Abstracts

Rationale: Aggression and irritability frequently occur in patients diagnosed with Lennox-Gastaut syndrome (LGS).¹ Benzodiazepines are often used to treat seizures in LGS, but have been associated with aggression.² This can lead to discontinuation of an effective therapy. Clobazam, a 1,5-benzodiazepine, was FDA-approved in October 2011 for the treatment of seizures associated with LGS. With data from a Phase III, randomized controlled trial of clobazam in LGS, we conducted post-hoc analyses of aggression-related adverse events, with emphasis on time to onset and resolution. Methods: The CONTAIN trial,³ a prospective, double-blind, placebo-controlled study, compared 3 oral dosages of clobazam 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 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 safety population included all patients who received ≥1 dose of study drug or placebo. We searched the adverse event database for the preferred terms of aggression, irritability, abnormal behavior, perserveration, and negativism, using MedDRA terms as a guide (identified as aggression-related events). Results: As previously reported,³ 301 patients were screened, 238 were randomized, 217 comprised the modified, intention-to-treat population (efficacy analyses), and 177 completed the study. Four patients discontinued because of aggression (1 medium- and 3 high-dosage patients). A total of 37/238 patients (15.5%) experienced a total of 43 aggression-related events. As anticipated, occurrence of aggression- related events was dosage-related. Time to onset for the majority of events in the medium- and high-dosage groups was during the 3-week titration period, while in the placebo- and low-dosage groups, time to onset was distributed throughout the course of the 15-week study. Resolution occurred for 43%, 40%, 63%, and 73% of events in the placebo, and low-, medium-, and high-dosage groups respectively. More than 50% of events resolved within 40 days, and all patients who received high-dosage clobazam who resolved did so within ~60 days. Conclusions: From these subanalyses, we determined that 1) onset of aggression-related events was dosage-related, 2) onset of the majority of the events was during titration, and 3) the majority resolved, contrary to standard belief about aggression outcomes, especially in the medium- and high-dosage groups. These data provide important information for counseling patients and their families who are experiencing aggression with clobazam therapy. References: ¹Glauser TA. Epilepsia. 2004;45(Suppl. 5):23-6. ²Weisman AM, et al. Int Clin Psychopharmacol. 1998;13:183-8. ³Ng YT, et al. Neurology. 2011;77:1473-81.