Adjunctive levetiracetam in the treatment of Chinese and Japanese adults with generalized tonic-clonic seizures: A double-blind, randomized, placebo-controlled trial

Liwen Wu, Kazuichi Yagi, Zhen Hong, Weiping Liao, Xuefeng Wang, Dong Zhou, Yushi Inoue, Yoko Ohtsuka, Mutsuo Sasagawa, Kiyohito Terada, Xinlu Du, Yoshihiro Muramoto, Tomonobu Sano, Liwen Wu, Kazuichi Yagi, Zhen Hong, Weiping Liao, Xuefeng Wang, Dong Zhou, Yushi Inoue, Yoko Ohtsuka, Mutsuo Sasagawa, Kiyohito Terada, Xinlu Du, Yoshihiro Muramoto, Tomonobu Sano

Abstract

Objective: To assess the efficacy, safety, and tolerability of adjunctive levetiracetam (LEV) in Chinese and Japanese adults with generalized tonic-clonic (GTC) seizures (N01159; NCT01228747).

Methods: This double-blind, randomized, placebo-controlled, multicenter phase III trial comprised: 4-week retrospective and 4-week prospective baseline, 12-week dose-adjustment, and 16-week evaluation periods. Chinese and Japanese patients ≥16 years old with idiopathic generalized, symptomatic generalized, or undetermined epilepsy with GTC seizures received a single-blind placebo during the prospective baseline, and then were randomized 1:1 to placebo or LEV 1,000 mg/day administered twice daily. Patients reporting GTC seizures up to week 8 had the LEV dosage increased to 3,000 mg/day. The primary efficacy variable was percent reduction from combined baseline in GTC seizures/week during the 28-week treatment period.

Results: Overall, 251 patients were randomized (208 from China; 43 from Japan); 141 (56.2%) completed the 28-week treatment period. Least-squares mean percent reduction from combined baseline in GTC seizures/week (treatment period) was placebo 12.6% versus LEV 68.8% (95% confidence interval, 44.0-68.2; p < 0.0001). GTC seizure frequency reduction occurred in both patients with idiopathic and symptomatic generalized epilepsy. The 50% responder rate (treatment period) was placebo 28.4% versus LEV 77.8%. Freedom from GTC seizures (evaluation period) was placebo 3.1% versus LEV 29.6%. Incidence of treatment-emergent adverse events (TEAEs; treatment period) was placebo 52.0% versus LEV 57.1%; most frequently nasopharyngitis, protein in urine, decreased platelet count, and pyrexia. Incidence of TEAEs leading to discontinuation was 4.8% versus 3.2%; incidence of serious TEAEs was 3.2% versus 0.8% for placebo and LEV, respectively; 3 patients taking placebo died versus none taking LEV.

Significance: In this trial, adjunctive LEV 1,000-3,000 mg/day was effective in reducing GTC seizure frequency in Chinese and Japanese patients ≥16 years old with GTC seizures. Seizure reduction occurred in both patients with idiopathic and symptomatic generalized epilepsy. LEV was well tolerated in this population.

Keywords: Efficacy; Generalized tonic–clonic seizure; Levetiracetam; Safety/tolerability.

Figures

Figure 1
Figure 1
Patient disposition. FAS, full analysis set; LEV, levetiracetam; PBO, placebo.
Figure 2
Figure 2
A, Median percent reduction from combined baseline in generalized tonic–clonic seizures/week during the 28‐week treatment period (full analysis set); p‐values versus placebo calculated using ANCOVA. B, Median percent reduction from combined baseline in generalized tonic–clonic seizures/week for patients with idiopathic and symptomatic generalized epilepsy during the 28‐week treatment period. ANCOVA, analysis of covariance; GTC, generalized tonic–clonic; IQR, interquartile range; LEV, levetiracetam.
Figure 3
Figure 3
A, Median percent reduction from combined baseline in generalized tonic–clonic seizures/week during the 16‐week evaluation period; p‐values versus placebo calculated using ANCOVA. B, Generalized tonic–clonic seizure 50% responder rates during the 28‐week treatment and 16‐week evaluation periods (full analysis set); p‐values versus placebo calculated using logistic regression. ANCOVA, analysis of covariance; GTC, generalized tonic–clonic; IQR, interquartile range; LEV, levetiracetam.

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