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Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a historical-control phase III study.

ABSTRACT: Eslicarbazepine acetate (ESL, Aptiom®) is a once-daily (QD) anticonvulsant, approved as adjunctive treatment of partial-onset seizures (POS). It is extensively converted after oral administration to eslicarbazepine, and is believed to exert its effect through inhibition of voltage-gated sodium channels. The possible role of ESL as monotherapy to treat POS has not yet been established.This study was an 18-week, multicenter, randomized double-blind trial of gradual conversion to ESL monotherapy in adults with POS not well controlled by 1-2 antiepileptic drugs (AEDs), using historical data as the control. The study comprised an 8-week baseline period, a 2-week titration period, a 6-week AED conversion period, a 10-week monotherapy period, and either a 1-week taper period or optional entry to an open-label extension study. The primary endpoint compared the Kaplan-Meier (KM)-estimated 112-day exit rate with a threshold value calculated from the historical controls.There were 172 randomized patients; 154 (90%) entered the AED conversion period and 121 (70%) completed the study. The KM-estimated exit rates [confidence interval (CI)] were 15.6% [8.1-28.7%] for ESL 1200 mg, and 12.8% [7.5-21.5%] for ESL 1600 mg. The upper limits of the 95% CI KM-estimates were below the pre-specified threshold for historical control of 65.3%, indicating that ESL was efficacious in reducing seizure-related exits, compared with historical control. During the 18-week double-blind treatment period, median reductions in standardized seizure frequency occurred with ESL 1200 mg (36.1%) and ESL 1600 mg (47.5%). The responder rates (a 50% or greater reduction in seizure frequency from baseline) during the 18-week double-blind period and the monotherapy period, respectively, were 35.2% and 38.9% for ESL 1200 mg, and 46.0% and 46.0% for ESL 1600 mg. The overall adverse event profile was consistent with the known safety profile of ESL.These findings indicate that ESL monotherapy (1200 and 1600 mg QD) was efficacious and well tolerated in this study.NCT01091662 ; EudraCT No. 2010-018684-42.

SUBMITTER: Jacobson MP

PROVIDER: S-EPMC4397697 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a historical-control phase III study.

Jacobson Mercedes P MP Pazdera Ladislav L Bhatia Perminder P Grinnell Todd T Cheng Hailong H Blum David D

BMC neurology 20150328

<h4>Background</h4>Eslicarbazepine acetate (ESL, Aptiom®) is a once-daily (QD) anticonvulsant, approved as adjunctive treatment of partial-onset seizures (POS). It is extensively converted after oral administration to eslicarbazepine, and is believed to exert its effect through inhibition of voltage-gated sodium channels. The possible role of ESL as monotherapy to treat POS has not yet been established.<h4>Methods</h4>This study was an 18-week, multicenter, randomized double-blind trial of gradu ...[more]

PMID: 25880756

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Project description:To assess the efficacy and safety of eslicarbazepine acetate (ESL) as monotherapy in North American patients with partial-onset seizures (POS).This multicenter, randomized, double-blind "withdrawal to monotherapy" study used historical control data as the comparator. Adults with POS medically uncontrolled by one to two antiepileptic drugs gradually converted to ESL monotherapy. Following an 8-week baseline period, patients were randomized 2:1 to receive ESL 1,600 mg (n = 128) or 1,200 mg QD (n = 65) for 18 weeks. The primary end point was the proportion of patients meeting predefined exit criteria (signifying worsening seizure control). Treatment was considered effective if the 95% upper confidence limit (UCL) for the Kaplan-Meier estimated exit rate was lower than the exit rate threshold calculated from the historical control (65.3%).Kaplan-Meier estimated exit rates were: ESL 1,600 mg, 28.7% (95% CI 21.2-38.1%) and 1,200 mg, 44.4% (32.5-58.3%). The difference between doses was not significant (p = 0.07). For both doses, the 95% UCLs for the exit rate were ? 65.3%; ESL monotherapy was considered superior to the historical control. There was no statistically significant increase in the risk of study exit related to carbamazepine use. Nine (7.6%) and five patients (8.3%) remained seizure-free during the 10-week monotherapy period, while taking ESL 1,600 and 1,200 mg, respectively. The reductions in median standardized seizure frequency (seizures per 28 days) between baseline and the 18-week treatment period were: ESL 1,600 mg, 42% and 1,200 mg, 31%. Treatment-emergent adverse events (TEAEs) occurring in ? 10% of patients were dizziness, headache, fatigue, somnolence, nausea, and nasopharyngitis. The TEAE most frequently leading to discontinuation was hyponatremia (2.1%).ESL was efficacious and well tolerated as monotherapy in North American patients, and led to a reduction in seizure frequency. Exit rates for ESL 1,600 and 1,200 mg QD were superior to the historical control; the difference in exit rates between doses was not statistically significant.

Project description:To assess efficacy and safety of once-daily 8 or 12 mg perampanel, a noncompetitive ?-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor antagonist, when added to concomitant antiepileptic drugs (AEDs) in the treatment of drug-resistant partial-onset seizures.This was a multicenter, double-blind, placebo-controlled trial (ClinicalTrials.gov identifier: NCT00699972). Patients (?12 years, with ongoing seizures despite 1-3 AEDs) were randomized (1:1:1) to once-daily perampanel 8 mg, 12 mg, or placebo. Following baseline (6 weeks), patients entered a 19-week double-blind phase: 6-week titration (2 mg/week increments to target dose) followed by a 13-week maintenance period. Percent change in seizure frequency was the primary endpoint; 50% responder rate was the primary endpoint for EU registration.Of 388 patients randomized and treated, 387 provided seizure frequency data. Using this intent-to-treat population over the double-blind phase, the median percent change in seizure frequency was -21.0%, -26.3%, and -34.5% for placebo and perampanel 8 and 12 mg, respectively (p = 0.0261 and p = 0.0158 for 8 and 12 mg vs placebo, respectively). Fifty percent responder rates during the maintenance period were 26.4%, 37.6%, and 36.1%, respectively, for placebo, perampanel 8 mg, and perampanel 12 mg; these differences were not statistically significant for 8 mg (p = 0.0760) or 12 mg (p = 0.0914). Sixty-eight (17.5%) patients discontinued, including 40 (10.3%) for adverse events. Most frequent treatment-emergent adverse events were dizziness, somnolence, irritability, headache, fall, and ataxia.This trial demonstrated that once-daily, adjunctive perampanel at doses of 8 or 12 mg improved seizure control in patients with uncontrolled partial-onset seizures. Doses of perampanel 8 and 12 mg were safe, and tolerability was acceptable.This study provides Class I evidence that once-daily 8 and 12 mg doses of adjunctive perampanel are effective in patients with uncontrolled partial-onset seizures.

Project description:Introduction:Up to 30% of the patients diagnosed with epilepsy will continue suffering from seizures despite treatment with antiepileptic drugs, either in monotherapy or polytherapy. Hence, there remains the need to develop new effective and well-tolerated therapies. Aim:The objective of this article was to review the evidence for the efficacy and safety of eslicarbazepine acetate (ESL) as adjunctive treatment in adult patients with focal onset seizures. Evidence review:ESL is the newest, third-generation, single enantiomer member of the dibenzazepine family. Following oral administration, ESL is rapidly and extensively metabolized by hepatic first-pass hydrolysis to the active metabolite eslicarbazepine, which has linear, dose-proportional pharmacokinetics and low potential for drug-drug interactions. Eslicarbazepine works as a competitive blocker of the voltage gated sodium channels; unlike carbamazepine (CBZ) and oxcarbazepine (OXC), it has a lower affinity for the resting state of the channels, and reduces their availability by selectively enhancing slow inactivation. Efficacy and safety of ESL have been assessed in four randomized, Phase III clinical trials: the median relative reduction in standardized seizure frequency was 33.4% and 37.8% in the ESL 800 and 1,200 mg daily dose groups, and the responder rates were 33.8% and 43.1%, respectively. The incidence of treatment-emergent adverse events (TEAEs) increased with raising the dosage (ESL 400 mg: 63.8%, ESL 800 mg: 67.0%, ESL 1,200 mg: 73.1%). The TEAEs were generally mild to moderate in intensity, and the most common were dizziness, somnolence, headache and nausea. Open-label studies confirmed the findings from the pivotal trials and demonstrated sustained therapeutic effect of ESL over time and improvement of tolerability profile in patients switching from OXC/CBZ. No unexpected safety signals emerged over >5 years of follow-up. Conclusion:Once-daily adjunctive ESL at the doses of 800 and 1,200 mg was effective to reduce the seizure frequency and was fairly well tolerated in adults with focal onset epilepsy. Starting treatment at 400 mg/day, followed by 400 mg increments every 7-14 days, could provide the optimal balance of efficacy and tolerability.

Dataset Information

Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a historical-control phase III study.

Publications

Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: a historical-control phase III study.

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