Alexis Arzimanoglou1, Jose Ferreira2, Andrew Satlin3, Omar Olhaye4, Dinesh Kumar5, Shobha Dhadda6, Francesco Bibbiani7. 1. Department of Paediatric Clinical Epileptology, Sleep Disorders and Functional Neurology, University Hospitals of Lyon (HCL), Member of the European Reference Network EpiCARE, Lyon's Neuroscience Research Center, 59 Bld. Pinel, 60700 Lyon, France. Electronic address: aarzimanoglou@orange.fr. 2. Department of Pediatrics, University of South Florida, School of Medicine, 2 Tampa General Cir, Tampa, FL 33606, USA; Pediatric Neurology, St. Joseph's Children's Hospital, 3001 W Doctor M.L.K Jr. Blvd, Tampa, FL 33607, USA; Pediatric Epilepsy and Neurology Specialists (PENS), 508 S. Habana Ave, Suite 340, Tampa, FL 33609, USA. Electronic address: jferreira@pensresearch.org. 3. Formerly of Eisai Neurology Business Group, Eisai Inc., 100 Tice Boulevard, Woodcliff Lake, NJ 07677, USA. Electronic address: andrew.satlin@gmail.com. 4. Formerly of Eisai Neurology Business Group, Eisai Inc., 100 Tice Boulevard, Woodcliff Lake, NJ 07677, USA. Electronic address: omar.olhaye@gmail.com. 5. Eisai Neurology Business Group, Eisai Inc., 100 Tice Boulevard, Woodcliff Lake, NJ 07677, USA. Electronic address: dinesh_kumar@eisai.com. 6. Eisai Neurology Business Group, Eisai Inc., 100 Tice Boulevard, Woodcliff Lake, NJ 07677, USA. Electronic address: shobha_dhadda@eisai.com. 7. Formerly of Eisai Neurology Business Group, Eisai Inc., 100 Tice Boulevard, Woodcliff Lake, NJ 07677, USA. Electronic address: fbibbiani@yahoo.com.
Abstract
OBJECTIVE: Evaluate the long-term safety, tolerability, and behavioral effects of adjunctive rufinamide in pediatric patients (≥1 to <4 years old) with inadequately controlled seizures associated with Lennox-Gastaut syndrome (LGS). METHODS: Study 303 (ClinicalTrials.gov identifier NCT01405053) was a multicenter, randomized, open-label, Phase III trial. Patients were randomized (2:1) to oral suspension rufinamide (≤45 mg/kg/day) or any other investigator-chosen antiepileptic drug (AED) for a 2-year treatment period. Primary safety/tolerability assessments included monitoring of treatment-emergent adverse events (TEAEs) and serious TEAEs. Behavioral effects were assessed via the Child Behavior Checklist (CBCL) using the Total Problems score and change from baseline in CBCL Total Problems score. CBCL subscores were also evaluated. RESULTS: The Safety Analysis Set included 37 patients (rufinamide: n = 25; any other AED: n = 12). TEAE incidence was similar between the rufinamide (88.0%) and any-other-AED groups (83.3%); serious TEAE incidence was also similar between treatment groups (40.0% and 41.7%, respectively). Between treatment groups, the difference in the least squares mean CBCL Total Problems score across time was not significant (p = 0.7083), behavior outcomes were similar across all endpoints, and there were no consistent trends in CBCL subscores. SIGNIFICANCE: Long-term (2 years) adjunctive rufinamide was well tolerated in pediatric patients with LGS. Behavioral outcomes were comparable between the rufinamide and any-other-AED groups, however the small sample size and difficulties assessing behavior in this population should be noted. The challenges of this study raise the issue of revising how studies in very young children with rare and complex epilepsies are performed.
RCT Entities:
OBJECTIVE: Evaluate the long-term safety, tolerability, and behavioral effects of adjunctive rufinamide in pediatric patients (≥1 to <4 years old) with inadequately controlled seizures associated with Lennox-Gastaut syndrome (LGS). METHODS: Study 303 (ClinicalTrials.gov identifier NCT01405053) was a multicenter, randomized, open-label, Phase III trial. Patients were randomized (2:1) to oral suspension rufinamide (≤45 mg/kg/day) or any other investigator-chosen antiepileptic drug (AED) for a 2-year treatment period. Primary safety/tolerability assessments included monitoring of treatment-emergent adverse events (TEAEs) and serious TEAEs. Behavioral effects were assessed via the Child Behavior Checklist (CBCL) using the Total Problems score and change from baseline in CBCL Total Problems score. CBCL subscores were also evaluated. RESULTS: The Safety Analysis Set included 37 patients (rufinamide: n = 25; any other AED: n = 12). TEAE incidence was similar between the rufinamide (88.0%) and any-other-AED groups (83.3%); serious TEAE incidence was also similar between treatment groups (40.0% and 41.7%, respectively). Between treatment groups, the difference in the least squares mean CBCL Total Problems score across time was not significant (p = 0.7083), behavior outcomes were similar across all endpoints, and there were no consistent trends in CBCL subscores. SIGNIFICANCE: Long-term (2 years) adjunctive rufinamide was well tolerated in pediatric patients with LGS. Behavioral outcomes were comparable between the rufinamide and any-other-AED groups, however the small sample size and difficulties assessing behavior in this population should be noted. The challenges of this study raise the issue of revising how studies in very young children with rare and complex epilepsies are performed.