Efficacy and safety of FINTEPLA (fenfluramine) for the treatment of seizures associated with Lennox-Gastaut syndrome: a randomized, double-blind, placebo-controlled clinical trial
Abstract number :
852
Submission category :
4. Clinical Epilepsy / 4C. Clinical Treatments
Year :
2020
Submission ID :
2423186
Source :
www.aesnet.org
Presentation date :
12/7/2020 9:07:12 AM
Published date :
Nov 21, 2020, 02:24 AM
Authors :
Kelly Knupp, Children’s Hospital Colorado; Ingrid Scheffer - The University of Melbourne and The Royal Children’s Hospital and the Florey Institute and Murdoch Children's Research Institute; Berten Ceulemans - Antwerp University Hospital; Joseph Sullivan
Rationale:
Lennox-Gastaut syndrome (LGS) is a treatment-resistant developmental and epileptic encephalopathy with multiple seizure types. The aim of this phase 3 clinical trial was to evaluate the safety and efficacy of fenfluramine (FFA) in patients with LGS (NCT03355209).
Method:
Patients aged 2-35 years with confirmed LGS were randomized to placebo or adjunctive FFA (0.2 or 0.7mg/kg/day) following a 4-week baseline to establish monthly drop in seizure frequency (MDSF; per 28 days). After 2 weeks’ titration, patients were treated for 12 weeks. The primary efficacy endpoint was % change from baseline in MDSF in the 0.7mg/kg/day FFA group (rank ANCOVA). Secondary endpoints included % change from baseline in MDSF in the 0.2mg/kg/day FFA group and ≥ 50% responder rate and clinical global impression of improvement (CGI-I) for both doses. Statistical analyses were controlled for multiplicity using a gatekeeping approach, where the primary and key secondary endpoints were arranged in a hierarchy and tested sequentially.
Results:
A total of 263 patients were randomized (placebo, n=87; FFA 0.2mg/kg/day, n=89; FFA 0.7mg/kg/day, n=87). Median age was 13 years with a median baseline MDSF of 77 (range 2-2943). Median number of concomitant antiepileptic drugs (AEDs) was 3 (range 1-5). Median prior AED failures was 7 (range 1-20). The study met its primary efficacy endpoint: Patients taking FFA 0.7mg/kg/day achieved -19.9% estimated median difference from placebo (ESM; Hodges-Lehmann estimate) in MDSF from baseline (P=0.001). In the FFA 0.2mg/kg/day group, ESM did not reach statistical significance (‑10.5%; P=0.09). More patients in the FFA groups achieved ≥ 50% response; more investigators and caregivers rated patients “Much Improved” or “Very Much Improved” on CGI-I compared with placebo (Table). FFA was particularly effective in reducing generalized tonic clonic seizure (GTC) frequency (Figure). ~43% of patients experienced GTCs (median baseline 11.5-18.3; range 1-198), with FFA treatment resulting in a median % difference from placebo of -61.9% (P< 0.0001) and -49.4% (P=0.0007) for the 0.2mg/kg/day and 0.7mg/kg/day groups. Most common adverse events included decreased appetite, somnolence, fatigue, vomiting, diarrhea, irritability, seizure, and pyrexia. No cases of valvular heart disease (VHD) or pulmonary arterial hypertension (PAH) were observed.
Clinical Epilepsy