Efficacy and safety of extended-release oxcarbazepine (Oxtellar XR™) as adjunctive therapy in patients with refractory partial-onset seizures: a randomized controlled trial.

Publisher: Wiley-Blackwell Country of Publication: Denmark NLM ID: 0370336 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1600-0404 (Electronic) Linking ISSN: 00016314 NLM ISO Abbreviation: Acta Neurol Scand Subsets: MEDLINE

Publication: Copenhagen : Wiley-Blackwell
Original Publication: Copenhagen Munksgaard

Anticonvulsants/*therapeutic use ; Carbamazepine/*analogs & derivatives ; Epilepsies, Partial/*drug therapy; Adolescent ; Adult ; Aged ; Anticonvulsants/pharmacokinetics ; Carbamazepine/pharmacokinetics ; Carbamazepine/therapeutic use ; Dose-Response Relationship, Drug ; Double-Blind Method ; Drug Delivery Systems ; Female ; Follow-Up Studies ; Humans ; International Cooperation ; Male ; Middle Aged ; Oxcarbazepine ; Retrospective Studies ; Statistics, Nonparametric ; Young Adult

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.
(© 2013 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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Investigator: B Abou-Khalil; R Brower; D Burdette; J Cantero; M Carran; W Chumley; S Chung; J DeCerce; V Dhaduk; S Evans; J Feldman; G Ferencz; J Fessler; M Fisher; S Flitman; R Gerner; G Gibson; M Harris; R Hull; W Ibrahim; AF Jacobson; B Kirmani; P Klein; MM Mahdad; G Marsella; L Mate; SL McPherson; G Morris; P Olenjiczak; T Pang; R Pardo; J Pollard; J Savit; B Shihabuddin; L Strom; T Swanson; D Teeple; A Todorov; S Uddin; B Vazquez; R Verson; T Vidic; RA Wallis; E Waterhouse; R Yapundich; SN Ahmed; JF Clement; N Pillay; M Veilleux; J Alemán-Pedroza; F Castro-Farfan; E Díaz-Juarez; J Escamilla-Garza; J Pérez-Garcia; R Rángel-Guerra; M Renteria-Bilbao; S Reyes-Morales; I Rodriguez-Leyva; J Ruiz-Sandoval; G Sanchez-Arrioja; S Silva-Sanchez; F Vega-Boada; N Deleva; R Kalpachki; S Kastrev; D Maslarov; N Petrova; P Shotekov; I Staikov; P Stamenova; P Tsvetanov; Z Zahariev; S Basic; J Glavic; H Hecimovic; A Jurjevic; A Mrden; Z Poljakovic; R Susak; W Brola; P Czapinski; A Czlonkowska; W Drozdowski; U Fiszer; M Kapelusiak-Pielok; M Mazurkiewicz-Beldinska; W Moskal; E Motta; M Nastaj; G Opala; K Pierzchala; A Radman; T Rosochowicz; J Rozniecki; A Tutaj; A Wlodek; M Zubiel; CA Bulboaca; M Chiru; S Manescu; I Marginean; C Zaharia; A Agafina; G Avakyan; A Belova; B Beyn; E Bogdanov; A Gofman; A Gustov; N Koroleva; V Laskov; N Maslova; G Mishin; E Pankratov; N Pizova; I Poverenova; A Skoromets; E Vostrikova; E Yakupov; L Zaslavskiy
Keywords: adjunctive therapy; extended-release oxcarbazepine; partial-onset seizures; refractory epilepsy

0 (Anticonvulsants)
33CM23913M (Carbamazepine)
VZI5B1W380 (Oxcarbazepine)

Date Created: 20131224 Date Completed: 20140917 Latest Revision: 20211021

20221213

PMC4033571

10.1111/ane.12207

24359313