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Efficacy and safety of pregabalin versus levetiracetam as adjunctive therapy in patients with partial seizures: a randomized, double-blind, noninferiority trial.

Epilepsia (2014-06-07)
Gaetano Zaccara, Mary Almas, Verne Pitman, Lloyd Knapp, Holly Posner
ABSTRACT

To assess the comparative efficacy and safety of pregabalin and levetiracetam for the reduction of seizure frequency in patients with partial seizures. This was a randomized, double-blind, flexible-dose, parallel-group noninferiority study of pregabalin and levetiracetam (randomized 1:1) as adjunctive treatment in adult patients with refractory partial seizures. The study included a 6-week baseline phase, 4-week dose-escalation phase, and 12-week maintenance phase. The primary endpoint was the proportion of patients with a ≥ 50% reduction in 28-day seizure rate during the 12-week maintenance phase, as compared with baseline. Noninferiority of pregabalin was declared if the lower limit of the 95% confidence interval (CI) for the difference in responder rates was greater than the prespecified noninferiority margin of -12%. A key secondary endpoint was the percent change from baseline in 28-day seizure rate during the dose-escalation and maintenance phases. Five hundred nine patients were randomized to pregabalin (n = 254) or levetiracetam (n = 255) and 418 (208 pregabalin, 210 levetiracetam) completed the maintenance phase. With both pregabalin and levetiracetam, the proportion of patients with a ≥ 50% reduction in 28-day seizure rate was 0.59 (difference between groups [95% CI], 0.00 [-0.08 to 0.09]). Because the lower bound of the 95% CI was greater than the prespecified noninferiority margin of -12%, pregabalin was not inferior to levetiracetam. There was no significant difference between pregabalin and levetiracetam in the percent change in 28-day seizure rate (median difference [95% CI], 4.1 [-2.6 to 10.9], p = 0.3571). In a post hoc analysis, the proportion of patients who were seizure-free for the maintenance phase was lower with pregabalin (8.4%) than with levetiracetam (16.2%), p = 0.0155. Safety profiles were similar and consistent with prior trials. These results indicate that pregabalin is noninferior, and has a similar tolerability, to levetiracetam as adjunctive therapy in reducing seizure frequency in patients with partial seizures.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
γ-Aminobutyric acid, ≥99%
Supelco
γ-Aminobutyric acid, analytical standard
Sigma-Aldrich
Levetiracetam, ≥98% (HPLC)
Supelco
Levetiracetam, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
γ-Aminobutyric acid, BioXtra, ≥99%
Supelco
Levetiracetam solution, 1.0 mg/mL in methanol, ampule of 1 mL, certified reference material, Cerilliant®
Sigma-Aldrich
Piracetam
USP
Levetiracetam, United States Pharmacopeia (USP) Reference Standard
Piracetam, European Pharmacopoeia (EP) Reference Standard
Levetiracetam impurity D, European Pharmacopoeia (EP) Reference Standard
Levetiracetam, European Pharmacopoeia (EP) Reference Standard
Vigabatrin impurity D, European Pharmacopoeia (EP) Reference Standard
USP
Levetiracetam Racemic Mixture, United States Pharmacopeia (USP) Reference Standard