Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome

Abstract

Objective: To evaluate efficacy and safety of clobazam, a 1,5-benzodiazepine, as adjunctive therapy for Lennox-Gastaut syndrome (LGS).

Methods: Patients aged 2-60 years were randomized to placebo or clobazam 0.25, 0.5, or 1.0 mg/kg/day. Study consisted of 4-week baseline, 3-week titration, and 12-week maintenance phases, followed by a 2- or 3-week taper or continuation in an open-label extension. Primary endpoint was percentage decrease in mean weekly drop seizure rates during maintenance vs baseline phases for modified intention-to-treat (mITT) population. Secondary outcomes included other seizure types, responder rates, and physicians' and caregivers' global assessments.

Results: A total of 305 patients were screened, 238 were randomized, and 217 composed the mITT population. Of patients enrolled after a protocol amendment, 125/157 (79.6%) completed. Average weekly drop seizure rates decreased 12.1% for placebo vs 41.2% (p = 0.0120), 49.4% (p = 0.0015), and 68.3% (p < 0.0001) for the clobazam 0.25-, 0.5-, and 1.0-mg/kg/day groups. Responder rates (≥50%) were 31.6% (placebo) vs 43.4% (p = 0.3383), 58.6% (p = 0.0159), and 77.6% (p < 0.0001) for clobazam 0.25-, 0.5-, and 1.0-mg/kg/day groups. Physicians' and caregivers' assessments indicated clobazam significantly improved symptoms. Somnolence, pyrexia, upper respiratory infections, and lethargy were the most frequent adverse events reported for clobazam.

Conclusions: Clobazam significantly decreased weekly drop seizure rates in LGS. No new safety signals were identified.

Classification of evidence: This study provides Class II evidence that clobazam as adjunctive therapy is efficacious, in a dosage-dependent manner, in reducing mean weekly drop seizure rates of patients with LGS over 12 weeks.

Figure 1. Study design

Low-dosage clobazam = target of 0.25 mg/kg/day (maximum, 10 mg/day); medium-dosage clobazam = target of 0.5 mg/kg/day (maximum, 20 mg/day); high-dosage clobazam = target of 1.0 mg/kg/day (maximum, 40 mg/day). *Patients not directly continuing in the open-label extension study tapered off study drug in a 2- or 3-week taper period, depending on weight, with the final visit 1 week after the last dose.

Figure 2. Patient disposition

AE = adverse event. *Patient's primary reason for discontinuation was “other.” AE was recorded as a secondary reason for discontinuation; this patient was included in the safety analysis of patients who discontinued because of AEs.

Figure 3. Mean percentage decreases (95% CI = confidence intervals) in weekly rate of seizures from the baseline to maintenance period

(A) Drop seizures. (B) Total (drop and nondrop) seizures. The p values were calculated from 2-sided, pairwise comparison of each clobazam dosage with placebo (analysis of covariance) with treatment, pooled center, and baseline seizure rate as model effects.

Figure 4. Responder rates

Percentages of patients with ≥25%, ≥50%, ≥75%, and 100% decreases from baseline to maintenance period in average weekly rate of drop seizures increased with increasing clobazam dosage. The logistic regression model was unable to provide valid estimates of statistical significance for the 100% response threshold. *p < 0.01 vs placebo. **p < 0.05 vs placebo.