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    Clinical Trial Results:
    A Historical-controlled, Multicenter, Double-blind, Randomized Trial to Assess the Efficacy and Safety of Conversion to Lacosamide 400 mg/day Monotherapy in Subjects with Partial-onset Seizures

    Summary
    EudraCT number
    2007-005439-27
    Trial protocol
    GB   IE   ES   AT   DK   PT   IT   FR   DE  
    Global end of trial date
    06 Dec 2012

    Results information
    Results version number
    v1(current)
    This version publication date
    28 Jun 2016
    First version publication date
    15 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SP0902
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00520741
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB BIOSCIENCES INC
    Sponsor organisation address
    8010 ARCO CORPORATE DRIVE, RALEIGH, United States, 27617
    Public contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, +49 2173 4815 15, clinicaltrials@ucb.com
    Scientific contact
    Clinical Trial Registries and Results Disclosure, UCB BIOSCIENCES GmbH, +49 2173 48 15 15, clinicaltrials@ucb.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Feb 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Dec 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this trial is to demonstrate the efficacy and safety of conversion to LCM 400 mg/day monotherapy for partial-onset seizures (with or without secondary generalization) in subjects 16 to 70 years of age who are withdrawn from 1 to 2 marketed Anti-epileptic Drug (AEDs).
    Protection of trial subjects
    Usual and customary measures to minimize discomfort for study blood testing procedures.
    Background therapy
    Not applicable
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    02 Aug 2007
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    2 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 332
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Poland: 35
    Country: Number of subjects enrolled
    Australia: 16
    Country: Number of subjects enrolled
    Canada: 21
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    United Kingdom: 5
    Worldwide total number of subjects
    425
    EEA total number of subjects
    56
    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)
    4
    Adults (18-64 years)
    408
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 160 sites in the United States of America (USA), Canada, Europe, and Australia.The maximum duration of a subject’s trial participation is 30 weeks. The Participant Flow refers to the Safety Set (SS) population which consists of all patients who received at least one dose of study medication.

    Pre-assignment
    Screening details
    Subjects were randomized 3:1 to one of two therapeutic doses of Lacosamide, 400 mg/day or 300 mg/day, to ensure a study design comparable to the historical control. One subject was randomized at 2 sites and excluded from 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
    Blinding implementation details
    Not applicable

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Lacosamide 300 mg/day
    Arm description
    Lacosamide 300 mg/dayLacosamide : 50 mg and 100 mg tablets provided for 150 mg twice daily dosing for up to 20 weeks.Subjects were randomized 3:1 to one of two therapeutic doses of Lacosamide, 400 mg/day or 300 mg/day, to ensure a study design comparable to the historical control.
    Arm type
    Experimental

    Investigational medicinal product name
    Lacosamide
    Investigational medicinal product code
    Lacosamide LCM
    Other name
    Vimpat
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    - 50 mg and 100 mg tablets provided for 200 mg twice daily dosing for up to 20 weeks - 50 mg and 100 mg tablets provided for 150 mg twice daily dosing for up to 20 weeks

    Arm title
    Lacosamide 400 mg/day
    Arm description
    Lacosamide 400 mg/dayLacosamide : 50 mg and 100 mg tablets provided for 200 mg twice daily dosing for up to 20 weeks.Subjects were randomized 3:1 to one of two therapeutic doses of Lacosamide, 400 mg/day or 300 mg/day, to ensure a study design comparable to the historical control.
    Arm type
    Experimental

    Investigational medicinal product name
    Lacosamide
    Investigational medicinal product code
    Lacosamide LCM
    Other name
    Vimpat
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    - 50 mg and 100 mg tablets provided for 200 mg twice daily dosing for up to 20 weeks - 50 mg and 100 mg tablets provided for 150 mg twice daily dosing for up to 20 weeks

    Number of subjects in period 1
    Lacosamide 300 mg/day Lacosamide 400 mg/day
    Started
    106
    319
    Completed
    69
    194
    Not completed
    37
    125
         SAE, non-fatal + AE, non-serious non-fatal
             -
             1
         Protocol deviation
             2
             15
         Unsatisfactory compliance of subject
             4
             3
         Lack of efficacy
             11
             30
         SAE, non-fatal
             -
             8
         Other reasons for premature termination
             -
             6
         AE, serious fatal
             -
             3
         Consent withdrawn by subject
             -
             11
         AE, non-serious non-fatal
             16
             44
         Lost to follow-up
             4
             4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lacosamide 300 mg/day
    Reporting group description
    Lacosamide 300 mg/dayLacosamide : 50 mg and 100 mg tablets provided for 150 mg twice daily dosing for up to 20 weeks.Subjects were randomized 3:1 to one of two therapeutic doses of Lacosamide, 400 mg/day or 300 mg/day, to ensure a study design comparable to the historical control.

    Reporting group title
    Lacosamide 400 mg/day
    Reporting group description
    Lacosamide 400 mg/dayLacosamide : 50 mg and 100 mg tablets provided for 200 mg twice daily dosing for up to 20 weeks.Subjects were randomized 3:1 to one of two therapeutic doses of Lacosamide, 400 mg/day or 300 mg/day, to ensure a study design comparable to the historical control.

    Reporting group values
    Lacosamide 300 mg/day Lacosamide 400 mg/day Total
    Number of subjects
    106 319 425
    Age Categorical
    Units: Subjects
        <=18 years
    3 7 10
        Between 18 and 65 years
    99 303 402
        >=65 years
    4 9 13
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    41.4 ± 14.3 40.4 ± 12.5 -
    Gender Categorical
    Units: Subjects
        Female
    50 169 219
        Male
    56 150 206
    Race/Ethnicity, Customized
    Units: Subjects
        White
    91 246 337
        Black
    9 53 62
        Asian
    0 1 1
        Other
    6 19 25
    Height
    Units: centimeter
        arithmetic mean (standard deviation)
    169.72 ± 10.69 169.01 ± 10.87 -
    Weight
    Units: kilogram
        arithmetic mean (standard deviation)
    81.62 ± 19.53 82.13 ± 21.3 -
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    28.22 ± 5.74 28.67 ± 6.64 -
    Average Baseline Seizure Frequency per 28 days
    Units: seizures/28 days
        arithmetic mean (standard deviation)
    10.1 ± 8.82 10.22 ± 8.88 -

    End points

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    End points reporting groups
    Reporting group title
    Lacosamide 300 mg/day
    Reporting group description
    Lacosamide 300 mg/dayLacosamide : 50 mg and 100 mg tablets provided for 150 mg twice daily dosing for up to 20 weeks.Subjects were randomized 3:1 to one of two therapeutic doses of Lacosamide, 400 mg/day or 300 mg/day, to ensure a study design comparable to the historical control.

    Reporting group title
    Lacosamide 400 mg/day
    Reporting group description
    Lacosamide 400 mg/dayLacosamide : 50 mg and 100 mg tablets provided for 200 mg twice daily dosing for up to 20 weeks.Subjects were randomized 3:1 to one of two therapeutic doses of Lacosamide, 400 mg/day or 300 mg/day, to ensure a study design comparable to the historical control.

    Subject analysis set title
    Lacosamide 400 mg/Day
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Lacosamide (LCM) 400 mg/day Lacosamide : 50 mg and 100 mg tablets provided for 200 mg twice daily dosing for up to 20 weeks. This study had a single inferential test of the primary efficacy variable for the LCM 400 mg/day treatment arm which was to be compared to an external historical control. As such, no adjustment for multiplicity was required. Additional analyses of the primary efficacy variable for the LCM 400 mg/day and LCM 300 mg/day treatment arms was for exploratory or supportive purposes only. The analysis of the LCM 300 mg/day arm is exploratory due to the 3:1 randomization ratio. Therefore the LCM 300 mg/day arm is not reported for this Outcome Measure.

    Primary: Percentage of Subjects (using Kaplan-Meier) Who Are Identified As Meeting At Least 1 Pre-defined Exit Criteria By Day 112 Relative To The Start of Withdrawal of Background Antiepileptic Drug(s)

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    End point title
    Percentage of Subjects (using Kaplan-Meier) Who Are Identified As Meeting At Least 1 Pre-defined Exit Criteria By Day 112 Relative To The Start of Withdrawal of Background Antiepileptic Drug(s) [1]
    End point description
    Pre-defined exit criteria: 1. A 2-fold or greater increase in average monthly (28-day) partial seizure frequency (motor and non-motor) compared to average monthly partial seizure frequency (motor and non-motor) during the Baseline Phase 2. A 2-fold or greater increase in consecutive 2-day partial seizure frequency (motor and non-motor) versus the highest consecutive 2-day partial seizure frequency (motor and non-motor) that occurred during the Baseline Phase. Note: if the highest consecutive 2-day partial seizure frequency during the Baseline Phase is 1, a 2-day partial seizure frequency of ≥3 is required to meet this exit criterion 3. Occurrence of a single generalized tonic-clonic seizure if none had occurred in the 6 months prior to randomization 4. A prolongation or worsening of overall seizure duration, frequency, type or pattern considered by the investigator as serious enough to warrant trial discontinuation 5. Status epilepticus, or new onset of serial/cluster seizures
    End point type
    Primary
    End point timeframe
    16 Weeks Maintenance Period (approximately 112 days)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to System limitations, a statistical analysis could not be entered. Full results including statistical analysis of this Primary and the Secondary Variable "Percentage of Subjects (Using Kaplan-Meier) Who Are Identified as Meeting at Least 1 Pre-defined Exit Criteria by Day 112, Withdrew Due to Adverse Event (AE) or Withdrew Due to Lack of Efficacy During The Maintenance Period" are available on www.clinicaltrials.gov (NCT00520741).
    End point values
    Lacosamide 400 mg/Day
    Number of subjects analysed
    284
    Units: percentage of subjects
    number (not applicable)
        percentage of subjects
    30
    No statistical analyses for this end point

    Secondary: Time to First Occurrence of Any Exit Event During The Maintenance Period

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    End point title
    Time to First Occurrence of Any Exit Event During The Maintenance Period
    End point description
    The time to first occurrence (days) of any exit event was estimated using Kaplan-Meier methods and was based on the time from the start of the Maintenance Phase to the earliest date a subject met an exit criterion. Subjects who discontinued during the Maintenance Phase due to non-exit criteria reasons or who completed the Maintenance Phase before 112 days and did not meet an exit criterion were censored as of the last Maintenance Phase dose date. Subjects completing 112 days in the Maintenance Phase were censored as of Day 112.
    End point type
    Secondary
    End point timeframe
    16 Weeks Maintenance Period (approximately 112 days)
    End point values
    Lacosamide 300 mg/day Lacosamide 400 mg/day
    Number of subjects analysed
    26
    82
    Units: days
    median (full range (min-max))
        days
    39 (1 to 80)
    45 (3 to 102)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects (using Kaplan-Meier) Who are Identified as Meeting at Least 1 Pre-defined Exit Criteria by Day 112, Withdrew due to Adverse Event (AE) or Withdrew due to Lack of Efficacy During The Maintenance Period

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    End point title
    Percentage of Subjects (using Kaplan-Meier) Who are Identified as Meeting at Least 1 Pre-defined Exit Criteria by Day 112, Withdrew due to Adverse Event (AE) or Withdrew due to Lack of Efficacy During The Maintenance Period
    End point description
    Subjects were classified as having an exit event if they experienced at least 1 of the following events during the Maintenance Phase as of Day 112: 1. Met at least 1 exit criterion based on the calculations applied for the Primary Efficacy Analysis 2. Withdrawal due to AE with onset during the Maintenance Phase 3. Withdrew prematurely due to lack of efficacy during the Maintenance Phase The date the subject experienced the event was set to the earliest date the subject met an exit criterion or the date of the last Maintenance Phase dose for subjects not meeting an exit criterion but withdrawing due to an AE or lack of efficacy. The secondary analysis is only conducted on the Lacosamide 400 mg/day group.
    End point type
    Secondary
    End point timeframe
    16 Weeks Maintenance Period (approximately 112 days)
    End point values
    Lacosamide 400 mg/Day
    Number of subjects analysed
    284
    Units: percentage of subjects
    number (not applicable)
        percentage of subjects
    32.3
    No statistical analyses for this end point

    Secondary: Duration of Monotherapy Treatment During the Monotherapy Phase of The Maintenance Period (Visit 9 - Visit 12)

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    End point title
    Duration of Monotherapy Treatment During the Monotherapy Phase of The Maintenance Period (Visit 9 - Visit 12)
    End point description
    Days on Monotherapy Treatment were defined as the number of days during the Monotherapy Phase when the subject took Lacosamide (LCM) only (ie, the total number of days exposed to LCM during the Monotherapy Phase minus any days where a concomitant or rescue Anti-epileptic Drug (AED) was taken by the subject). The days on Monotherapy Treatment did not need to be consecutive.
    End point type
    Secondary
    End point timeframe
    Visit 9 - Visit 12 (approximately 10 weeks)
    End point values
    Lacosamide 300 mg/day Lacosamide 400 mg/day
    Number of subjects analysed
    86
    254
    Units: days
    median (full range (min-max))
        days
    71 (1 to 100)
    71 (2 to 105)
    No statistical analyses for this end point

    Secondary: Clinical Global Impression of Change (CGIC) From Baseline To Last Visit

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    End point title
    Clinical Global Impression of Change (CGIC) From Baseline To Last Visit
    End point description
    For the assessment of the Clinical Global Impression of Change (CGIC), the investigator should provide his/her assessment of the subject’s clinical status, compared to Baseline, including an evaluation of seizure frequency and intensity, the occurrence of AEs, and subject’s functional status. He was asked the following:Please check the number that best describes the subject’s condition over the past 4 weeks compared to Baseline: 1. Very much improved 2. Much improved 3. Minimally improved 4. No change 5. Minimally worse 6. Much worse 7. Very much worse
    End point type
    Secondary
    End point timeframe
    Baseline; Last Visit (approximately 27 weeks)
    End point values
    Lacosamide 300 mg/day Lacosamide 400 mg/day
    Number of subjects analysed
    99
    284
    Units: participants
        Very much improved
    21
    56
        Much improved
    33
    116
        Minimally improved
    18
    42
        No change
    8
    18
        Minimally worse
    6
    16
        Much worse
    8
    23
        Very much worse
    1
    1
        Not done
    4
    12
    No statistical analyses for this end point

    Secondary: Patient's Global Impression of Change (PGIC) From Baseline To Last Visit

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    End point title
    Patient's Global Impression of Change (PGIC) From Baseline To Last Visit
    End point description
    For the assessment of the Patient’s Global Impression of Change, the subject should provide his/her assessment of his/her own clinical status, compared to Baseline, including an evaluation of seizure frequency and intensity, the occurrence of AEs, and subject’s functional status.The subject was asked to answer the following: Over the past 4 weeks, how have you felt compared to before you entered this clinical trial? (Please check the number that best describes your condition.) 1. Very much improved 2. Much improved 3. Minimally improved 4. No change 5. Minimally worse 6. Much worse 7. Very much worse
    End point type
    Secondary
    End point timeframe
    Baseline; Last Visit (approximately 27 weeks)
    End point values
    Lacosamide 300 mg/day Lacosamide 400 mg/day
    Number of subjects analysed
    99
    284
    Units: participants
        Very much improved
    24
    81
        Much improved
    33
    93
        Minimally improved
    15
    37
        No change
    10
    15
        Minimally worse
    3
    19
        Much worse
    7
    22
        Very much worse
    3
    3
        Not done
    4
    14
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) were collected from Baseline (week -8) up to the end of the study (week 22). Only Treatment-Emergent Adverse Events (TEAEs) are presented.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    9.1
    Reporting groups
    Reporting group title
    Lacosamide 300 mg/day
    Reporting group description
    Lacosamide 300 mg/day Lacosamide : 50 mg and 100 mg tablets provided for 150 mg twice daily dosing for up to 20 weeks. Subjects were randomized 3:1 to one of two therapeutic doses of Lacosamide, 400 mg/day or 300 mg/day, to ensure a study design comparable to the historical control.

    Reporting group title
    Lacosamide 400 mg/day
    Reporting group description
    Lacosamide 400 mg/day Lacosamide : 50 mg and 100 mg tablets provided for 200 mg twice daily dosing for up to 20 weeks. Subjects were randomized 3:1 to one of two therapeutic doses of Lacosamide, 400 mg/day or 300 mg/day, to ensure a study design comparable to the historical control.

    Serious adverse events
    Lacosamide 300 mg/day Lacosamide 400 mg/day
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 106 (3.77%)
    21 / 319 (6.58%)
         number of deaths (all causes)
    0
    3
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Limb injury
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polytraumatism
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Subdural haematoma
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory acidosis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 106 (0.94%)
    6 / 319 (1.88%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic induced encephalopathy
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Sudden unexplained death in epilepsy
         subjects affected / exposed
    0 / 106 (0.00%)
    2 / 319 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Conversion disorder
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination, auditory
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination, visual
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 106 (0.94%)
    0 / 319 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Food poisoning
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glossitis
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 106 (0.00%)
    1 / 319 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Lacosamide 300 mg/day Lacosamide 400 mg/day
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    74 / 106 (69.81%)
    215 / 319 (67.40%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    21 / 106 (19.81%)
    45 / 319 (14.11%)
         occurrences all number
    32
    58
    Dizziness
         subjects affected / exposed
    19 / 106 (17.92%)
    86 / 319 (26.96%)
         occurrences all number
    26
    121
    Convulsion
         subjects affected / exposed
    17 / 106 (16.04%)
    29 / 319 (9.09%)
         occurrences all number
    22
    36
    Somnolence
         subjects affected / exposed
    15 / 106 (14.15%)
    29 / 319 (9.09%)
         occurrences all number
    19
    35
    Cognitive disorder
         subjects affected / exposed
    7 / 106 (6.60%)
    6 / 319 (1.88%)
         occurrences all number
    8
    6
    Tremor
         subjects affected / exposed
    8 / 106 (7.55%)
    23 / 319 (7.21%)
         occurrences all number
    8
    23
    Eye disorders
    Vision blurred
         subjects affected / exposed
    6 / 106 (5.66%)
    19 / 319 (5.96%)
         occurrences all number
    6
    25
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    12 / 106 (11.32%)
    32 / 319 (10.03%)
         occurrences all number
    14
    37
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    8 / 106 (7.55%)
    17 / 319 (5.33%)
         occurrences all number
    10
    17
    Anxiety
         subjects affected / exposed
    7 / 106 (6.60%)
    11 / 319 (3.45%)
         occurrences all number
    8
    13
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    13 / 106 (12.26%)
    46 / 319 (14.42%)
         occurrences all number
    16
    57
    Diarrhoea
         subjects affected / exposed
    7 / 106 (6.60%)
    21 / 319 (6.58%)
         occurrences all number
    9
    22
    Vomiting
         subjects affected / exposed
    2 / 106 (1.89%)
    23 / 319 (7.21%)
         occurrences all number
    2
    27
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    4 / 106 (3.77%)
    16 / 319 (5.02%)
         occurrences all number
    5
    20
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    9 / 106 (8.49%)
    11 / 319 (3.45%)
         occurrences all number
    9
    13
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 106 (4.72%)
    16 / 319 (5.02%)
         occurrences all number
    6
    19
    Nasopharyngitis
         subjects affected / exposed
    7 / 106 (6.60%)
    28 / 319 (8.78%)
         occurrences all number
    8
    30

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Oct 2007
    Protocol Amendment 1 dated 18 Oct 2007 provided the following key changes. Based on the date of the amendment, 1 subject was randomized prior to this amendment. The wording “post-Baseline” was removed from the definitions of exit criteria 1 and 2 to avoid confusion since all exit criteria were defined relative to the start of the withdrawal of Background AEDs. In addition, the wording “the highest” was removed from the definition of exit criterion 2 because the assessment of exit criterion 2 was based on the earliest occurrence of a doubling in the 2-day seizure frequency during the Maintenance Phase. A sentence was added describing a calculation worksheet that was provided to site personnel to assist with the calculation of average seizure frequency for determination of whether a subject had met exit criterion 1, 2, 3, or 5 (refer to Section 6.2.1 of the protocol). Eight inclusion and exclusion criteria (inclusion criteria #6, #7, #8, and #9, and exclusion criteria #3, #6, #8, and #22) were revised to improve clarity or further define the criteria, based on the original intent. Two exclusion criteria (#11 and #12) were modified to correct omissions in the original criteria. Five exclusion criteria (#9, #10, #11, #14, and #29) were modified and two exclusion criteria (#31 and #32) were added to further exclude specific populations considered inappropriate for a conversion to monotherapy study. The criteria for withdrawal of a subject requiring a modification to the AED dose(s) between Visit 1 and Visit 5 was changed to between Visit 1 and Visit 6.
    18 Oct 2007
    If concomitant narcotic use became necessary, the investigator was instructed to contact the medical monitor; restrictions in concomitant AED or benzodiazepine use were clarified (refer to Section 4.6 of the protocol). A revision was made to clarify that 1 dose reduction was allowed once the subject had taken at least 1 dose of Maintenance Phase study medication (refer to Section 8.1.1 of the protocol). A clarification was made regarding the prediction interval for an estimate of the combined pseudo-placebo exit rate (the lower 95% prediction interval was changed to the lower limit of a 2-sided 95% prediction interval), and the statement that the 95% prediction interval for the historical control provides 95% confidence that a single repeated study would yield a pseudo-placebo exit rate of 67.8% or higher was changed to a 97.5% confidence level (refer to Section 11.1.2 of the protocol). The remainder of the changes in this amendment were minor or administrative.
    26 Sep 2008
    Protocol Amendment 2 dated 26 Sep 2008 provided the following key changes. Based on the date of the amendment, 44 subjects were randomized prior to this amendment. The secondary efficacy parameter, “duration of monotherapy treatment,” was changed to “during the Monotherapy Phase.” The statement regarding the Taper Phase (refer to Section 4.2 and Section 4.4.1 of the protocol) was modified to permit flexibility in the length of taper, based on discussion between the investigator and the medical monitor. Select inclusion, exclusion, and withdrawal criteria were revised (refer to Section 4.3 of the protocol). Exclusion criteria based on previous and current drug use (ie, ethosuximide, felbamate, vigabatrin) were detailed. The withdrawal criteria were differentiated into those that required subject discontinuation and those that may have resulted in subject discontinuation. The criterion for withdrawal of a subject requiring a modification to the AED dose(s) was changed from between Visit 1 and Visit 6 to between Visit 3 and Visit 6. The section on withdrawal of background AEDs was revised to allow for a slower taper of the primary background AED to ensure adequate safety for the subjects (refer to Section 4.6.1 of the protocol). The allowable window for Visit 12 was clarified to be at least 112 days between Visit 6 and Visit 12. Description of the Transition Phase was revised to clarify when reintroduction/initiation of background AEDs may begin (refer to Section 5.7 of the protocol).
    26 Sep 2008
    Text was added to indicate details regarding calculations required for the assessment of exit criteria 1 and 2 (primary variables) in the statistical analysis plan (SAP) (refer to Section 11.1.2 of the protocol). Evaluation of explanatory variables was revised to clearly specify pre-planned analyses for evaluating the influence of potential differences in Baseline demographics between the LCM 400mg/day group and the historical-control population (refer to Section 11.1.3.2 of the protocol). In the statistical analysis of secondary variables, text was revised to clarify the duration of monotherapy treatment was during the Monotherapy Phase and treatment-emergent adverse events (TEAEs) would be tabulated by Medical Dictionary for Regulatory Activities (MedDRA) system organ class (SOC; refer to Section 11.1.4 of the protocol). A statement was added regarding the evaluation of the impact of missing values on the assessment of Primary efficacy using sensitivity analyses (refer to Section 11.1.7 of the protocol). The remainder of the changes in this amendment were minor or administrative.
    21 Jan 2010
    Protocol Amendment 3 dated 21 Jan 2010 provided the following key changes. Based on the date of the amendment, 144 subjects were randomized prior to this amendment. Text associated with primary efficacy exit criterion 1 was deleted as recommended by the Food and Drug Administration (FDA) through review of the SAP for this study. Detail was added to the protocol to allow subjects who, in consultation with the investigator, choose to initiate treatment with commercially available LCM upon completion of or withdrawal from the study, to do so without taper. The ECG- and cardiac-related exclusion and withdrawal criteria, and liver function test (LFT) withdrawal criteria were revised across LCM studies to reflect the sponsor’s current understanding of the safety profile of LCM based on a comprehensive review of the data from clinical studies. Exclusion criteria regarding past use of LCM, past or current use of VNS, and suicidality were also revised to include subjects deemed appropriate for enrollment. The AEs of special interest were revised to reflect the sponsor’s current understanding of the potential risks of LCM based on a comprehensive review of the data from clinical studies and commitments to regulatory agencies. The statistical methods were updated to clarify the evaluation of efficacy data for subjects who discontinue from the study due to non-exit criteria reasons. The remainder of the changes in this amendment was minor or administrative.
    04 Aug 2010
    Protocol Amendment 4 dated 04 Aug 2010 provided the following key changes. Based on the date of the amendment, 203 subjects were randomized prior to this amendment. Based on the recent publication of French et al (2010) noting a revised historical-control exit rate (0.653) relative to the French et al (2005) draft of the White Paper (0.678), the historical-control exit rate and sample size were updated. The remainder of the changes in this amendment were minor or administrative.
    07 Jan 2011
    Protocol Amendment 5 dated 07 Jan 2011 provided the following key changes. Based on the date of the amendment, 258 subjects were randomized prior to this amendment. The primary purposes of this protocol amendment were to modify an exclusion criterion regarding prior use of LCM, to add an exclusion criterion for known sodium channelopathy, and to revise withdrawal criteria and follow-up recommendations for abnormal LFTs. The rationales for these changes are described below. The decision to exclude subjects with prior use of LCM beyond a single iv administration for acute treatment was based on an FDA recommendation (16 Dec 2010). The decision to exclude subjects with known channelopathies, such as Brugada syndrome, from clinical studies with LCM was based on an FDA recommendation (17 Aug 2010). The basis for this recommendation was a theoretical concern that enhanced slow inactivation of sodium channels by LCM may be proarrhythmic in subjects with sodium channelopathies. The decision to reinsert additional withdrawal criteria and follow-up recommendations for abnormal LFTs was based on the following: Newly adopted FDA Guidance on Drug-Induced Liver Injury (Jul 2009) and a recommendation from the FDA to re-insert previously included wording regarding additional withdrawal criteria and follow-up recommendations for abnormal LFTs in LCM protocols.
    07 Jan 2011
    Although no new liver-related safety issues with LCM were identified, LFT abnormality was added as a postmarketing adverse drug reaction in the LCM Company Core Data Sheet, and the EU Summary of Product Characteristics. Therefore, LCM protocols were amended to reflect this addition. With these revisions, liver-related safety signals continued to be detected via protocol directed monitoring and additional follow-up in ongoing and future LCM clinical studies. The remainder of the changes in this amendment were minor or administrative.
    22 Jul 2011
    Protocol Amendment 6 dated 22 Jul 2011 provided the following key changes. Based on the date of the amendment, 320 subjects were randomized prior to this amendment. The primary purposes of this protocol amendment were to revise the exclusion criterion related to a history of suicidality, add a withdrawal criterion related to suicidality, add a list of anticipated serious adverse events (SAEs), and to add a third category of AEs to be reported immediately on occurrence. The rationale for these changes is described below. As recommended by the US FDA, the Columbia-Suicide Severity Rating Scale (C-SSRS) was added to evaluate and identify subjects at risk for suicide while participating in a clinical study of a drug with central nervous system (CNS) activity (FDA, Guidance for Industry and Investigators, 2010). A list of anticipated SAEs was included in this amendment in compliance with the recent US FDA guidance on safety reporting requirements for studies conducted under an open IND (effective 28 Mar 2011; FDA, Guidance for Industry and Investigators, 2010). To meet the requirements of safety reporting and for consistency with the safety reporting currently being done for LCM “suspected transmission of an infectious agent via a medicinal product” was included as a further category of AEs to be reported immediately on occurrence. The remainder of the changes in this amendment were minor or administrative.

    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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