Efficacy and safety of brivaracetam for partial-onset seizures in 3 pooled clinical studies

Elinor Ben-Menachem, Rūta Mameniškienė, Pier Paolo Quarato, Pavel Klein, Jessica Gamage, Jimmy Schiemann, Martin E Johnson, John Whitesides, Belinda McDonough, Klaus Eckhardt, Elinor Ben-Menachem, Rūta Mameniškienė, Pier Paolo Quarato, Pavel Klein, Jessica Gamage, Jimmy Schiemann, Martin E Johnson, John Whitesides, Belinda McDonough, Klaus Eckhardt

Abstract

Objective: To assess the efficacy, safety, and tolerability of adjunctive brivaracetam (BRV), a selective, high-affinity ligand for SV2A, for treatment of partial-onset (focal) seizures (POS) in adults.

Methods: Data were pooled from patients (aged 16-80 years) with POS uncontrolled by 1 to 2 antiepileptic drugs receiving BRV 50, 100, or 200 mg/d or placebo, without titration, in 3 phase III studies of BRV (NCT00490035, NCT00464269, and NCT01261325, ClinicalTrials.gov, funded by UCB Pharma). The studies had an 8-week baseline and a 12-week treatment period. Patients receiving concomitant levetiracetam were excluded from the efficacy pool.

Results: In the efficacy population (n = 1,160), reduction over placebo (95% confidence interval) in baseline-adjusted POS frequency/28 days was 19.5% (8.0%-29.6%) for 50 mg/d (p = 0.0015), 24.4% (16.8%-31.2%) for 100 mg/d (p < 0.00001), and 24.0% (15.3%-31.8%) for 200 mg/d (p < 0.00001). The ≥50% responder rate was 34.2% (50 mg/d, p = 0.0015), 39.5% (100 mg/d, p < 0.00001), and 37.8% (200 mg/d, p = 0.00003) vs 20.3% for placebo (p < 0.01). Across the safety population groups (n = 1,262), 90.0% to 93.9% completed the studies. Treatment-emergent adverse events (TEAEs) were reported by 68.0% BRV overall (n = 803) and 62.1% placebo (n = 459). Serious TEAEs were reported by 3.0% (BRV) and 2.8% (placebo); 3 patients receiving BRV and one patient receiving placebo died. TEAEs in ≥5% patients taking BRV (vs placebo) were somnolence (15.2% vs 8.5%), dizziness (11.2% vs 7.2%), headache (9.6% vs 10.2%), and fatigue (8.7% vs 3.7%).

Conclusions: Adjunctive BRV was effective and generally well tolerated in adults with POS.

Classification of evidence: This analysis provides Class I evidence that adjunctive BRV is effective in reducing POS frequency in adults with epilepsy and uncontrolled seizures.

© 2016 American Academy of Neurology.

Figures

Figure 1. Study designs and patient disposition
Figure 1. Study designs and patient disposition
(A) Designs of phase III fixed-dose studies N01253, N01252, and N01358. Concomitant levetiracetam was limited to ≤20% of patients in studies N01252 and N01253 and was not permitted in study N01358. (B) Patient disposition (safety population). aPatients taking BRV 5 or 20 mg/d were excluded from the pooled analysis. BRV = brivaracetam; LTFU = long-term follow-up; PBO = placebo.
Figure 2. Primary efficacy outcomes
Figure 2. Primary efficacy outcomes
(A) Percent reduction over placebo in baseline-adjusted POS frequency/28 days. (B) ≥50% responder rate. BRV = brivaracetam; POS = partial-onset seizure.
Figure 3. Secondary efficacy outcomes
Figure 3. Secondary efficacy outcomes
(A) Median percent reduction in POS frequency from baseline. (B) Seizure freedom. (C) Categorized percent reduction in POS frequency per 28 days. BRV = brivaracetam; POS = partial-onset seizure.

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