Efficacy and safety of eslicarbazepine acetate as adjunctive treatment in adults with refractory partial‐onset seizures: A randomized, double‐blind, placebo‐controlled, parallel‐group phase III study

Abstract

SUMMARYPurpose: To study the efficacy and safety of eslicarbazepine acetate (ESL) as adjunctive therapy for refractory partial seizures in adults with ‡4 partial-onset seizures (simple or complex, with or without secondary generalization) per 4 weeks despite treatment with 1-2 antiepileptic drugs (AEDs). Methods: This multicenter, parallel-group study had an 8-week, single-blind, placebo baseline phase, after which patients were randomized to placebo (n = 102) or once-daily ESL 400 mg (n = 100), 800 mg (n = 98), or 1,200 mg (n = 102) in the double-blind treatment phase. ESL starting dose was 400 mg; thereafter, ESL was titrated at weekly 400-mg steps to the full maintenance dose (12 weeks). Results: Seizure frequency adjusted per 4 weeks over the maintenance period (primary endpoint) was significantly lower than placebo in the ESL 1,200-mg (p = 0.0003) and 800-mg (p = 0.0028) groups [analysis of covariance (ANCOVA) of logtransformed seizure frequency]. Responder rate was 20% (placebo), 23% (400 mg), 34% (800 mg), and 43% (1,200 mg). Median relative reduction in seizure frequency was 16% (placebo), 26% (400 mg), 36% (800 mg), and 45% (1,200 mg). The most frequent concomitant AEDs were carbamazepine (56-62% of patients), lamotrigine (25-27%), and valproic acid (22-28%). Similar efficacy results were obtained in patients administered ESL with or without carbamazepine as concomitant AED. Discontinuation rates caused by adverse events (AEs) were 3.9% (placebo), 4% (400 mg), 8.2% (800 mg), and 19.6% (1,200 mg). AEs in >10% of any group were dizziness, headache, and diplopia. Most AEs were mild or moderate. Discussion: ESL, 800 and 1,200 mg once-daily, was well tolerated and more effective than placebo in patients who were refractory to treatment with one or two concomitant AEDs.

Exposure-safety and efficacy response relationships and population pharmacokinetics of eslicarbazepine acetate

“…The three ESL Phase 3 studies (2093‐301 [NCT00957684], 2093‐302 [NCT00957047], and 2093‐304 [NCT00988429], hereafter defined as Studies 301, 302, and 304; registered at ClinicalTrials.gov) were randomized, double‐blind, placebo−controlled, multicenter studies assessing the efficacy and tolerability of oral QD adjunctive ESL 400 mg (Studies 301 and 302 only), 800 mg, and 1200 mg 14, 15, 16. One thousand four hundred and 47 adult patients with at least four FOS within the 4‐week period prior to screening despite treatment with 1‐3 concomitant AEDs were randomized to treatment.…”

“…A population PK model for eslicarbazepine was previously developed13 using data from Phase 3 Studies 301, 302, and 30314, 15, 17 and was later refined using data from 11 Phase 1 studies and three Phase 3 studies (Studies 301, 302, and 304). Data from 500/1039 of the subjects included in the current model were also included in the previously developed model.…”

Eslicarbazepine acetate as adjunctive therapy in clinical practice: ESLADOBA study

“…Nevertheless, the incidence of refractory epilepsy remains high, and 20%‐40% of the patients with newly diagnosed epilepsy will become refractory to treatment, with potentially devastating consequences 1. Besides the concerns about efficacy, the majority of the currently available AEDs are commonly associated with a risk of adverse events 2. Therefore, there is still a need to further develop AEDs that are effective and safe in the treatment of this condition, especially because add‐on therapy with newer AEDs is suggested for patients with refractory epilepsy 3…”

“…The efficacy and safety/tolerability of ESL as adjunctive AED have been established in several randomized controlled trials (RCTs) 2, 6, 7, 8. In general, the patients enrolled in these studies had long‐standing epilepsy (mean duration in three phase III trials was equal to or over 22 years in all treatment groups,9 a high seizure frequency in the four prior weeks to screening,8, 9 and the majority was treated with two concomitant AEDs8, 9), indicating that the populations included severe refractory patients.…”

“…When compared to the phase III trials,2, 6, 7, 8 this study will potentially allow us to evaluate a less refractory population by focusing on patients exclusively treated with one baseline AED.…”