Abstracts

Rationale: Lennox−Gastaut syndrome (LGS) is a childhood-onset epilepsy comprising multiple seizure types, slow spike-wave EEG, and cognitive impairment. More than 90% of children with LGS have drug-resistant seizures. For these patients, combination therapy with more than 1 AED –particularly those with different mechanisms of action – may achieve improved seizure control. Clobazam (CLB) is a 1,5-benzodiazepine indicated in the US for the adjunctive treatment of seizures associated with LGS in patients ≥2 years of age. Post hoc analysis of data from a randomized, double-blind, placebo-controlled study in patients with LGS evaluated efficacy of CLB in combination with the most often prescribed concomitant AEDs. Methods: In the CONTAIN (NCT00518713) study, patients maintained on 1-3 concomitant AEDs were randomly assigned to placebo, low (0.25 mg/kg [max: 10 mg/d], medium (0.5 mg/kg [max: 20 mg/d], or high (1.0 mg/kg [max: 40 mg/d] dosage CLB over a three-week titration and 12-week maintenance period. Polytherapy efficacy with CLB was evaluated post hoc by comparing median percent reduction in average weekly drop seizure rate from baseline to maintenance for each CLB dosage vs placebo in subgroups of patients receiving the most common (≥30%) concomitant AEDs (valproic acid, VPA; lamotrigine, LTG; levetiracetam, LEV; topiramate, TPM). Two-sided pair-wise comparisons used the Wilcoxon signed-rank test with normal approximation. Seizure response (≥50% reduction in mean weekly drop seizures from baseline to maintenance) was also assessed by CLB dosage in concomitant AED subgroups. Results: Patients were mean (SD) 12.4 (9.0) years old, with baseline mean (SD) 86.6 (161.5) drop seizures/week; 35.3% were treated with concomitant VPA, 32.8% with LTG, 31.5% with LEV, and 30.3% with TPM. Patients receiving concomitant VPA or TPM experienced significantly greater median reductions in average weekly drop seizures with add-on medium (VPA: 71.2%, TPM: 71.2%) or high (VPA: 81.8% and TPM: 87.3%) dosage CLB compared with PBO/VPA (31.6%, P<0.05) and PBO/TPM (47.6%, P<0.05) (Figure 1). Patients in the high dosage CLB/LTG group had significantly greater seizure reduction vs PBO/LTG (87.3% vs 46.2%, P<0.05), as did patients in all 3 CLB dosage groups/LEV (63.7%, 51.2%, and 73.8% for low, medium, and high dosage CLB/LEV vs 33.6% for PBO/LEV, P<0.05). Similarly, greater proportions of patients treated with any dosage of CLB/concomitant AED achieved ≥50% reduction in weekly drop seizures from baseline vs placebo/concomitant AED, except low dosage CLB/VPA and /LTG (Figure 2). Approximately twice as many patients treated with CLB/TPM and CLB/LEV were ≥50% responders vs those treated with PBO/TPM or PBO/LEV. Conclusions: Patients in this post hoc analysis who were treated with medium and high dosage CLB in combination with VPA, LTG, LEV, or TPM experienced improved seizure control, with no notable differences between non-randomized treatments. CLB reduced seizure rates when added to AEDs with different mechanisms of action in patients with LGS. Funding: Funded by Lundbeck