Fenfluramine in the treatment of Dravet syndrome: Results of a third randomized, placebo-controlled clinical trial.

Objective: This study was undertaken to assess the safety and efficacy of fenfluramine in the treatment of convulsive seizures in patients with Dravet syndrome.

Methods: This multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial enrolled patients with Dravet syndrome, aged 2-18 years with poorly controlled convulsive seizures, provided they were not also receiving stiripentol. Eligible patients who had ≥6 convulsive seizures during the 6-week baseline period were randomized to placebo, fenfluramine .2 mg/kg/day, or fenfluramine .7 mg/kg/day (1:1:1 ratio) administered orally (maximum dose = 26 mg/day). Doses were titrated over 2 weeks and maintained for an additional 12 weeks. The primary endpoint was a comparison of the monthly convulsive seizure frequency (MCSF) during baseline and during the combined titration-maintenance period in patients given fenfluramine .7 mg/kg/day versus patients given placebo.

Results: A total of 169 patients were screened, and 143 were randomized to treatment. Mean age was 9.3 ± 4.7 years (±SD), 51% were male, and median baseline MCSF in the three groups ranged 12.7-18.0 per 28 days. Patients treated with fenfluramine .7 mg/kg/day demonstrated a 64.8% (95% confidence interval = 51.8%-74.2%) greater reduction in MCSF compared with placebo (p < .0001). Following fenfluramine .7 mg/kg/day, 72.9% of patients had a ≥50% reduction in MCSF compared with 6.3% in the placebo group (p < .0001). The median longest seizure-free interval was 30 days in the fenfluramine .7 mg/kg/day group compared with 10 days in the placebo group (p < .0001). The most common adverse events (>15% in any group) were decreased appetite, somnolence, pyrexia, and decreased blood glucose. All occurred in higher frequency in fenfluramine groups than placebo. No evidence of valvular heart disease or pulmonary artery hypertension was detected.

Significance: The results of this third phase 3 clinical trial provide further evidence of the magnitude and durability of the antiseizure response of fenfluramine in children with Dravet syndrome.