Long-term safety, efficacy, and quality of life outcomes with adjunctive brivaracetam treatment at individualized doses in patients with epilepsy: An up to 11-year, open-label, follow-up trial

Abstract

Objective: To evaluate long-term safety/tolerability of brivaracetam at individualized doses ≤200 mg/d (primary) and maintenance of efficacy over time (secondary) in adults with focal seizures or primary generalized seizures (PGS) enrolled in phase 3, open-label, long-term follow-up trial N01199 (NCT00150800).

Methods: Patients ≥16 years of age who had completed double-blind, placebo-controlled adjunctive brivaracetam trials NCT00175825, NCT00490035, NCT00464269, or NCT00504881 were eligible. Outcomes included safety, efficacy, and quality of life.

Results: The safety set included 667 patients (focal seizures, 97.8%; PGS, 2.2%); the efficacy set included 648 patients with focal seizures and 15 patients with PGS. Overall, 49.2% of patients had ≥48 months of exposure. Treatment-emergent adverse events (TEAEs) occurred in 91.2% of all patients (91.3% of focal seizures group), brivaracetam discontinuation due to TEAEs in 14.8%, drug-related TEAEs in 56.7%, and serious TEAEs in 22.8%. The most common TEAEs in the focal seizures group (≥15%) were headache (25.3%) and dizziness (21.9%). Mean changes from baseline in Hospital Anxiety and Depression Scale scores at last value during 2-year evaluation were -0.7 (standard deviation [SD] = 4.3) and -0.2 (SD = 4.4) overall. In the focal seizures group, median reduction from baseline in focal seizure frequency/28 days was 57.3%, 50% responder rate was 55.6%, and 6-month and 12-month seizure freedom rates were 30.3% and 20.3%, respectively. Efficacy outcomes improved by exposure duration cohort and then stabilized through the 108-month cohort. Mean improvement from baseline in Patient-Weighted Quality of Life in Epilepsy Inventory total score (efficacy set) was 5.7 (SD = 16.1, Cohen's d = 0.35) at month 12 and 6.5 (SD = 18.0, Cohen's d = 0.36) at month 24.

Significance: Adjunctive brivaracetam was well tolerated, with a good safety profile in long-term use in adults with epilepsy at individualized doses. Approximately half of the patients remained in the trial at 4 years. Brivaracetam reduced focal seizure frequency versus baseline. Efficacy improved with increasing exposure duration and remained stable through the 9-year cohort.

Keywords: antiepileptic drug; focal seizure; hospital anxiety and depression scale; primary generalized seizure; seizure control; tolerability.

Conflict of interest statement

T.J.O. has received support from and/or has served as a paid consultant for Eisai Pharmaceuticals, National Health and Medical Research Council, National Institute of Neurological Disorders and Stroke, Praxis Precision Medicines, Royal Melbourne Hospital Neuroscience Foundation, UCB Pharma, and Zynerba Pharmaceuticals. S.B., A.‐L.S., and S.Y. are employees of UCB Pharma. S.B. has received UCB Pharma stocks from his employment. Q.H. was an employee of UCB Pharma at the time when the trial was conducted. V.B. has no conflicts of interest to report. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

© 2020 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.

Figures

FIGURE 1

Fifty percent responder rate for focal seizure frequency from baseline of previous trial (focal seizure efficacy set). M, months; m, month; n, number of patients who achieved at least a 50% reduction in focal seizure frequency from baseline; N, total number of patients assessed in each exposure duration cohort. aPercentages for the overall summary for each exposure duration cohort were relative to the number of patients included in the cohort; exposure duration cohorts defined groups of patients with at least the specified duration of exposure

FIGURE 2

Continuous seizure freedom for ≥6 months and ≥12 months at any time during brivaracetam treatment in patients with focal seizures (focal seizure efficacy set). Percentages are relative to the number of patients within each exposure duration cohort. Patients had to have seizure diary entries for at least 90% of days within the seizure‐free interval. Patients whose duration of brivaracetam treatment was less than the duration of seizure freedom failed for seizure freedom. an = number of patients who reported no seizures with brivaracetam for at least 6 and 12 months at any time during treatment. bn = number of patients who reported no seizures with brivaracetam for at least 6 and 12 months at any time during the cohort interval. <?oxy_insert_start ?>m, month; N, total number of patients assessed in each exposure duration cohort<?oxy_insert_end ?>