Less Convulsive Seizures by Fenfluramin Medication in Stiripentol Treated Patients with Dravet's Syndrome: Results from Randomized, Placebo-controlled Phase 3 Clinical Trial

Rationale: Fenfluramine (FFA) has recently been shown in a Phase 3 clinical trial to reduce convulsive seizure frequency in patients with Dravet syndrome (DS) who were not treated with stiripentol (STP) compared to placebo. Here we report the results of a second Phase 3 clinical trial comparing FFA to placebo in patients with DS receiving an antiepileptic drug (AED) regimen including STP but still with poor seizure control.

Methods: Children and young adults (aged 2 to 18 years) with a diagnosis of DS who were receiving an AED regimen that included stable doses of STP were eligible for enrollment. Patients who demonstrated ≥6 convulsive seizures during the 6-week baseline period were randomly assigned to receive FFA 0.5 mg/kg/day (maximum 20 mg/day) or placebo. A dose of FFA 0.5 mg/kg/day provides comparable exposure to 0.8 mg/kg/day in patients not taking STP. After a 3-week blinded titration period, patients were maintained on their randomized dose for an additional 12 weeks. The number and type of seizures were recorded daily in an electronic diary by caregivers. The primary efficacy endpoint was the change in convulsive seizure frequency between FFA and placebo during the combined titration and maintenance periods compared with the baseline period.

Results: A total of 87 patients (median age 9 years, range 2–19) were randomized in the study. The mean baseline convulsive seizure frequency across both groups was about 25 convulsive seizures per month. The study met its primary endpoint: patients treated with FFA (n = 43) achieved a 54.7% greater reduction in monthly convulsive seizure frequency compared with placebo (n = 44, p < 0.001). FFA was also superior to placebo in both key secondary endpoints. In the FFA group, 53.5% demonstrated a clinically meaningful (≥ 50%) reduction in monthly convulsive seizures compared with 6.8% in the placebo group (p < 0.001). The median longest seizure-free interval was 22 days in the FFA group compared with 13 days in the placebo group (p < 0.005). Additionally, a profound (≥ 75%) reduction in monthly convulsive seizure frequency was achieved by 32.6% of the FFA group compared with 2.3% of the placebo group (p = 0.004). The most common adverse events (AEs) were decreased appetite (44% FFA, 11% placebo), fatigue (26% FFA, 5% placebo), and diarrhea (23% FFA, 7% placebo). Discontinuations due to an AE occurred in 2 and 1 patients in the FFA and placebo groups, respectively. Prospective cardiac monitoring throughout the study demonstrated no clinical or echocardiographic evidence of cardiac valvular heart disease (VHD) or pulmonary hypertension.

Conclusions: FFA demonstrated robust efficacy in this Phase 3 trial in patients with DS on a current AED regimen that contained stable doses of STP. FFA was generally well tolerated, with no clinical and/or echocardiographic signs of cardiac VHD or pulmonary hypertension. FFA may represent an important and effective new treatment option for patients with DS.