Abstracts

Rationale: Perampanel, a non-competitive AMPA receptor antagonist, has demonstrated efficacy in preclinical seizure models and was well tolerated at doses of 2 12 mg/day in phase II clinical studies. In a randomized, double-blind, placebo-controlled phase III trial (study 305), perampanel 8 and 12 mg/day demonstrated efficacy in primary study endpoints as adjunctive therapy in patients with refractory partial seizures. Here we report results from analyses of complex partial plus secondarily generalized (CP+SG) seizure and secondarily generalized (SG) seizure subgroups in study 305. Change in CP+SG seizures was a secondary efficacy endpoint (ClinicalTrials.gov identifier: NCT00699582).Methods: Patients (?12 years) experiencing uncontrolled partial seizures despite treatment with 1 3 antiepileptic drugs were included. Following a 6-week Baseline, patients were randomized (1:1:1) to receive once-daily placebo, perampanel 8 mg, or perampanel 12 mg. The Double-blind Phase consisted of a 6-week Titration Period (dose increased in 2 mg increments per week up to 8 or 12 mg/day, or the highest tolerable dose) and a 13-week Maintenance Period. Dose reductions were permitted for intolerance. Seizure frequency was recorded daily in a diary. Percent change in seizure frequency/28 days (Double-blind Phase compared with Baseline) and responder rate (patients with ?50% reduction in seizure frequency in the Maintenance Period) were assessed for CP+SG seizures and SG seizures in the Full Intent-To-Treat (ITT) analysis set (all patients who received study drug and provided any seizure data during the Double-blind Phase). Here we present efficacy data according to the actual dose (defined as last dose) of perampanel achieved for Full ITT patients who completed the study.Results: Of 389 randomized patients, 386 were included in the Full ITT set and 321 completed the study. The numbers of patients achieving each dose were: placebo n=120; perampanel 2 mg n=1; 4 mg n=3; 6 mg n=19; 8 mg n=99; 10 mg n=9; 12 mg n=70. Median percent changes in CP+SG seizure frequency were -9.5% for placebo (n=111), 22.4% for perampanel 2 mg (n=1), -31.8% for 4 mg (n=3), -47.1% for 6 mg (n=17), -31.8% for 8 mg (n=91), -26.5% for 10 mg (n=9), and -14.8% for 12 mg (n=64). Responder rates for CP+SG seizures for placebo, perampanel 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg were 16.2%, 0%, 0%, 41.2%, 39.6%, 33.3%, and 34.4%, respectively. Median percent changes in SG seizure frequency were -13.5% for placebo (n=42), -76.3% for perampanel 6 mg (n=4), -41.2% for 8 mg (n=35), -84.6% for 10 mg (n=2), and -44.4% for 12 mg (n=26). No completing patients with SG seizures at baseline had a final dose of 2 mg or 4 mg. Responder rates for SG seizures for placebo, perampanel 6 mg, 8 mg, 10 mg, and 12 mg were 26.2%, 75%, 40%, 100%, and 42.3%, respectively.Conclusions: Perampanel decreased seizure frequency and increased responder rate, compared with placebo, in patients with severe, clinically important seizure types (CP+SG and SG seizures). Support: Eisai Inc.