Effect of lifetime antiepileptic drug treatment history on efficacy and tolerability of adjunctive brivaracetam in adults with focal seizures: Posthoc analysis of a randomized, placebo-controlled trial

Objective: To evaluate the efficacy and tolerability of adjunctive brivaracetam (BRV) in adults with focal seizures by the number of lifetime (previous and concomitant) antiepileptic drugs (AEDs). Methods: Post-hoc analysis of data from N01358 (NCT01261325), a randomized, double-blind, placebo (PBO)controlled Phase III trial evaluating BRV 100 and 200 mg/day in patients >= 16 years of age with uncontrolled focal seizures. Efficacy and tolerability outcomes were assessed for the 12-week Treatment Period in subgroups of patients with 1-2, 3-4, 5-6, or >= 7 lifetime AEDs. Results: 764 patients received at least one dose of trial medication (BRV: 503; PBO: 261; Safety Set), of whom 14.3% had 1-2, 20.8% had 3-4, 21.3% had 5-6, and 43.6% had >= 7 lifetime AEDs. In all lifetime AED subgroups, > 85% of patients completed the trial. Patients with a higher number of lifetime AEDs had a younger age at epilepsy onset, longer epilepsy duration, and higher baseline seizure frequency. In patients on BRV, 50% responder rates were 49.3%, 44.4%, 47.2% and 27.4% in patients with 1-2 (n = 75), 3-4 (n = 99), 5-6 (n = 108) and >= 7 (n = 219) lifetime AEDs; 75% responder rates were 36.0%, 21.2%, 22.2% and 12.3%. In patients on PBO, 50% responder rates were 35.3%, 25.9%, 20.4% and 15.9% in patients with 1-2 (n = 34), 3-4 (n = 58), 5-6 (n = 54) and >= 7 (n = 113) lifetime AEDs; 75% responder rates were 26.5%, 6.9%, 3.7% and 4.4%. The Kaplan-Meier estimated probability of patients achieving a sustained 50% or 75% response from the first day of treatment was generally higher in patients with a lower number of lifetime AEDs (both in patients on BRV and PBO). In patients on adjunctive BRV, the incidence of drug related treatment-emergent adverse events (TEAEs) was 34.7%, 26.0%, 44.4% and 47.7% in patients with 1-2 (n = 75), 3-4 (n = 100), 5-6 (n = 108) and >= 7 (n = 220) lifetime AEDs; the incidence of discontinuations due to TEAEs was 1.3%, 3.0%, 8.3% and 10.5%. Conclusions: This post-hoc analysis suggests a numerically higher response to adjunctive BRV in patients with fewer lifetime AEDs. The lowest response was observed in patients with >= 7 lifetime AEDs, although these patients could also benefit from adjunctive BRV treatment. Patients with fewer lifetime AEDs had lower discontinuation of BRV due to TEAEs.