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    Clinical Trial Results:
    A multicenter, double-blind, double-dummy, randomized, positive- controlled study comparing the efficacy and safety of Lacosamide (200 to 600 mg/day) to controlled release Carbamazepine (400 to 1200 mg/day), used as monotherapy in subjects (≥ 16 years) newly or recently diagnosed with Epilepsy and experiencing partial-onset or generalized tonic-clonic seizures.

    Summary
    EudraCT number
    2010-019765-28
    Trial protocol
    DE   BE   CZ   FI   SE   HU   ES   PT   PL   SK   GB   GR   IT   LV   LT   BG   Outside EU/EEA  
    Global end of trial date
    07 Aug 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    10 Feb 2016
    First version publication date
    10 Feb 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SP0993
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01243177
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB BIOSCIENCES GmbH
    Sponsor organisation address
    Alfred-Nobel-Str. 10, Monheim, Germany, 40789
    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)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000402-PIP02-11
    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
    17 Sep 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Aug 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study is to compare the efficacy and safety of Lacosamide ( LCM 200 to 600 mg/day) to Carbamazepine controlled release (CBZ-CR 400 to 1200 mg/day) used as monotherapy for at least 1 year, efficacy being measured as a primary endpoint by 6-month seizure freedom, in newly or recently diagnosed epilepsy subjects. The study will employ a noninferiority design to show at least a similar benefit-risk balance for LCM compared with CBZ-CR, using 6-month seizure freedom as primary endpoint.
    Protection of trial subjects
    During the study conduct the following measurements were in place in order to protect the trial subjects: ECG measurements, lab including pharmacokinetic (PK) measurements, neurological examinations (complete, brief), HLA-B*1502 allele, HLA-A*3101 allele testing for subjects of Asian ancestry.
    Background therapy
    Not applicable
    Evidence for comparator
    Carbamazepine is considered an efficacious treatment as monotherapy for partial-onset seizure (POS), is a first choice for treatment for POS and is the most commonly used reference treatment for POS. Carbamazepine-controlled release (CBZ-CR) formulation was used as it minimizes Adverse Events (AEs) and was foreseen to limit the number of discontinuations versus the immediate release formulation of CBZ. In addition, there is precedence for the selection of CBZ-CR as the active comparator in an EU monotherapy registration study (ie, LEV N01061).
    Actual start date of recruitment
    27 Apr 2011
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    4 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 22
    Country: Number of subjects enrolled
    Bulgaria: 42
    Country: Number of subjects enrolled
    Czech Republic: 25
    Country: Number of subjects enrolled
    Finland: 12
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Germany: 74
    Country: Number of subjects enrolled
    Greece: 8
    Country: Number of subjects enrolled
    Hungary: 52
    Country: Number of subjects enrolled
    Italy: 32
    Country: Number of subjects enrolled
    Latvia: 3
    Country: Number of subjects enrolled
    Lithuania: 19
    Country: Number of subjects enrolled
    Poland: 39
    Country: Number of subjects enrolled
    Portugal: 32
    Country: Number of subjects enrolled
    Romania: 88
    Country: Number of subjects enrolled
    Russian Federation: 36
    Country: Number of subjects enrolled
    Slovakia: 32
    Country: Number of subjects enrolled
    Spain: 50
    Country: Number of subjects enrolled
    Sweden: 34
    Country: Number of subjects enrolled
    Switzerland: 8
    Country: Number of subjects enrolled
    Ukraine: 34
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    Canada: 34
    Country: Number of subjects enrolled
    Mexico: 9
    Country: Number of subjects enrolled
    United States: 44
    Country: Number of subjects enrolled
    Australia: 32
    Country: Number of subjects enrolled
    Japan: 20
    Country: Number of subjects enrolled
    Philippines: 17
    Country: Number of subjects enrolled
    Korea, Republic of: 47
    Country: Number of subjects enrolled
    Thailand: 19
    Worldwide total number of subjects
    886
    EEA total number of subjects
    586
    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)
    25
    Adults (18-64 years)
    742
    From 65 to 84 years
    116
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    This study started to enroll in April 2011 and concluded in August 2015.

    Pre-assignment
    Screening details
    Participant Flow refers to the Safety Analysis Set which is defined as all randomized subjects who took at least 1 dose of study medication and is identical with the Full Analysis 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
    Carer, Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Lacosamide
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Vimpat
    Investigational medicinal product code
    LCM
    Other name
    Lacosamide
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    • Strengths: 50 mg / 100 mg • Form: tablets • Dosage: total daily target dose of 200 mg, 400 mg or 600 mg. 1 dose reduction was allowed from either 600 mg to 500 mg or from 400 mg to 300 mg total daily dose • Duration: up to 118 weeks

    Arm title
    Carbamazepine-Controlled Release (CBZ-CR)
    Arm description
    -
    Arm type
    Active comparator

    Investigational medicinal product name
    Tegretol Retard
    Investigational medicinal product code
    CBZ-CR
    Other name
    Carbamazepine controlled release
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    • Strengths: 200 mg • Form: tablets • Dosage: total daily target dose of 400 mg, 800 mg or 1200 mg. 1 dose reduction was allowed from either 1200 mg to 1000 mg or from 800 mg to 600 mg total daily dose • Duration: up to 118 weeks

    Number of subjects in period 1
    Lacosamide Carbamazepine-Controlled Release (CBZ-CR)
    Started
    444
    442
    Completed
    266
    264
    Not completed
    178
    178
         SAE, non-fatal + AE, non-serious non-fatal
             -
             1
         Other Reason
             11
             12
         Protocol deviation
             11
             10
         Lack of efficacy
             47
             31
         SAE, non-fatal
             7
             9
         AE, serious fatal
             -
             1
         SAE, fatal + SAE, non-fatal
             1
             -
         AE, non-serious non-fatal
             40
             58
         Consent withdrawn by subject
             46
             38
         Lost to follow-up
             15
             18

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lacosamide
    Reporting group description
    -

    Reporting group title
    Carbamazepine-Controlled Release (CBZ-CR)
    Reporting group description
    -

    Reporting group values
    Lacosamide Carbamazepine-Controlled Release (CBZ-CR) Total
    Number of subjects
    444 442 886
    Age Categorical
    Units: Subjects
        <=18 years
    27 19 46
        Between 18 and 65 years
    355 366 721
        >=65 years
    62 57 119
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    41.9 ± 17.9 41.8 ± 17.2 -
    Gender Categorical
    Units: Subjects
        Male
    243 232 475
        Female
    201 210 411

    End points

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    End points reporting groups
    Reporting group title
    Lacosamide
    Reporting group description
    -

    Reporting group title
    Carbamazepine-Controlled Release (CBZ-CR)
    Reporting group description
    -

    Subject analysis set title
    Per Protocol Set (Lacosamide treated subjects)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The Per Protocol Set (PPS) was defined as containing all subjects in the Full Analysis Set (FAS) who did not have any important protocol deviations determined to impact the interpretation of primary efficacy.

    Subject analysis set title
    Per Protocol Set (CBZ-CR treated subjects)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The Per Protocol Set (PPS) was defined as containing all subjects in the Full Analysis Set (FAS) who did not have any important protocol deviations determined to impact the interpretation of primary efficacy.

    Primary: Proportion of subjects remaining seizure free for 6 consecutive months (26 consecutive weeks) of treatment following stabilization at the last evaluated dose for each subject

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    End point title
    Proportion of subjects remaining seizure free for 6 consecutive months (26 consecutive weeks) of treatment following stabilization at the last evaluated dose for each subject
    End point description
    The proportion of subjects remaining seizure free for 6 months (26 weeks) was estimated using Kaplan-Meier methods.
    End point type
    Primary
    End point timeframe
    6 consecutive months (26 consecutive weeks) of treatment following stabilization at the last evaluated dose for each subject
    End point values
    Lacosamide Carbamazepine-Controlled Release (CBZ-CR) Per Protocol Set (Lacosamide treated subjects) Per Protocol Set (CBZ-CR treated subjects)
    Number of subjects analysed
    444
    442
    408
    397
    Units: percentage of subjects
    number (confidence interval 95%)
        percentage of subjects (95 % CI)
    89.8 (86.8 to 92.8)
    91.1 (88.2 to 94)
    91.4 (88.5 to 94.3)
    92.8 (90.1 to 95.6)
    Statistical analysis title
    Statistical Analysis (FAS)
    Statistical analysis description
    This was a noninf. assessment of LCM vs CBZ-CR for the proportion of subjects remaining seizure free for 6 months at the last evaluated dose. The hypothesis was: H0: [S(t)LCM] - [S(t)CBZ-CR] <= -12 % vs HA: [S(t)LCM] - [S(t)CBZ-CR] > -12 %, where S(t) (t= 182 days) is the cumulative rate of subjects remaining seizure free for 6 months following stabilization at the last eval. dose (also known as survivorship function), and -12 % represents the noninf. margin based on absolute difference.
    Comparison groups
    Lacosamide v Carbamazepine-Controlled Release (CBZ-CR)
    Number of subjects included in analysis
    886
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    Method
    Mantel Haenszel
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.5
         upper limit
    2.8
    Notes
    [1] - The analysis was stratified based on the number of seizures in the 3 months preceding enrollment (≤2 and >2). The difference in proportion of subjects seizure free on LCM versus CBZ-CR and a corresponding 95 % two-sided confidence interval were produced using Mantel Haenszel methods. The lower limit of the confidence interval was >-12 %, noninferiority of LCM to CBZ-CR was demonstrated. Additionally, the lower confidence limit relative to the CBZ-CR seizure freedom rate was >- 20 %.
    Statistical analysis title
    Statistical Analysis (PPS)
    Statistical analysis description
    This was a noninf. assessment of LCM vs CBZ-CR for the proportion of subjects remaining seizure free for 6 months at the last evaluated dose. The hypothesis was: H0: [S(t)LCM] - [S(t)CBZ-CR] <= -12 % vs HA: [S(t)LCM] - [S(t)CBZ-CR] > -12 %, where S(t) (t= 182 days) is the cumulative rate of subjects remaining seizure free for 6 months following stabilization at the last eval. dose (also known as survivorship function), and -12 % represents the noninf. margin based on absolute difference.
    Comparison groups
    Per Protocol Set (Lacosamide treated subjects) v Per Protocol Set (CBZ-CR treated subjects)
    Number of subjects included in analysis
    805
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    Method
    Mantel Haenszel
    Parameter type
    Median difference (final values)
    Point estimate
    -1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.3
         upper limit
    2.7
    Notes
    [2] - The analysis was stratified based on the number of seizures in the 3 months preceding enrollment (≤2 and >2). The difference in proportion of subjects seizure free on LCM versus CBZ-CR and a corresponding 95 % two-sided confidence interval were produced using Mantel Haenszel methods. The lower limit of the confidence interval was >-12 %, noninferiority of LCM to CBZ-CR was demonstrated. Additionally, the lower confidence limit relative to the CBZ-CR seizure freedom rate was >- 20 %.

    Primary: Number of subjects with at least one treatment-emergent Adverse Event (AE) during the Treatment Phase (up to 113 weeks)

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    End point title
    Number of subjects with at least one treatment-emergent Adverse Event (AE) during the Treatment Phase (up to 113 weeks) [3]
    End point description
    An Adverse Event is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. Treatment-emergent AEs were defined as AEs that started on or after the date of first dose of study medication and within 30 days following the date of final study medication administration, or AEs whose intensity worsened on or after the date of first dose of study medication and within 30 days following the date of last dose.
    End point type
    Primary
    End point timeframe
    Duration of the Treatment Phase (up to 113 weeks)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypothesis testing was planned for this endpoint. Results were summarized using descriptive statistics only.
    End point values
    Lacosamide Carbamazepine-Controlled Release (CBZ-CR)
    Number of subjects analysed
    444
    442
    Units: Participants
        Number of subjects
    328
    332
    No statistical analyses for this end point

    Primary: Number of subjects who withdraw from the study due to a treatment-emergent Adverse Event (AE) during the Treatment Phase (up to 113 weeks)

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    End point title
    Number of subjects who withdraw from the study due to a treatment-emergent Adverse Event (AE) during the Treatment Phase (up to 113 weeks) [4]
    End point description
    An Adverse Event is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. Treatment-emergent AEs were defined as AEs that started on or after the date of first dose of study medication and within 30 days following the date of final study medication administration, or AEs whose intensity worsened on or after the date of first dose of study medication and within 30 days following the date of last dose.
    End point type
    Primary
    End point timeframe
    Duration of the Treatment Phase (up to 113 weeks)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypothesis testing was planned for this endpoint. Results were summarized using descriptive statistics only.
    End point values
    Lacosamide Carbamazepine-Controlled Release (CBZ-CR)
    Number of subjects analysed
    444
    442
    Units: Participants
        Number of subjects
    47
    69
    No statistical analyses for this end point

    Primary: Number of subjects with at least one treatment-emergent Serious Adverse Event (SAE) during the Treatment Phase (up to 113 weeks)

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    End point title
    Number of subjects with at least one treatment-emergent Serious Adverse Event (SAE) during the Treatment Phase (up to 113 weeks) [5]
    End point description
    An Adverse Event is any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. A Serious Adverse Event must meet 1 or more predefined criteria like death, life-threatening, etc. Treatment-emergent AEs were defined as AEs that started on or after the date of first dose of study medication and within 30 days following the date of final study medication administration, or AEs whose intensity worsened on or after the date of first dose of study medication and within 30 days following the date of last dose.
    End point type
    Primary
    End point timeframe
    Duration of the Treatment Phase (up to 113 weeks)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical hypothesis testing was planned for this endpoint. Results were summarized using descriptive statistics only.
    End point values
    Lacosamide Carbamazepine-Controlled Release (CBZ-CR)
    Number of subjects analysed
    444
    442
    Units: Participants
        Number of subjects
    32
    43
    No statistical analyses for this end point

    Secondary: Proportion of subjects remaining seizure free for 12 consecutive months (52 consecutive weeks) following stabilization at the last evaluated dose for each subject

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    End point title
    Proportion of subjects remaining seizure free for 12 consecutive months (52 consecutive weeks) following stabilization at the last evaluated dose for each subject
    End point description
    The proportion of subjects remaining seizure free for 12 months (52 weeks) was estimated using Kaplan-Meier methods.
    End point type
    Secondary
    End point timeframe
    12 consecutive months of treatment following stabilization at the last evaluated dose for each subject
    End point values
    Lacosamide Carbamazepine-Controlled Release (CBZ-CR)
    Number of subjects analysed
    444
    442
    Units: percentage of subjects
    number (confidence interval 95%)
        percentage of subjects (95 % CI)
    77.8 (73.4 to 82.2)
    82.7 (78.5 to 86.8)
    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 during the whole study from Screening Phase (Week 0) over Evaluation, Maintenance and End of Study Phase up to 121 weeks.
    Adverse event reporting additional description
    Adverse Events refer to the Safety Analysis Set consisting of all randomized subjects who took at least 1 dose of study medication.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Carbamazepine-Controlled Release (CBZ-CR)
    Reporting group description
    -

    Reporting group title
    Lacosamide
    Reporting group description
    -

    Serious adverse events
    Carbamazepine-Controlled Release (CBZ-CR) Lacosamide
    Total subjects affected by serious adverse events
         subjects affected / exposed
    46 / 442 (10.41%)
    36 / 444 (8.11%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acoustic neuroma
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaplastic astrocytoma
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Gait disturbance
         subjects affected / exposed
    0 / 442 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 442 (0.23%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inflammation
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Metrorrhagia
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Tendon rupture
         subjects affected / exposed
    0 / 442 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 442 (0.23%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin injury
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Accident
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alcohol poisoning
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Smear cervix abnormal
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urine albumin/creatinine ratio increased
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 442 (0.23%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial haemorrhage
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (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
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea paroxysmal nocturnal
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Antiphospholipid syndrome
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aplastic anaemia
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    2 / 442 (0.45%)
    4 / 444 (0.90%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complex partial seizures
         subjects affected / exposed
    1 / 442 (0.23%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 442 (0.23%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 442 (0.00%)
    2 / 444 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyskinesia
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Motor neurone disease
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic intolerance
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Preictal state
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures with secondary generalisation
         subjects affected / exposed
    3 / 442 (0.68%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 442 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    2 / 442 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    2 / 442 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychomotor hyperactivity
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Trigeminal nerve disorder
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness unilateral
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Hernial eventration
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress urinary incontinence
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 442 (0.23%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         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
    Rash macular
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis allergic
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    2 / 442 (0.45%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash generalised
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Addison's disease
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 442 (0.23%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 442 (0.00%)
    1 / 444 (0.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dengue fever
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculous pleurisy
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    1 / 442 (0.23%)
    0 / 444 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Carbamazepine-Controlled Release (CBZ-CR) Lacosamide
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    181 / 442 (40.95%)
    165 / 444 (37.16%)
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    35 / 442 (7.92%)
    7 / 444 (1.58%)
         occurrences all number
    36
    8
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    41 / 442 (9.28%)
    53 / 444 (11.94%)
         occurrences all number
    52
    61
    Headache
         subjects affected / exposed
    58 / 442 (13.12%)
    60 / 444 (13.51%)
         occurrences all number
    78
    82
    Somnolence
         subjects affected / exposed
    41 / 442 (9.28%)
    27 / 444 (6.08%)
         occurrences all number
    47
    28
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    49 / 442 (11.09%)
    34 / 444 (7.66%)
         occurrences all number
    55
    38
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    23 / 442 (5.20%)
    26 / 444 (5.86%)
         occurrences all number
    30
    32
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    29 / 442 (6.56%)
    29 / 444 (6.53%)
         occurrences all number
    37
    42

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Dec 2010
    Global Protocol Amendment 1 dated 13 Dec 2010 provided the following primary and other key revisions. No subjects were randomized prior to the date of this amendment. The primary purpose of this substantial protocol amendment was to add an exclusion criterion for known sodium channelopathy and revise withdrawal criteria and follow-up recommendations for abnormal liver function tests (LFTs). The rationales for these changes are described below. The decision to exclude subjects with known channelopathies, such as Brugada syndrome, from clinical studies with Lacosamide (LCM) was based on a recommendation from the US FDA (17 Aug 2010). The basis for this request was a theoretical concern that enhanced slow inactivation of sodium channels by LCM may be proarrhythmic in subjects with sodium channelopathies. The decision to re-insert additional withdrawal criteria and follow-up recommendations for abnormal LFTs was based on the following: 1. Newly adopted FDA Guidance on Drug-Induced Liver Injury (July 2009) and a recommendation from the US FDA to re-insert previously included wording regarding additional withdrawal criteria and follow-up recommendations for abnormal LFTs in LCM protocols. 2. Although no new liver-related safety issues with LCM have been identified, LFT abnormal has been added as a postmarketing adverse drug reaction in the LCM Company Core Data Sheet (CCDS) and the EU Summary of Product Characteristics (SmPC). Therefore, LCM protocols are being 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.
    13 Dec 2010
    Other key revisions included the following: - Clarification that minors were included in some countries if legally permitted - Addition of language with regard to male contraception - Clarification of the guidance followed in the analysis of the primary efficacy variable - Change of the Screening Phase from 7 days ±2 days to 7 days ±5 days - Removal of the desmethyl metabolite of LCM from bioanalytical analysis - Clarification that the fasting period prior to blood sample collection for additional laboratory tests (fasting serum lipid levels and thyroid and sex hormone concentrations) should be 8 hours - Further clarification for the sites The remainder of the changes in this amendment were minor or administrative in nature.
    18 Nov 2011
    Global Protocol Amendment 2, dated 18 Nov 2011 provided the following key revisions. A total of 61 subjects (32 subjects and 29 subjects in the LCM and CBZ-CR treatment groups, respectively) were randomized prior to the date of this amendment. The primary purposes of this substantial protocol amendment were to revise the exclusion criteria related to a history of suicidality and to add withdrawal criteria related to suicidality. The rationale for these changes is described below. As required 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, 2010). The sponsor’s name was also changed to UCB BIOSCIENCES GmbH, and specific Sponsor contact information was updated. The remainder of the changes in this amendment were minor or administrative in nature.
    01 Aug 2012
    Global Protocol Amendment 3, dated 01 Aug 2012 provided the following key revisions. A total of 206 subjects (103 subjects and 103 subjects in the LCM and CBZ-CR treatment groups, respectively) were randomized prior to the date of this amendment. The primary purpose of this substantial protocol amendment was to provide clarification for the efficacy variables, withdrawal criteria (eg, following a seizure that occurred after dose reduction), and the use of concomitant medications that may have interacted with study medication. The remainder of the changes in this amendment were minor or administrative in nature.
    27 Nov 2012
    Global Protocol Amendment 4, dated 27 Nov 2012 provided the following key revisions. A total of 313 subjects (156 subjects and 157 subjects in the LCM and CBZ-CR treatment groups, respectively) were randomized prior to the date of this amendment. With the expansion of SP0993 to investigational sites in the US, and based on a request from the US FDA, a primary purpose of this substantial protocol amendment was to include language that reflected the FDA’s requirements. Exclusion criterion 11 (regarding prior treatment of epilepsy with any antiepileptic drug (AED)) was modified to indicate that acute and subacute seizure treatment was accepted with a maximum of 2 weeks duration and if treatment was stopped “at least 3 days prior to randomization” formerly “at least 1 week before Visit 1”). This change decreased the duration of time during which subjects could potentially go untreated before initiating study medication in SP0993, therefore increasing subject safety. Most withdrawal seizures were expected to occur within 72 hours of AED withdrawal, and most AEDs (including benzodiazepines) were expected to be cleared within this time period with little potential for drug interactions. A withdrawal criterion was clarified for situations in which a subject experienced a seizure during the Evaluation Phase at the maximum dosage of study medication. Section 7.8.3.4 of the protocol (Permitted agents whose plasma levels may be affected by CBZ) was updated with the addition of alprazolam and the deletion of amitriptyline (amitriptyline use as an antidepressant is disallowed in Section 7.8.2 of the Protocol). The remainder of the changes in this amendment were minor or administrative in nature.
    14 Mar 2013
    Global Protocol Amendment 5, dated 14 Mar 2013 provided the following key revisions. This amendment was submitted only to local ethic committees in Spain and was not implemented by any site, therefore, no subjects were randomized under this amendment. Human leukocyte antigen (HLA)-A*3101 is associated with an increased risk of CBZ-induced cutaneous adverse drug reactions in people of European descent and the Japanese. Although there are insufficient data supporting a recommendation for HLA-A*3101 screening before starting CBZ treatment (Tegretol Prolonged Release 200mg, SmPC of Carbamazepine-United Kingdom; Drug Safety Update Dec 2012, vol 6, issue 5: A1), the protocol was updated based on a recommendation from the Japanese regulatory authorities (Pharmaceuticals and Medical Devices Agency [PMDA]) to exclude subjects of Asian ancestry who tested positive for the HLA-A*3101 allele. This was in addition to the exclusion of subjects of Asian ancestry who tested positive for the HLA-B*1502 allele. Screening of subjects of Asian ancestry for the HLA-A*3101 allele was previously included in a country-specific protocol amendment (Protocol Amendment 4.2 [Japan]) and was then incorporated with the global Protocol Amendment 5.
    14 Mar 2013
    Contraceptive measures for male participants (exclusion criterion 30) were deleted because preclinical studies did not find any LCM-related findings at any dose level on male reproductive function. Lacosamide did not show any effects on reproductive function in male rats and no abnormalities in the F1 offspring of male rats were observed in peri-postnatal study. Female contraception requirements (exclusion criterion 27) were adjusted based on World Health Organization (WHO) guidance on highly effective methods of contraception for women of childbearing potential taking enzyme-inducing AEDs (WHO, 2010). In Section 7.8.2 of the protocol (Concomitant non-AED treatments), text regarding antidepressant and neuroleptic use was modified to permit the introduction of antidepressants (eg, serotonin-selective reuptake inhibitors [SSRIs]) that do not cause drug interaction issues and do not interfere with epilepsy therapy. In Section 7.8.3.4 of the protocol (Permitted agents whose plasma levels may be affected by CBZ), alprazolam was removed as a permitted medication. This change was made in order to be consistent with other sections of the protocol that limit the use of benzodiazepines. The remainder of the changes in this amendment were minor or administrative in nature.
    20 May 2013
    Global Protocol Amendment 6 dated 20 May 2013 included all of the changes in Protocol Amendment 5 and also provided the following key revisions. A total of 476 subjects (239 subjects and 237 subjects in the LCM and CBZ-CR treatment groups, respectively) were randomized prior to the date of this amendment. In Section 7.8.2 of the protocol (Concomitant non-AED treatments), the following sentence was deleted in this amendment: “Oral contraceptive use is allowed if ethinylestradiol dosage is at least 50 μg per intake.” This correction was made to be consistent with exclusion criterion 27 that no longer required a minimum dosage of ethinylestradiol (modification in global Protocol Amendment 5).

    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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