Study of Rufinamide in Pediatric Subjects 1 to Less Than 4 Years of Age With Lennox-Gastaut Syndrome Inadequately Controlled With Other Anti-epileptic Drugs

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

This study was designed to evaluate the cognitive effect, safety, and pharmacokinetics (PK) of rufinamide on Lennox-Gastaut Syndrome (LGS) inadequately controlled in pediatric participants already taking other anti-epileptic drugs.

Study Overview

• Status: Completed
• Conditions: Lennox-Gastaut Syndrome
• Intervention / Treatment: Drug: Rufinamide; Drug: Any other approved Antiepileptic Drug

• Study Type: Interventional
• Enrollment (Actual): 37
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Saskatoon, Canada, S7N 0W8
  • Alberta
    • Calgary, Alberta, Canada, T2T 5C7
    • Edmonton, Alberta, Canada, T6G 2B7
  • Ontario
    • Toronto, Ontario, Canada, M2K 2W2
• France
  • Bron, France
  • Marseille, France
  • Paris, France
• Greece
  • Ambelokipi Athens, Greece
  • Patra, Greece
  • Pendeli Athens, Greece
  • Thessaloniki, Greece
• Italy
  • Mantova, Italy, 46100
  • Roma, Italy, '00165
  • Salerno, Italy, 84131
  • MN
    • Mantua, MN, Italy
  • PI
    • Calambrone, PI, Italy
    • Pisa, PI, Italy
  • PV
    • Pavia, PV, Italy
• Poland
  • Elblag, Poland
  • Gdansk, Poland
  • Kielce, Poland
  • Poznan, Poland
  • Rzeszow, Poland, 35-301
  • Warszawa, Poland
• South Africa
  • Cape Town, South Africa
• United States
  • California
    • San Diego, California, United States, 92123
  • Colorado
    • Aurora, Colorado, United States, 80045
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
  • Florida
    • Gulf Breeze, Florida, United States, 32561
    • Miami, Florida, United States
    • Tampa, Florida, United States, 33609
    • Wellington, Florida, United States, 33414
  • Georgia
    • Augusta, Georgia, United States, 30912
  • Illinois
    • Chicago, Illinois, United States, 60637
  • Kentucky
    • Lexington, Kentucky, United States, 40536
  • Louisiana
    • Shreveport, Louisiana, United States, 71103
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
  • New Jersey
    • Gibbsboro, New Jersey, United States, 08026
  • New York
    • Rochester, New York, United States, 14642
  • Ohio
    • Akron, Ohio, United States
    • Akson, Ohio, United States, 44308
    • Columbus, Ohio, United States, 43205
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
    • Pittsburgh, Pennsylvania, United States, 15224
  • Texas
    • Austin, Texas, United States, 78723
    • San Antonio, Texas, United States, 78258
  • Virginia
    • Norfolk, Virginia, United States, 23510

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 3 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Key Inclusion:

1. Clinical diagnosis of LGS, which might include the presence of a slow background electroencephalogram (EEG) rhythm, slow spikes-waves pattern (less than 3 Hz), the presence of polyspikes; care should be taken not to include benign myoclonic epilepsy of infancy, atypical benign partial epilepsy (pseudo-Lennox syndrome), or continuous spike-waves of slow sleep (CSWS).
2. On a fixed and documented dose of one to three concomitant regionally approved antiepileptic drugs (AEDs) for a minimum of 4 weeks prior to randomization with an inadequate response to treatment.
3. Consistent seizure documentation (i.e., no uncertainty of the presence of seizures) during the pre-randomization phase.

Key Exclusion:

1. Familial short QT syndrome
2. Prior treatment with rufinamide within 30 days of baseline visit or discontinuation of rufinamide treatment due to safety issues related to rufinamide

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Rufinamide	Drug: Rufinamide; Rufinamide up to 45 mg/kg/day, in 2 divided doses, administered as oral suspension (40 mg/mL) as an add-on to the subject's existing regimen of 1-3 antiepileptic drugs (AEDs)
ACTIVE_COMPARATOR: Any other approved AED	Drug: Any other approved Antiepileptic Drug; Any other approved AED: any other approved AED of the investigator's choice as an add-on to the subject's existing regimen of 1-3 anti-epileptic drugs (AEDs)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Child Behavior Checklist (CBCL) Total Problem T-scores at the End of 2-year Treatment Period	CBCL: 99-item questionnaire measures specific behavioral problems or developmental delays, answered by a parent/legal guardian or suitable caregiver. Each item were rated using 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). Total Problem score was sum of all the problem areas plus 1 additional item, ranging from 0 to 198. Total raw scores are converted to t-scores with mean of 50 and standard deviation (SD) of 10. T-scores were standardized test scores that indicate same degree of elevation in problems relative to the normative sample of peers. Higher scores were indicative of more problems.	End of Treatment Period (up to approximately Week 106)
Change From Baseline in CBCL Total Problem T-Scores at End of 2-year Treatment Period	CBCL: 99-item questionnaire measures specific behavioral problems or developmental delays, answered by a parent/legal guardian or suitable caregiver. Each item were rated using 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). Total Problem score was sum of all the problem areas plus 1 additional item, ranging from 0 to 198. Total raw scores are converted to t-scores with mean of 50 and standard deviation (SD) of 10. T-scores were standardized test scores that indicate same degree of elevation in problems relative to the normative sample of peers. Higher scores were indicative of more problems.	Baseline and End of Treatment Period (up to approximately Week 106)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Withdrawal From Treatment Due to an Adverse Event or Lack of Efficacy	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.	Baseline up to the End of the Treatment Period (up to approximately Week 106)
Percent Change in Total Seizure Frequency Per 28 Days	The frequency per 28 days was defined as (S/D)*28 where, S was equal to the sum of the seizures reported in the participant seizure diary during the specified time interval and D was 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.	Baseline up to End of the Treatment Period (up to approximately Week 106)
Percent Change in Seizure Frequency by Individual Seizure Type Per 28 Days	The frequency per 28 days was defined as (S/D)*28 where, S was equal to the sum of the seizures reported in the participant seizure diary during the specified time interval and D was 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.	Baseline up to End of Treatment Period (up to approximately Week 106)
Incidence of Worsening of Seizures	Worsening of seizures was summarized by the incidence of participants 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.	Baseline up to End of Treatment Period (up to approximately Week 106)
Change From Baseline in CBCL Sub Scores at Week 106	CBCL: 99-item questionnaire, measures behavioral problems/developmental delays, answered by parent/guardian/caregiver. Each item rated on 3-point scale (0=Not True,1=Somewhat/Sometimes True, 2=Very/Often True). 99 items were combined to give scores for 8 problem area scales, where 1 for each 8 syndrome (emotionally reactive, anxious/depressed, somatic, withdrawn, sleep, attention, aggressive behavior, and other problems) were calculated, range: 0 (normal) to 16 (clinical behavior) and 3 summary scores (internalizing, externalizing, and total problems). All 3 summary scores reported scaled to T-scores. Total Problem score was sum of all the problem areas plus 1 additional item, ranging from 0 to 198. Total raw score were converted to t-scores with mean of 50 and SD of 10. T-scores were standardized test scores that indicate same degree of elevation in problems relative to normative sample of peers. Higher scores were indicative of more problems.	Baseline and Week 106
Change From Baseline in Language Development Survey (LDS) Scores During Maintenance Period	LDS, a caregiver-administered survey consisted of 8-item questionnaire and vocabulary list of 310 words organized within 14 semantic categories. List contained high frequency words (e.g. more), less common words (e.g. hamburger), and lexical chunks (e.g. Sesame Street). Average LDS score, calculated by dividing total number of words across all valid phrases by number of phrases with greater than (>) 0words; for participants with no words, average was 0. This value was compared to standardized chart to obtain percentile rating. LDS provided 2 scores: average phrase length (number of words/phrase) and number of endorsed vocabulary words. LDS phrase length was categorized into delay (less than or equal to [<=] 20th percentile) and no delay (>20th percentile). LDS vocabulary was categorized into delay(<=15th percentile)and no delay(>15th percentile). Both raw scores were used to provide 2 normative scores based on child's age in months. Higher scores indicated better language development.	Baseline, Weeks 24, 56, 88, and 106
Change From Baseline in Total Score of Quality of Life in Childhood Epilepsy (QoLCE) Scale	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 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. 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.	Baseline and Week 106
Change From Baseline in Sub-scores in QoLCE	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.	Baseline and Week 106

Collaborators and Investigators

• Sponsor: Eisai Inc.
• Investigators: Principal Investigator: Alexis Arzimanoglou Arzimanoglou, Hopital Femme-Mere-Enfant Service D'Epilepsie -5eme etage 59 Boulevard Pinel Bron, France

Publications and helpful links

General Publications

• Brigo F, Jones K, Eltze C, Matricardi S. Anti-seizure medications for Lennox-Gastaut syndrome. Cochrane Database Syst Rev. 2021 Apr 7;4(4):CD003277. doi: 10.1002/14651858.CD003277.pub4.
• Auvin S, Williams B, McMurray R, Kumar D, Perdomo C, Malhotra M. Novel seizure outcomes in patients with Lennox-Gastaut syndrome: Post hoc analysis of seizure-free days in rufinamide Study 303. Epilepsia Open. 2019 Mar 13;4(2):275-280. doi: 10.1002/epi4.12314. eCollection 2019 Jun.
• Arzimanoglou A, Ferreira J, Satlin A, Olhaye O, Kumar D, Dhadda S, Bibbiani F. Evaluation of long-term safety, tolerability, and behavioral outcomes with adjunctive rufinamide in pediatric patients (>/=1 to <4 years old) with Lennox-Gastaut syndrome: Final results from randomized study 303. Eur J Paediatr Neurol. 2019 Jan;23(1):126-135. doi: 10.1016/j.ejpn.2018.09.010. Epub 2018 Sep 27.
• Arzimanoglou A, Ferreira JA, Satlin A, Mendes S, Williams B, Critchley D, Schuck E, Hussein Z, Kumar D, Dhadda S, Bibbiani F. Safety and pharmacokinetic profile of rufinamide in pediatric patients aged less than 4 years with Lennox-Gastaut syndrome: An interim analysis from a multicenter, randomized, active-controlled, open-label study. Eur J Paediatr Neurol. 2016 May;20(3):393-402. doi: 10.1016/j.ejpn.2015.12.015. Epub 2016 Jan 11.

Study record dates

Study Major Dates

• Study Start (ACTUAL): June 16, 2011
• Primary Completion (ACTUAL): November 2, 2015
• Study Completion (ACTUAL): November 2, 2015

Study Registration Dates

• First Submitted: July 27, 2011
• First Submitted That Met QC Criteria: July 27, 2011
• First Posted (ESTIMATE): July 29, 2011

Study Record Updates

• Last Update Posted (ACTUAL): August 6, 2019
• Last Update Submitted That Met QC Criteria: July 12, 2019
• Last Verified: February 1, 2016

More Information

Terms related to this study

• Keywords: Central Nervous System
• Additional Relevant MeSH Terms: Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epileptic Syndromes; Disease; Genetic Diseases, Inborn; Epilepsy; Syndrome; Lennox Gastaut Syndrome; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Anticonvulsants; Rufinamide
• Other Study ID Numbers: E2080-G000-303