Epilepsy Study Consortium

We evaluate the impact of independent, central review of epilepsy syndromes and seizure classification in randomized controlled treatment trials of Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS). Central review of two recent trials determined that 5.6% of enrolled DS participants and 3.4% of enrolled LGS participants pending randomization did not meet criteria for the epilepsy syndrome under study. Furthermore, 23% of DS participants and 32% of LGS participants had at least one seizure reclassified; 63.8% of DS sites and 78% of LGS sites had at least one participant with a seizure reclassification. Independent, central review of participants in pediatric ASM trials improves consistency across study sites, as well as overall accuracy of syndromic diagnosis and seizure classification, and may reduce placebo response rate.

OBJECTIVE: To assess the efficacy and safety of adjunctive perampanel for treating drug-resistant PGTC seizures in patients with IGE. BACKGROUND: The AMPA receptor antagonist perampanel is approved in 40 countries for the adjunctive treatment of partial-onset seizures with or without secondary generalization in patients with epilepsy aged 蠅12 years (蠅18 years in Canada). DESIGN/METHODS: Patients (蠅12 years; confirmed IGE; 蠅3 PGTC seizures in 8 weeks prior to randomization; 1-3 concomitant antiepileptic drugs) were recruited from 78 sites in 16 countries. This trial (NCT01393743) had Pre-randomization (4-week screening; 4-8 week Baseline), Randomization (4-week Titration, 13-week Maintenance, 4-week Follow-up), and Extension Phases. Patients were randomized (1:1) under double-blind conditions to placebo or perampanel 2 mg/day, uptitrated in weekly 2-mg increments to 8 mg/day or maximum-tolerated dose. Primary endpoints were percent change in PGTC seizure frequency per 28 days (Titration and Maintenance vs Baseline) and 50[percnt] responder rate (蠅50[percnt] reduction in PGTC seizure frequency during Maintenance vs Baseline). Adverse events (AEs) were recorded. RESULTS: Of 164 randomized patients, 162 comprised the full analysis set (perampanel, n=81; placebo, n=81). Median percent changes in PGTC seizure frequency (-76.5[percnt] vs -38.4[percnt]; P<0.0001), 50[percnt] responder rate (64.2[percnt] vs 39.5[percnt]; P=0.0019), and tonic-clonic seizure-free rate (30.9[percnt] vs 12.3[percnt]) all favored perampanel vs placebo. In the safety set (n=163), treatment-emergent AEs occurred in 82.7[percnt] of perampanel-treated patients (vs placebo, 72.0[percnt]). The AEs most frequently reported with perampanel vs placebo were dizziness (32.1[percnt] vs 6.1[percnt]), fatigue (14.8[percnt] vs 6.1[percnt]), and headache (12.3[percnt] vs 9.8[percnt]). Six perampanel-treated (7.4[percnt]) and seven placebo-treated (8.5[percnt]) patients experienced serious AEs, including two deaths (accidental drowning [perampanel] and sudden unexpected death in epilepsy [placebo]). CONCLUSIONS: Adjunctive perampanel improved control of drug-resistant PGTC seizures in patients aged 蠅12 years with IGE. Perampanel was well tolerated, with safety profile consistent with previous observations. Study Supported by: Eisai Inc