Abstracts

Rationale: Oxcarbazepine (OXC) is an antiepileptic drug (AED) with broad-spectrum efficacy in children and adults. Supernus Pharmaceuticals, Inc. is developing SPN-804, a novel, extended-release (ER) formulation of OXC that may provide convenient, once-daily epilepsy treatment, reduce the dose- and peak-dose-related side effects of the original OXC formulation, and facilitate adherence to therapy. As there are often major differences in response by geographic area in clinical trials, we evaluated the efficacy and safety of adjunctive OXC ER in adults with partial seizures from a North American subpopulation of a multicenter, randomized, double-blind, placebo-controlled, 3-arm study. In the overall results, a statistically significant separation from placebo on the primary endpoint was found for SPN-804 2400 mg/d (P=0.003); for SPN-804 1200 mg/d, a trend to significance was seen (P=0.077).Methods: Adults, aged 18-65 years with refractory partial epilepsy despite 1-3 concomitant AEDs were enrolled. Seizure frequency was assessed at baseline over 4-8 weeks (minimum 3 seizures/28 days for inclusion). Patients were randomized to 1 of 3 adjunctive treatment groups (SPN-804 1200 mg/d, SPN-804 2400 mg/d, or placebo) while stable AEDs were continued. Study drug was titrated to target dose over 4 weeks and then maintained for 12 weeks. The primary endpoint was the median percentage change in partial seizure frequency per 28 days from baseline (PCH_T). Secondary endpoints included seizure-free rates. Safety assessments were also conducted.Results: Of 366 patients comprising the intent-to-treat population, 116 (31.7%) were studied at centers in Canada, Mexico, and the United States. Mean patient age was 38.9 (range: 18-66); 45.7% were male. For the primary endpoint, both doses of SPN-804 provided a statistically significant reduction in median seizure frequency per 28 days vs placebo (median PCH_T: -34.50, SPN-804 1200 mg/d, P=0.021; -52.65, SPN-804 2400 mg/d, P=0.006; -13.30, placebo). In the maintenance period, seizure freedom was achieved by 20%, 8%, and 2% of patients taking SPN-804 2400 mg/d, SPN-804 1200 mg/d, and placebo, respectively. No new adverse events or safety signals were evident in this subpopulation. Conclusions: In this subpopulation analysis from a multinational study, both SPN-804 1200 mg/d and 2400 mg/d were significantly superior to placebo in reducing partial seizure frequency change from baseline per 28 days. These results are similar to those published in subpopulation analyses from other AED trials. The placebo response rate in this analysis was roughly half that seen in the total study population (25%), perhaps contributing to the differences seen between the full and subpopulation analyses. In general, secondary endpoint results supported primary results. SPN-804 appears to be an effective, well-tolerated option for adjunctive treatment of partial seizures in adults. This study was funded by Supernus Pharmaceuticals, Inc.