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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
    		 v2
    This version publication date
    12 Jun 2019
    First version publication date
    16 Jun 2016
    Other versions
    		 v1 , v3
    Version creation reason

    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
    155 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 antiepileptic drug (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 Lennox-Gastaut Syndrome (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.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Jun 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)
    13
    Children (2-11 years)
    24
    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
    		 Subjects took part in the study at 19 investigative sites in the United States, Canada, France, Greece, Italy, and Poland from 16 June 2011 to 02 November 2015.

    Pre-assignment
    Screening details
    		 A total of 43 subjects were screened, out of which 37 subjects were randomized and treated in the study.

    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
    		 Subjects received rufinamide oral suspension as an add-on therapy to the subject’s existing regimen of 1 to 3 AEDs. Subjects underwent a 2 week Titration Period during which rufinamide dose was increased from 10 milligram per kilogram per day (mg/kg/day) in increments of 10 mg/kg/day every 3 days to 40 mg/kg/day and thereafter in increments of 5 mg/kg/day to the target maintenance dose of 45 mg/kg/day (all daily treatments were to be administered in 2 equally divided doses). Rufinamide dose reached at the end of the Titration period were to be maintained the same throughout the 104-week Maintenance Period. At the end of Maintenance Period, rufinamide dose should be tapered (as needed) over a period of 2 weeks.
    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 Approved Antiepileptic Drug (AED)
    Arm description
    		 Subjects received any other approved AED of the investigator’s choice, dosed according to the investigator’s usual practice, added to the subject’s existing regimen of 1 to 3 AEDs. At the end of Maintenance Period, the AED comparator would be discontinued 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 Approved Antiepileptic Drug (AED)
    Started
    25
    12
    Completed
    15
    4
    Not completed
    10
    8
         Consent withdrawn by subject
    3
    4
         Adverse event, non-fatal
    3
    -
         Not specified
    -
    1
         Subject's choice
    2
    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
    		 Subjects received rufinamide oral suspension as an add-on therapy to the subject’s existing regimen of 1 to 3 AEDs. Subjects underwent a 2 week Titration Period during which rufinamide dose was increased from 10 milligram per kilogram per day (mg/kg/day) in increments of 10 mg/kg/day every 3 days to 40 mg/kg/day and thereafter in increments of 5 mg/kg/day to the target maintenance dose of 45 mg/kg/day (all daily treatments were to be administered in 2 equally divided doses). Rufinamide dose reached at the end of the Titration period were to be maintained the same throughout the 104-week Maintenance Period. At the end of Maintenance Period, rufinamide dose should be tapered (as needed) over a period of 2 weeks.

    Reporting group title
    Any Other Approved Antiepileptic Drug (AED)
    Reporting group description
    		 Subjects received any other approved AED of the investigator’s choice, dosed according to the investigator’s usual practice, added to the subject’s existing regimen of 1 to 3 AEDs. At the end of Maintenance Period, the AED comparator would be discontinued according to the investigator’s usual practice.

    Reporting group values
    		 Rufinamide Any Other Approved Antiepileptic Drug (AED) Total
    Number of subjects
    		 25 12 37
    Age categorical
    Units: Subjects
    Age continuous
    Units: months
        arithmetic mean (standard deviation)
    		 28.3 ± 9.99 29.8 ± 9.85 -
    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
    		 Subjects received rufinamide oral suspension as an add-on therapy to the subject’s existing regimen of 1 to 3 AEDs. Subjects underwent a 2 week Titration Period during which rufinamide dose was increased from 10 milligram per kilogram per day (mg/kg/day) in increments of 10 mg/kg/day every 3 days to 40 mg/kg/day and thereafter in increments of 5 mg/kg/day to the target maintenance dose of 45 mg/kg/day (all daily treatments were to be administered in 2 equally divided doses). Rufinamide dose reached at the end of the Titration period were to be maintained the same throughout the 104-week Maintenance Period. At the end of Maintenance Period, rufinamide dose should be tapered (as needed) over a period of 2 weeks.

    Reporting group title
    Any Other Approved Antiepileptic Drug (AED)
    Reporting group description
    		 Subjects received any other approved AED of the investigator’s choice, dosed according to the investigator’s usual practice, added to the subject’s existing regimen of 1 to 3 AEDs. At the end of Maintenance Period, the AED comparator would be discontinued according to the investigator’s usual practice.

    Primary: Child Behavior Checklist (CBCL) Total Problem T-scores at the End of 2-year Treatment Period

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    End point title
    		 Child Behavior Checklist (CBCL) Total Problem T-scores at the End of 2-year Treatment Period
    End point description
    CBCL:99-item questionnaire to measure specific behavioral problems/developmental delays, completed by a parent/legal guardian/caregiver. Items rated on 3-point scale(0=Not True, 1=Somewhat/Sometimes True, 2=Very True/ Often True). 99-items were combined to give 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). Total problem score:sum of all problem areas plus 1 additional item. Total raw scores converted to t-scores. T-scores were standardized test scores that indicate same degree of elevation in problems relative to normative sample of peers. High scores indicated more problems. Full analysis set(FAS):randomized subjects who received rufinamide/any other approved add-on AED of investigator’s choice and had baseline and at least 1 postdose cognition measurement, at given time period.
    End point type
    Primary
    End point timeframe
    End of Treatment Period (up to approximately Week 106)
    End point values
    		 Rufinamide Any Other Approved Antiepileptic Drug (AED)
    Number of subjects analysed
    15
    4
    Units: score on a scale
        arithmetic mean (standard deviation)
    55.7 ± 15.81
    54.8 ± 4.5
    Statistical analysis title
    		 CBCL Total Problems Score
    Statistical analysis description
    The primary statistical model for comparing the 2 treatment groups was an analysis of covariance (ANCOVA) mixed model for repeated measures with baseline score, age, and sex as covariates, and treatment, week, and treatment by week interaction as factors.
    Comparison groups
    Any Other Approved Antiepileptic Drug (AED) v Rufinamide
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6928 [1]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean difference
    Point estimate
    2.601
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.5
         upper limit
    		 15.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.558
    Notes
    [1] - P-value is based on ANCOVA Least Square (LE) mean analysis for Week 106 of the study.

    Primary: Change From Baseline in CBCL Total Problem T-Scores at End of 2-year Treatment Period

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    End point title
    		 Change From Baseline in CBCL Total Problem T-Scores at End of 2-year Treatment Period [2]
    End point description
    CBCL:99-item questionnaire to measure specific behavioral problems/developmental delays, completed by a parent/legal guardian/caregiver. Items rated on 3-point scale(0=Not True,1=Somewhat/Sometimes True,2=Very True/ Often True).99-items were combined to give 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).Total problem score: sum of all problem areas plus 1 additional item.Total raw scores converted to t-scores. T-scores were standardized test scores that indicate same degree of elevation in problems relative to normative sample of peers. High scores indicated more problems. FAS: randomized subjects who received rufinamide/any other approved add-on AED of investigator’s choice and had baseline and at least 1 postdose cognition measurement. "n":subjects evaluable at given time period.
    End point type
    Primary
    End point timeframe
    Baseline and End of Treatment Period (up to approximately Week 106)
    Notes
    [2] - 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 statistical analyses were planned for this primary end point.
    End point values
    		 Rufinamide Any Other Approved Antiepileptic Drug (AED)
    Number of subjects analysed
    24
    9
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline (n = 24, 8)
    56.6 ± 11.27
    62.8 ± 13.07
        Change at Week 106 (n = 15, 3)
    -0.3 ± 15.72
    -6.7 ± 0.58
    No statistical analyses for this end point

    Other pre-specified: Time to Withdrawal From Treatment

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    End point title
    		 Time to Withdrawal From Treatment
    End point description
    Withdrawal from either rufinamide or other AED was due to the occurrence of an adverse event or for lack of efficacy. Data was obtained till Week 106 and was extrapolated using Kaplan-Meier method to determine the overall survival time (in weeks) to withdrawal from treatment (excluding taper) due to an adverse event or lack efficacy. The FAS for other efficacy variable had randomized subjects who received rufinamide or any other add-on AED of the investigator’s choice and had a baseline efficacy assessment and at least 1 postbaseline efficacy assessment. The 95 percent (%) confidence interval was not calculated, since less than 50% of population was available for analysis, therefore we added -9999.0 and 99999 as space-fillers.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to the End of the Treatment Period (up to approximately Week 106)
    End point values
    		 Rufinamide Any Other Approved Antiepileptic Drug (AED)
    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

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

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    End point title
    		 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 was equal to the sum of the seizures reported in the subject seizure diary during the specified time interval and D was equal to the number of days with non-missing data in the subject seizure diary for the specified study phase. The number of seizures was assessed and recorded by the subject’s parent(s)/caregiver(s) in the subject seizure diary. Analysis was performed on the FAS for other efficacy variable included randomized subjects who received rufinamide or any other add-on AED of the investigator’s choice and had a baseline efficacy assessment and at least 1 post baseline efficacy assessment. The FAS for other efficacy variable had randomized subjects who received rufinamide or any other add-on AED of the investigator’s choice and had a baseline efficacy assessment and at least 1 postbaseline efficacy assessment, at given time period.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to End of the Treatment Period (up to approximately Week 106)
    End point values
    		 Rufinamide Any Other Approved Antiepileptic Drug (AED)
    Number of subjects analysed
    24
    8
    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: Percent Change in Seizure Frequency by Individual Seizure Type Per 28 Days

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    End point title
    		 Percent Change in Seizure Frequency by Individual Seizure Type Per 28 Days
    End point description
    The frequency per 28 days was defined as (S/D)*28 where, S was equal to the sum of the seizures reported in the subject seizure diary during the specified time interval and D was equal to the number of days with non-missing data in the subject seizure diary for the specified study phase. The number of seizures was assessed and recorded by the subject’s parent(s)/caregiver(s) in the subject seizure diary. The FAS for other efficacy variable had randomized subjects who received rufinamide or any other add-on AED of the investigator’s choice and had a baseline efficacy assessment and at least 1 postbaseline efficacy assessment. Here "n" were subjects evaluable at given time period.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to End of Treatment Period (up to approximately Week 106)
    End point values
    		 Rufinamide Any Other Approved Antiepileptic Drug (AED)
    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 54.0)
    No statistical analyses for this end point

    Other pre-specified: Incidence of Worsening of Seizures

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    End point title
    		 Incidence of Worsening of Seizures
    End point description
    Worsening of seizures was summarized by the incidence of subjects with doubling in total seizure frequency, doubling 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. Analysis was performed on the FAS for other efficacy variable included randomized subjects who received rufinamide or any other add-on AED of the investigator’s choice and had a baseline efficacy assessment and at least 1 post baseline efficacy assessment.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to End of Treatment Period (up to approximately Week 106)
    End point values
    		 Rufinamide Any Other Approved Antiepileptic Drug (AED)
    Number of subjects analysed
    24
    9
    Units: subjects
    number (not applicable)
        Doubling in total seizure frequency
    4
    1
        Doubling in frequency of major seizures
    5
    1
        Occurrence of a new seizure type
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in CBCL Sub Scores at Week 106

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    End point title
    		 Change From Baseline in CBCL Sub Scores at Week 106
    End point description
    CBCL:99-item questionnaire to measure specific behavioral problems/developmental delays, completed by a parent/legal guardian/caregiver. Items rated on 3-point scale(0=Not True,1=Somewhat/Sometimes True,2=Very True/Often True).99-items were combined to give 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).Total problem score:sum of all problem areas plus 1 additional item.Total raw scores converted to t-scores.T-scores were standardized test scores that indicate same degree of elevation in problems relative to normative sample of peers. High scores indicated more problems. FAS:randomized subjects who received rufinamide/any other approved add-on AED of investigator’s choice, had a baseline efficacy and at least 1 postbaseline efficacy assessment "n":subjects evaluable at given time period.
    End point type
    Other pre-specified
    End point timeframe
    Baseline and Week 106
    End point values
    		 Rufinamide Any Other Approved Antiepileptic Drug (AED)
    Number of subjects analysed
    24
    9
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline: Total emotional reactive scores (n=24,8)
    59.0 ± 8.13
    60.9 ± 8.64
        Week 106: Total emotional reactive scores (n=15,3)
    -1.1 ± 9.30
    -1.3 ± 6.11
        Baseline: Total anxious/depression scores (n=24,8)
    56.4 ± 7.48
    54.6 ± 6.67
        Week 106: Total anxious/depression scores (n=15,3)
    0.5 ± 8.87
    0.7 ± 1.15
        Baseline: Total somatic complaints scores (n=24,8)
    59.4 ± 8.13
    54.9 ± 4.70
        Week 106: Total somatic complaints scores (n=15,3)
    0.1 ± 11.24
    -1.7 ± 2.89
        Baseline: Total withdrawn scores (n=24,8)
    71.5 ± 11.2
    72.1 ± 11.03
        Week 106: Total withdrawn scores (n=15,3)
    -2.2 ± 13.22
    -7.0 ± 9.54
        Baseline: Total sleep problems scores (n=24,8)
    57.8 ± 10.72
    62.4 ± 8.57
        Week 106: Total sleep problem scores (n=15,3)
    -1.9 ± 12.30
    -5.7 ± 7.57
        Baseline: Total attention problems scores (n=24,8)
    59.3 ± 9.17
    65.9 ± 10.72
        Week 106: Total attention problems scores (n=15,3)
    -1.1 ± 4.65
    -7.7 ± 2.52
        Baseline: Total aggressive behavior scores(n=24,8)
    52.5 ± 5.01
    58.6 ± 12.07
        Week106: Total aggressive behavior scores (n=15,3)
    3.2 ± 6.26
    -0.3 ± 2.89
        Baseline: Total internalizing scores (n=24,8)
    61.6 ± 10.78
    60.6 ± 9.71
        Week 106: Total internalizing scores (n=15,3)
    -1.5 ± 13.73
    -2.7 ± 1.53
        Baseline: Total externalizing scores (n=24,8)
    47.5 ± 11.22
    58.1 ± 15.92
        Week 106: Total externalizing scores (n=15,3)
    4.7 ± 10.07
    -3.7 ± 3.51
    No statistical analyses for this end point

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

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    End point title
    		 Change From Baseline in Language Development Survey (LDS) Scores During Maintenance Period
    End point description
    LDS:caregiver-administered survey with 8-item questionnaire and vocabulary list of 310 words organized within 14 semantic categories. List had high frequency words, less common words, and lexical chunks. Average LDS score, calculated by dividing total number of words across all valid phrases by number of phrases with greater than(>)0words; for subjects with no words, average was 0. This value was compared to standardized chart to obtain percentile rating.LDS yield 2 scores: average phrase length (number of words/phrase) and number of endorsed vocabulary words.LDS phrase length, categorized into delay (less than or equal to[<=]20th percentile); no delay(>20th percentile). LDS vocabulary, categorized into delay(<=15th percentile);no delay(>15th percentile). Both raw scores were used to provide 2normative scores based on child’s age in months. Higher score means better language development. Analysis was done on FAS for other efficacy variable."n":subjects evaluable at given time period.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Weeks 24, 56, 88, and 106
    End point values
    		 Rufinamide Any Other Approved Antiepileptic Drug (AED)
    Number of subjects analysed
    24
    9
    Units: words
    arithmetic mean (standard deviation)
        Baseline: LDS average phrase length (n=24,9)
    0.3 ± 0.87
    0 ± 0.00
        Change at Week24:LDS average phrase length(n=23,8)
    0.2 ± 1.11
    0.7 ± 1.28
        Change at Week56:LDS average phrase length(n=21,7)
    0.1 ± 1.02
    0.0 ± 0.00
        Change at Week88:LDS average phrase length(n=18,4)
    0.1 ± 1.03
    0.0 ± 0.00
        Change atWeek106:LDS average phrase length(n=16,4)
    0.4 ± 1.12
    0.0 ± 0.00
        Baseline: LDS Vocabulary Score (n=24,9)
    10.4 ± 37.72
    0.6 ± 1.67
        Change at Week 24: LDS Vocabulary Score (n=23,8)
    7.1 ± 21.55
    4.8 ± 8.22
        Change at Week 56: LDS Vocabulary Score (n=21,7)
    17.9 ± 39.24
    -0.40 ± 2.15
        Change at Week 88: LDS Vocabulary Score (n=18,4)
    25.4 ± 49.87
    0.0 ± 0.00
        Change at Week 106: LDS Vocabulary Score (n=16,4)
    39.6 ± 75.62
    1.0 ± 2.00
    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
    QoLCE: 76-item questionnaire designed specifically to measure quality of life in children with epilepsy. QOLCE consists of 16 quality of life subscales(14 multi-item and 2 single item). Each subscales had number of items/questions with responses as excellent, very good, good, fair, and poor. They were changed to 1, 2, 3, 4,and 5 as per instructions. Then changed on scale of 100, where 1 is equal to(=) 0, 2=25, 3=50, 4=75, and 5=100. Items corresponding to each subscale were marked and there mean score was score of that subscale. Form was completed by parent or caregiver who interacted with the child on consistent, daily basis and took 20 to 30minutes to complete. The higher the score, better the child’s quality of life.FAS for other efficacy variable had randomized subjects who received rufinamide or any other add-on AED of investigator’s choice and had baseline efficacy assessment and at least 1 postbaseline efficacy assessment. Here "n" were subjects evaluable at given time period.
    End point type
    Other pre-specified
    End point timeframe
    Baseline and Week 106
    End point values
    		 Rufinamide Any Other Approved Antiepileptic Drug (AED)
    Number of subjects analysed
    24
    9
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline (n =24, 9)
    50.4 ± 10.05
    49.6 ± 7.88
        Change at Week 106 (n=15, 4)
    -1.3 ± 8.49
    1.5 ± 1.00
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Sub-scores in QoLCE

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    End point title
    		 Change From Baseline in Sub-scores in QoLCE
    End point description
    The QoLCE was a 76-item questionnaire designed specifically to measure quality of life in children with epilepsy. QOLCE consists of 16 quality of life subscales (14 multi-item and 2 single item). Each subscales had number of items or questions with responses as excellent, very good, good, fair, and poor. They were changed to 1, 2, 3, 4, and 5 as per instructions. Then changed on a scale of 100, where 1=0, 2=25, 3=50, 4=75, and 5=100. Items corresponding to each subscale were marked and there mean score was score of that subscale. 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 higher the score, the better the child’s quality of life. FAS: randomized subjects who received rufinamide or any other add-on AED of the investigator’s choice and had a baseline efficacy assessment and at least 1 postbaseline efficacy assessment. Here "n" were subjects evaluable at given time period.
    End point type
    Other pre-specified
    End point timeframe
    Baseline and Week 106
    End point values
    		 Rufinamide Any Other Approved Antiepileptic Drug (AED)
    Number of subjects analysed
    24
    9
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline: Physical restriction (n=24,9)
    50.1 ± 10.33
    49.9 ± 8.23
        Change at Week 106: Physical restriction (n=15,4)
    -1.0 ± 7.51
    -6.8 ± 7.32
        Baseline: Energy/Fatigue (n=24,9)
    51.6 ± 10.48
    44.3 ± 4.55
        Change at Week 106: Energy/Fatigue (n=15,4)
    -3.1 ± 12.22
    2.8 ± 4.11
        Baseline: Attention/Concentration (n=24,9)
    49.9 ± 10.14
    51.1 ± 9.05
        Change at Week 106:Attention/Concentration(n=15,4)
    -2.1 ± 7.31
    2.5 ± 6.24
        Baseline: Memory (n=24,9)
    50.2 ± 9.54
    52.6 ± 6.57
        Change at Week 106: Memory (n=15,4)
    -0.5 ± 12.18
    0.5 ± 1.00
        Baseline: Language (n=24,9)
    49.8 ± 10.42
    53.1 ± 4.43
        Change at Week 106: Language (n=15,4)
    -0.5 ± 9.63
    -0.5 ± 11.56
        Baseline: Other cognitive (n=24,9)
    48.6 ± 10.32
    53.1 ± 7.54
        Change at Week 106: Other cognitive (n=15,4)
    0.3 ± 6.19
    -1.0 ± 4.00
        Baseline: Depression (n=24,9)
    51.2 ± 9.27
    45.3 ± 10.59
        Change at Week 106: Depression (n=15,4)
    -2.6 ± 11.64
    2.3 ± 8.62
        Baseline: Anxiety (n=24,9)
    50.1 ± 10.27
    48.5 ± 12.29
        Change at Week 106: Anxiety (n=15,4)
    -0.1 ± 12.12
    1.3 ± 6.90
        Baseline: Control/Helplessness (n=24,9)
    50.7 ± 9.31
    47.8 ± 12.27
        Change at Week 106: Control/Helplessness (n=15,4)
    0.2 ± 10.90
    3.0 ± 11.52
        Baseline: Self-esteem (n=24,9)
    50.1 ± 10.18
    50.5 ± 10.98
        Change at Week 106: Self-esteem (n=15,4)
    -1.3 ± 9.48
    -6.0 ± 8.08
        Baseline: Social interactions (n=24,9)
    49.9 ± 10.56
    50.5 ± 8.48
        Change at Week 106: Social interactions (n=15,4)
    -1.5 ± 11.64
    4.0 ± 5.89
        Baseline: Social activities (n=24,9)
    50.5 ± 10.50
    46.6 ± 3.96
        Change at Week 106: Social activities (n=15,4)
    0.9 ± 11.30
    3.5 ± 3.70
        Baseline: Stigma (n=24,9)
    48.9 ± 11.06
    50.7 ± 8.07
        Change at Week 106: Stigma (n=15,4)
    -0.1 ± 12.67
    4.5 ± 10.25
        Baseline: Behavior (n=24,9)
    51.4 ± 10.39
    45.8 ± 9.33
        Change at Week 106: Behavior (n=15,4)
    0.2 ± 5.92
    7.3 ± 6.55
        Baseline: General-health (n=24,9)
    50.5 ± 10.02
    49.0 ± 8.40
        Change at Week 106: General health (n=15,4)
    -1.3 ± 10.98
    -2.0 ± 10.86
        Baseline: Quality-of-life (n=24,9)
    49.5 ± 9.71
    50.7 ± 9.98
        Change at Week 106: Quality-of-life (n=15,4)
    1.1 ± 9.46
    3.3 ± 12.28
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Visit 1 up to 30 days after the last study visit, or until resolution, whichever came first (up to approximately Week 106)
    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
    		 Subjects received rufinamide 10 milligram per kilogram per day (mg/kg/day), oral suspension, followed by 10 mg/kg/day increments every 3 days to 40 mg/kg/day, and then increased by 5mg/kg/day to the target maintenance level of 45 mg/kg/day (in 2 divided doses) from Week 0 (Baseline) to Week 1 in Titration Period, further followed by, rufinamide 45 mg/kg/day, oral suspension, from Week 2 to Week 106 in Maintenance Period. Rufinamide was administered as an add-on to the subject’s existing regimen of 1-3 antiepileptic drugs (AEDs). During the Taper Period, only subjects who received rufinamide were discontinued gradually over a period of 2 weeks, as deemed necessary by the investigator.

    Reporting group title
    Any other approved antiepileptic drug (AED)
    Reporting group description
    		 Subjects received any other approved AED of the investigator’s choice, dosed according to the investigator’s usual practice, added to the subject’s existing regimen of 1 to 3 AEDs.

    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
         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
    26 Oct 2011
    Following amendment changes were made: 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 electrocardiogram (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 subjects have completed 6 months of treatment; added amylase and lipase samples to list of laboratory tests per United States Food and Drug Administration(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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