Time course of drug-related treatment-emergent adverse side effects of brivaracetam.

Objective: Treatment-emergent adverse events (TEAEs) in clinical trials are typically reported for the full duration of the treatment period including titration and maintenance. Drug-related central nervous system (CNS) TEAEs are common with antiseizure medications (ASMs) and can affect drug tolerability. In this report, we test the hypothesis that drug-related CNS TEAEs have early onset and decrease with time. Unlike prior ASM clinical trials, a novel design was used for brivaracetam (BRV) without initial drug titration allowing assessment of habituation to TEAEs separate from dose titration.
Methods: Data were pooled from three studies (N01252 [NCT00490035], N01253 [NCT00464269], N01358 [NCT01261325]) in adult patients (≥16 years of age) with focal seizures receiving BRV adjunctive therapy. This post hoc analysis reports data on the prevalence and incidence of all drug-related CNS TEAEs and all TEAEs over time in patients who received BRV doses of 50-200 mg/day (without titration) vs. placebo during a 12-week treatment period.
Results: A total of 1262 patients received the following: placebo (n = 459), BRV 50 mg/day (n = 200), BRV 100 mg/day (n = 353), and BRV 200 mg/day (n = 250). Both the incidence (p < .0001) and prevalence (p < .0001) of drug-related CNS TEAEs (all with frequency ≥ 5%) changed across time with peak TEAEs in week 1 then significantly reducing over the first 6 weeks for prevalence and the first 3 weeks for incidence.
Conclusions: Drug-related CNS TEAEs occurred early and substantially habituated over several weeks. TEAEs of ASMs might be better represented by division into early and late phases to guide clinician monitoring and patient expectations.
Competing Interests: Declaration of competing interest Dr. Meador has received research support from the National Institutes of Health and Sunovion Pharmaceuticals, and travel support from UCB Pharma. The Epilepsy Study Consortium pays Dr. Meador's university for his research consultant time related to Eisai, GW Pharmaceuticals, NeuroPace, Novartis, Supernus, Upsher-Smith Laboratories, and UCB Pharma. C. Laloyaux, S. Elmoufti, T. Gasalla, and M. Martin are employees of UCB Pharma. J. Fishman was an employee of UCB Pharma at the time this analysis was conducted. Dr. Klein has served as a consultant for Abbott; served on medical advisory boards for Alliance and Aquestive; was a consultant for Aquestive, Eisai, SK Life Sciences, Sunovion, and UCB Pharma; a speaker for Aquestive, Eisai, Sunovion, and UCB Pharma; and has received research support from Lundbeck.
(Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)