Abstracts

Rationale: The number, unpredictability, and severity of seizures experienced by patients with Dravet syndrome (DS) negatively impact quality of life for patients, caregivers, and their families. Additionally, parents often report that children cognitively regress or lose abilities during periods of high day-to-day seizure frequency or after status epilepticus. Therefore, the ability of a treatment to provide prolonged “windows” of seizure freedom may have positive effects on both quality of life and neurodevelopment. Here, we apply the time-to-event (TTE) analytic approach to determine seizure-free interval and time to reach 6-week baseline seizure frequency in patients with DS treated with fenfluramine.

Methods: In this post-hoc TTE analysis of data from a randomized, placebo-controlled trial in patients with DS (ages 2-18 years), we compared time to reach pre-randomization monthly convulsive seizure frequency (MCSF) in patients receiving adjunctive fenfluramine (0.7 or 0.2 mg/kg/day) or placebo. After a 6-week baseline, patients were randomized to dose groups, were titrated to a target dose over a 2-week maintenance period, and then remained on treatment for an additional 12 weeks. TTE was defined as the time for patients to reach the number of convulsive seizures they had experienced during the 6-week baseline period post-randomization. Differences between Kaplan-Meier TTE curves for active vs placebo groups were assessed by log-rank test. Waterfall plots presented individual-level TTE data.

Results: 142 patients with DS were randomized to fenfluramine 0.7 mg/kg/day (n=48), fenfluramine 0.2 mg/kg/day (n=46), or placebo (n=48) (median age, 9 years). Median time to reach baseline seizure count was 13.7, 11.1, and 6.0 weeks in fenfluramine 0.7 mg/kg/day, fenfluramine 0.2 mg/kg/day, and placebo groups, respectively (P< 0.001 for both FFA groups vs placebo). The proportion of patients who never reached baseline seizure count was 65% in the fenfluramine 0.7 mg/kg/day group (