Abstracts

This study assessed the dose-range relationships of rufinamide versus placebo for efficacy, safety, tolerability, and pharmacokinetics in patients with inadequately controlled partial seizures. Patients (age range, 15-65 y) with inadequately controlled partial seizures, with or without secondary generalization, and on 1 to 3 concomitant antiepileptic drugs (AEDs) were enrolled in this double-blind, randomized, placebo-controlled, parallel-group study. Patients with [ge]9 seizures on stable AED dosages during baseline (3 months) were eligible for a 3-month double-blind treatment phase (DB). These patients were randomized equally to 1 of 5 treatment groups: rufinamide 200 mg/d, 400 mg/d, 800 mg/d, and 1600 mg/d, or placebo. Primary efficacy was seizure frequency per 28 days in DB; secondary efficacy included seizure frequency ratio and response to treatment ([ge]25% reduction in seizure frequency per 28 days vs baseline). Safety and tolerability were evaluated by adverse events (AEs), vital signs, and laboratory tests. Trough levels of AEDs were obtained at baseline; plasma sampling for AEDs and rufinamide levels was done before randomization and at scheduled visits. Of the 737 patients enrolled in the study, 647 were randomized. A statistically significant linear trend of dose response for seizure frequency per 28 days in DB ([italic]p[/italic]=0.003) and for treatment responders ([italic]p[/italic]=0.0035) was observed in favor of rufinamide. Median seizure frequency ratio was significantly reduced in patients treated with 400 mg/d (11%, [italic]p[/italic]=0.0274), 800 mg/d (16%, [italic]p[/italic]=0.0123), and 1600 mg/d (17%, [italic]p[/italic]=0.0163) of rufinamide compared to placebo. AEs were generally similar to placebo for all rufinamide doses [le]800 mg/d. At 1600 mg/d, dizziness, somnolence, diplopia, and nystagmus were reported [ge]2 times as frequently as placebo and the lower doses of rufinamide. Serious AEs occurred in 21 rufinamide-treated (4.1%) and 5 placebo (3.8%) patients. Plasma rufinamide levels increased dose-proportionally with doses [le]800 mg/d, but a slight reduction was observed with doses [gt]800 mg/d. Concomitant use of phenytoin, primidone, or phenobarbital resulted in an approximate 25% increase in plasma clearance (CL) of rufinamide; patients using valproate experienced an approximate 22% decrease in rufinamide plasma CL. Rufinamide did not significantly alter plasma levels of other concomitant AEDs. Efficacy of rufinamide was demonstrated in a dose-dependent manner and rufinamide dosages up to 1600 mg/d were generally well tolerated. Plasma levels of rufinamide increased in a dose-proportional manner up to 800 mg/d. Rufinamide concentrations were slightly altered by certain concomitantly administered AEDs, however a change in rufinamide dosage may not be required. (Supported by Eisai Inc.)