title: Efficacy and safety of extended-release oxcarbazepine (Oxtellar XR™) as adjunctive therapy in patients with refractory partial-onset seizures: a randomized controlled trial.
abstract: OBJECTIVE
  To evaluate the efficacy, tolerability, and safety of once-daily 1200 mg and 2400 mg SPN-804 (Oxtellar XR™, Supernus Pharmaceuticals), an extended-release tablet formulation of oxcarbazepine (OXC), added to 1-3 concomitant antiepileptic drugs (AEDs) in adults with refractory partial-onset seizures, with or without secondary generalization.
  
  
  METHODS
  The Prospective, Randomized Study of OXC XR in Subjects with Partial Epilepsy Refractory (PROSPER) study was a multinational, randomized, double-blind, parallel-group Phase 3 study. The primary efficacy endpoint was median percent reduction from baseline in monthly (28-day) seizure frequency for the 16-week double-blind treatment period in the intent-to-treat (ITT) population with analyzable seizure data. Other efficacy analyses included proportion of patients with ≥ 50% seizure reduction, proportion of patients seizure free, and the relationship between clinical response and plasma concentration.
  
  
  RESULTS
  Median percent reduction was -28.7% for placebo, -38.2% (P = 0.08 vs placebo) for once-daily SPN-804 1200 mg, and -42.9% (P = 0.003) for SPN-804 2400 mg. Responder rates were 28.1%, 36.1% (P = 0.08), and 40.7% (P = 0.02); 16-week seizure-free rates in a pragmatic ITT analysis were 3.3%, 4.9% (P = 0.59), and 11.4% (P = 0.008), respectively. When data were analyzed separately for study site clusters, a post hoc analysis demonstrated that both SPN-804 dosages were significantly superior to placebo in median percent seizure reduction (placebo: -13.3%; 1200 mg: -34.5%, P = 0.02; 2400 mg: -52.7%, P = 0.006) in the North American study site cluster. A concentration-response analysis also supported a clinically meaningful effect for 1200 mg. Adverse event types reflected the drug's established profile. Adverse event frequency was consistent with a pharmacokinetic profile in which SPN-804 produces lower peak plasma concentrations vs immediate-release OXC. Once-daily dosing was not associated with any new safety signals.
  
  
  CONCLUSIONS
  Adjunctive once-daily SPN-804 improved seizure control in patients with inadequately controlled partial-onset seizures. Adverse event occurrence and discontinuations due to adverse events suggest improved tolerability vs previously published data with immediate-release OXC.
authors.affiliation: NYU Comprehensive Epilepsy Center, New York, NY, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: French
authors.forename: P
authors.initials: P
authors.lastname: Baroldi
authors.forename: S T
authors.initials: ST
authors.lastname: Brittain
authors.forename: J K
authors.initials: JK
authors.lastname: Johnson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002220:Carbamazepine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D016503:Drug Delivery Systems; D004828:Epilepsies, Partial / Q000188:drug therapy*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007391:International Cooperation; D008297:Male; D008875:Middle Aged; D000078330:Oxcarbazepine; D012189:Retrospective Studies; D018709:Statistics, Nonparametric; D055815:Young Adult
chemical_list: D000927:Anticonvulsants; D002220:Carbamazepine; D000078330:Oxcarbazepine
keywords: adjunctive therapy; extended-release oxcarbazepine; partial-onset seizures; refractory epilepsy