Conversion to eslicarbazepine acetate monotherapy: A pooled analysis of 2 phase III studies

Abstract

Objective: To assess the efficacy and safety of eslicarbazepine acetate (ESL) monotherapy.

Methods: This post hoc pooled analysis of 2 randomized double-blind studies (093-045 and -046) included adults with partial-onset seizures medically uncontrolled by 1 or 2 antiepileptic drugs (AEDs). Following the baseline period (8 weeks), eligible patients were randomized 2:1 to receive ESL 1,600 mg or 1,200 mg once daily for 18 weeks; the primary endpoint was study exit by meeting predefined exit criteria (signifying worsening seizure control). In each study, treatment was considered effective if the upper 95% confidence limit for exit rate was lower than the historical control threshold (65.3%).

Results: Pooled exit rates were as follows: ESL 1,600 mg = 20.6% (95% confidence interval: 15.6%-26.8%); ESL 1,200 mg = 30.8% (23.0%-40.5%). Use of 2 baseline AEDs or rescue medication, US location, epilepsy duration ≥20 years, and higher maximum baseline seizure frequency were associated with higher exit risks. Median percent reductions in standardized seizure frequency between baseline and the 18-week double-blind period were as follows: ESL 1,600 mg = 43.2%; ESL 1,200 mg = 35.7%; baseline carbamazepine use was associated with smaller reductions. Safety profiles were similar between ESL doses.

Conclusions: Exit rates for ESL monotherapy (1,600 mg and 1,200 mg once daily) were lower than the historical control threshold, irrespective of baseline AED use and region, with no additional safety concerns identified. Clinical factors and location clearly influence treatment responses in conversion-to-monotherapy trials.

Classification of evidence: This pooled analysis provides Class IV evidence that for adults with medically uncontrolled partial-onset seizures, ESL monotherapy is well tolerated and effective.

Figure 1. Kaplan–Meier analysis of exit rates (efficacy population): Pooled population (A) and individual studies and pooled population (B)

CI = confidence interval; ESL = eslicarbazepine acetate; QD = once-daily; US = United States.

Figure 2. Subgroup analyses of exit rates (pooled efficacy population): Influence of geographic region on exit rate (US vs non-US regions) (A), of baseline AED use (AEDs used by ≥15% of patients) on exit rate (B), and of patient characteristics on risk of study exit (pooled efficacy population) (C)

Note that for age, baseline body weight, and maximum 2- or 28-day seizure rate, the hazard ratio is displayed for a single unit change; otherwise, it is shown for the referenced group compared to those without the stated factor. VPA included all dosage forms combined unless otherwise stated (including VPA, sodium valproate, divalproex sodium, etc.). ^aBZD derivatives used before study treatment (prior), after initiation of the AED conversion period as rescue or emergency medication (after), or only after study treatment (not prior, after). AED = antiepileptic drug; B/L = baseline; BZD = benzodiazepine; CBZ = carbamazepine; CI = confidence interval; CP = complex partial seizure; duration = duration of epilepsy; ESL = eslicarbazepine acetate; LEV = levetiracetam; LTG = lamotrigine; OXC = oxcarbazepine; PHT = phenytoin; SGTC = secondarily generalized tonic-clonic seizures (also referred to as complex partial seizures with secondary generalization); sz = seizure; TOP = topiramate; US = United States; VNS = vagal nerve stimulator; VPA = valproic acid.

Figure 3. Median percentage reduction in standardized seizure frequency overall and by baseline AED

Median percentage reduction in standardized seizure frequency (seizures per 28 days; between baseline and the 18-week treatment period) overall and by baseline AED (for AEDs used by ≥15% of patients during baseline; efficacy population). AED = antiepileptic drug; CBZ = carbamazepine; ESL = eslicarbazepine acetate; LEV = levetiracetam; LTG = lamotrigine; VPA = valproic acid.