Abstracts

Rationale: In a Phase II study, clobazam (CLB), a 1,5-benzodiazepine, decreased the weekly frequency of drop seizures associated with Lennox-Gastaut syndrome (LGS). We conducted a Phase III trial to demonstrate the efficacy and safety of CLB for LGS. Methods: This prospective, double-blind, placebo-controlled trial compared 3 oral dosages of CLB with placebo as adjunctive therapy for LGS. Patients 2 to 60 years of age with LGS (documented by both clinical and electroencephalographic criteria) enrolled at 66 sites. Following a 4-week baseline phase, patients who had ?2 drop seizures per week were randomized to placebo or 1 of 3 dosages of clobazam (0.25, 0.5, and 1.0 mg/kg/day), up to a maximum daily dosage of 40 mg. Treatment included a 3-week titration phase, followed by a 12-week maintenance phase. The primary endpoint was the percentage decrease in mean weekly frequency of drop seizures during the maintenance vs. baseline phases for the modified intention-to-treat (mITT) population. The mITT analysis included all patients who had entered the maintenance phase. Secondary and exploratory outcomes included response rate thresholds for drop seizures (e.g., ?75%, ?50%, ?25%); mean weekly frequencies of non-drop seizures; and physicians and caregivers global assessments. Safety assessments included periodic physical examinations, laboratory evaluations, and adverse event information. Statistical significance was prespecified as p?0.01 for primary endpoints and p?0.05 for secondary measures. Results: 301 patients were screened, 238 were randomized, 217 comprised the mITT population, and 177 completed the study. At baseline, patients mean age was 12.4 years. 60.5% were male. Demographics and clinical characteristics were similar between groups. There was a statistically significant decrease in mean weekly frequency of drop seizures in all three groups receiving CLB vs. placebo (table). The low dosage, 0.25 mg/kg/day, did not achieve statistical significance by the p?0.01 criterion. In addition, CLB resulted in statistically significant dosage-related increases in the numbers of patients experiencing ?75% and ?50% decreases in drop seizures vs. placebo for the high-dosage group (63% vs. 11% and 78% vs. 32%, p?0.05) and the medium-dosage group (38% vs. 11% and 59% vs. 32%, p?0.05), respectively. High-dosage CLB decreased the frequency of non-drop seizures vs. placebo (not statistically significant), and all 3 dosages led to improvements in global assessments by physicians and caregivers vs. placebo (p?0.05). Somnolence, lethargy, drooling, upper respiratory infections, and behavioral abnormalities were the most frequent treatment-emergent, adverse events reported for CLB in this trial. Conclusions: In this study, clobazam 0.5 and 1.0 mg/kg/day statistically significantly decreased the weekly frequency of drop seizures associated with LGS. Clobazam was generally safe and well-tolerated.