day. If the investigator felt that a subject required a dose that was higher than 300 mg/day, the dose was increased to a maximum of 400 mg/day once the target dose of 300 mg/day was reached. If 50 mg/day of YKP3089 was not tolerated, the subject was withdrawn from the study. The dose adjustments occurred in weekly increments of 100 mg/day or 50 mg/day.

    Arm title
    		 DB YKP3089 400 mg to YKP3089 OLE
    Arm description
    		 80 subjects from YKP3089 400 mg/day group entered the open-label extension phase from the double-blind treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    YKP3089
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were supplied with YKP3089 50 mg and 100 mg tablets to be taken orally in the morning. Study drug could have been taken with or without food. The initial target dose for the open-label extension phase was 300 mg/day. However, if a subject was not able to tolerate the 300 mg/day dose, YKP3089 dose was reduced to a minimum of 50 mg/day. If the investigator felt that a subject required a dose that was higher than 300 mg/day, the dose was increased to a maximum of 400 mg/day once the target dose of 300 mg/day was reached. If 50 mg/day of YKP3089 was not tolerated, the subject was withdrawn from the study. The dose adjustments occurred in weekly increments of 100 mg/day or 50 mg/day.

    Arm title
    		 Placebo DB to YKP3089 OLE
    Arm description
    		 91 subjects from Placebo group entered the open-label extension phase from the double-blind treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    YKP3089
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were supplied with YKP3089 50 mg and 100 mg tablets to be taken orally in the morning. Study drug could have been taken with or without food. The initial target dose for the open-label extension phase was 300 mg/day. However, if a subject was not able to tolerate the 300 mg/day dose, YKP3089 dose was reduced to a minimum of 50 mg/day. If the investigator felt that a subject required a dose that was higher than 300 mg/day, the dose was increased to a maximum of 400 mg/day once the target dose of 300 mg/day was reached. If 50 mg/day of YKP3089 was not tolerated, the subject was withdrawn from the study. The dose adjustments occurred in weekly increments of 100 mg/day or 50 mg/day.

    Number of subjects in period 2 [1]
    		DB YKP3089 100 mg to YKP3089 OLE DB YKP3089 200 mg to YKP3089 OLE DB YKP3089 400 mg to YKP3089 OLE Placebo DB to YKP3089 OLE
    Started
    95
    90
    80
    91
    Completed
    21
    19
    14
    16
    Not completed
    74
    71
    66
    75
         Consent withdrawn by subject
    7
    9
    3
    16
         Death
    1
    3
    2
    1
         Other
    3
    1
    3
    3
         Adverse event
    6
    6
    7
    9
         Lost to follow-up
    1
    1
    3
    2
         Entered EAP/Navigator
    39
    28
    32
    30
         Lack of efficacy
    17
    23
    14
    13
         Protocol deviation
    -
    -
    2
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 356 of 360 subjects entered open-label extension period; 4 subjects have an answer of 'No' to the question 'if subject going to OLE' without more details.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    YKP3089 (100 mg qd)
    Reporting group description
    		 100 mg YKP3089 was administrated daily during 18-week double-blind treatment period (including a 6-week titration phase and 12-week maintenance phase), followed by a 3-week blinded study drug taper period (for subjects leaving the study) or a 2-week blinded conversion period (for subjects participating in the open-label extension), with a final follow-up visit 2 weeks after the last dose of study drug.

    Reporting group title
    YKP3089 (200 mg qd)
    Reporting group description
    		 200 mg YKP3089 was administrated daily during 18-week double-blind treatment period (including a 6-week titration phase and 12-week maintenance phase), followed by a 3-week blinded study drug taper period (for subjects leaving the study) or a 2-week blinded conversion period (for subjects participating in the open-label extension), with a final follow-up visit 2 weeks after the last dose of study drug.

    Reporting group title
    YKP3089 (400 mg qd)
    Reporting group description
    		 400 mg YKP3089 was administrated daily during 18-week double-blind treatment period (including a 6-week titration phase and 12-week maintenance phase), followed by a 3-week blinded study drug taper period (for subjects leaving the study) or a 2-week blinded conversion period (for subjects participating in the open-label extension), with a final follow-up visit 2 weeks after the last dose of study drug.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was administrated daily during 18-week double-blind treatment period (including a 6-week titration phase and 12-week maintenance phase), followed by a 3-week blinded study drug taper period (for subjects leaving the study) or a 2-week blinded conversion period (for subjects participating in the open-label extension), with a final follow-up visit 2 weeks after the last dose of study drug.

    Reporting group values
    		 YKP3089 (100 mg qd) YKP3089 (200 mg qd) YKP3089 (400 mg qd) Placebo Total
    Number of subjects
    		 108 110 111 108 437
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 106 107 110 104 427
        From 65-84 years
    		 2 3 1 4 10
    Age continuous
    Units: years
        median (full range (min-max))
    		 37.5 (19 to 66) 40.5 (19 to 69) 38.0 (21 to 66) 38.0 (19 to 70) -
    Gender categorical
    Units: Subjects
        Female
    		 51 56 59 50 216
        Male
    		 57 54 52 58 221
    Subject analysis sets

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population included all randomized subjects.

    Subject analysis set title
    MITT population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    MITT population includes all randomized subjects with at least 1 dose of YKP3089 or placebo and had any postbaseline seizure data.

    Subject analysis set title
    MITT-M population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    MITT-M population includes all randomized subjects who completed the titration phase, took at least 1 dose of YKP3089 or placebo in the maintenance phase, and had any maintenance phase seizure data.

    Subject analysis set title
    PP population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PP population includes all randomized subjects with no major protocol deviations, and had at least 80% compliance with study.

    Subject analysis set title
    SE population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Evaluable (SE) population was the same as the ITT population.

    Subject analysis set title
    OLE-EA population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    OLE-EA population includes all subjects who entered in open-label extension phase, took at least one dose of open-label study medication, and had any seizure data recorded in open-label extension seizure diary.

    Subject analysis sets values
    		 ITT population MITT population MITT-M population PP population SE population OLE-EA population
    Number of subjects
    437
    434
    397
    398
    437
    355
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    427
    427
        From 65-84 years
    10
    10
    Age continuous
    Units: years
        median (full range (min-max))
    38.0 (19 to 70)
    38.0 (19 to 70)
    Gender categorical
    Units: Subjects
        Female
    216
    216
        Male
    221
    221

    End points

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    End points reporting groups
    Reporting group title
    YKP3089 (100 mg qd)
    Reporting group description
    		 100 mg YKP3089 was administrated daily during 18-week double-blind treatment period (including a 6-week titration phase and 12-week maintenance phase), followed by a 3-week blinded study drug taper period (for subjects leaving the study) or a 2-week blinded conversion period (for subjects participating in the open-label extension), with a final follow-up visit 2 weeks after the last dose of study drug.

    Reporting group title
    YKP3089 (200 mg qd)
    Reporting group description
    		 200 mg YKP3089 was administrated daily during 18-week double-blind treatment period (including a 6-week titration phase and 12-week maintenance phase), followed by a 3-week blinded study drug taper period (for subjects leaving the study) or a 2-week blinded conversion period (for subjects participating in the open-label extension), with a final follow-up visit 2 weeks after the last dose of study drug.

    Reporting group title
    YKP3089 (400 mg qd)
    Reporting group description
    		 400 mg YKP3089 was administrated daily during 18-week double-blind treatment period (including a 6-week titration phase and 12-week maintenance phase), followed by a 3-week blinded study drug taper period (for subjects leaving the study) or a 2-week blinded conversion period (for subjects participating in the open-label extension), with a final follow-up visit 2 weeks after the last dose of study drug.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was administrated daily during 18-week double-blind treatment period (including a 6-week titration phase and 12-week maintenance phase), followed by a 3-week blinded study drug taper period (for subjects leaving the study) or a 2-week blinded conversion period (for subjects participating in the open-label extension), with a final follow-up visit 2 weeks after the last dose of study drug.
    Reporting group title
    DB YKP3089 100 mg to YKP3089 OLE
    Reporting group description
    		 95 subjects from YKP3089 100 mg/day group entered the open-label extension phase from the double-blind treatment period.

    Reporting group title
    DB YKP3089 200 mg to YKP3089 OLE
    Reporting group description
    		 90 subjects from YKP3089 200 mg/day group entered the open-label extension phase from the double-blind treatment period.

    Reporting group title
    DB YKP3089 400 mg to YKP3089 OLE
    Reporting group description
    		 80 subjects from YKP3089 400 mg/day group entered the open-label extension phase from the double-blind treatment period.

    Reporting group title
    Placebo DB to YKP3089 OLE
    Reporting group description
    		 91 subjects from Placebo group entered the open-label extension phase from the double-blind treatment period.

    Subject analysis set title
    ITT population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population included all randomized subjects.

    Subject analysis set title
    MITT population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    MITT population includes all randomized subjects with at least 1 dose of YKP3089 or placebo and had any postbaseline seizure data.

    Subject analysis set title
    MITT-M population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    MITT-M population includes all randomized subjects who completed the titration phase, took at least 1 dose of YKP3089 or placebo in the maintenance phase, and had any maintenance phase seizure data.

    Subject analysis set title
    PP population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    PP population includes all randomized subjects with no major protocol deviations, and had at least 80% compliance with study.

    Subject analysis set title
    SE population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The Safety Evaluable (SE) population was the same as the ITT population.

    Subject analysis set title
    OLE-EA population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    OLE-EA population includes all subjects who entered in open-label extension phase, took at least one dose of open-label study medication, and had any seizure data recorded in open-label extension seizure diary.

    Primary: Percentage Change in Seizure Frequency per 28 Days During the Double-Blind Treatment Period for the United States and Rest of the World

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    End point title
    		 Percentage Change in Seizure Frequency per 28 Days During the Double-Blind Treatment Period for the United States and Rest of the World
    End point description
    The primary efficacy endpoint for the United States and the ROW was defined as the percentage change from pretreatment baseline period in seizure frequency (average monthly seizure rate per 28 days) of Type B, Type C, and Type D seizures during the double-blind treatment period. The primary efficacy endpoint values below will be based on the MITT population.
    End point type
    Primary
    End point timeframe
    Double-blind treatment period
    End point values
    		 YKP3089 (100 mg qd) YKP3089 (200 mg qd) YKP3089 (400 mg qd) Placebo
    Number of subjects analysed
    108
    109
    111
    106
    Units: percent
    median (full range (min-max))
        Baseline (n)
    9.5 (3.5 to 202)
    11 (4 to 418)
    9 (4 to 638)
    8.4 (4 to 704)
        Endpoint (n)
    5.8 (0 to 164.6)
    5.8 (0 to 373.7)
    3.8 (0 to 424.9)
    6.8 (0.7 to 640.8)
        Change from Baseline (%)
    -35.5 (-100 to 206)
    -55 (-100 to 191)
    -55 (-100 to 167)
    -24 (-91 to 198)
    Statistical analysis title
    		 ANCOVA for Percentage Change in Seizure in DB
    Statistical analysis description
    The primary analysis for this primary efficacy endpoint will be based on the MITT population. The testing strategy for this primary efficacy analysis is to compare each of the YKP3089 dosage groups with the placebo group. Due to multiple treatment comparisons, a step-down procedure will be used to ensure the overall type I error rate is controlled at the 5% level. The hierarchy for comparisons is YKP3089 200 mg vs placebo, YKP3089 400 mg vs placebo, YKP3089 100 mg vs placebo.
    Comparison groups
    YKP3089 (100 mg qd) v YKP3089 (200 mg qd) v YKP3089 (400 mg qd) v Placebo
    Number of subjects included in analysis
    434
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.007 [2]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [1] - An analysis of covariance (ANCOVA) model will be fit to the ranked values of the primary efficacy endpoint. The ANCOVA will have terms for ranked baseline seizure rate and randomized treatment group. Ties will be handled using TIES=MEAN. It should be noted that the primary efficacy analysis uses a non-parametric approach. Because of this, effect sizes are not estimated and tested directly, since testing is made on the rank of the primary efficacy value.
    [2] - p-value (YKP3089 100 mg qd vs Placebo) = 0.007 p-value (YKP3089 200 mg qd vs Placebo) < 0.001 p-value (YKP3089 400 mg qd vs Placebo) < 0.001

    Primary: Responder Rate (at Least 50% Reduction in Seizure Frequency) During the Maintenance Phase for Europe, Australia, New Zealand, and South Africa

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    End point title
    		 Responder Rate (at Least 50% Reduction in Seizure Frequency) During the Maintenance Phase for Europe, Australia, New Zealand, and South Africa
    End point description
    The primary efficacy endpoint for Europe, Australia, New Zealand, and South Africa is the responder rate (responder is defined as a ≥ 50% reduction during the maintenance phase of double-blind treatment period in seizure frequency from baseline period). The primary efficacy endpoint values below will be based on the MITT-M population.
    End point type
    Primary
    End point timeframe
    During maintenance phase of double-blind treatment period
    End point values
    		 YKP3089 (100 mg qd) YKP3089 (200 mg qd) YKP3089 (400 mg qd) Placebo
    Number of subjects analysed
    102
    98
    95
    102
    Units: percent
    number (not applicable)
        Responder – Yes (n)
    41
    55
    61
    26
        Responder – No (n)
    61
    43
    34
    76
        Responder – Yes (%)
    40.2
    56.1
    64.2
    25.5
        Responder – No (%)
    59.8
    43.9
    35.8
    74.5
    Statistical analysis title
    		 Fisher Exact Test for Responder Rate in DB
    Statistical analysis description
    The primary analysis for this primary efficacy endpoint will be based on the MITT-M population. The testing strategy for this primary efficacy analysis is to compare each of the YKP3089 dosage groups with the placebo group. Due to multiple treatment comparisons, a step-down procedure will be used to ensure the overall type I error rate is controlled at the 5% level. The hierarchy for comparisons is YKP3089 200 mg vs placebo, YKP3089 400 mg vs placebo, YKP3089 100 mg vs placebo.
    Comparison groups
    YKP3089 (100 mg qd) v YKP3089 (200 mg qd) v YKP3089 (400 mg qd) v Placebo
    Number of subjects included in analysis
    397
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.036 [3]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [3] - p-value (YKP3089 100 mg qd vs Placebo) = 0.036 p-value (YKP3089 200 mg qd vs Placebo) < 0.001 p-value (YKP3089 400 mg qd vs Placebo) < 0.001

    Other pre-specified: Percent Change in Seizure Frequency per 28-Day During Open-Label Extension period

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    End point title
    		 Percent Change in Seizure Frequency per 28-Day During Open-Label Extension period
    End point description
    This efficacy endpoint was defined as the percentage change from pretreatment baseline period in seizure frequency (average monthly seizure rate per 28 days) of Type B, Type C, and Type D seizures during the open-label extension phase. The efficacy endpoint values below will be based on the OLE-EA population.
    End point type
    Other pre-specified
    End point timeframe
    During open-label extension phase
    End point values
    		 DB YKP3089 100 mg to YKP3089 OLE DB YKP3089 200 mg to YKP3089 OLE DB YKP3089 400 mg to YKP3089 OLE Placebo DB to YKP3089 OLE OLE-EA population
    Number of subjects analysed
    95
    90
    79
    91
    355
    Units: percent
    median (full range (min-max))
        Percent Change from Baseline
    -63.32 (-100.0 to 85.3)
    -57.58 (-100.0 to 174.8)
    -60.60 (-100.0 to 409.5)
    -63.21 (-100.0 to 256.4)
    -61.56 (-100.0 to 409.5)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    During the double-blind treatment period
    Adverse event reporting additional description
    The incidence of Treatment-Emergent Adverse Events (TEAEs) was presented in the Safety Evaluable Population (SE population) during the double-blind treatment period. Similar data was observed during Open-Label Extension Phase (OLE-SE Population).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    YKP3089 (100 mg qd)
    Reporting group description
    		 100 mg YKP3089 was administrated daily during 18-week double-blind treatment period (including a 6-week titration phase and 12-week maintenance phase), followed by a 3-week blinded study drug taper period (for subjects leaving the study) or a 2-week blinded conversion period (for subjects participating in the open-label extension), with a final follow-up visit 2 weeks after the last dose of study drug.

    Reporting group title
    YKP3089 (200 mg qd)
    Reporting group description
    		 200 mg YKP3089 was administrated daily during 18-week double-blind treatment period (including a 6-week titration phase and 12-week maintenance phase), followed by a 3-week blinded study drug taper period (for subjects leaving the study) or a 2-week blinded conversion period (for subjects participating in the open-label extension), with a final follow-up visit 2 weeks after the last dose of study drug.

    Reporting group title
    YKP3089 (400 mg qd)
    Reporting group description
    		 400 mg YKP3089 was administrated daily during 18-week double-blind treatment period (including a 6-week titration phase and 12-week maintenance phase), followed by a 3-week blinded study drug taper period (for subjects leaving the study) or a 2-week blinded conversion period (for subjects participating in the open-label extension), with a final follow-up visit 2 weeks after the last dose of study drug.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo was administrated daily during 18-week double-blind treatment period (including a 6-week titration phase and 12-week maintenance phase), followed by a 3-week blinded study drug taper period (for subjects leaving the study) or a 2-week blinded conversion period (for subjects participating in the open-label extension), with a final follow-up visit 2 weeks after the last dose of study drug.

    Serious adverse events
    		 YKP3089 (100 mg qd) YKP3089 (200 mg qd) YKP3089 (400 mg qd) Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 108 (9.26%)
    4 / 110 (3.64%)
    8 / 111 (7.21%)
    6 / 108 (5.56%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 110 (0.00%)
    1 / 111 (0.90%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 110 (0.00%)
    1 / 111 (0.90%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immunoglobulins decreased
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 110 (0.00%)
    1 / 111 (0.90%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Concussion
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 110 (0.00%)
    0 / 111 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 110 (0.00%)
    1 / 111 (0.90%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 110 (0.91%)
    1 / 111 (0.90%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 110 (0.91%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 110 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 110 (0.00%)
    0 / 111 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 110 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 110 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 110 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 110 (0.00%)
    2 / 111 (1.80%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 110 (0.00%)
    2 / 111 (1.80%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 110 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 110 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nystagmus
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 110 (0.00%)
    2 / 111 (1.80%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 108 (1.85%)
    1 / 110 (0.91%)
    1 / 111 (0.90%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 110 (0.00%)
    1 / 111 (0.90%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 110 (0.00%)
    0 / 111 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 110 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 110 (0.00%)
    1 / 111 (0.90%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 110 (0.00%)
    0 / 111 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 110 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    0 / 108 (0.00%)
    1 / 110 (0.91%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    2 / 108 (1.85%)
    0 / 110 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 108 (0.93%)
    0 / 110 (0.00%)
    0 / 111 (0.00%)
    0 / 108 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess jaw
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 110 (0.00%)
    0 / 111 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infectious colitis
         subjects affected / exposed
    0 / 108 (0.00%)
    0 / 110 (0.00%)
    0 / 111 (0.00%)
    1 / 108 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 YKP3089 (100 mg qd) YKP3089 (200 mg qd) YKP3089 (400 mg qd) Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    60 / 108 (55.56%)
    80 / 110 (72.73%)
    92 / 111 (82.88%)
    67 / 108 (62.04%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 108 (1.85%)
    3 / 110 (2.73%)
    3 / 111 (2.70%)
    6 / 108 (5.56%)
         occurrences all number
    2
    3
    3
    6
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    20 / 108 (18.52%)
    23 / 110 (20.91%)
    40 / 111 (36.04%)
    9 / 108 (8.33%)
         occurrences all number
    20
    23
    40
    9
    Dizziness
         subjects affected / exposed
    19 / 108 (17.59%)
    22 / 110 (20.00%)
    35 / 111 (31.53%)
    15 / 108 (13.89%)
         occurrences all number
    19
    22
    35
    15
    Headache
         subjects affected / exposed
    11 / 108 (10.19%)
    12 / 110 (10.91%)
    12 / 111 (10.81%)
    6 / 108 (5.56%)
         occurrences all number
    11
    12
    12
    6
    Balance disorder
         subjects affected / exposed
    3 / 108 (2.78%)
    2 / 110 (1.82%)
    10 / 111 (9.01%)
    0 / 108 (0.00%)
         occurrences all number
    3
    2
    10
    0
    Nystagmus
         subjects affected / exposed
    3 / 108 (2.78%)
    4 / 110 (3.64%)
    5 / 111 (4.50%)
    1 / 108 (0.93%)
         occurrences all number
    3
    4
    5
    1
    Ataxia
         subjects affected / exposed
    2 / 108 (1.85%)
    4 / 110 (3.64%)
    5 / 111 (4.50%)
    1 / 108 (0.93%)
         occurrences all number
    2
    4
    5
    1
    Dysarthria
         subjects affected / exposed
    2 / 108 (1.85%)
    3 / 110 (2.73%)
    7 / 111 (6.31%)
    0 / 108 (0.00%)
         occurrences all number
    2
    3
    7
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    13 / 108 (12.04%)
    19 / 110 (17.27%)
    27 / 111 (24.32%)
    9 / 108 (8.33%)
         occurrences all number
    13
    19
    27
    9
    Gait disturbance
         subjects affected / exposed
    1 / 108 (0.93%)
    6 / 110 (5.45%)
    9 / 111 (8.11%)
    3 / 108 (2.78%)
         occurrences all number
    1
    6
    9
    3
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 108 (0.93%)
    3 / 110 (2.73%)
    5 / 111 (4.50%)
    3 / 108 (2.78%)
         occurrences all number
    1
    3
    5
    3
    Eye disorders
    Diplopia
         subjects affected / exposed
    8 / 108 (7.41%)
    11 / 110 (10.00%)
    17 / 111 (15.32%)
    2 / 108 (1.85%)
         occurrences all number
    8
    11
    17
    2
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 108 (1.85%)
    3 / 110 (2.73%)
    10 / 111 (9.01%)
    1 / 108 (0.93%)
         occurrences all number
    2
    3
    10
    1
    Nausea
         subjects affected / exposed
    7 / 108 (6.48%)
    1 / 110 (0.91%)
    10 / 111 (9.01%)
    1 / 108 (0.93%)
         occurrences all number
    7
    1
    10
    1
    Vomiting
         subjects affected / exposed
    2 / 108 (1.85%)
    3 / 110 (2.73%)
    6 / 111 (5.41%)
    0 / 108 (0.00%)
         occurrences all number
    2
    3
    6
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 108 (3.70%)
    1 / 110 (0.91%)
    6 / 111 (5.41%)
    3 / 108 (2.78%)
         occurrences all number
    4
    1
    6
    3
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 108 (2.78%)
    4 / 110 (3.64%)
    3 / 111 (2.70%)
    6 / 108 (5.56%)
         occurrences all number
    3
    4
    3
    6
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 108 (2.78%)
    1 / 110 (0.91%)
    6 / 111 (5.41%)
    1 / 108 (0.93%)
         occurrences all number
    3
    1
    6
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Jan 2014
    The following is a summary of the major changes implemented with Protocol Amendment 1 (global amendment dated on 07 Jan 2014 for all countries except France, Germany, Korea, and the United Kingdom, for which the amendment date was 09 Jan 2014): • Reduced the initial starting dose to 50 mg/day and slowed the titration rate to improve tolerability. • Clarified the definition of uncontrolled partial seizures. • Provided guidance on contraception for male subjects. • Allowed the first dose of study drug to be given at the investigator’s site. • Revised the timelines for the data monitoring committee review of data. • Added a 50 mg/day dosing card.
    20 Mar 2015
    The following is a summary of the major changes implemented with Protocol Amendment 2 (global amendment dated 20 Mar 2015 for all countries): • Removed interim analysis. • Provided details of proposed statistical procedures. • Added lacosamide as one of the concomitant AEDs in the pharmacokinetic (PK) analysis.
    17 Jun 2019
    The following changes were implemented with Protocol Amendment 3 (global amendment dated 17 Jun 2019 for all countries except Germany for which the amendment date was 16 Aug 2019): • Updated SK Life Science Inc.’s address.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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