Abstracts

Rationale: Perampanel, a non-competitive AMPA receptor antagonist, was recently shown to be effective and well tolerated as adjunctive therapy in patients with uncontrolled partial seizures in a phase III randomized, double-blind, placebo-controlled trial (study 305, ClinicalTrials.gov identifier: NCT00699582). Here we report further safety and tolerability data from study 305.Methods: Patients aged ?12 years with uncontrolled partial seizures receiving stable doses of 1-3 concomitant antiepileptic drugs were included. Following a 6-week Baseline, patients were randomized (1:1:1) to once-daily oral treatment with placebo, perampanel 8 mg, or perampanel 12 mg for 19 weeks (Double-blind Phase: 6-week Titration, 13-week Maintenance). The primary efficacy endpoint was percent change in seizure frequency. Safety and tolerability endpoints were assessed in the safety population (all subjects who were randomized, received study drug and had at least one post-dose safety assessment).Results: Of 389 patients randomized, 386 (placebo n=136; perampanel 8 mg n=129; perampanel 12 mg n=121) were included in the safety population. Of these, 349 (90.4%) completed the Titration Period and 321 (83.2%) completed the Maintenance Period. The overall incidence of treatment-emergent adverse events (TEAEs) was 68.4% with placebo, 86.8% with 8 mg and 86.0% with 12 mg. Most TEAEs were of mild or moderate severity severe TEAEs were reported in 6.6% of placebo-treated patients, 9.3% of 8 mg patients and 10.7% of 12 mg patients. In the Titration Period the most common TEAEs were: dizziness (4.4%, 25.6% and 43.8% with placebo, 8 mg and 12 mg, respectively); somnolence (2.9%, 12.4% and 15.7%, respectively) and fatigue (5.1%, 9.3% and 11.6%, respectively). The most frequent TEAEs in the Maintenance Period were: dizziness (4.8%, 5.1% and 14.4%, respectively); headache (4.0%, 6.8% and 4.8%, respectively) and fatigue (2.4%, 4.2% and 6.7%, respectively). The occurrence of serious adverse events (SAEs) in placebo, 8 mg and 12 mg patients was 5.1%, 7.8% and 9.9%, respectively. Epilepsy-related SAEs occurred in two placebo patients (1.5%), three 8 mg patients (2.3%), and one 12 mg patient (0.8%). No deaths were reported in this study. Discontinuations due to TEAEs were higher in perampanel-treated patients compared with placebo (4.4%, 9.3%, and 19% with placebo, 8 mg, and 12 mg, respectively). TEAEs led to dose interruption/adjustment in 3.7%, 20.9% and 28.1% of placebo, 8 mg, and 12 mg patients, respectively. No abnormal trends in laboratory tests, including QTc, were observed. Incidences of CPK and GGT >5x ULN were low and occurred more frequently in placebo patients. Reports of rashes were few (placebo n=2; 8 mg n=6; 12 mg n=3).Conclusions: The most common TEAEs occurred more frequently when perampanel doses were increasing during Titration than in the Maintenance Period when doses were stable. Tolerability was acceptable across the dosing range in this study. Support: Eisai Inc.