Adjunctive brivaracetam for uncontrolled focal and generalized epilepsies: Results of a phase III, double‐blind, randomized, placebo‐controlled, flexible‐dose trial

Abstract

SUMMARYPurpose: To evaluate the safety and tolerability of adjunctive brivaracetam (BRV), a high-affinity synaptic vesicle protein 2A (SV2A) ligand, in adults with uncontrolled epilepsy. Efficacy was also assessed in patients with focal seizures as a secondary objective, and explored by descriptive analysis in patients with generalized seizures. Methods: This was a phase III, randomized, double-blind, placebo (PBO)-controlled flexible dose trial (N01254/NCT00504881) in adults (16-70 years) with uncontrolled epilepsy (up to 20% could be patients with generalized epilepsy). After a prospective 4-week baseline, patients were randomized (3:1) to b.i.d. BRV or PBO, initiated at 20 mg/day and increased, as needed, to 150 mg/day during an 8-week dose-finding period. This was followed by an 8-week stable-dose maintenance period. The treatment period comprised the dose-finding period plus the maintenance period (16 weeks). Key Findings: A total of 480 patients were randomized (BRV 359, PBO 121); of these, 431 had focal epilepsy and 49 had generalized epilepsy. Ninety percent BRV-and 91.7% PBO-treated patients completed the study. Similar proportions of patients (BRV 66.0%, PBO 65.3%) reported adverse events (AEs) during the treatment period. AEs led to treatment discontinuation in 6.1% and 5.0% of BRV-and PBO-treated patients, respectively. The incidence of AEs declined from the dose-finding (BRV 56.0%, PBO 55.4%) to the maintenance (BRV 36.8%, PBO 40.9%) period. The most frequent AEs during the treatment period were headache (BRV 14.2% vs. PBO 19.8%), somnolence (BRV 11.1% vs. PBO 4.1%), and dizziness (BRV 8.6% vs. PBO 5.8%). The incidence of psychiatric AEs was similar for BRV and PBO (BRV 12.3%, PBO 11.6%). In patients with focal seizures, the baseline-adjusted percent reduction in seizure frequency/week in the BRV group (n = 323) over PBO (n = 108) was 7.3% (p = 0.125) during the treatment period. The median percent reduction in baseline-adjusted seizure frequency/ week was 26.9% BRV versus 18.9% PBO (p = 0.070), and the ≥50% responder rate was 30.3% BRV versus 16.7% PBO (p = 0.006). In patients with generalized seizures only, the number of seizure days/week decreased from 1.42 at baseline to 0.63 during the treatment period in BRV-treated patients (n = 36), and from 1.47 at baseline to 1.26 during the treatment period in PBO-treated patients (n = 13). The median percent reduction from baseline in generalized seizure days/week was 42.6% versus 20.7%, and the ≥50% responder rate was 44.4% versus 15.4% in BRV-treated and PBO-treated patients, respectively. Significance: Adjunctive BRV given at individualized tailored doses (20-150 mg/day) was well tolerated in adults with uncontrolled epilepsy, and our results provided support for further evaluation of efficacy in reducing focal and generalized seizures.

Brivaracetam, a Novel Antiepileptic Drug: Is it Effective and Safe? Results from One Phase III Randomized Trial

“…Although there was only a limited group receiving concomitant levetiracetam (<20%), this finding has been reported in other studies (2,3,10,11). These results suggest that using levetiracetam in combination with brivaracetam decreases the effect of brivaracetam.…”

Progress report on new antiepileptic drugs: A summary of the Twelfth Eilat Conference (EILAT XII)

“…Incidence of TEAEs was highest during the dose-finding period, decreasing during the A c c e p t e d M a n u s c r i p t 31 maintenance period (brivaracetam: 56.0% to 36.8%, placebo: 55.4 to 40.9%) (Kwan et al, 2014).…”

“…Two fixed-dose (N01253; NCT00464269 and N01252; NCT00490035) Ryvlin et al, 2014), and one flexible dose (N01254; NCT00504881) (Kwan et al, 2014), prospective, multicenter, randomized, double-blind, placebo-controlled, parallel-group Phase III trials have been completed.…”

“…In the approximately 20% of patients who received concomitant levetiracetam, no additional benefit in responder rates were seen (brivaracetam 50 mg/day: 12.8%, 100 mg/day: 15.0%, and placebo: 18.9%) (UCB, data on file). Study N01254 (Kwan et al, 2014) enrolled adult patients with focal (n=431) and generalized (n=49) epilepsy, with uncontrolled seizures despite treatment with 1-3…”

Adjunctive brivaracetam for patients with refractory partial seizures: A meta-analysis of randomized placebo-controlled trials

“…A previous meta-analysis involving two dose-ranging phase II studies showed that BRV might be efficacious and well tolerated as an adjunctive treatment in patients with refractory partial onset seizures (Gao et al, 2013). Recently, there have been increasing interests in the application of BRV in epilepsy patients and at least three phase III trials were published in year 2014 (Biton et al, 2014;Ryvlin et al, 2014;Kwan et al, 2014). Owing to recently published phase III clinical trials, the previous meta-analysis has become outdated.…”