Abstracts

Rationale: In a Phase III study (CONTAIN), clobazam (CLB), a 1,5-benzodiazepine, significantly decreased weekly frequencies of drop and total seizures associated with Lennox-Gastaut syndrome (LGS).¹ We conducted a post-hoc subanalysis to evaluate CLB s efficacy with concomitant lamotrigine or valproate therapy.Methods: The CONTAIN trial, a prospective, double-blind, placebo-controlled study, compared 3 oral dosages of CLB with placebo as adjunctive therapy for LGS. Patients (pts) 2 to 60 years of age with LGS (documented by both clinical and EEG criteria) enrolled. Following a 4-week baseline phase, pts who had ?2 drop seizures per week were randomized to placebo or 1 of 3 dosages of CLB (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 percentage decrease in mean weekly drop seizure rate during maintenance vs. baseline phases for the modified intention-to-treat (mITT) population. The mITT analysis included all pts who had ?1 daily seizure measurement during the maintenance phase. In this post-hoc subanalysis, we evaluated results from baseline to 12-week maintenance phase for pts who also received lamotrigine or valproate therapy, the 2 most common concomitant AEDs in CONTAIN. We also used study data in a population PK model to assess the interactions of CLB and its metabolite (N-CLB) with lamotrigine or valproate.Results: As previously reported¹, 301 pts were screened, 238 were randomized, 217 comprised the mITT population, and 177 completed the study. At baseline, pts mean age was 12.4 years, and 60.5% were male. Demographics and clinical characteristics were similar between groups. CLB statistically significantly decreased the weekly frequencies of drop and total seizures associated with LGS.¹ For 72 pts receiving concomitant lamotrigine, all CLB groups achieved a greater mean percentage decrease in average weekly rate of drop seizures from baseline to maintenance period vs. placebo (table). For 113 pts receiving concomitant valproate, all CLB dosage groups had a greater mean reduction in average weekly rate of drop attacks from baseline to the maintenance period vs. placebo. Efficacy appeared to be dosage-dependent for pts receiving CLB and either concomitant lamotrigine or valproate, consistent with the overall results. A Kruskal-Wallis approach indicated there were no significant effects between CLB or N-CLB and lamotrigine or valproate concentrations.Conclusions: In the CONTAIN trial, clobazam was consistently efficacious in decreasing weekly rates of drop seizures from baseline to the maintenance phase compared with placebo for patients receiving either concomitant lamotrigine or valproate. Efficacy appeared to be dosage-dependent, consistent with the overall results. Further, no dosage adjustment of either lamotrigine or valproate appears to be required when coadministered with clobazam. References: ¹Conry J, et al. Epilepsia. 2010;Abstract #1.283.