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    Clinical Trial Results:
    A Multicenter, Randomized, Controlled, Open-label Study to Evaluate the Cognitive Development Effects and Safety, and Pharmacokinetics of Adjunctive Rufinamide Treatment in Pediatric Subjects 1 to less than 4 years of age with Inadequately Controlled Lennox-Gastaut Syndrome

    Summary
    EudraCT number
    		 2010-023505-36
    Trial protocol
    		 FR   IT   GR   Outside EU/EEA  
    Global end of trial date
    02 Nov 2015

    Results information
    Results version number
    		 v1
    This version publication date
    16 Jun 2016
    First version publication date
    16 Jun 2016
    Other versions
    		 v2 , v3

    Trial information

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    Trial identification
    Sponsor protocol code
    E2080-G000-303
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01405053
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Eisai
    Sponsor organisation address
    100 Tice Boulevard, Woodcliff Lake, United States, 07677
    Public contact
    Eisai Call Center, Eisai Inc., 888 422-4743, EUMedInfo@eisai.net
    Scientific contact
    Eisai Call Center, Eisai Inc., 888 422-4743, EUMedInfo@eisai.net
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000709-PIP01-09
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Nov 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effect of 2 drug regimens consisting of either rufinamide or any other approved AED of the investigator's choice as an add-on to the subject's existing regimen of 1-3 AEDs on the overall safety and tolerability of rufinamide in subjects aged 1 to less than 4 years of age with inadequately controlled LGS. To characterize the age group specific pharmacokinetics of rufinamide in a pediatric population, 1 to less than 4 years of age, with inadequately controlled LGS, using the population approach. To evaluate the effect of rufinamide as adjunctive treatment on the cognitive development and behavioral effects in a pediatric population, 1 to less than 4 years of age, with inadequately controlled LGS.
    Protection of trial subjects
    This study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following: - Principles of the World Medical Association Declaration of Helsinki (World Medical Association, 2008) - International Conference on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, International Conference on Harmonisation of Pharmaceuticals for Human Use - Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and Institutional Review Board (IRB) regulations and applicable sections of US 21 CFR Part 312 - European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies conducted within any European Union (EU) country. All suspected unexpected serious adverse reactions were reported, as required, to the Competent Authorities of all involved EU member states. - Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP Subject Information and Informed Consent.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Apr 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 9
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    United States: 16
    Worldwide total number of subjects
    37
    EEA total number of subjects
    20
    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)
    25
    Children (2-11 years)
    12
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 43 participants were consented and screened; 6 were screen failures (4 failed to meet inclusion or exclusion criteria, 1 withdrew consent, and 1 was excluded for other reasons) and 37 were randomized into the study (25 randomized to rufinamide and 12 to any other antiepileptic drug (AED)).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rufinamide
    Arm description
    		 During the Titration Period, rufinamide was administered at 10 mg/kg/day (administered in 2 equally divided doses) and increased at 10 mg/kg/day increments every 3 days to 40 mg/kg/day, then increased by 5 mg/kg/day to the target maintenance level of 45 mg/kg/day. In case of tolerability issues, the drug could be titrated more slowly or titrated to a lower dose at the investigator’s discretion. Only participants on rufinamide participated in the Taper Period and only those that completed the Taper Period at the end of the study had a Final or Follow-up Visit. Participants that discontinued rufinamide early were tapered (if deemed necessary by the investigator) before starting add-on AED. Add-on AEDs were titrated according to the investigator’s usual practice.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rufinamide
    Investigational medicinal product code
    E2080
    Other name
    Inovelon, Banzel
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Rufinamide up to 45 mg/kg/day was administered in 2 divided doses as an oral suspension (40 mg/mL).

    Arm title
    		 Any other antiepileptic drugs (AEDs)
    Arm description
    		 Any approved AED of the investigator's choice, dosed according to the investigator's usual practice, added to the participant's existing regimen of 1 to 3 AEDs. Add-on AEDs were titrated according to the investigator's usual practice.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    lamotrigine
    Investigational medicinal product code
    Other name
    Lamictal
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dosed according to the investigator's usual practice.

    Investigational medicinal product name
    clobazam
    Investigational medicinal product code
    Other name
    Onfi
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dosed according to the investigator's usual practice.

    Investigational medicinal product name
    topiramate
    Investigational medicinal product code
    Other name
    Trokendi XR
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dosed according to the investigator's usual practice.

    Investigational medicinal product name
    phenobarbital
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dosed according to the investigator's usual practice.

    Investigational medicinal product name
    valproic acid
    Investigational medicinal product code
    Other name
    Depakene, Stavzor
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dosed according to the investigator's usual practice.

    Investigational medicinal product name
    zonisamide
    Investigational medicinal product code
    Other name
    Zonegran
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dosed according to the investigator's usual practice.

    Number of subjects in period 1
    		Rufinamide Any other antiepileptic drugs (AEDs)
    Started
    25
    12
    Completed
    15
    4
    Not completed
    10
    8
         Participant choice
    2
    -
         Consent withdrawn by subject
    3
    4
         Adverse event, non-fatal
    3
    -
         Not specified
    -
    1
         Participant's choice
    -
    1
         Inadequate therapeutic effect
    2
    1
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rufinamide
    Reporting group description
    		 During the Titration Period, rufinamide was administered at 10 mg/kg/day (administered in 2 equally divided doses) and increased at 10 mg/kg/day increments every 3 days to 40 mg/kg/day, then increased by 5 mg/kg/day to the target maintenance level of 45 mg/kg/day. In case of tolerability issues, the drug could be titrated more slowly or titrated to a lower dose at the investigator’s discretion. Only participants on rufinamide participated in the Taper Period and only those that completed the Taper Period at the end of the study had a Final or Follow-up Visit. Participants that discontinued rufinamide early were tapered (if deemed necessary by the investigator) before starting add-on AED. Add-on AEDs were titrated according to the investigator’s usual practice.

    Reporting group title
    Any other antiepileptic drugs (AEDs)
    Reporting group description
    		 Any approved AED of the investigator's choice, dosed according to the investigator's usual practice, added to the participant's existing regimen of 1 to 3 AEDs. Add-on AEDs were titrated according to the investigator's usual practice.

    Reporting group values
    		 Rufinamide Any other antiepileptic drugs (AEDs) Total
    Number of subjects
    		 25 12 37
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    		 28.3 ( 9.99 ) 29.8 ( 9.83 ) -
    Gender categorical
    Units: Subjects
        Female
    		 11 2 13
        Male
    		 14 10 24

    End points

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    End points reporting groups
    Reporting group title
    Rufinamide
    Reporting group description
    		 During the Titration Period, rufinamide was administered at 10 mg/kg/day (administered in 2 equally divided doses) and increased at 10 mg/kg/day increments every 3 days to 40 mg/kg/day, then increased by 5 mg/kg/day to the target maintenance level of 45 mg/kg/day. In case of tolerability issues, the drug could be titrated more slowly or titrated to a lower dose at the investigator’s discretion. Only participants on rufinamide participated in the Taper Period and only those that completed the Taper Period at the end of the study had a Final or Follow-up Visit. Participants that discontinued rufinamide early were tapered (if deemed necessary by the investigator) before starting add-on AED. Add-on AEDs were titrated according to the investigator’s usual practice.

    Reporting group title
    Any other antiepileptic drugs (AEDs)
    Reporting group description
    		 Any approved AED of the investigator's choice, dosed according to the investigator's usual practice, added to the participant's existing regimen of 1 to 3 AEDs. Add-on AEDs were titrated according to the investigator's usual practice.

    Primary: Child Behavior Checklist (CBCL) Total Problems T-Scores at the end of the 2-Year Treatment Period and Change from Baseline

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    End point title
    		 Child Behavior Checklist (CBCL) Total Problems T-Scores at the end of the 2-Year Treatment Period and Change from Baseline
    End point description
    The CBCL is a 99-item survey completed by a parent/legal guardian or suitable caregiver (referred to as the rater) of the participant and provided T-scores for all problem area scales and the summary scores to identify behavioral problems or developmental delays. Items were rated using a 3-point scale (0=Not True, 1=Somewhat/Sometimes True, 2=Very True/ Often True) to indicate how often or typical the behavior was. The 99 items were combined to yield scores for 8 problem area scales (emotionally reactive, anxious/depressed, somatic complaints, withdrawn, sleep problems, attention problems, aggressive behavior, and other problems) and 3 summary scores (internalizing, externalizing, and total problems). The Total Problem score was the sum of all the problem areas plus 1 additional item. The T-scores were standardized test scores that indicate the same degree of elevation in problems on each of the scales relative to the normative sample of peers. High scores indicate more problems.
    End point type
    Primary
    End point timeframe
    Baseline and End of Treatment Period (Week 106)
    End point values
    		 Rufinamide Any other antiepileptic drugs (AEDs)
    Number of subjects analysed
    24 [1]
    9 [2]
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Total T-Score
    55.7 ( 15.81 )
    54.8 ( 4.5 )
        Change from baseline T-Score
    -0.3 ( 15.72 )
    -6.7 ( 0.58 )
    Notes
    [1] - n = 15
    [2] - n = 4, 3
    Statistical analysis title
    		 CBCL Total Problems Score
    Statistical analysis description
    The primary statistical model for comparing the 2 treatment groups was ANCOVA mixed model for repeated measures with baseline score, age, and sex as covariates, and treatment, week, and treatment by week interaction as factors. Statistical analysis for the Actual and Change from Baseline (Week 0) data presented for the primary efficacy endpoint was not calculated.
    Comparison groups
    Rufinamide v Any other antiepileptic drugs (AEDs)
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6928 [3]
    Method
    		 ANCOVA
    Confidence interval
    Notes
    [3] - P-value is based on ANCOVA Least Square (LE) mean analysis for Week 106 of the study. LS mean (SE): Rufinamide = 56.346 (2.720) and Any other AED = 53.746 (5.953).

    Other pre-specified: Shift from Baseline to Week 106 in Child Behavior Checklist (CBCL) Subscores

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    End point title
    		 Shift from Baseline to Week 106 in Child Behavior Checklist (CBCL) Subscores
    End point description
    The CBCL 1.5 – 5 is a 99-item survey designed to record the problem behaviors of preschoolers. Each item describes a specific behavior and the rater (parent or caretaker) is asked to rate its frequency on a three-point Likert scale ((0=Not True, 1=Somewhat/Sometimes True, 2=Very True/ Often True) to indicate how often or typical the behavior was. The scoring gives a summary profile of 8 problem area scales (emotionally reactive, anxious/depressed, somatic complaints, withdrawn, sleep problems, attention problems, aggressive behavior, and other problems) and 3 summary scores (internalizing, externalizing, and total problems). A T-score of 63 and above for summary scales and of 70 and above for syndrome and DSM-oriented scales, are generally considered clinically significant; values between 60 and 63 for summary scales or between 65 and 70 for syndrome and DSM-oriented scales, identify the borderline clinical range; values under 60 or under 65 are considered not-clinical.
    End point type
    Other pre-specified
    End point timeframe
    Baseline to End of Treatment Period (Week 106)
    End point values
    		 Rufinamide Any other antiepileptic drugs (AEDs)
    Number of subjects analysed
    24
    9
    Units: Percentage of participants
    number (not applicable)
        Total emotional reactive scores (n = 15, 3)
    100
    100
        Total anxious/depression scores (n = 15, 3)
    100
    100
        Total withdrawn scores (n = 15, 3)
    100
    100
        Total sleep problem scores (n = 15, 3)
    100
    100
        Total attention problems scores (n = 15, 3)
    100
    100
        Total aggressive behavior scores (n = 15, 3)
    100
    100
        Total internalizing scores (n = 15, 3)
    100
    100
        Total externalizing scores (n = 15, 3)
    100
    100
    No statistical analyses for this end point

    Other pre-specified: Percent Change in Seizure Frequency by Individual Seizure Type per 28 Days Relative to Baseline

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    End point title
    		 Percent Change in Seizure Frequency by Individual Seizure Type per 28 Days Relative to Baseline
    End point description
    The frequency per 28 days was defined as (S/D)*28 where, S is equal to the sum of the seizures reported in the Participant Diary during the specified time interval and D is equal to the number of days with non-missing data in the Participant Seizure diary for the specified study phase. The number of seizures was assessed and recorded by the participant's parent(s)/caregiver(s) in the participant seizure diary. The participant's parent(s)/caregiver(s) were trained by the investigator in how to recognize, classify, and complete the diary. The multiple cohorts of participants included participants treated with rufinamide or other AED for at least 1, 2, 4, 6, 10, 14, 18, 22, and 26.5 months.
    End point type
    Other pre-specified
    End point timeframe
    Baseline to End of Treatment Period (Week 106)
    End point values
    		 Rufinamide Any other antiepileptic drugs (AEDs)
    Number of subjects analysed
    24
    9
    Units: Percent change in seizure frequency
    median (full range (min-max))
        Partial seizures (n=12, 2)
    -39.8 (-100 to 52281.9)
    -57.65 (-98.1 to -17.2)
        Absence seizures (n=11 , 5)
    -23.6 (-100 to 86.8)
    -49.7 (-98.9 to 1846.7)
        Atypical absence seizures (n=14, 4)
    -70.95 (-100 to 16825.4)
    4.9 (-90.9 to 1189.7)
        Myoclonic seizures (n=13, 4)
    -24.6 (-73.3 to 11462.4)
    -27.9 (-60.9 to 130.2)
        Clonic seizures (n=6, 2)
    -60.85 (-100 to 140.4)
    -48.35 (-54.2 to -42.5)
        Tonic-atonic seizures (n=17, 4)
    -35.2 (-100 to 1250.6)
    -31.8 (-81.9 to -4)
        Primary generalized tonic-clonic seizures (n=7, 1)
    -97.8 (-100 to 37.6)
    -96.6 (-96.6 to -96.6)
        Other seizures (N=10, 3)
    -90.65 (-100 to 183.8)
    -100 (-100 to -54)
    Statistical analysis title
    		 Partial seizures
    Statistical analysis description
    The median difference and the 95% confidence interval were based on the Hodges-Lehmann method.
    Comparison groups
    Any other antiepileptic drugs (AEDs) v Rufinamide
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9011
    Method
    		 Wilcoxon sum rank test
    Parameter type
    		 Median difference (final values)
    Point estimate
    -19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -52380
         upper limit
    		 82.8
    Statistical analysis title
    		 Absence seizures
    Statistical analysis description
    The median difference and the 95% confidence interval were based on the Hodges-Lehmann method.
    Comparison groups
    Any other antiepileptic drugs (AEDs) v Rufinamide
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7427
    Method
    		 Wilcoxon rank sum test
    Parameter type
    		 Median difference (final values)
    Point estimate
    -23.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -75.3
         upper limit
    		 1822.5
    Statistical analysis title
    		 Atypical absence seizures
    Statistical analysis description
    The median difference and the 95% confidence interval were based on the Hodges-Lehmann method.
    Comparison groups
    Any other antiepileptic drugs (AEDs) v Rufinamide
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.367
    Method
    		 Wilcoxon rank sum test
    Parameter type
    		 Median difference (final values)
    Point estimate
    50.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -139.2
         upper limit
    		 1190.5
    Statistical analysis title
    		 Myoclonic seizures
    Statistical analysis description
    The median difference and the 95% confidence interval were based on the Hodges-Lehmann method.
    Comparison groups
    Any other antiepileptic drugs (AEDs) v Rufinamide
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9563
    Method
    		 Wilcoxon rank sum test
    Parameter type
    		 Median difference (final values)
    Point estimate
    4.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -93.8
         upper limit
    		 146
    Statistical analysis title
    		 Clonic seizures
    Statistical analysis description
    The median difference and the 95% confidence interval were based on the Hodges-Lehmann method.
    Comparison groups
    Any other antiepileptic drugs (AEDs) v Rufinamide
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Wilcoxon rank sum test
    Parameter type
    		 Median difference (final values)
    Point estimate
    12.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -194.6
         upper limit
    		 57.5
    Statistical analysis title
    		 Tonic-Atonic Seizures
    Statistical analysis description
    The median difference and the 95% confidence interval were based on the Hodges-Lehmann method.
    Comparison groups
    Any other antiepileptic drugs (AEDs) v Rufinamide
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7524
    Method
    		 Wilcoxon rank sum test
    Parameter type
    		 Median difference (final values)
    Point estimate
    4.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -57.3
         upper limit
    		 56.1
    Statistical analysis title
    		 Primary generalized tonic clonic seizures
    Statistical analysis description
    The median difference and the 95% confidence interval were based on the Hodges-Lehmann method.
    Comparison groups
    Any other antiepileptic drugs (AEDs) v Rufinamide
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Wilcoxon rank sum test
    Parameter type
    		 Median difference (final values)
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -134.2
         upper limit
    		 3.4
    Statistical analysis title
    		 Other seizures
    Statistical analysis description
    The median difference and the 95% confidence interval were based on the Hodges-Lehmann method.
    Comparison groups
    Any other antiepileptic drugs (AEDs) v Rufinamide
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4266
    Method
    		 Wilcoxon rank sum test
    Parameter type
    		 Median difference (final values)
    Point estimate
    -2.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -237.8
         upper limit
    		 46

    Other pre-specified: Overall Percent Change in Total Seizure Frequency per 28 Days

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    End point title
    		 Overall Percent Change in Total Seizure Frequency per 28 Days
    End point description
    The frequency per 28 days was defined as (S/D)*28 where, S is equal to the sum of the seizures reported in the Participant Diary during the specified time interval and D is equal to the number of days with non-missing data in the Participant Seizure diary for the specified study phase. The number of seizures was assessed and recorded by the participant's parent(s)/caregiver(s) in the participant seizure diary. The participant's parent(s)/caregiver(s) were trained by the investigator in how to recognize, classify, and complete the diary. The multiple cohorts of participants included participants treated with rufinamide or other AED for at least 1, 2, 4, 6, 10, 14, 18, 22, and 26.5 months.
    End point type
    Other pre-specified
    End point timeframe
    Baseline to End of the Treatment Period (Week 106)
    End point values
    		 Rufinamide Any other antiepileptic drugs (AEDs)
    Number of subjects analysed
    24
    9
    Units: Percent change in seizure frequency
        median (full range (min-max))
    -7.05 (-79.2 to 3644.1)
    -20.15 (-83.3 to 143.1)
    No statistical analyses for this end point

    Other pre-specified: Incidence of Worsening of Seizures Any Time

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    End point title
    		 Incidence of Worsening of Seizures Any Time
    End point description
    Worsening of seizures was defined as the doubling in total seizure frequency or in frequency of major seizures (generalized tonic-clonic, drop attacks) or occurrence of new seizure type during each successive 3 to 4 month visit interval of the Maintenance Period relative to baseline. Cohorts included participants treated with rufinamide or other-AED for at least 1, 2, 4, 6, 10, 14, 18, 22, and 26.5 months. The number of seizures was assessed and recorded by the participant's parent(s)/caregiver(s) in the participant seizure diary. The participant's parent(s)/caregiver(s) were trained by the investigator in how to recognize, classify, and complete the diary. Sample sizes were small so these results should be interpreted with caution.
    End point type
    Other pre-specified
    End point timeframe
    Baseline to the End of the Treatment Period (Week 106)
    End point values
    		 Rufinamide Any other antiepileptic drugs (AEDs)
    Number of subjects analysed
    24
    9
    Units: Percentage of participants
    number (not applicable)
        Doubling in total seizure frequency
    16.7
    11.1
        Doubling in frequency of major seizures
    20.8
    11.1
    No statistical analyses for this end point

    Other pre-specified: Mean Change From Baseline in Language Development Survey (LDS) Average Phrase Length Score During the Maintenance Period

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    End point title
    		 Mean Change From Baseline in Language Development Survey (LDS) Average Phrase Length Score During the Maintenance Period
    End point description
    The LDS was a parent-administered survey that measured a child's expressive vocabulary and beginning word combinations. It included 310 words organized within 14 semantic categories (e.g., toys, body parts, food, animals, people). The list contained high frequency words (e.g., "more"), less common words (e.g., "hamburger"), and lexical chunks (e.g., "all gone", "night, night", "Sesame Street"). The parent was asked to indicate words on the list that the child spontaneously produced but were also allowed to add additional words spoken by the child. The average LDS score was calculated by dividing the total number of words across all valid phrases by the number of phrases with greater than 0 words; for participants with no words, the average is 0. This value is compared to a standardized chart to obtain a percentile rating. Greater than 20th percentile suggests no delayed phrase development while less than or equal to 20th percentile suggests delayed phrase development.
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 24, Baseline to Week 56, Baseline to Week 88, and Baseline to Week 106 (End of the Treatment Period)
    End point values
    		 Rufinamide Any other antiepileptic drugs (AEDs)
    Number of subjects analysed
    24
    9
    Units: Average phrase length
    arithmetic mean (standard deviation)
        Week 24 (n = 23, 8)
    0.2 ( 1.11 )
    0.7 ( 1.28 )
        Week 56 (n= 21, 7)
    0.1 ( 1.02 )
    0 ( 0 )
        Week 88 (n = 18, 4)
    0.1 ( 1.03 )
    0 ( 0 )
        Week 106 (n = 16, 4)
    0.4 ( 1.12 )
    0 ( 0 )
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Language Development Survey (LDS) Vocabulary Score During the Maintenance Period

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    End point title
    		 Change From Baseline in Language Development Survey (LDS) Vocabulary Score During the Maintenance Period
    End point description
    The LDS was a parent-administered survey that measured a child's expressive vocabulary and beginning word combinations. It included 310 words organized within 14 semantic categories (e.g., toys, body parts, food, animals, people). The list contained high frequency words (e.g., "more"), less common words (e.g., "hamburger"), and lexical chunks (e.g., "all gone", "night, night", "Sesame Street"). The parent was asked to indicate words on the list that the child spontaneously produced but were also allowed to add additional words spoken by the child. The LDS vocabulary score was calculated by counting the number of vocabulary words endorsed (including non-English words and words added by the respondent) up to a maximum of 315 words. This value was compared to a standardized chart to obtain a percentile rating. The LDS vocabulary score can be categorized into delayed vocabulary development (≤15th percentile) or no delayed vocabulary development (>15th percentile).
    End point type
    Other pre-specified
    End point timeframe
    Baseline to Week 24, Baseline to Week 56, Baseline to Week 88, and Baseline to Week 106 (End of the Treatment Period)
    End point values
    		 Rufinamide Any other antiepileptic drugs (AEDs)
    Number of subjects analysed
    24
    9
    Units: Number of words
    arithmetic mean (standard deviation)
        Week 24 (n = 23, 8)
    7.1 ( 21.55 )
    4.8 ( 8.22 )
        Week 56 (n = 21, 7)
    17.9 ( 39.24 )
    -0.4 ( 2.15 )
        Week 88 (n = 18, 4)
    25.4 ( 49.87 )
    0 ( 0 )
        Week 106 (n = 16, 4)
    39.6 ( 75.62 )
    1 ( 2 )
    No statistical analyses for this end point

    Other pre-specified: Change from Baseline in Total Score of Quality of Life in Childhood Epilepsy (QoLCE) Scale

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    End point title
    		 Change from Baseline in Total Score of Quality of Life in Childhood Epilepsy (QoLCE) Scale
    End point description
    The QoLCE was a 76-item questionnaire designed specifically to measure quality of life in children with epilepsy. It contained 16 subscales covering seven domains of life function: physical activities, social activities, cognition, emotional well-being, behavior, general health, and general quality of life. The form was completed by a parent or caregiver who interacted with the child on a consistent, daily basis and took about 20 to 30 minutes to complete. The items were combined into 13 scales and 3 of the items were used to represent an overall score in 3 separate areas. The full score was 100. The higher the score, the better the child's quality of life.
    End point type
    Other pre-specified
    End point timeframe
    Baseline to the End of the Treatment Period
    End point values
    		 Rufinamide Any other antiepileptic drugs (AEDs)
    Number of subjects analysed
    24
    9
    Units: Scores on a scale
        arithmetic mean (standard deviation)
    -0.3 ( 7.87 )
    1.4 ( 1.81 )
    No statistical analyses for this end point

    Other pre-specified: Mean Change from Baseline in Sub-scores in Quality of Life In Childhood Epilepsy (QoLCE) at End of Treatment Period

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    End point title
    		 Mean Change from Baseline in Sub-scores in Quality of Life In Childhood Epilepsy (QoLCE) at End of Treatment Period
    End point description
    The QoLCE was a 76-item questionnaire designed specifically to measure quality of life in children with epilepsy. It contained 16 subscales covering seven domains of life function: Physical activities, social activities, cognition, emotional well-being, behavior, general health, and general quality of life. The form was completed by a parent or caregiver who interacted with the child on a consistent, daily basis and took about 20 to 30 minutes to complete. The items were combined into 13 scales and 3 of the items were used to represent an overall score in 3 separate areas. The full score was 100. The higher the score, the better the child's quality of life.
    End point type
    Other pre-specified
    End point timeframe
    Baseline to End of Treatment Period (Week 106)
    End point values
    		 Rufinamide Any other antiepileptic drugs (AEDs)
    Number of subjects analysed
    24
    9
    Units: Scores on a scale
    arithmetic mean (standard deviation)
        Physical restriction
    -0.3 ( 7.82 )
    -2.8 ( 8 )
        Energy/Fatigue
    -3 ( 11.29 )
    1.4 ( 3.17 )
        Attention/Concentration
    -0.5 ( 10.97 )
    0.4 ( 5.46 )
        Memory
    -0.9 ( 10.46 )
    0.4 ( 0.88 )
        Language
    0.8 ( 10.11 )
    -0.4 ( 7.16 )
        Other cognitive
    0.8 ( 8.34 )
    0.1 ( 4.62 )
        Depression
    -1.1 ( 10.34 )
    1.6 ( 5.8 )
        Anxiety
    0.1 ( 10.75 )
    -0.2 ( 12.17 )
        Control/Helplessness
    0.9 ( 10.1 )
    3.3 ( 8.61 )
        Self-esteem
    -0.1 ( 9.86 )
    0.6 ( 9.06 )
        Social interactions
    -0.7 ( 10.26 )
    2.9 ( 5.18 )
        Social activities
    -0.2 ( 11.07 )
    6.2 ( 6.85 )
        Stigma
    1.1 ( 11.77 )
    2.2 ( 7.1 )
        Behavior
    0.5 ( 5.9 )
    1.6 ( 7.67 )
        General health
    0.8 ( 9.92 )
    -3.7 ( 9.6 )
        Quality-of-life
    2.6 ( 9.24 )
    -0.4 ( 11.93 )
    No statistical analyses for this end point

    Other pre-specified: Overall Survival-Time to Withdrawal from Rufinamide or Other Antiepileptic Drug (AED) (Excluding Taper)

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    End point title
    		 Overall Survival-Time to Withdrawal from Rufinamide or Other Antiepileptic Drug (AED) (Excluding Taper)
    End point description
    Withdrawal from either rufinamide or other AED was due to the occurrence of an adverse event or for lack of efficacy. Kaplan-Meier estimation was used to determine the overall survival time (in weeks) to withdrawal from treatment (excluding taper) due to an adverse event or lack efficacy. The 95% confidence interval was not calculated for these data points, therefore we added 99999.0 and -9999.0 as space-fillers.
    End point type
    Other pre-specified
    End point timeframe
    Baseline to the End of the Treatment Period (Week 106)
    End point values
    		 Rufinamide Any other antiepileptic drugs (AEDs)
    Number of subjects analysed
    24
    9
    Units: Weeks
        median (confidence interval 95%)
    142 (-9999 to 99999)
    28 (17.7 to 99999)
    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 Visit 1 through 30 days after the last study visit, or until resolution, whichever came first. All serious AEs were followed to resolution, or stabilization if resolution was unlikely. Approximately 108 weeks.
    Adverse event reporting additional description
    Only treatment-emergent AEs (TEAEs) and serious TEAEs were reported. TEAEs were defined as an AE that had an onset date, or a worsening in severity from baseline (pretreatment), on or after the first dose of study drug and up to 7 days following study drug discontinuation. AEs were graded on a 3-point scale (mild, moderate, severe).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Rufinamide
    Reporting group description
    		 During the Titration Period, rufinamide was administered at 10 mg/kg/day (administered in 2 equally divided doses) and increased at 10 mg/kg/day increments every 3 days to 40 mg/kg/day, then increased by 5 mg/kg/day to the target maintenance level of 45 mg/kg/day. In case of tolerability issues, the drug could be titrated more slowly or titrated to a lower dose at the investigator’s discretion. Only participants on rufinamide participated in the Taper Period and only those that completed the Taper Period at the end of the study had a Final or Follow-up Visit. Participants that discontinued rufinamide early were tapered (if deemed necessary by the investigator) before starting add-on AED. Add-on AEDs were titrated according to the investigator’s usual practice.

    Reporting group title
    Any other approved antiepileptic drug (AED)
    Reporting group description
    		 Any approved AED of the investigator's choice, dosed according to the investigator's usual practice, added to the participant's existing regimen of 1 to 3 AEDs. Add-on AEDs were titrated according to the investigator's usual practice.

    Serious adverse events
    		 Rufinamide Any other approved antiepileptic drug (AED)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 25 (40.00%)
    5 / 12 (41.67%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Joint dislocation pathological
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Generalized tonic-clonic seizure
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 25 (4.00%)
    3 / 12 (25.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blindness
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 12 (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
    Pneumonia aspiration
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 12 (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 / 25 (4.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory syncytial virus bronchiolitis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 12 (8.33%)
         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
    		 Rufinamide Any other approved antiepileptic drug (AED)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 25 (84.00%)
    10 / 12 (83.33%)
    Investigations
    Blood Bicarbonate Decreased
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1
    Weight Decreased
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    0
    Injury, poisoning and procedural complications
    Lip Injury
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Post Procedural Complication
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Postoperative Fever
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Procedural Nausea
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Procedural Pain
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    Surgical and medical procedures
    Strabismus Correction
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Nervous system disorders
    Circadian Rhythm Sleep Disorder
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Cognitive Disorder
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Somnolence
         subjects affected / exposed
    5 / 25 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    7
    0
    General disorders and administration site conditions
    Gait disturbance
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1
    Pyrexia
         subjects affected / exposed
    4 / 25 (16.00%)
    3 / 12 (25.00%)
         occurrences all number
    6
    5
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    3 / 25 (12.00%)
    1 / 12 (8.33%)
         occurrences all number
    3
    1
    Diarrhoea
         subjects affected / exposed
    4 / 25 (16.00%)
    3 / 12 (25.00%)
         occurrences all number
    4
    5
    Nausea
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Vomiting
         subjects affected / exposed
    7 / 25 (28.00%)
    1 / 12 (8.33%)
         occurrences all number
    10
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 25 (16.00%)
    2 / 12 (16.67%)
         occurrences all number
    6
    2
    Lower Respiratory Tract Congestion
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 12 (0.00%)
         occurrences all number
    4
    0
    Nasal Congestion
         subjects affected / exposed
    3 / 25 (12.00%)
    0 / 12 (0.00%)
         occurrences all number
    4
    0
    Respiratory Tract Congestion
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Rhinitis Allergic
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Stridor
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Upper Respiratory Tract Congestion
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    Skin and subcutaneous tissue disorders
    Dermatitis Diaper
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Rash
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 12 (8.33%)
         occurrences all number
    4
    2
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Irritability
         subjects affected / exposed
    3 / 25 (12.00%)
    1 / 12 (8.33%)
         occurrences all number
    3
    1
    Sleep Disorder
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    Bronchitis
         subjects affected / exposed
    3 / 25 (12.00%)
    0 / 12 (0.00%)
         occurrences all number
    6
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    1
    Otitis Media
         subjects affected / exposed
    4 / 25 (16.00%)
    0 / 12 (0.00%)
         occurrences all number
    7
    0
    Pharyngitis Streptococcal
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Pneumonia
         subjects affected / exposed
    4 / 25 (16.00%)
    0 / 12 (0.00%)
         occurrences all number
    6
    0
    Sinusitis
         subjects affected / exposed
    4 / 25 (16.00%)
    1 / 12 (8.33%)
         occurrences all number
    4
    1
    Upper Respiratory Tract Infection
         subjects affected / exposed
    7 / 25 (28.00%)
    4 / 12 (33.33%)
         occurrences all number
    16
    4
    Urinary Tract Infection
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    3 / 25 (12.00%)
    1 / 12 (8.33%)
         occurrences all number
    5
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Nov 2010
    • 21 Mar 2011, v2.0 (revision): corrected EudraCT number from 2010-23505-36 to 2010-023505-36 • 13 Apr 2011, v3.0 (revision): typographical errors for section references corrected • 26 Oct 2011, v4.0 (Amendment 01): to satisfy health authority requests, added a minimum of 25% of rufinamide-treated subjects will be between 2 and 3 years of age and that every effort will be made to include a younger population (between 1 and 3 years of age); revised exclusion for prior use of rufinamide; added blood volume required; added instructions if screening visit is extended, added duplicate, consecutive ECGs at Visit 2 and Visits 5, 6, and 7 for steady state and maximum observed concentration (Cmax); baseline ECG prior to dosing and Visits 5, 6, and 7 approximately 4 to 6 hours after drug administration; changed qualified designated reader to central reader and additional clarification for screening ECG; added measurement of head circumference at baseline, Visits 8, 10, 13, and at Follow-up/Final Visit or early discontinuation.
    03 Apr 2013
    Reduced from 8 to 4 weeks the minimum required time on AEDs before randomization, and required that AED doses be documented; allowed historical seizure diaries to satisfy inclusion criteria in lieu of seizure diaries that would be compiled during the Screening Period, thus allowing the Screening Period to be shortened to expedite recruitment; changed criterion for interim analysis compilation to allow reporting of data within the time frame requested by regulators, even if fewer than 75 patients have completed 6 months of treatment; added amylase and lipase samples to list of laboratory tests per FDA request for subject safety.

    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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