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

Authors

  • Patrick Kwan,

    Corresponding author
    1. Division of Neurology, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China
    2. Departments of Medicine and Neurology, The University of Melbourne, Royal Melbourne Hospital, Melbourne, Victoria, Australia
    • Address correspondence to Patrick Kwan, Division of Neurology, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China. E-mail: patrickkwan@cuhk.edu.hk

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  • Eugen Trinka,

    1. Department of Neurology, Christian-Doppler-Klinik, Paracelsus Medical University, Salzburg, Austria
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  • Wim Van Paesschen,

    1. Department of Neurology, University Hospital Gasthuisberg, Leuven, Belgium
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  • Ivan Rektor,

    1. First Department of Neurology, St. Anne's University Hospital, School of Medicine, and Central European Centre for Technology (CEITEC), Masaryk University, Brno, Czech Republic
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  • Martin E. Johnson,

    1. UCB Pharma, Biostatistics US Group, Raleigh, North Carolina, U.S.A
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  • Sarah Lu

    1. UCB Pharma, CNS, Raleigh, North Carolina, U.S.A
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Summary

Purpose

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.

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