Abstracts

Rationale: Clobazam (CLB) is approved in over 100 countries for the treatment of anxiety and/or the adjunctive treatment of epilepsy. Anticonvulsant effects of CLB were first reported by Gastaut in 1978. CLB is the only 1,5 benzodiazepine used in the treatment of epilepsy and was developed to decrease the side effects of 1,4-benzodiazepines while maintaining efficacy. This study evaluates the safety and efficacy of CLB as adjunctive therapy in subjects with Lennox-Gastaut Syndrome (LGS).Methods: Subjects from 2-30 years of age with LGS were enrolled in a randomized, double-blind, dose finding study. The study consisted of a 4-week baseline, 3-week titration and 4-week maintenance period. Subjects not continuing into the long term open-label study had up to a 3-week taper period. Subjects must have been on stable doses of 1-3 AEDs which may have included ketogenic diet and VNS. Subjects with ≥2 drop seizures per week were randomized to low dose (target 0.25 mg/kg/day) or high dose (target 1.0 mg/kg/day) with maximum doses of 10 or 40 mg/day, respectively. The primary efficacy outcome was the reduction in number of drop seizures from the baseline period compared to the maintenance period. Safety of CLB was evaluated by lab assessments, electrocardiogram, vital signs, physical and neurological exams and adverse event (AE) assessments.Results: Sixty-eight subjects were randomized and received study drug (low dose, n=32; high dose, n=36); 42 (62%) males and 26 (38% females). Ages ranged from 1.8 to 25.7 years of age; 21% <5 years, 51% 5–10 years, 21% 11-17 years and 7% ≥18 years. There was a statistically significant reduction in the weekly drop seizure rate (maintenance vs. baseline) in the high 85%(p<0.0001) and low 12%(p=0.0162) groups and between treatment groups (p<0.0001). Significant differences were found between low and high dose in reducing weekly drop seizures by ≥25% (56.3% low, 88.9% high, p=0.0025), ≥50% (37.5% low, 83.3% high, p=0.0001), and ≥75% (25.0% low, 66.7% high, p=0.0006). There was a difference between treatment groups in becoming 100% free of drop seizures with 8 in high dose and 2 in low dose (p=0.0629). High dose clobazam produced statistically significant median reductions in the frequency of non-drop seizures (62%, p=0.0108), as compared to low dose treatment (7%, p=0.3910). Treatment-emergent AEs were experienced by 85% of subjects with 46% mild, 35% moderate, and 4% severe. There were no definitely treatment related AEs; 13.2% were not related, 7.4% unlikely, 22.1% possibly and 42.6% probably related. AEs contributed to the premature discontinuation of 9 subjects (13%). Five treatment emergent serious AEs (SAEs) were reported in 4 subjects (3 high and 1 low dose), none resulting in premature termination, all resolved.Conclusions: Drop seizures were significantly reduced in both the high & low dose CLB groups, high dose was more effective. Non-drop seizures also decreased in both the high & low dose groups. There were very few SAEs, all of which resolved. There were no definitely treatment related AEs and the majority were mild or moderate in severity.