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).¹ We conducted a post-hoc subanalysis to evaluate the degree to which patients who had previously received therapy with other benzodiazepines (BZDs) responded to subsequent clobazam therapy during CONTAIN.Methods: CONTAIN,¹ a prospective, double-blind, placebo-controlled study, 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. Following a 4-week baseline phase, patients 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 modified intention-to-treat (mITT) analysis included all patients who had 1 daily seizure measurement during the maintenance phase. Patients must not have been on any long-term BZD treatment for any chronic illness for at least 30 days prior to screening. However, patients were allowed to have entered the study if they had used BZDs as rescue therapy within the 30 days prior to screening, with a limit of 1 rescue per day up to an average of once per week. Patients with a clinically significant history of an allergic reaction or significant sensitivity to BZDs were excluded. We evaluated efficacy and safety parameters for patients with previous BZD use in the mITT population.Results: As previously reported,¹ 301 patients were screened, 238 were randomized, 217 comprised the mITT population (efficacy analyses), and 177 completed the study. Of the 217 mITT patients, 128 patients (59%) had previous BZD use. Demographics and clinical characteristics for this subgroup were similar to those of the overall population. Response to CLB in each of the treatment groups was similar to that of the overall population and statistically significantly greater than for placebo (table). A substantial percentage of these patients reported having received clonazepam prior to the CONTAIN trial. The placebo response for patients with previous BZD use was substantially lower than the placebo response in the total population. In addition, CLB resulted in greater 75% and 50% responder rates in drop seizures vs. placebo for the high-dosage group (65.2% vs. 8.8% and 73.9% vs. 23.5%, unadjusted p 0.05) and the medium-dosage group (30.6% vs. 8.8% and 50.0% vs. 23.5%, unadjusted p 0.05), respectively, for patients with previous BZD use. Somnolence, lethargy, drooling, upper respiratory infections, and pyrexia were the most frequent treatment-emergent adverse events reported for CLB in this analysis, similar to the result for the overall trial.Conclusions: In this subanalysis of the CONTAIN study, efficacy and safety results for clobazam patients with prior BZD experience were equally robust to the results for the overall population. ¹Ng YT, et al. Neurology. 2011;77:1473 81.