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Brivaracetam in Unverricht‐Lundborg disease ( EPM 1): Results from two randomized, double‐blind, placebo‐controlled studies
Author(s) -
Kälviäinen Reetta,
Genton Pierre,
Andermann Eva,
Andermann Frederick,
Magaudda Adriana,
Frucht Steven J.,
Schlit AnneFrançoise,
Gerard Danielle,
Loge Christine,
Rosenstiel Philipp
Publication year - 2016
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.13275
Subject(s) - tolerability , placebo , myoclonus , medicine , anesthesia , randomized controlled trial , adverse effect , adjunctive treatment , clinical endpoint , randomization , alternative medicine , pathology
Summary Objective To evaluate efficacy, tolerability, and safety of adjunctive brivaracetam ( BRV ) in patients with Unverricht‐Lundborg disease ( EPM 1). Methods Two prospective, multicenter, double‐blind, phase III trials (N01187/ NCT 00357669; N01236/ NCT 00368251) in patients (≥16 years) with genetically ascertained EPM 1, showing moderate–severe myoclonus (action myoclonus score ≥30/160), randomized (1:1:1) to twice‐daily BRV (N01187: 50 or 150 mg/day; N01236: 5 or 150 mg/day), or placebo. Both studies comprised a baseline period (2 weeks), 2‐week up‐titration period, 12‐week stable‐dose maintenance period, and down‐titration or entry into long‐term follow‐up study. Symptoms of myoclonus were assessed by Unified Myoclonus Rating Scale ( UMRS ). Primary efficacy end point was percent reduction from baseline in action myoclonus score ( UMRS section 4) at last treatment visit. Safety assessments included treatment‐emergent adverse events ( TEAE s). Results N01187: 50 patients randomized, 47 completed; N01236: 56 patients randomized, 54 completed. Median (min–max) percent reduction from baseline in action myoclonus score is the following—N01187: placebo 5.6 (−81.3 to 53.8), pooled BRV group (primary efficacy analysis) 21.4 (−50.0 to 73.6), BRV 50 mg/day 26.3 (−35.8 to 69.2), BRV 150 mg/day 16.9 (−50.0 to 73.6); N01236: placebo 17.5 (−170 to 61.5), BRV 5 mg/day −4.6 (−430 to 81.8), BRV 150 mg/day (primary efficacy analysis) 12.3 (−58.3 to 96.9). Estimated differences versus placebo were not statistically significant. TEAE s were reported by 72–75% placebo‐treated and 56–83% BRV ‐treated patients. Significance Effect of BRV on action myoclonus was not statistically significant. However, action myoclonus score showed wide intrapatient variability and may not have been the optimal tool to measure severity of myoclonus in EPM 1. Both studies had very high completion rates (95.3% overall), and a high percentage of patients (88.7% overall) entered long‐term follow‐up; both likely to be influenced by good tolerability. These studies demonstrate the feasibility of rigorous trials in progressive myoclonic epilepsy.