Abstracts

Rationale: Brivaracetam (BRV, ucb 34714) is a novel SV2A ligand, shown to be more potent and efficacious than levetiracetam in animal models of epilepsy. However, unlike levetiracetam, BRV also has inhibitory activity at neuronal voltage-dependent sodium channels. Study N01193 was designed to evaluate the efficacy and tolerability of BRV when used as adjunctive treatment in patients with refractory partial-onset seizures.Methods: Phase II, double-blind, randomized, parallel-group, placebo-controlled, dose-ranging study. Patients (age 16-65 yrs) with focal epilepsy, uncontrolled on 1-2 antiepileptic drugs, were included if they experienced ≥4 partial-onset seizures (with/without secondary generalization) per 4 weeks baseline. Eligible patients were randomized to 5, 20, or 50 mg/day BRV (BRV5, BRV20, BRV50 respectively), administered BID without uptitration, or placebo (PBO). Efficacy was assessed as reduction from baseline in weekly seizure frequency, responder rate (response defined as ≥50% seizure frequency reduction) and seizure freedom rate, assessed over a 7 week treatment period. Primary efficacy analysis was based on a mixed effect model, comparing log-transformed weekly seizure frequencies. Tolerability was assessed by evaluating adverse events (AEs).Results: Intent-to-treat population consisted of 208 patients (PBO n=54, BRV5 n=50, BRV20 n=52, BRV50 n=52); 197 completed the study. Reductions in weekly partial-onset seizure frequency over PBO were 9.8% (BRV5; p=0.240), 14.9% (BRV20; p=0.062) and 22.1% (BRV50; p=0.004). Median percent reductions in seizure frequency from baseline were 21.7% (PBO), 29.9% (BRV5), 42.6% (BRV20) and 53.1% (BRV50). Responder rates were 16.7% (PBO), 32.0% (BRV5), 44.2% (BRV20) and 55.8% (BRV50). Seizure freedom rates were 1.9% (PBO), 8.0% (BRV5), 7.7% (BRV20) and 7.7% (BRV50). BRV was well tolerated; AEs were mild-to-moderate and similar between BRV and PBO groups in terms of frequency.Conclusions: BRV was efficacious and well tolerated as adjunctive treatment in adults with refractory partial-onset seizures with/without secondary generalization and showed a strong dose-response relationship. BRV’s tolerability profile was favorable at all doses studied and similar to that of PBO. BRV 50 mg/day appears to be the most effective dose (responder rate 55.8%, seizure freedom rate 7.7%) and to be an appropriate dose for this patient population. UCB S.A. Funded