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 N01114 was conducted to evaluate the efficacy and tolerability of BRV when used as adjunctive treatment in patients with refractory partial-onset epilepsy.Methods: Phase II, double-blind, randomised, parallel-group, placebo-controlled, dose-ranging study. Patients (age 16-65 yrs) with focal epilepsy, uncontrolled on 1-2 antiepileptic drugs, experiencing ≥4 partial-onset seizures (with/without secondary generalisation) per 4-week baseline, were included. Eligible patients were randomised to BRV 50 mg/day (BRV50), BRV 150 mg/day (BRV150), or placebo (PBO), administered BID. BRV dosing was initiated at 50 mg/day, with 3-week titration for BRV150. 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 maintenance 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), laboratory parameters, ECG and vital signs.Results: 157 patients were randomised (PBO n=52, BRV50 n=53, BRV150 n=52); 148 completed the study. Primary efficacy endpoint of reduction in weekly partial-onset seizure frequency over PBO was 14.7% for BRV50 (p=0.093) and 13.6% for BRV150 (p=0.124). Median percent reductions in partial-onset seizure frequency from baseline were 18.9% (PBO), 38.2% (BRV50; p=0.017 vs. PBO) and 30.0% (BRV150; p=0.113 vs. PBO). Responder rates were 23.1% (PBO), 39.6% (BRV50) and 33.3% (BRV150). Seizure freedom rates were 1.9% (PBO), 9.4% (BRV50) and 5.9% (BRV150). BRV was well tolerated. AEs reported were mild-to-moderate and their incidence was similar between treatment groups. Conclusions: Although the study failed to show statistically significant differences between treatment and PBO in the primary efficacy analysis, there was a clear differentiation on active treatment, as supported by secondary endpoints, such as seizure reduction from baseline. Increasing the BRV dose to 150 mg/day did not add therapeutic efficacy in this study. BRV was well tolerated, with a tolerability profile similar to that of PBO. BRV 50 mg/day appears to be an appropriate dose for this patient population (responder rate 39.6%, seizure freedom rate 9.4%). UCB S.A. Funded