Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures: A randomized historical-control phase III study based in North America

Michael R. Sperling, Jay Harvey, Todd Grinnell, Hailong Cheng, David Blum

Research output: Contribution to journalArticle

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Abstract

Summary Objective To assess the efficacy and safety of eslicarbazepine acetate (ESL) as monotherapy in North American patients with partial-onset seizures (POS). Methods 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%). Results 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%). Significance 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.

Original languageEnglish (US)
Pages (from-to)546-555
Number of pages10
JournalEpilepsia
Volume56
Issue number4
DOIs
StatePublished - Jan 1 2015

Fingerprint

North America
Seizures
Safety
Nasopharyngitis
eslicarbazepine acetate
Hyponatremia
Carbamazepine
Dizziness
Therapeutics
Anticonvulsants
Nausea
Fatigue
Headache

Keywords

  • Anticonvulsants
  • Antiepileptic drugs
  • Eslicarbazepine acetate
  • Monotherapy
  • Partial-onset seizures
  • Refractory epilepsy

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Efficacy and safety of conversion to monotherapy with eslicarbazepine acetate in adults with uncontrolled partial-onset seizures : A randomized historical-control phase III study based in North America. / Sperling, Michael R.; Harvey, Jay; Grinnell, Todd; Cheng, Hailong; Blum, David.

In: Epilepsia, Vol. 56, No. 4, 01.01.2015, p. 546-555.

Research output: Contribution to journalArticle

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abstract = "Summary Objective To assess the efficacy and safety of eslicarbazepine acetate (ESL) as monotherapy in North American patients with partial-onset seizures (POS). Methods 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{\%}). Results 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{\%}). Significance 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.",
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AU - Cheng, Hailong

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N2 - Summary Objective To assess the efficacy and safety of eslicarbazepine acetate (ESL) as monotherapy in North American patients with partial-onset seizures (POS). Methods 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%). Results 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%). Significance 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.

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