Tolerability and efficacy of adjunctive brivaracetam in adults with focal seizures by concomitant antiseizure medication use: Pooled results from three phase 3 trials

Abstract

Objective: This study was undertaken to evaluate safety/tolerability and efficacy of adjunctive brivaracetam (BRV) in patients on one or two concomitant antiseizure medications (ASMs) and in patients on one specific concomitant ASM.

Methods: Post hoc analysis was made of double-blind trials (N01252/NCT00490035, N01253/NCT00464269, and N01358/NCT01261325) in adults with focal seizures randomized to BRV (50-200 mg/day; approved therapeutic dose range for adults) or placebo with concomitant ASM regimen unchanged throughout a 12-week evaluation period. Outcomes were analyzed in patients on one or two concomitant ASMs, and those on concomitant carbamazepine (CBZ), lamotrigine (LTG), oxcarbazepine (OXC), or valproate (VPA) only.

Results: Patients randomized to BRV with one or two concomitant ASMs, respectively (n = 181/557), reported similar incidences of treatment-emergent adverse events (TEAEs; 68.0%/66.4%), drug-related TEAEs (41.4%/41.5%), and TEAEs leading to discontinuation (6.6%/5.4%). Respective values for patients randomized to placebo with one or two concomitant ASMs (n = 95/331) were 60.0%/60.7% (TEAEs), 32.6%/30.2% (drug-related TEAEs), and 2.1%/4.5% (TEAEs leading to discontinuation). The incidences of TEAEs, drug-related TEAEs, and TEAEs leading to discontinuation by specific concomitant ASM (CBZ, LTG, OXC, VPA) were similar to the overall incidences in patients taking one concomitant ASM. In patients on one or two concomitant ASMs, respectively, 50% responder rates were numerically higher on BRV (42.3%/36.8% [n = 175/511]) versus placebo (18.3%/19.5% [n = 93/298]). Patients with one or two ASMs on BRV (n = 175/509) versus placebo (n = 92/298) also had numerically higher 100% responder rates (BRV, 9.1%/4.5%; placebo, 1.1%/.3%) and seizure freedom (6.9%/3.7%; 1.1%/0). For patients taking concomitant CBZ, LTG, OXC, or VPA, efficacy was numerically higher with BRV (n = 54/30/27/27) versus placebo (n = 34/13/10/14-15; 50% responder rates: BRV, 31.5%/30.0%/40.7%/70.4%; placebo, 17.6%/7.7%/20.0%/33.3%; 100% responder rates: BRV, 5.6%/10.0%/11.1%/11.1%; placebo, 0 for all; seizure freedom: BRV, 3.7%/6.7%/7.4%/11.1%; placebo, 0 for all).

Significance: Therapeutic doses of BRV were efficacious and well tolerated regardless of the number of concomitant ASMs (one or two) or specific concomitant ASM (CBZ, LTG, OXC, VPA).

Keywords: antiepileptic drug; epilepsy; randomized controlled trials; safety.

Conflict of interest statement

P.R. has received speaker or consultant fees from Arvelle Therapeutics, Eisai, GW Pharmaceuticals, LivaNova, and UCB Pharma. S.D., S.E., F.F., C.L., and X.N. are salaried employees of UCB Pharma and receive stock or stock options from their employment. V.B. has no conflicts of interest to disclose.

© 2022 UCB Pharma. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

Figures

FIGURE 1

Overall incidence of (A) treatment‐emergent adverse events (TEAEs) classified as psychiatric disorders and (B) TEAEs potentially associated with behavioral disorders by number of concomitant antiseizure medications (ASMs) and specific concomitant ASMs in patients on one concomitant ASM (patients received placebo or brivaracetam [BRV] in addition to a single concomitant ASM; safety set). CBZ, carbamazepine; LTG, lamotrigine; OXC, oxcarbazepine; VPA, valproate.

FIGURE 2

Efficacy outcomes by number of concomitant antiseizure medications (ASMs) and specific concomitant ASMs in patients on one concomitant ASM (patients received placebo or brivaracetam [BRV] in addition to a single concomitant ASM; intent‐to‐treat). (A) Fifty percent responder rate in focal seizures. (B) One hundred percent responder rate in focal seizures. (C) Seizure freedom (all seizure types). Patients were defined as having a 100% responder rate if they had a 100% reduction from baseline in focal seizure frequency. Patients were classified as seizure‐free if they did not report any seizure (any type, including focal seizures, generalized seizures, and unclassified seizures), and had completed their seizure diary for at least 90% of days during the treatment period and did not discontinue during the treatment period. Three patients were excluded from the 100% responder rate and seizure freedom analyses because the only seizures they reported occurred on the first day of the 100% responder rate seizure analysis period, which was 1 day before the seizure freedom analysis period commenced. CBZ, carbamazepine; LTG, lamotrigine; OXC, oxcarbazepine; VPA, valproate.