title: Examining the clinical utility of lacosamide: pooled analyses of three phase II/III clinical trials.
abstract: BACKGROUND
  Lacosamide is an antiepileptic drug (AED) approved for the adjunctive treatment of partial-onset seizures in adults. Completed phase II/III clinical trials of lacosamide provide a valuable opportunity to evaluate clinically relevant aspects of the resulting large patient pool.
  
  
  OBJECTIVE
  To provide insight into the clinical utility of lacosamide by performing a priori-defined and post hoc analyses on a large, pooled patient population.
  
  
  METHODS
  Pooled data from three randomized, double-blind, multicentre, placebo-controlled phase II/III trials.
  
  
  METHODS
  Adult patients with partial-onset seizures with or without secondary generalization (N = 1294).
  
  
  METHODS
  Four- to six-week titration followed by 12-week maintenance treatment with lacosamide (Vimpat®) 200, 400 or 600 mg/day or placebo.
  
  
  METHODS
  A priori-defined primary efficacy variables for the pooled analysis were change in seizure frequency per 28 days and the proportion of patients experiencing a ≥50% reduction in seizure frequency (50% responder rate) from Baseline to the Maintenance Phase; a priori-defined secondary efficacy variables were the proportion of patients achieving a ≥75% reduction in seizure frequency from Baseline to the Maintenance Phase (75% responder rate), the proportion of Maintenance Phase completers remaining seizure free throughout the entire Maintenance Phase and the percentage of seizure-free days during the Maintenance Phase for patients entering the Maintenance Phase. The pooled analyses of the change in seizure frequency, and 50% and 75% responder rates were performed with an intent-to-treat (ITT) approach, including all patients receiving at least one dose of trial medication and having at least one post-baseline efficacy assessment. Similar analyses of the two primary efficacy variables and 75% responder rates were also performed using a modified ITT population (ITTm) that included ITT patients who entered the Maintenance Phase. Additional post hoc efficacy analyses were an evaluation of onset of efficacy and assessment of efficacy in patients grouped by prior surgical history and individual concomitant AED use. In addition, pharmacokinetic-pharmacodynamic modelling was performed, and safety data were assessed.
  
  
  RESULTS
  In this pooled analysis of 1294 difficult-to-treat patients, all three dosages of lacosamide (200, 400 and 600 mg/day) showed a significant improvement compared with placebo for median percent seizure reduction (ITT and ITTm; p < 0.05 for 200 mg/day, p < 0.001 for 400 and 600 mg/day), as well as for 50% responder rate (ITT and ITTm; p < 0.05 for 200 mg/day, p < 0.001 for 400 and 600 mg/day). Evaluation of 75% responder rate in the phase II/III pooled population showed that a significantly higher proportion of patients randomized to lacosamide 400 or 600 mg/day achieved a ≥75% reduction in seizure frequency compared with placebo (ITT and ITTm; p < 0.001); statistical significance was not observed for lacosamide 200 mg/day (ITT and ITTm). A total of 2.7%, 3.3% and 4.8% of patients completing the Maintenance Phase in the lacosamide 200, 400 and 600 mg/day groups, respectively, experienced no seizures throughout the entire Maintenance Phase (placebo group = 0.9%). The mean change from baseline in the percentage of seizure-free days in patients entering the Maintenance Phase for the phase II/III pool was 8.0%, 11.6% and 14.7% with lacosamide 200 (p = 0.077), 400 (p < 0.001) and 600 (p < 0.001) mg/day groups, respectively, compared with 6.1% in the placebo group. The onset of efficacy relative to placebo was evident by the first week of treatment with lacosamide. Efficacy was similar in lacosamide-treated patients reporting prior surgical intervention for epilepsy compared to lacosamide-treated patients with no prior surgical intervention. Lacosamide showed a reduction in seizures, regardless of the concomitant AEDs used. The preferred pharmacokinetic-pharmacodynamic model (E(max)) supported the therapeutic dose range of lacosamide, and no additional safety concerns were identified in the phase II/III pooled analysis.
  
  
  CONCLUSIONS
  Results of these a priori-defined and post hoc pooled data analyses from phase II/III trials demonstrate that lacosamide effectively reduces seizures in patients at all three dosages evaluated with an early onset of efficacy, regardless of patient surgical history and concomitant AED regimen.
authors.affiliation: Barrow Neurological Institute, Phoenix, Arizona, USA. steve.chung@chw.edu
authors.forename: Steve
authors.initials: S
authors.lastname: Chung
authors.forename: Elinor
authors.initials: E
authors.lastname: Ben-Menachem
authors.forename: Michael R
authors.initials: MR
authors.lastname: Sperling
authors.forename: William
authors.initials: W
authors.lastname: Rosenfeld
authors.forename: Nathan B
authors.initials: NB
authors.lastname: Fountain
authors.forename: Selim
authors.initials: S
authors.lastname: Benbadis
authors.forename: David
authors.initials: D
authors.lastname: Hebert
authors.forename: Jouko
authors.initials: J
authors.lastname: Isojärvi
authors.forename: Pamela
authors.initials: P
authors.lastname: Doty
mesh_terms: D000081:Acetamides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000328:Adult; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004828:Epilepsies, Partial / Q000188:drug therapy* / Q000503:physiopathology / Q000601:surgery; D005260:Female; D006801:Humans; D000078334:Lacosamide; D008297:Male; D008954:Models, Biological; D015337:Multicenter Studies as Topic; D016032:Randomized Controlled Trials as Topic; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000081:Acetamides; D000927:Anticonvulsants; D000078334:Lacosamide