Abstracts

Rationale: Perampanel (PER) is a selective, noncompetitive AMPA antagonist approved as adjunctive treatment for partial-onset seizures. To examine efficacy and safety of PER based on number of concomitant antiepileptic drugs (AEDs) at baseline, a post hoc analysis of 3 phase 3 trials was conducted. Baseline predictors of efficacy were also examined to determine whether any characteristics were more predictive of efficacy.Methods: Data from 3 phase 3 trials were included in this analysis. Patients aged 12 yrs on a stable dose of 1, 2, or 3 AEDs were randomized to concomitantly receive 2, 4, 8, or 12 mg PER or placebo (PBO).Studies consisted of 6-week prerandomization baseline, followed by 19-week double-blind phase (6-week titration+13-week maintenance periods). Efficacy end points included percent decrease in seizure frequency and 50% responder rate, based on number of AEDs at baseline. To determine significant baseline predictors of 50% responder rate, 17 logistic models were built, each with 1 variable; 4 significant variables were fitted in another logistic model for variable selection. Safety and tolerability of PER by number of AEDs at baseline were also evaluated.Results: 1480 and 1478 patients were included in safety and efficacy analyses, respectively. Overall, 206 (13.9%), 749 (50.7%), and 523 (35.4%) patients were on 1, 2, or 3 AEDs, respectively. Though age, sex, and seizure type were similar across groups, time since diagnosis was less with 1 AED than either 2 or 3 (18.8, 21.1, and 21.9 years since diagnosis in the 1-, 2-, and 3-AED groups, respectively [P<0.0001 for 1 vs 3 AEDs and P=0.002 for 1 vs 2 AEDs]). Median rate of seizures at baseline was also significantly higher in 3-AED group compared with 1- or 2-AED groups (14.0 vs 9.7, 10.8, respectively; P<0.05). Table 1 shows percent decrease in seizure frequency and responder rates. Fewer AEDs at baseline were a predictor of PER efficacy. Patients on 1 AED at baseline were significantly more likely to be a responder than patients on 3 AEDs (OR=1.55, 95% CI: 1.07-2.24; P<0.02). Four variables were identified as baseline predictors for improved treatment outcomes: 1 vs 3 AEDs at baseline, P=0.047; unknown vs CNS infection etiology, P=0.048; noninducer vs inducer concomitant AED, P=0.0003; and presence vs absence of secondarily generalized seizures, P=0.0019. Use of inducers was increasingly higher with more AEDs, with potential decreased exposure of perampanel. Incidence of treatment-emergent adverse events (TEAEs) at the highest PER dose (12 mg) was similar regardless of AEDs at baseline (92.9%, 88.3%, 89.0% for 1, 2, and 3 AEDs, respectively). TEAEs in PBO cohorts ranged between 61.7% and 70.7%. In all AED groups, most common TEAEs were dizziness, somnolence, headache, occurring in 10% of all PER patients.Conclusions: In this post-hoc analysis, fewer AEDs at baseline was associated with the greatest efficacy. In all AED groups, PER provided a benefit in seizure reduction, with similar rates of TEAEs.