Fenfluramine (FINTEPLA) in Dravet syndrome: Results of a third randomized, placebo-controlled clinical trial (Study 3)
Abstract number :
853
Submission category :
4. Clinical Epilepsy / 4C. Clinical Treatments
Year :
2020
Submission ID :
2423187
Source :
www.aesnet.org
Presentation date :
12/7/2020 9:07:12 AM
Published date :
Nov 21, 2020, 02:24 AM
Authors :
Joseph Sullivan, University of California San Francisco, Benioff Children’s Hospital; Lieven Lagae - University Hospitals KU Leuven, Leuven; J. Helen Cross - NIHR BRC Institute of Child Health; Orrin Devinsky - New York University Langone Medical Center;
Rationale:
Fenfluramine (FFA) has been shown in 2 global, randomized, placebo-controlled, phase 3 clinical trials (Study 1, Study 2) to significantly reduce monthly convulsive seizure frequency (MCSF) compared with placebo in patients with Dravet syndrome (DS). Here we report the results of a third international phase 3 clinical trial of FFA in DS.
Method:
Patients 2-18 years old with a diagnosis of DS and for whom convulsive seizures were not controlled by their current anti-epileptic drug regimen (which excluded stiripentol) were enrolled. Patients who had ≥ 6 convulsive seizures during the 6-week baseline period were randomized in a 1:1:1 ratio to FFA 0.7 mg/kg/day (maximum 26 mg/day), 0.2 mg/kg/day, or placebo. Daily doses were administered BID. After a 2-week 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 mean MCSF between FFA 0.7 mg/kg/day and placebo during the 14-week treatment period compared to the 6-week baseline observation period.
Results:
A total of 142 patients with DS enrolled in the study, were randomized to treatment (n=48, 0.7 mg/kg/day; n=46, 0.2 mg/kg/day; n=48, placebo), and received ≥1 dose. The median age of patients was 9 years (range 2-18 years). 134 patients (93.7%) completed the study (93.9%, 0.7 mg/kg/day; 97.8%, 0.2 mg/kg/day; 89.6%, placebo). Median MCSF across treatment groups was 14.3 seizures/month. For the primary endpoint, FFA 0.7 mg/kg/day showed a 64.8% greater reduction in mean MCSF vs placebo (P< 0.0001). The median percent reduction from baseline in MCSF was 73.7% for FFA 0.7 mg/kg/day vs 7.6% for placebo. Significantly more FFA-treated patients achieved ≥ 50% or ≥ 75% reduction in MCSF as well as significantly longer seizure-free intervals vs placebo (Table 1). Efficacy of 0.7 mg/kg/day exceeded 0.2 mg/kg/day for all endpoints, suggesting a dose-response relationship. More investigators and caregivers rated patients much improved/very much improved (Table 2). The incidence of serious treatment-emergent adverse events was low and similar in all 3 groups (4.2%, placebo; 6.5%, 0.2 mg/kg/day; 6.3%, 0.7 mg/kg/day). Prospective cardiac safety monitoring throughout the study demonstrated no clinical or echocardiographic evidence of valvular heart disease or pulmonary hypertension.
Clinical Epilepsy