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    Clinical Trial Results:
    A DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, PARALLEL-GROUP, MULTICENTER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF LACOSAMIDE AS ADJUNCTIVE THERAPY FOR UNCONTROLLED PRIMARY GENERALIZED TONIC-CLONIC SEIZURES IN SUBJECTS WITH IDIOPATHIC GENERALIZED EPILEPSY

    Summary
    EudraCT number
    2011-003100-21
    Trial protocol
    PT   SK   HU   DE   ES   CZ   BE   IT   PL   FR   BG   RO  
    Global end of trial date
    05 Jun 2019

    Results information
    Results version number
    v2(current)
    This version publication date
    07 Jun 2020
    First version publication date
    21 Dec 2019
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Alignment with final posting on ClinicalTrials.gov after NIH review.

    Trial information

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    Trial identification
    Sponsor protocol code
    SP0982
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02408523
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB BIOSCIENCES, Inc.
    Sponsor organisation address
    8010 Arco Corporate Drive, Raleigh, United States, NC 27617
    Public contact
    Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
    Scientific contact
    Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000402-PIP03-17
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Jun 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the efficacy of oral lacosamide (LCM) vs placebo as adjunctive therapy for uncontrolled primary generalized tonic-clonic (PGTC) seizures in subjects with idiopathic generalized epilepsy (IGE) currently taking 1 to 3 concomitant anti-epileptic drugs (AEDs) independent of the number of prior failed AEDs
    Protection of trial subjects
    During the conduct of the study all participants were closely monitored.
    Background therapy
    Background therapy as permitted in the protocol.
    Evidence for comparator
    Not Applicable
    Actual start date of recruitment
    23 Apr 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 17
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Brazil: 15
    Country: Number of subjects enrolled
    Bulgaria: 13
    Country: Number of subjects enrolled
    China: 5
    Country: Number of subjects enrolled
    Czech Republic: 15
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Hungary: 13
    Country: Number of subjects enrolled
    Israel: 7
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Japan: 30
    Country: Number of subjects enrolled
    Mexico: 1
    Country: Number of subjects enrolled
    Poland: 16
    Country: Number of subjects enrolled
    Portugal: 1
    Country: Number of subjects enrolled
    Romania: 8
    Country: Number of subjects enrolled
    Russian Federation: 30
    Country: Number of subjects enrolled
    Slovakia: 11
    Country: Number of subjects enrolled
    Korea, Democratic People's Republic of: 6
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    United States: 30
    Worldwide total number of subjects
    242
    EEA total number of subjects
    99
    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)
    17
    Adolescents (12-17 years)
    32
    Adults (18-64 years)
    191
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study started to enroll patients in April 2015 and concluded in May 2019.

    Pre-assignment
    Screening details
    Completed study was defined as meeting any exit criteria or completing the 24-week Treatment Period with < 2 PGTCS. After Treatment Period participants enrolled either in a 4-week Transition Period (entered EP0012) or up to a 4-week Taper Period and a 30-day Safety Follow-up Period (did not enter EP0012). Participant Flow refers to the Safety Set.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Placebo 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400 mg/day for adult and pediatric participants >= 50 kg. Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants < 30 kg). Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo tablet
    Investigational medicinal product code
    Other name
    PBO
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400mg/day for adult and pediatric participants >= 50 kg.

    Investigational medicinal product name
    Placebo oral solution
    Investigational medicinal product code
    Other name
    PBO
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants < 30 kg or maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg).

    Arm title
    Lacosamide
    Arm description
    Lacosamide 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400 mg/day for adult and pediatric participants with more or equal than (>=) 50 kilograms (kg). Lacosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants with less than (<) 30 kg). Lasosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg).
    Arm type
    Experimental

    Investigational medicinal product name
    Lacosamide tablet
    Investigational medicinal product code
    SPM927
    Other name
    Vimpat
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lacosamide 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400mg/day for adult and pediatric participants >= 50 kg.

    Investigational medicinal product name
    Lacosamide oral solution
    Investigational medicinal product code
    SPM927
    Other name
    Vimpat
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Lacosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants < 30 kg or maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg).

    Number of subjects in period 1
    Placebo Lacosamide
    Started
    121
    121
    Completed Treatment period
    110
    103
    Enrolled Transition Period
    108 [1]
    101 [2]
    Enrolled Taper Period
    7 [3]
    9 [4]
    Enrolled Safety Follow-up Period
    10 [5]
    11 [6]
    Completed
    110
    103
    Not completed
    11
    18
         Protocol deviation
    1
    2
         Sponsor request
    1
    -
         Lack of efficacy
    -
    1
         Adverse event, non-fatal
    4
    10
         Did not satisfy extension conditions
    -
    1
         Consent withdrawn by subject
    3
    1
         Lost to follow-up
    2
    3
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Number of participants at the milestone reflects those who completed the study at the end of Visit 10 (Week 24)/ Early Termination (ET) and have been eligible to participate in an open-label extension study (EP0012).
    [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 the milestone reflects those who completed the study at the end of Visit 10 (Week 24)/ Early Termination (ET) and have been eligible to participate in an open-label extension study (EP0012).
    [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 the milestone reflects those who completed the study at the end of Visit 10 (Week 24)/ Early Termination (ET) and chose not to continue in EP0012. They completed an up to 4 weeks blinded taper followed by the End of Taper Visit.
    [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 the milestone reflects those who completed the study at the end of Visit 10 (Week 24)/ Early Termination (ET) and chose not to continue in EP0012. They completed an up to 4 weeks blinded taper followed by the End of Taper Visit.
    [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 the milestone reflects those who completed the End of Taper Visit and entered a 30-day (-1/+3 days) Safety Follow-up Period.
    [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 the milestone reflects those who completed the End of Taper Visit and entered a 30-day (-1/+3 days) Safety Follow-up Period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400 mg/day for adult and pediatric participants >= 50 kg. Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants < 30 kg). Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg).

    Reporting group title
    Lacosamide
    Reporting group description
    Lacosamide 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400 mg/day for adult and pediatric participants with more or equal than (>=) 50 kilograms (kg). Lacosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants with less than (<) 30 kg). Lasosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg).

    Reporting group values
    Placebo Lacosamide Total
    Number of subjects
    121 121 242
    Age categorical
    Units: Subjects
        <=18 years
    27 28 55
        Between 18 and 65 years
    93 92 185
        >=65 years
    1 1 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    27.64 ± 12.45 27.82 ± 13.13 -
    Gender categorical
    Units: Subjects
        Male
    45 55 100
        Female
    76 66 142

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400 mg/day for adult and pediatric participants >= 50 kg. Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants < 30 kg). Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg).

    Reporting group title
    Lacosamide
    Reporting group description
    Lacosamide 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400 mg/day for adult and pediatric participants with more or equal than (>=) 50 kilograms (kg). Lacosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants with less than (<) 30 kg). Lasosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg).

    Subject analysis set title
    Placebo (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Placebo 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400mg/day for adult and pediatric participants >= 50 kg. Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants < 30 kg). Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg). Participants formed the Full Analysis Set (FAS).

    Subject analysis set title
    Lacosamide (FAS)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Lacosamide 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400 mg/day for adult and pediatric participants with more or equal than (>=) 50 kilograms (kg). Lacosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants with less than (<) 30 kg). Lasosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg). Participants formed the FAS.

    Subject analysis set title
    Placebo (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Placebo 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400mg/day for adult and pediatric participants >= 50 kg. Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants < 30 kg). Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg). Participants formed the Safety Set (SS).

    Subject analysis set title
    Lacosamide (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Lacosamide 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400 mg/day for adult and pediatric participants with more or equal than (>=) 50 kilograms (kg). Lacosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants with less than (<) 30 kg). Lasosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg). Participants formed the SS.

    Subject analysis set title
    Placebo (SS) Treatment Period
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants received the following treatment during the Treatment Period (Week 0 to Week 24): Placebo 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400mg/day for adult and pediatric participants >= 50 kg. Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants < 30 kg). Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg). Participants formed the Safety Set (SS).

    Subject analysis set title
    Lacosamide (SS) Treatment Period
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants received the following treatment during the Treatment Period (Week 0 to Week 24): Lacosamide 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400 mg/day for adult and pediatric participants with more or equal than (>=) 50 kilograms (kg). Lacosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants with less than (<) 30 kg). Lasosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg). Participants formed the SS.

    Subject analysis set title
    Placebo (SS) Transition Period
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    At the end of Visit 10 (Week 24)/ Early Termination (ET), study participants who completed the study may have been eligible to participate in an open-label extension study (EP0012). Study participants who chose to enroll in the open-label extension study proceeded to a blinded 4-week Transition Period. Participants randomized to Placebo in the Treatment Period transitioned to double-blind Lacosamide: Lacosamide 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 100 mg/day until final dose of 400 mg/day at Week 4 for adult and pediatric participants >= 50 kg. Lacosamide oral solution 10 mg/ml: starting with 2 mg/kg/day at Week 1. Weekly increase in steps of 2 mg/kg/day until final dose of 8 mg/kg/day at Week 4 for pediatric participants < 30 kg and 0 kg to < 50 kg. Participants formed the SS.

    Subject analysis set title
    Lacosamide (SS) Transition Period
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    At the end of Visit 10 (Week 24)/ Early Termination (ET), study participants who completed the study may have been eligible to participate in an open-label extension study (EP0012). Study participants who chose to enroll in the open-label extension study proceeded to a blinded 4-week Transition Period. Participants randomized to Lacosaminde in the Treatment Period continued to receive double-blind Lacosamide: Lacosamide 50 mg tablets: minim (min) 300 mg/day to maximum (max) 400 mg/day from Week 1 to Week 3 and final dose of 400 mg/day at Week 4 for adult and pediatric participants >= 50 kg. Lacosamide oral solution 10 mg/ml: min 8 mg/kg/day to max 12 mg/kg/day from Week 1 to Week 4 for pediatric participants < 30 kg. Lacosamide oral solution 10 mg/ml: min 6 mg/kg/day to max 8 mg/kg/day from Week 1 to Week 3 and final dose of 8 mg/kg/day at Week 4 for pediatric participants 30 kg to < 50 kg. Participants formed the SS.

    Subject analysis set title
    Placebo (SS) Taper Period
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Study participants completing Visit 10 (Week 24) or the ET Visit who chose not to continue in EP0012 must have completed an up to 4 weeks blinded taper followed by the End of Taper Visit. Participants randomized to Placebo in the Treatment Period continued to receive Placebo: Placebo 50 mg tablets: starting with maximum dose achieved during the Treatment Period. Weekly decrease in steps of 100 mg/day until no treatment received for adult and pediatric participants >= 50 kg. Placebo oral solution 10 mg/ml: starting with maximum dose achieved during the Treatment Period. Weekly decrease in steps of 2 mg/kg/day or 3 mg/kg/day until no treatment received for pediatric participants < 30 kg and 0 kg to < 50 kg. Participants formed the SS.

    Subject analysis set title
    Lacosamide (SS) Taper Period
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Study participants completing Visit 10 (Week 24) or the ET Visit who chose not to continue in EP0012 must have completed an up to 4 weeks blinded taper followed by the End of Taper Visit. Participants randomized to Lacosamide in the Treatment Period continued to receive Lacosamide: Lacosamide 50 mg tablets: starting with maximum dose achieved during the Treatment Period. Weekly decrease in steps of 100 mg/day until no treatment received for adult and pediatric participants >= 50 kg. Lacosamide oral solution 10 mg/ml: starting with maximum dose achieved during the Treatment Period. Weekly decrease in steps of 2 mg/kg/day or 3 mg/kg/day until no treatment received for pediatric participants < 30 kg and 0 kg to < 50 kg. Participants formed the SS.

    Subject analysis set title
    Placebo (SS) Safety Follow-up Period
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    There was a 30-day (-1/+3 days) Safety Follow-up Period for study participants who completed the End of Taper Visit. The Safety Follow-up Period consisted of a clinic visit 2 weeks after the End of Taper Visit followed 2 weeks later by a telephone contact (TC). Participants did not receive any treatment during this period. Participants formed the SS.

    Subject analysis set title
    Lacosamide (SS) Safety Follow-up Period
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    There was a 30-day (-1/+3 days) Safety Follow-up Period for study participants who completed the End of Taper Visit. The Safety Follow-up Period consisted of a clinic visit 2 weeks after the End of Taper Visit followed 2 weeks later by a telephone contact (TC). Participants did not receive any treatment during this period. Participants formed the SS.

    Primary: Time to the second primary generalized tonic clonic (PGTC) seizure during the 24-week Treatment Period from Visit 2 (Week 0) to Visit 10 (Week 24)

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    End point title
    Time to the second primary generalized tonic clonic (PGTC) seizure during the 24-week Treatment Period from Visit 2 (Week 0) to Visit 10 (Week 24)
    End point description
    The primary efficacy variable was the time to the second primary generalized tonic clonic seizure (PGTCS) during the 24-week Treatment Period. Relative difference between groups (LCM vs Placebo) was expressed as Hazard Ratio. The indicated measured values are the observed number of events of second PGTCS in the treatment period which form the basis of the statistical analysis of the time to event analysis. The hazard ratio compares 2 treatment groups for the times to a specified number of events (125) for the combined treatment groups, and so both the number of events and the times until those events pertain to the computation of the hazard ratio. A Hazard Ratio below 1 indicates time to second PGTCS was improved for LCM compared to Placebo. The FAS was a subset of the SS that consisted of all study participants with at least 1 seizure diary assessment during the Treatment Period. 1 patient from the LCM group was randomized after the 125th event and did not appear in this analysis.
    End point type
    Primary
    End point timeframe
    During the Treatment Period from Visit 2 (Week 0) to Visit 10 (Week 24)
    End point values
    Placebo (FAS) Lacosamide (FAS)
    Number of subjects analysed
    121
    119
    Units: events
        number (not applicable)
    76
    49
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Comparison of LCM versus Placebo was based on a Cox proportional hazards regression model with an effect for treatment, stratifying for the following combinations of study participants’ Baseline PGTCS frequency and Development from interactive response technology (IRT) (<= 2 per 28 days in the Combined Baseline Period and Pediatric, <= 2 per 28 days in the Combined Baseline Period and Adult, and > 2 per 28 days in the Combined Baseline Period). The reference group was Placebo.
    Comparison groups
    Lacosamide (FAS) v Placebo (FAS)
    Number of subjects included in analysis
    240
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [1]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.54
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.377
         upper limit
    0.774
    Notes
    [1] - Wald's method was used to calculate the p-value, Hazard Ratio (HR) and confidence intervals (CIs).

    Secondary: Percentage of participants with seizure freedom for primary generalized tonic clonic (PGTC) seizures during the 24-week Treatment Period from Visit 2 (Week 0) to Visit 10 (Week 24)

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    End point title
    Percentage of participants with seizure freedom for primary generalized tonic clonic (PGTC) seizures during the 24-week Treatment Period from Visit 2 (Week 0) to Visit 10 (Week 24)
    End point description
    A seizure-free day from primary generalized tonic clonic seizures (PGTCS) was defined as a day where no PGTCS were reported in the seizure diary and PGTCS were assessed, which was estimated using Kaplan-Meier (KM) methods. The Full Analysis Set (FAS) was a subset of the Safety Set (SS) that consisted of all study participants with at least 1 seizure diary assessment during the Treatment Period. 1 patient from the Lacosamide (FAS) group was randomized after the 125th event and did not appear in this analysis.
    End point type
    Secondary
    End point timeframe
    During the Treatment Period from Visit 2 (Week 0) to Visit 10 (Week 24)
    End point values
    Placebo (FAS) Lacosamide (FAS)
    Number of subjects analysed
    121
    118
    Units: percentage of participants
        number (confidence interval 95%)
    17.3 (10.3 to 24.3)
    31.0 (22.4 to 39.6)
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    The key secondary efficacy variable was evaluated using an extended Mantel-Haenszel testing procedure. Baseline PGTCS Frequency from Combined Baseline and development (age from interactive response technology (IRT)) were calculated from IRT. Stratified difference in proportion of subjects who are seizure-free from PGTCS on Lacosamide (FAS) vs Placebo (FAS).
    Comparison groups
    Placebo (FAS) v Lacosamide (FAS)
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.011 [2]
    Method
    Mantel-Haenszel
    Parameter type
    KM seizure free of LCM vs Placebo
    Point estimate
    14.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.2
         upper limit
    25.1
    Notes
    [2] - Superiority of LCM vs Placebo p-value was based on a chi-square test on 1 degree of freedom.

    Secondary: Time to the first primary generalized tonic clonic (PGTC) seizure during the Treatment Period from Visit 2 (Week 0) to Visit 10 (Week 24)

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    End point title
    Time to the first primary generalized tonic clonic (PGTC) seizure during the Treatment Period from Visit 2 (Week 0) to Visit 10 (Week 24)
    End point description
    The secondary efficacy variable was the time to the first primary generalized tonic clonic seizure (PGTCS) during the 24-week Treatment Period. Relative difference between groups (Lacosamide vs Placebo) was expressed as Hazard Ratio. The indicated measured values are the observed number of events of first PGTCS in the treatment period which form the basis of the statistical analysis of the time to event analysis. The hazard ratio compares 2 treatment groups for the times to the number of events for the combined treatment groups, and so both the number of events and the times until those events pertain to the computation of the hazard ratio. A Hazard Ratio below 1 indicates time to second PGTCS was improved for LCM compared to Placebo. The FAS was a subset of the SS that consisted of all study participants with at least 1 seizure diary assessment during the Treatment Period. 1 patient from the LCM group was randomized after the 125th event and did not appear in this analysis.
    End point type
    Secondary
    End point timeframe
    During the Treatment Period from Visit 2 (Week 0) to Visit 10 (Week 24)
    End point values
    Placebo (FAS) Lacosamide (FAS)
    Number of subjects analysed
    121
    118
    Units: events
    97
    79
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Comparison of LCM versus Placebo was based on a Cox proportional hazards regression model with an effect for treatment, stratifying for the following combinations of study participants’ Baseline PGTCS frequency and Development from interactive response technology (IRT) (<= 2 per 28 days in the Combined Baseline Period and Pediatric, <= 2 per 28 days in the Combined Baseline Period and Adult, and > 2 per 28 days in the Combined Baseline Period). The reference group was Placebo.
    Comparison groups
    Placebo (FAS) v Lacosamide (FAS)
    Number of subjects included in analysis
    239
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.012 [3]
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.683
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.507
         upper limit
    0.921
    Notes
    [3] - Wald's method was used to calculate the p-value, Hazard Ratio (HR) and confidence intervals (CIs).

    Secondary: Percentage of participants with at least one adverse event (AE) as reported spontaneously by the subject and/or caregiver or observed by the investigator

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    End point title
    Percentage of participants with at least one adverse event (AE) as reported spontaneously by the subject and/or caregiver or observed by the investigator
    End point description
    An AE was any untoward medical occurrence in a patient or clinical investigation study participant administered a pharmaceutical product that did not necessarily have a causal relationship with this treatment. An AE could therefore have been any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of an investigational medicinal product (IMP), whether or not related to the IMP. The Safety Set (SS) was a subset of the Randomized Set (RS) and consisted of all study participants who had been treated with at least 1 dose of study medication, either LCM or Placebo.
    End point type
    Secondary
    End point timeframe
    From Visit 1 (Week -4) to End of Study Period (up to Week 36)
    End point values
    Placebo (SS) Lacosamide (SS)
    Number of subjects analysed
    121
    121
    Units: percentage of participants
        number (not applicable)
    81.8
    82.6
    No statistical analyses for this end point

    Secondary: Plasma Concentrations of Lacosamide

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    End point title
    Plasma Concentrations of Lacosamide
    End point description
    Lacosamide plasma concentration was expressed in micrograms per milliliter (μg/mL). Means and standard deviation (SD) were only calculated if at least 2/3 of the concentrations were quantified at the respective timepoint. Values Below Limit of Quantification (BLQ) were replaced by value of 0 in calculations of means and SDs. The Safety Set (SS) was a subset of the Randomized Set (RS) and consisted of all study participants who had been treated with at least 1 dose of study medication, either LCM or Placebo.
    End point type
    Secondary
    End point timeframe
    During the Treatment Period from Visit 2 (Week 0) to Visit 10 (Week 24)
    End point values
    Placebo (SS) Lacosamide (SS)
    Number of subjects analysed
    0 [4]
    121
    Units: ug/mL
    arithmetic mean (standard deviation)
        Visit 5, Week 6 (Titration)
    ±
    8.610961 ± 3.705438
        Visit 10, Week 24 (Maintenance)
    ±
    8.074427 ± 3.948749
        Early Termination Visit
    ±
    8.138085 ± 4.913627
    Notes
    [4] - Data not collected from participants in Placebo (SS) Arm/Group.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from Week 1 to End of Study Period (up to Week 36).
    Adverse event reporting additional description
    TEAEs counts are for each study period: Treatment Period, Transition Period for participants who entered EP0012 (NCT02408549) and Taper Period followed by Safety Follow-up Period for participants not entering EP0012. AEs reported for PBO participants during the Transition Period occur when they have switched to LCM.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Placebo (SS) Treatment Period
    Reporting group description
    Participants received the following treatment during the Treatment Period (Week 0 to Week 24): Placebo 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400mg/day for adult and pediatric participants >= 50 kg. Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants < 30 kg). Placebo oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg). Participants formed the Safety Set (SS).

    Reporting group title
    Lacosamide (SS) Treatment Period
    Reporting group description
    Participants received the following treatment during the Treatment Period (Week 0 to Week 24): Lacosamide 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 50 mg or 100 mg/day were allowed. Maximal dose 400 mg/day for adult and pediatric participants with more or equal than (>=) 50 kilograms (kg). Lacosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 12 mg/kg/day for pediatric participants with less than (<) 30 kg). Lasosamide oral solution 10 mg/ml: starting with 2 mg/kg/day, titrations steps (1 mg/kg/day to 2 mg/kg/day; maximal dose 8 mg/kg/day for pediatric participants 30 kg to < 50 kg). Participants formed the SS.

    Reporting group title
    Placebo (SS) Transition Period
    Reporting group description
    At the end of Visit 10 (Week 24)/ Early Termination (ET), study participants who completed the study may have been eligible to participate in an open-label extension study (EP0012). Study participants who chose to enroll in the open-label extension study proceeded to a blinded 4-week Transition Period. Participants randomized to Placebo in the Treatment Period transitioned to double-blind Lacosamide: Lacosamide 50 mg tablets: starting with 100 mg/day at Week 1. Weekly increase in steps of 100 mg/day until final dose of 400 mg/day at Week 4 for adult and pediatric participants >= 50 kg. Lacosamide oral solution 10 mg/ml: starting with 2 mg/kg/day at Week 1. Weekly increase in steps of 2 mg/kg/day until final dose of 8 mg/kg/day at Week 4 for pediatric participants < 30 kg and 0 kg to < 50 kg. Participants formed the SS.

    Reporting group title
    Lacosamide (SS) Transition Period
    Reporting group description
    At the end of Visit 10 (Week 24)/ Early Termination (ET), study participants who completed the study may have been eligible to participate in an open-label extension study (EP0012). Study participants who chose to enroll in the open-label extension study proceeded to a blinded 4-week Transition Period. Participants randomized to Lacosaminde in the Treatment Period continued to receive double-blind Lacosamide: Lacosamide 50 mg tablets: minim (min) 300 mg/day to maximum (max) 400 mg/day from Week 1 to Week 3 and final dose of 400 mg/day at Week 4 for adult and pediatric participants >= 50 kg. Lacosamide oral solution 10 mg/ml: min 8 mg/kg/day to max 12 mg/kg/day from Week 1 to Week 4 for pediatric participants < 30 kg. Lacosamide oral solution 10 mg/ml: min 6 mg/kg/day to max 8 mg/kg/day from Week 1 to Week 3 and final dose of 8 mg/kg/day at Week 4 for pediatric participants 30 kg to < 50 kg. Participants formed the SS.

    Reporting group title
    Placebo (SS) Taper Period
    Reporting group description
    Study participants completing Visit 10 (Week 24) or the ET Visit who chose not to continue in EP0012 must have completed an up to 4 weeks blinded taper followed by the End of Taper Visit. Participants randomized to Placebo in the Treatment Period continued to receive Placebo: Placebo 50 mg tablets: starting with maximum dose achieved during the Treatment Period. Weekly decrease in steps of 100 mg/day until no treatment received for adult and pediatric participants >= 50 kg. Placebo oral solution 10 mg/ml: starting with maximum dose achieved during the Treatment Period. Weekly decrease in steps of 2 mg/kg/day or 3 mg/kg/day until no treatment received for pediatric participants < 30 kg and 0 kg to < 50 kg. Participants formed the SS.

    Reporting group title
    Lacosamide (SS) Taper Period
    Reporting group description
    Study participants completing Visit 10 (Week 24) or the ET Visit who chose not to continue in EP0012 must have completed an up to 4 weeks blinded taper followed by the End of Taper Visit. Participants randomized to Lacosamide in the Treatment Period continued to receive Lacosamide: Lacosamide 50 mg tablets: starting with maximum dose achieved during the Treatment Period. Weekly decrease in steps of 100 mg/day until no treatment received for adult and pediatric participants >= 50 kg. Lacosamide oral solution 10 mg/ml: starting with maximum dose achieved during the Treatment Period. Weekly decrease in steps of 2 mg/kg/day or 3 mg/kg/day until no treatment received for pediatric participants < 30 kg and 0 kg to < 50 kg. Participants formed the SS.

    Reporting group title
    Placebo (SS) Safety Follow-up Period
    Reporting group description
    There was a 30-day (-1/+3 days) Safety Follow-up Period for study participants who completed the End of Taper Visit. The Safety Follow-up Period consisted of a clinic visit 2 weeks after the End of Taper Visit followed 2 weeks later by a telephone contact (TC). Participants did not receive any treatment during this period. Participants formed the SS.

    Reporting group title
    Lacosamide (SS) Safety Follow-up Period
    Reporting group description
    There was a 30-day (-1/+3 days) Safety Follow-up Period for study participants who completed the End of Taper Visit. The Safety Follow-up Period consisted of a clinic visit 2 weeks after the End of Taper Visit followed 2 weeks later by a telephone contact (TC). Participants did not receive any treatment during this period. Participants formed the SS.

    Serious adverse events
    Placebo (SS) Treatment Period Lacosamide (SS) Treatment Period Placebo (SS) Transition Period Lacosamide (SS) Transition Period Placebo (SS) Taper Period Lacosamide (SS) Taper Period Placebo (SS) Safety Follow-up Period Lacosamide (SS) Safety Follow-up Period
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 121 (3.31%)
    8 / 121 (6.61%)
    0 / 108 (0.00%)
    3 / 101 (2.97%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    1 / 11 (9.09%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 121 (0.83%)
    0 / 108 (0.00%)
    0 / 101 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 121 (0.00%)
    0 / 108 (0.00%)
    0 / 101 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    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
    Road traffic accident
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 121 (0.00%)
    0 / 108 (0.00%)
    0 / 101 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    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
    Head injury
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 121 (0.00%)
    0 / 108 (0.00%)
    1 / 101 (0.99%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 121 (0.00%)
    0 / 108 (0.00%)
    0 / 101 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    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
    Investigations
    Transaminases increased
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 121 (0.83%)
    0 / 108 (0.00%)
    0 / 101 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 121 (0.00%)
    0 / 108 (0.00%)
    0 / 101 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    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
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 121 (0.00%)
    2 / 121 (1.65%)
    0 / 108 (0.00%)
    1 / 101 (0.99%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 121 (0.00%)
    2 / 121 (1.65%)
    0 / 108 (0.00%)
    0 / 101 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    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
    Grand mal convulsion
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 121 (0.83%)
    0 / 108 (0.00%)
    1 / 101 (0.99%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 121 (0.83%)
    0 / 108 (0.00%)
    0 / 101 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 121 (0.83%)
    0 / 108 (0.00%)
    0 / 101 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clonic convulsion
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 121 (0.00%)
    0 / 108 (0.00%)
    0 / 101 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 121 (0.83%)
    0 / 108 (0.00%)
    0 / 101 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 121 (0.83%)
    0 / 108 (0.00%)
    0 / 101 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 121 (0.83%)
    0 / 108 (0.00%)
    1 / 101 (0.99%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 121 (0.83%)
    0 / 108 (0.00%)
    0 / 101 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 121 (0.00%)
    1 / 121 (0.83%)
    0 / 108 (0.00%)
    0 / 101 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 121 (0.83%)
    0 / 121 (0.00%)
    0 / 108 (0.00%)
    0 / 101 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo (SS) Treatment Period Lacosamide (SS) Treatment Period Placebo (SS) Transition Period Lacosamide (SS) Transition Period Placebo (SS) Taper Period Lacosamide (SS) Taper Period Placebo (SS) Safety Follow-up Period Lacosamide (SS) Safety Follow-up Period
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    41 / 121 (33.88%)
    60 / 121 (49.59%)
    27 / 108 (25.00%)
    5 / 101 (4.95%)
    3 / 7 (42.86%)
    2 / 9 (22.22%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    Injury, poisoning and procedural complications
    Laceration
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 121 (0.00%)
    0 / 108 (0.00%)
    0 / 101 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 121 (0.00%)
    0 / 108 (0.00%)
    0 / 101 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    7 / 121 (5.79%)
    26 / 121 (21.49%)
    10 / 108 (9.26%)
    3 / 101 (2.97%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    7
    34
    10
    3
    0
    0
    0
    0
    Somnolence
         subjects affected / exposed
    17 / 121 (14.05%)
    18 / 121 (14.88%)
    7 / 108 (6.48%)
    0 / 101 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    17
    19
    7
    0
    0
    0
    0
    0
    Headache
         subjects affected / exposed
    12 / 121 (9.92%)
    16 / 121 (13.22%)
    5 / 108 (4.63%)
    0 / 101 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    13
    18
    5
    0
    0
    0
    0
    0
    Drooling
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 121 (0.00%)
    0 / 108 (0.00%)
    0 / 101 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    Grand mal convulsion
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 121 (0.00%)
    0 / 108 (0.00%)
    0 / 101 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    6 / 121 (4.96%)
    8 / 121 (6.61%)
    2 / 108 (1.85%)
    0 / 101 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    6
    8
    2
    0
    0
    0
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 121 (1.65%)
    8 / 121 (6.61%)
    3 / 108 (2.78%)
    1 / 101 (0.99%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    8
    4
    1
    0
    0
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    7 / 121 (5.79%)
    11 / 121 (9.09%)
    2 / 108 (1.85%)
    0 / 101 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    7
    12
    3
    0
    0
    0
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 121 (0.83%)
    7 / 121 (5.79%)
    3 / 108 (2.78%)
    0 / 101 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    3
    10
    5
    0
    0
    0
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 121 (0.00%)
    0 / 108 (0.00%)
    0 / 101 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    4 / 121 (3.31%)
    8 / 121 (6.61%)
    2 / 108 (1.85%)
    1 / 101 (0.99%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    4
    12
    2
    1
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 121 (0.00%)
    0 / 121 (0.00%)
    0 / 108 (0.00%)
    0 / 101 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Sep 2012
    Protocol Amendment 1, dated 25 Sep 2012, provided the following key changes. The primary purpose of this substantial amendment was to identify significant changes to the study design including inclusion and exclusion criteria, as well as the addition of an independent data monitoring committee (IDMC). In addition, study secondary variables were changed to more accurately represent the study design. • The protocol was updated to include randomization stratified by age at informed consent (≥12 to <18 years of age vs ≥18 years of age). This was in order to maintain balance within each treatment arm and within the existing baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days for the 16-week Combined Baseline Period prior to randomization) as well as to provide greater control for variability when analyzing the primary efficacy variable (time to second seizure). • An inclusion criterion was added to include study participants of normal intelligence for age in the judgment of the investigator. Exclusion criteria were added or modified to further exclude study participants who had a diagnosis of developmental delay or mental retardation or a history of status epilepticus. The rationale for adding the inclusion/exclusion criteria was that study participants with developmental delay or mental retardation are more likely to have symptomatic rather than idiopathic seizures. • The inclusion criterion regarding the lower limit body weight for male and female study participants ≥12 years of age was changed from ≥ 30kg to ≥ 50kg. This was based on the observations collected to date from pediatric PK/tolerability studies.
    25 Sep 2012
    - Continuation 1 - • The text regarding the use of benzodiazepines was revised to clarify that up to 3 marketed antiepileptic drugs (AEDs) were allowed for study inclusion provided at least 1 of the 3 AEDs was a benzodiazepine regardless of indication. The intermittent use of a benzodiazepine was permitted for epilepsy indications only and limited to 2 doses per 28 days; intermittent use for non-epilepsy indications was prohibited. The rationale for this change was based on data from SP0961 in which approximately 20% of PGTCS study participants with idiopathic generalized epilepsy (IGE) used benzodiazepines. Study participants were not excluded from the study due to benzodiazepine use unless they were using benzodiazepines intermittently for indications other than epilepsy. This change was consistent with other PGTCS studies in regards to benzodiazepine use. • The secondary efficacy endpoint time to first PGTCS during the 24-week Treatment Period was added as a key secondary endpoint as UCB considers that LCM will improve the rate of seizure freedom in this difficult-to-treat population. A gatekeeping strategy was used to control Type I error. • For the assessment of the effect of LCM on quality of life in pediatric study participants, the SP0982 protocol was updated to include the Pediatric Quality of Life Inventory™ (PedsQL). The PedsQL is widely used in epilepsy and other therapeutic areas, and allows for comparison with other diseases. In addition, the PedsQL also allows for consistency across age groups and development programs, and is available in many languages for global clinical studies. • For the assessment of neurobehavior and cognition in pediatric study participants, the SP0982 protocol was updated to include the Achenbach Child Behavior Checklist (CBCL) and the Behavior Rating Inventory of Executive Function® (BRIEF), respectively. The addition of these assessments also allows for consistency across age groups and development programs.
    25 Sep 2012
    - Continuation 2 - • To ensure study participant safety, interim assessments for safety and futility were performed using an independent data monitoring committee (IDMC) due to the novel study design and primary endpoint in this patient population. Furthermore, a minority of study participants (~10%) in SP0961 showed an increase in absence seizures that, in this uncontrolled study, could not be distinguished between the drug vs the natural course of the disease and required additional examination in the current study. • SP0982 was an event-driven study where the statistical properties were based upon the number of events, not the number of study participants as is typical in most epilepsy studies (the primary efficacy variable was time to second PGTCS). As a result, the protocol was amended to reflect this focus. Furthermore, a maximum sample size of 250 study participants was introduced if 125 events were not observed on or before the 200th study participant randomized. This is standard for event-driven studies and represents an approximate 25% increase from the projected sample size, in case the event rate was lower than anticipated.
    11 Jul 2014
    Protocol Amendment 2, dated 11 Jul 2014, provided the following key changes. The primary purpose of this substantial amendment was to identify significant changes to the study design and the inclusion of pediatric study participants (≥4 to <12 years of age). In addition, the key study secondary efficacy variable was changed to more accurately represent the study design. • The protocol was updated to include randomization stratified by age at informed consent for study participants ≥4 to <12 years of age. This was in order to maintain balance within each treatment arm and within the existing baseline PGTCS frequency (≤2 per 28 days vs >2 per 28 days for the 16-week Combined Baseline Period prior to randomization) as well as provide greater control for variability when analyzing the primary efficacy variable (time to second seizure). • An inclusion criterion was modified to include study participants ≥4 years of age. Exclusion criteria were modified in regards to study participants who had a diagnosis of developmental delay or mental retardation or a history of status epilepticus. The rationale for modifying the exclusion criteria was that study participants with developmental delay or mental retardation are more likely to have symptomatic rather than idiopathic seizures. The rationale for modifying the exclusion criteria for study participants with a history of status epilepticus was to align with the withdrawal criteria (ie, a study participant may have been withdrawn from the study due to an episode of status epilepticus, a prolongation of seizure duration, a worsening of seizure frequency, or emergence of a new seizure type considered by the investigator to require intervention).
    08 Jun 2016
    Protocol Amendment 4, dated 08 Jun 2016, provided the following key changes. The primary purpose of this substantial amendment was to clarify elements of the study design including inclusion and exclusion criteria, exit criteria, and withdrawal criteria, as well as the duration of the Baseline Period, procedure for dividing the daily dose for the tablet formulation without breaking tablets, permitted and prohibited concomitant medication, consent for prescreening electroencephalogram (EEG), seizure count, temperature for storage of plasma samples, and determination of sample size. The protocol was also updated according to the new UCB protocol template, for example, with the addition of text regarding potential drug-induced liver injury (PDILI).
    07 Nov 2017
    Protocol Amendment 5, dated 07 Nov 2017, provided the following key changes. The primary purpose of this substantial amendment was to stop the study participants’ study participation once 125 events had been observed to avoid exposing study participants to Placebo unnecessarily and allow for flexible dosing of the treatment in the open-label follow-up study EP0012. In addition, the following changes were made: • The initial plan was to enroll 20% pediatric study participants out of a total sample size of approximately 200 study participants, which would have resulted in 40 pediatric study participants enrolled in the study. Due to a fluctuating event rate, the study was changed to enroll study participants until the 125th event occurred (an event was defined as the occurrence of the second PGTCS during the 24-week Treatment Period). Changing the number of pediatric study participants from 20% to 40 absolute ensured that at least 40 pediatric study participants were recruited while also limiting the number of required pediatric study participants in case more than 200 study participants were enrolled. This was considered appropriate in light of the extremely challenging recruitment of pediatric study participants in this study. Additionally, from the biostatistical point of view, increasing the number of pediatric study participants from 40 to 45 or 50 is very unlikely to yield significantly new or different safety information. • To update the introduction with regulatory information on the marketing authorization of Vimpat and to provide an update on the LCM clinical program. • To appropriately align the Inclusion Criterion 7.a with the examples given in the supportive table. • To clarify that Visit 5 was the beginning of the Maintenance Period (18 weeks). • To remove some blood sampling details from the protocol and refer to the laboratory manual.
    07 Nov 2017
    - Continuation - • To clarify the potential drug-induced liver injury (PDILI) criteria requiring immediate and permanent discontinuation of the investigational medicinal product (IMP). • To clarify that if the monitor had no direct access to the source electronic medical records, certified copies should have been generated by the investigator and verified by the monitor against the original medical record. • To make a minor clarification to the sentence about pooling strategies for age strata for consistency with the Statistical Analysis Plan (SAP).

    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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