Abstracts

Rationale: The Phase III CONTAIN study demonstrated the efficacy and safety of clobazam (CLB), a 1,5-benzodiazepine, in the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) for the modified intention-to-treat (mITT) and safety populations.¹ The mITT analyses (efficacy) included 217 patients (pts) who had entered the maintenance phase.¹ The safety analyses included all 238 pts who had received 1 dose of study drug or placebo.¹ Here we report the results of post-hoc analyses of the efficacy and safety of CLB for all pts who completed the 15-week trial.Methods: CONTAIN was a placebo-controlled trial that compared 3 oral dosages of CLB with placebo as adjunctive therapy for LGS. Pts 2 to 60 years of age with LGS (documented by both clinical and electroencephalographic criteria) enrolled at 66 sites.¹ Following a 4-week baseline phase, pts 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 max. daily dosage of 40 mg. Treatment included a 3-week titration phase, followed by a 12-week maintenance phase. For pts who completed the study, we determined the % decrease in mean weekly frequency of drop seizures during the maintenance vs. baseline phase. Secondary and exploratory outcomes included response rate thresholds for drop seizures (e.g., 100%, 75%, 50%, 25%); mean weekly decreases in frequencies of total seizures; and physicians and caregivers global assessments. Safety assessments included periodic physical examinations, laboratory evaluations, and adverse event information.Results: 301 pts were screened, 238 were randomized, 217 comprised the mITT population, and 177 completed the study. At baseline, mean age for the 177 completers was 11.5 years, and 58.8% were male. Demographics and clinical characteristics were similar between treatment groups. There were statistically significant decreases in mean weekly frequency of drop seizures in the high- and medium-dosage CLB groups vs. placebo (table). In addition, CLB resulted in statistically significant dosage-related increases in the percentages of pts experiencing 75% and 50% decreases in drop seizures vs. placebo for the high-dosage group (61% vs. 12% and 78% vs. 37%, unadjusted p<0.001) and the medium-dosage group (38% vs. 12% and 62% vs. 37%, unadjusted p 0.05), respectively. All 3 CLB dosages statistically significantly decreased the frequency of total seizures (drop + non-drop) vs. placebo (p 0.05), and the medium and high dosages led to improvements in global assessments by physicians and caregivers vs. placebo (p 0.01). Somnolence, lethargy, drooling, upper respiratory infections, and pyrexia were the most frequent treatment-emergent adverse events reported.Conclusions: The overall efficacy and safety of CLB were demonstrated in this 15-week, Phase III study. In these post-hoc subanalyses of the CONTAIN study, efficacy and safety results for CLB were similar between those 217 pts in the mITT population and those 177 pts who completed all 15 weeks of the study. ¹Ng YT, et al. Neurology. 2011;77:1473 81.