Rationale: LGS is a severe refractory childhood-onset epilepsy characterized by a triad of multiple seizure types (including drop seizures), intellectual disability, and certain electroencephalographic (EEG) abnormalities. Study 338 (NCT02834793) was a Phase III study that evaluated the efficacy and safety of adjunctive perampanel in patients aged ≥ 2 years with inadequately controlled seizures with LGS. Previously, real-world studies found that the number of baseline ASMs was associated with seizure control in patients receiving perampanel. Here, we present results from a post hoc analysis stratified by number of baseline ASMs (1, 2, or ≥ 3).
Methods: Study 338 enrolled patients (aged ≥ 2 years) with clinical and EEG confirmation of LGS diagnosis with disease onset before 11 years of age, who were receiving 1–4 concomitant ASMs at stable doses for ≥ 30 days before screening and had an average of ≥ 2 drop seizures/week during the Baseline Period. The study consisted of a randomized, double-blind, placebo-controlled Core Study (4–8-week Screening/Baseline, 6-week Titration, and 12-week Maintenance Periods), and open-label Extension Phase A (52 weeks) and Extension B (in Japan or countries without an Extended Access Program). The primary endpoint was median percent change from baseline in drop seizure frequency/28 days during the Titration and Maintenance Periods. Secondary endpoints included 50% and 75% responder and seizure-freedom rates for drop seizures and all seizures, and safety outcomes.
Results: Of 70 patients randomized in the Core Study (perampanel, n=34; placebo, n=36), 58 entered the Extension Phase. At baseline, the mean (standard deviation [SD]) age of patients was 14.0 (9.1) years, and the mean (SD) time since diagnosis was 9.1 (7.6) years. Most patients received at least 2 ASMs at baseline
(Core Study: 1 ASM, 4.3%; 2 ASMs, 27.5%; ≥ 3 ASMs, 68.1%; Extension Phase: 5.2%, 29.3%, and 65.5%, respectively). The most common ASMs at baseline were clobazam (50.0%), lamotrigine (31.4%), and rufinamide (28.6%). Table 1 presents efficacy outcomes throughout the study. The median percent reduction in drop seizure frequency/28 days was numerically higher with perampanel vs placebo in the Core Study, regardless of the number of baseline ASMs. With perampanel, the median reduction in drop seizure frequency was greater in patients receiving ≥ 3 ASMs (45.2%) vs 2 ASMs (13.4%) in the Core Study, but greater for 2 ASMs (40.6%) vs ≥ 3 ASMs (17.4%) in the Extension Phase. The incidences of treatment-emergent adverse events were comparable between treatment groups (Table 2).
Conclusions: Overall, adjunctive perampanel was efficacious and well tolerated in patients with LGS regardless of the number of baseline ASMs. There were some differences in efficacy outcomes between patients with 2 ASMs vs ≥ 3 ASMs; however, no consistent trend was observed. Interpretation is limited due to small sample size and future research is warranted.
Funding: Eisai Co., Ltd., Eisai Inc., and Eisai Ltd.