title: 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.
  
  
  CONCLUSIONS
  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.affiliation: Kuopio Epilepsy Center, Kuopio University Hospital and Institute of Clinical Medicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.
authors.forename: Reetta
authors.initials: R
authors.lastname: Kälviäinen
authors.affiliation: Henri Gastaut-Centre Saint Paul Hospital, Marseille, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Genton
authors.affiliation: Neurogenetics Unit and Epilepsy Research Group, Montreal Neurological Hospital and Institute, Montreal, Quebec, Canada.|Department of Neurology & Neurosurgery and Human Genetics, McGill University, Montreal, Quebec, Canada.
authors.forename: Eva
authors.initials: E
authors.lastname: Andermann
authors.affiliation: Seizure Clinic and Epilepsy Research Group, Montreal Neurological Hospital and Institute, Montreal, Quebec, Canada.|Departments of Neurology & Neurosurgery and Pediatrics, McGill University, Montreal, Quebec, Canada.
authors.forename: Frederick
authors.initials: F
authors.lastname: Andermann
authors.affiliation: Department of Neurosciences, Epilepsy Center, University of Messina, Messina, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Magaudda
authors.affiliation: Department of Neurology, Columbia University Medical Center, New York, New York, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Frucht
authors.affiliation: UCB Pharma, Braine-l'Alleud, Belgium.
authors.forename: Anne-Françoise
authors.initials: AF
authors.lastname: Schlit
authors.affiliation: UCB Pharma, Braine-l'Alleud, Belgium.
authors.forename: Danielle
authors.initials: D
authors.lastname: Gerard
authors.affiliation: UCB Pharma, Braine-l'Alleud, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: de la Loge
authors.affiliation: UCB Pharma, Smyrna, Georgia, U.S.A.
authors.forename: Philipp
authors.initials: P
authors.lastname: von Rosenstiel
mesh_terms: D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants / Q000627:therapeutic use*; D002998:Clonazepam / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005632:Fructose / Q000031:analogs & derivatives / Q000627:therapeutic use; D006801:Humans; D007555:Isoxazoles / Q000627:therapeutic use; D000077287:Levetiracetam; D008297:Male; D008875:Middle Aged; D010634:Phenobarbital / Q000627:therapeutic use; D010889:Piracetam / Q000031:analogs & derivatives / Q000627:therapeutic use; D011760:Pyrrolidinones / Q000627:therapeutic use*; D000077236:Topiramate; D016896:Treatment Outcome; D020194:Unverricht-Lundborg Syndrome / Q000188:drug therapy*; D014635:Valproic Acid / Q000627:therapeutic use; D055815:Young Adult; D000078305:Zonisamide
chemical_list: D000927:Anticonvulsants; D007555:Isoxazoles; D011760:Pyrrolidinones; D000077236:Topiramate; D005632:Fructose; D000077287:Levetiracetam; D000078305:Zonisamide; D002998:Clonazepam; D014635:Valproic Acid; C482793:brivaracetam; D010634:Phenobarbital; D010889:Piracetam
keywords: Antiepileptic drugs; Efficacy; Progressive myoclonic epilepsy; Tolerability; Unified Myoclonus Rating Scale