Brivaracetam in Unverricht-Lundborg disease (EPM1): Results from two randomized, double-blind, placebo-controlled studies.

Abstract

OBJECTIVE:

To evaluate efficacy, tolerability, and safety of adjunctive brivaracetam (BRV) in patients with Unverricht-Lundborg disease (EPM1).

METHODS:

Two prospective, multicenter, double-blind, phase III trials (N01187/NCT00357669; N01236/NCT00368251) in patients (≥16 years) with genetically ascertained EPM1, 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 (TEAEs).

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. TEAEs 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 EPM1. 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.

• Authors: Reetta Kälviäinen, Pierre Genton, Eva Andermann, Frederick Andermann, Adriana Magaudda, Steven J Frucht, Anne-Françoise Schlit, Danielle Gerard, Christine de la Loge, Philipp von Rosenstiel
• Journal: Epilepsia (Epilepsia) Vol. 57 Issue 2 Pg. 210-21 (Feb 2016) ISSN: 1528-1167 [Electronic] United States
• PMID: 26666500 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.

Chemical References

• Anticonvulsants
• Isoxazoles
• Pyrrolidinones
• Topiramate
• Fructose
• Levetiracetam
• Zonisamide
• Clonazepam
• Valproic Acid
• brivaracetam
• Phenobarbital
• Piracetam

Topics

• Adolescent
• Adult
• Anticonvulsants (therapeutic use)
• Clonazepam (therapeutic use)
• Dose-Response Relationship, Drug
• Double-Blind Method
• Drug Therapy, Combination
• Female
• Fructose (analogs & derivatives, therapeutic use)
• Humans
• Isoxazoles (therapeutic use)
• Levetiracetam
• Male
• Middle Aged
• Phenobarbital (therapeutic use)
• Piracetam (analogs & derivatives, therapeutic use)
• Pyrrolidinones (therapeutic use)
• Topiramate
• Treatment Outcome
• Unverricht-Lundborg Syndrome (drug therapy)
• Valproic Acid (therapeutic use)
• Young Adult
• Zonisamide