Abstracts

Rationale: Perampanel is a once-daily oral anti-seizure drug for partial-onset seizures (POS) and primary generalized tonic-clonic seizures. Study 335 (NCT01618695) was an Asia-Pacific, multicenter, randomized, double-blind, placebo-controlled, Phase III study of adjunctive perampanel (4, 8, or 12 mg/day) in patients aged >=12 years with refractory POS with or without secondarily generalized (SG) seizures. Here, we report a post hoc safety analysis examining the rate of TEAEs during the Titration, Pre-steady-state, and Maintenance Periods in patients who received perampanel and completed Study 335. Methods: Study 335 comprised a 19-week Double-blind Period (6-week Titration; 13-week Maintenance). During Titration, patients in the perampanel group received perampanel 2 mg/day before up-titration in weekly 2-mg increments to 4, 8, or 12 mg/day. For this analysis, the rate of TEAEs was analyzed by Treatment Period (Titration: Weeks 1-2 [4 mg], 1-4 [8 mg], 1-6 [12 mg]; Pre-steady-state: Weeks 3-5 [4 mg], 5-7 [8 mg], 7-9 [12 mg]; Maintenance: Weeks 6-19 [4 mg], 8-19 [8 mg], 10-19 [12 mg]) in patients who completed the study. Total exposure to perampanel for each period, in subject-months (1 month=28 days), was calculated as the sum of durations of exposure for all patients across that period. TEAE rates were calculated as the number of events divided by the total exposure, multiplied by 100.  Results: Overall, 707 patients with POS were treated during Study 335 (placebo, n=176; perampanel 4 mg, n=176; 8 mg, n=175; 12 mg, n=180). In total, 152/176 (86.4%) placebo-treated patients and 447/531 (84.2%) perampanel-treated patients (4 mg, n=156 [88.6%]; 8 mg, n=147 [84.0%]; 12 mg, n=144 [80.0%]) completed the 19-week Treatment Period. Total exposure to study drug (subject-months), overall rate of TEAEs, and the most common TEAEs during the Titration, Pre-steady-state, and Maintenance Periods are shown in Table 1 for the perampanel completer population. The overall rate of TEAEs per 100 subject-months was similar between the perampanel dose groups and, for all groups, was highest in the Titration Period (44.0-45.9), lower during Pre-steady-state (32.7-36.1), and at the lowest level during the Maintenance Period (15.8-19.3). The most common TEAEs per 100 subject-months during the Titration Period for all dose groups were dizziness (18.9-21.8) and somnolence (6.3-15.5); generally successively lower rates of these individual TEAEs were reported during the Pre-steady-state and Maintenance Periods (dizziness: 2.7-12.6 and 1.6-2.5; somnolence: 0.9-8.4 and 1.4-1.5, respectively; Table 1). Conclusions: These data suggest that adjunctive perampanel 4-12 mg/day is generally well tolerated in patients aged >=12 years with POS, with or without SG seizures. In general, the highest TEAE rate was reported during the Titration Period and decreased over time, suggesting tolerability to perampanel treatment may improve as a patient reaches the Maintenance Period. Funding: Eisai Inc.