Authors :
Joseph Sullivan, MD – University of California San Francisco; Nicola Specchio, MD, PhD – Bambino Gesù Children’s Hospital IRCCS; Orrin Devinsky, MD – NYU Langone Medical Center; Stéphane Auvin, MD, PhD – Robert Debré Children’s Hospital, APHP, Université Paris-Cité; Adam Strzelczyk, MD, MHBA – Goethe University Frankfurt; Antonio Gil-Nagel, MD, PhD – Hospital Ruber Internacional; David Dai, consultant – Syneos Health; Amélie Lothe, PhD – Zogenix International (now a part of UCB); Shikha Polega, PharmD – Zogenix, Inc. (now a part of UCB)
This is a Late Breaking abstractRationale: Dravet syndrome (DS) is a severe, treatment-resistant, developmental and epileptic encephalopathy characterized by high seizure burden, premature mortality, and adverse effects on quality of life of patients and caregivers.
Fenfluramine (FFA) is approved in the United States and Europe as adjunct treatment of patients with DS. We present a post-hoc, pooled analysis of two identical phase 3 clinical trials (NCT02682927, NCT02826863) using an alternative time-to-event (TTE) analysis of efficacy and focusing on the number of seizure-free days and the maximum duration of seizure-free intervals.
Methods: Following a 6-week baseline period, DS patients aged 2 to 18 years (median age, 9.0 years; 48% female) were randomized to placebo (n=88), FFA 0.7 mg/kg/day (n=88), or FFA 0.2 mg/kg/day (n=85) added to their baseline standard-of-care (SOC) regimen. TTE was defined as the time required during the 14-week treatment period to experience the same number of convulsive seizures as during the 6-week baseline period. Kaplan-Meier TTE curves were analyzed by log-rank test. The number of seizure-free days per 28 days was analyzed using a covariance model with treatment (2 levels) and age ( < 6 or ≥ 6 years) as factors, log baseline seizure-free days as a covariate, and log seizure-free days as the response. Wilcoxon rank sum test was used to analyze the longest duration of convulsive seizure-free days.
Results: The median number of seizures during baseline ranged from 22.0 to 28.5 in the treatment groups. A greater proportion of patients in the FFA groups never reached their baseline seizure count relative to placebo (Table, Figure). Kaplan-Meier analysis demonstrated that the probability of not reaching the baseline seizure count was greater with FFA than with placebo (FFA 0.7 mg/kg/day, 0.65; FFA 0.2 mg/kg/day, 0.35; placebo, 0.06; P < 0.0001 vs both FFA groups). For patients who reached their baseline seizure count, the median TTE was longer in the FFA groups than in the placebo group (FFA 0.7 mg/kg/day, 13.5 weeks; FFA 0.2 mg/kg/day, 10.7 weeks; placebo, 6.1 weeks). FFA-treated patients had more seizure-free days per month relative to placebo (Table). Median longest interval between seizures was significantly greater in the FFA groups (FFA 0.7 mg/kg/day, 28 days; FFA 0.2 mg/kg/day, 17 days; placebo, 10 days; P≤0.001 vs placebo in both dose groups).