OBJECTIVE:This study was undertaken to assess the safety and efficacy of fenfluramine in the treatment of convulsive seizures in patients with Dravet syndrome. METHODS:This multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial enrolled patients with Dravet syndrome, aged 2-18 years with poorly controlled convulsive seizures, provided they were not also receiving stiripentol. Eligible patients who had ≥6 convulsive seizures during the 6-week baseline period were randomized to placebo, fenfluramine .2 mg/kg/day, or fenfluramine .7 mg/kg/day (1:1:1 ratio) administered orally (maximum dose = 26 mg/day). Doses were titrated over 2 weeks and maintained for an additional 12 weeks. The primary endpoint was a comparison of the monthly convulsive seizure frequency (MCSF) during baseline and during the combined titration-maintenance period in patients given fenfluramine .7 mg/kg/day versus patients given placebo. RESULTS:A total of 169 patients were screened, and 143 were randomized to treatment. Mean age was 9.3 ± 4.7 years (±SD), 51% were male, and median baseline MCSF in the three groups ranged 12.7-18.0 per 28 days. Patients treated with fenfluramine .7 mg/kg/day demonstrated a 64.8% (95% confidence interval = 51.8%-74.2%) greater reduction in MCSF compared with placebo (p < .0001). Following fenfluramine .7 mg/kg/day, 72.9% of patients had a ≥50% reduction in MCSF compared with 6.3% in the placebo group (p < .0001). The median longest seizure-free interval was 30 days in the fenfluramine .7 mg/kg/day group compared with 10 days in the placebo group (p < .0001). The most common adverse events (>15% in any group) were decreased appetite, somnolence, pyrexia, and decreased blood glucose. All occurred in higher frequency in fenfluramine groups than placebo. No evidence of valvular heart disease or pulmonary artery hypertension was detected. SIGNIFICANCE:The results of this third phase 3 clinical trial provide further evidence of the magnitude and durability of the antiseizure response of fenfluramine in children with Dravet syndrome.
Objective: We aim to describe the effectiveness of fenfluramine (FFA) on generalized tonic-clonic seizures (GTCS) in patients with rare epilepsy syndromes. Background: Seizure refractoriness and frequent GTCS are hallmarks of developmental and epileptic encephalopathies (DEEs) and are 2 major risk factors for sudden unexpected death in epilepsy (SUDEP). Patients with 1–3 GTCS/year have up to a 16-fold greater risk of SUDEP. An analysis of SUDEP rates in patients with Dravet syndrome (DS) found a 5-fold lower SUDEP mortality rate in FFA-treated patients compared to historical controls. FFA has demonstrated reduced seizure burden in other rare epilepsies. Design/Methods: Studies where FFA was used to manage convulsive seizures associated with rare epilepsy syndromes were included. Initial FFA doses, duration of treatment (exposure) and reduction in GTCS or tonic-clonic seizures (TCS) are reported. Descriptive statistics were used. Results: We included data from 13 studies: 4 randomized-controlled trials (RCTs), 4 observational studies, 4 open-label studies, and 1 case series. In these studies, 561 patients were treated with FFA for DS (n=360), LGS (n=176), Sunflower syndrome (n=10), CDKL5 deficiency disorder (n=6), SCN8A-related disorder (n=3), and other DEEs (n=6). Of these, 396 (70.6%) patients experienced GTCS or TCS at baseline. FFA was generally initiated at 0.2 mg/kg/day and titrated per protocol or physician discretion; FFA exposure: 14 weeks–27 years. In 8 studies, the median percent reduction in GTCS ranged from 45.7%–90.8%. Among 8 studies, 7 reported at least half of the patients experienced ≥75% reduction in GTCS (or TCS); five studies reported more than half of patients were GTCS-free after FFA treatment. Conclusions: These results indicate that FFA led to a clinically significant reduction in GTCS (or TCS) frequency in patients with rare epilepsy syndromes, suggesting it may also reduce SUDEP rates in these disorders. Further research is needed to determine the impact of FFA on SUDEP in those patient populations. Disclosure: Dr. Cross has nothing to disclose. Dr. Devinsky has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai. Dr. Devinsky has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for California Cannabis Enterprises. Dr. Devinsky has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Engage. Dr. Devinsky has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Privateer Holdings. Dr. Devinsky has received personal compensation in the range of $1,000,000+ for serving on a Scientific Advisory or Data Safety Monitoring board for Receptor Holdings. Dr. Devinsky has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Rettco. Dr. Devinsky has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Silver Spike. Dr. Devinsky has received personal compensation in the range of $100,000-$499,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Tevard. Dr. Devinsky has received personal compensation in the range of $1,000,000+ for serving on a Scientific Advisory or Data Safety Monitoring board for Tilray. Dr. Devinsky has received personal compensation in the range of $100,000-$499,999 for serving as an officer or member of the Board of Directors for Engage. Dr. Devinsky has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for Tevard Biosciences. Dr. Devinsky has received stock or an ownership interest from Engage. Dr. Devinsky has received stock or an ownership interest from Empatica. Dr. Devinsky has received stock or an ownership interest from California Cannabis Enterprises. Dr. Devinsky has received stock or an ownership interest from Empatica. Dr. Devinsky has received stock or an ownership interest from Silver Spike. Dr. Devinsky has received stock or an ownership interest from Docklight Brands. Dr. Devinsky has received stock or an ownership interest from Egg Rock/Papa Barkley. Dr. Devinsky has received stock or an ownership interest from Leafly. Dr. Devinsky has received stock or an ownership interest from Left Coast Ventures. Dr. Devinsky has received stock or an ownership interest from Privateer Holdings. Dr. Devinsky has received stock or an ownership interest from Receptor Holdings. Dr. Devinsky has received stock or an ownership interest from Qstate. The institution of Dr. Devinsky has received research support from GW Pharma. The institution of Dr. Devinsky has received research support from Zogenix. The institution of Dr. Devinsky has received research support from PTC Pharma. The institution of Dr. Devinsky has received research support from NIH. The institution of Dr. Devinsky has received research support from DOD. The institution of Dr. Devinsky has received research support from NIH. The institution of Dr. Devinsky has received research support from Epilepsy Foundation. The institution of Dr. Devinsky has received research support from NIH. The institution of Dr. Devinsky has received research support from NIH. The institution of Dr. Devinsky has received research support from NSF. Dr. Devinsky has received intellectual property interests from a discovery or technology relating to health care. Dr. Devinsky has received intellectual property interests from a discovery or technology relating to health care. Dr. Devinsky has received publishing royalties from a publication relating to health care. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biocodex. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EISAI . Dr. Gil-Nagel has received personal compensation in the range of $0-$499 for serving as a Consultant for GW Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Angelini Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EISAI. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for GW Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for PTC Therapeutics . Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Stoke . Dr. Gil-Nagel has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Zogenix . Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Angelini Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for BIAL . Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for EISAI . Dr. Gil-Nagel has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for GW Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Jazz Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for PTC Therapeutics . Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for UCB Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Zogenix . The institution of Dr. Gil-Nagel has received research support from Jazz Pharmaceuticals. The institution of Dr. Gil-Nagel has received research support from PTC Therapeutics. The institution of Dr. Gil-Nagel has received research support from Zogenix. The institution of Dr. Gil-Nagel has received research support from Agencia Estatal Innovacion. The institution of Berten Ceulemans has received personal compensation in the range of $500-$4,999 for serving as a Consultant for zogenix. The institution of Berten Ceulemans has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for zogenix. Berten Ceulemans has received intellectual property interests from a discovery or technology relating to health care. Dr. Lagae has nothing to disclose. Dr. Knupp has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for zogenix. Dr. Knupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for encoded. Dr. Knupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for stoke. The institution of Dr. Knupp has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for GW pharmaceuticals. Dr. Knupp has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Epilepsy Research. An-Sofie Schoonjans has nothing to disclose. Dr. Ryvlin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Arvelle/Angelini. The institution of Dr. Ryvlin has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for UCB pharma. The institution of Dr. Ryvlin has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Angelini pharma. The institution of Dr. Ryvlin has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for UCB pharma. The institution of Dr. Ryvlin has received research support from Swiss National Fund. The institution of Dr. Ryvlin has received research support from European Commission (Horizon Europe). Dr. Thiele has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for GW Pharma. Dr. Thiele has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for zogenix. Dr. Thiele has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Aquestive. Dr. Thiele has received personal compensation in the range of $500-$4,999 for serving as a Consultant for West Therapeutics. Dr. Thiele has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai. Dr. Thiele has received personal compensation in the range of $500-$4,999 for serving as a Consultant for RegenxBio. Dr. Thiele has received personal compensation in the range of $500-$4,999 for serving as a Consultant for nobelpharma. An immediate family member of Dr. Thiele has received personal compensation in the range of $50,000-$99,999 for serving as a Consultant for Thor labs. Dr. Thiele has received personal compensation in the range of $0-$499 for serving as a Consultant for Biocodex. The institution of Dr. Thiele has received research support from GW Pharma. The institution of Dr. Thiele has received research support from Zogenix. Rima Nabbout has nothing to disclose. Dr. Lothe has received personal compensation for serving as an employee of UCB. Dr. Lothe has received personal compensation for serving as an employee of Zogenix International Limited. Dr. Lothe has stock in Zogenix . Shikha Polega has received personal compensation for serving as an employee of UCB. Shikha Polega has stock in UCB. Shikha Polega has stock in Zogenix.
Objective: To evaluate fenfluramine treatment on drop seizure frequency (DSF) in adults and patients who were dose-capped at 26mg/day in a randomized clinical trial (RCT) or open-label extension (OLE) for Lennox-Gastaut syndrome (LGS). Background: Treatment for LGS is individualized and may evolve as the syndrome persists and changes into adulthood. Patients weighing ≥37.5kg (ie, most adults) had their doses capped at 26 mg/day and therefore received doses ≤0.7mg/kg/day. Design/Methods: After 4-weeks' baseline in the RCT, LGS patients (2–35 years) were randomized to fenfluramine 0.7mg/kg/day (maximum, 26mg/day), fenfluramine 0.2mg/kg/day, or placebo for 2 weeks (titration) and 12 additional weeks. Eligible patients continuing into the OLE started on fenfluramine at 0.2mg/kg/day after a blinded 2-week taper. After 1 month, doses were titrated to effect/tolerability. Results: In the RCT, 76 adults (≥18–35 years) and 187 children/adolescents (2–17 years) were randomized to fenfluramine 0.7mg/kg/day (n=25 and 62, respectively), fenfluramine 0.2mg/kg/day (n=25 and 64), or placebo (n=26 and 61). Among both adults and children/adolescents, median DSF reduction from baseline was numerically greater in the 0.7mg/kg/day fenfluramine group (36.3%; P=0.0877 vs placebo [17.8%] and 20.3%; P=0.0106 vs placebo [4.8%]; nonparametric ANCOVA) and the 0.2mg/kg/day fenfluramine group (33.1%; P=0.1777 vs placebo [17.8%] and 7.2%; P=0.3268 vs placebo [4.8%]). Forty-seven patients weighed ≥37.5kg and were dose-capped at 26mg/day; median percentage reduction from baseline in DSF was greater than placebo (n=45) (35.3% vs 11.2%; P=0.0079 [ANCOVA]). In the OLE, 75% received ≤0.5mg/kg/day fenfluramine. Median reduction in DSF from baseline was 39.0% in adults (n=70) (P<0.0001, Wilcoxon signed rank test) and 25.6% in children/adolescents (n=171) (P=0.0037). Median percentage reductions in DSF were similar in patients weighing <37.5kg (28.3%; P=0.0127 [Wilcoxon signed rank test]) and ≥37.5kg (29.0%; P<0.0001). Conclusions: These data suggest that fenfluramine treatment results in effective, sustained DSF reduction in adults with LGS and patients weighing ≥37.5kg and dose-capped at 26mg/day. Disclosure: Dr. Knupp has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for zogenix. Dr. Knupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for encoded. Dr. Knupp has received personal compensation in the range of $500-$4,999 for serving as a Consultant for stoke. The institution of Dr. Knupp has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for GW pharmaceuticals. Dr. Knupp has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Epilepsy Research. Dr. Scheffer has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Xenon Pharmaceuticals. Dr. Scheffer has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Zynerba Pharmaceuticals. Dr. Scheffer has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Atheneum Partners. Dr. Scheffer has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BioMarin. The institution of Dr. Scheffer has received research support from National Health and Medical Research Council, Australia. The institution of Dr. Scheffer has received research support from National Health and Medical Research Council, Australia. The institution of Dr. Scheffer has received research support from National Health and Medical Research Council, Australia. The institution of Dr. Scheffer has received research support from National Health and Medical Research Council, Australia. The institution of Dr. Scheffer has received research support from National Health and Medical Research Council, Australia. The institution of Dr. Scheffer has received research support from National Health and Medical Research Council, Australia. The institution of Dr. Scheffer has received research support from Medical Research Future Fund, Australia. The institution of Dr. Scheffer has received research support from Medical Research Future Fund, Australia. The institution of Dr. Scheffer has received research support from Shenzhen Sanming Development Grant . Dr. Scheffer has received intellectual property interests from a discovery or technology relating to health care. Dr. Scheffer has received intellectual property interests from a discovery or technology relating to health care. Dr. Scheffer has received intellectual property interests from a discovery or technology relating to health care. Dr. Scheffer has received personal compensation in the range of $500-$4,999 for serving as a Travel/Conference/Speaker honoraria with BioMarin. Dr. Scheffer has received personal compensation in the range of $500-$4,999 for serving as a Travel/Conference/Speaker honoraria with UCB. Dr. Scheffer has received personal compensation in the range of $500-$4,999 for serving as a Travel/Conference/Speaker honoraria with Eisai. Dr. Scheffer has a non-compensated relationship as a Scientific Advisory Board, Trial Investigator with UCB that is relevant to AAN interests or activities. Dr. Scheffer has a non-compensated relationship as a Trial investigator with Eisai that is relevant to AAN interests or activities. Dr. Scheffer has a non-compensated relationship as a Scientific Advisory Board with Rogcon that is relevant to AAN interests or activities. Dr. Scheffer has a non-compensated relationship as a Scientific Advisory Board, Trial investigator with Zynerba Pharmaceuticals that is relevant to AAN interests or activities. Dr. Scheffer has a non-compensated relationship as a Scientific Advisory Board with Chiesi that is relevant to AAN interests or activities. Dr. Scheffer has a non-compensated relationship as a Scientific Advisory Board, Trial investigator with Encoded Therapeutics that is relevant to AAN interests or activities. Dr. Scheffer has a non-compensated relationship as a Journal Editorial Board with Neurology that is relevant to AAN interests or activities. Dr. Scheffer has a non-compensated relationship as a Journal Editorial Board with Epilepsy Currents that is relevant to AAN interests or activities. Dr. Scheffer has a non-compensated relationship as a Journal Editorial Board with Epileptic Disorders that is relevant to AAN interests or activities. Dr. Scheffer has a non-compensated relationship as a Trial investigator with Ovid Therapeutics that is relevant to AAN interests or activities. Dr. Scheffer has a non-compensated relationship as a Consultant with Atheneum Partners that is relevant to AAN interests or activities. Dr. Scheffer has a non-compensated relationship as a Trial investigator with GW Pharmaceuticals that is relevant to AAN interests or activities. Dr. Scheffer has a non-compensated relationship as a Trial investigator with Marinus that is relevant to AAN interests or activities. Dr. Scheffer has a non-compensated relationship as a Trial investigator with Zogenix that is relevant to AAN interests or activities. Dr. Scheffer has a non-compensated relationship as a Trial investigator with Ultragenyx that is relevant to AAN interests or activities. Dr. Scheffer has a non-compensated relationship as a Trial investigator with Anavex Life Sciences that is relevant to AAN interests or activities. The institution of Berten Ceulemans has received personal compensation in the range of $500-$4,999 for serving as a Consultant for zogenix. The institution of Berten Ceulemans has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for zogenix. Berten Ceulemans has received intellectual property interests from a discovery or technology relating to health care. Joseph Sullivan has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Epygenix. Joseph Sullivan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Stoke Therapeutics. The institution of Joseph Sullivan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Encoded Therapetucis. Joseph Sullivan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Invitate. Joseph Sullivan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Longboard. Joseph Sullivan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Greenwigh Biosciences. Joseph Sullivan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Knopp Biosciences. Joseph Sullivan has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Asceneuron. Joseph Sullivan has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Various Law Firms. Joseph Sullivan has received stock or an ownership interest from Epygenix Therapeutics. The institution of Joseph Sullivan has received research support from Zogenix. The institution of Joseph Sullivan has received research support from Marinus Pharmaceuticals. The institution of Joseph Sullivan has received research support from Stoke Therapeutics. The institution of Joseph Sullivan has received research support from Encoded Therapeutics. The institution of Joseph Sullivan has received research support from BioPharm solutions. The institution of Dr. Nickels has received research support from Zogenix. The institution of Dr. Nickels has received research support from Marinus. The institution of Dr. Nickels has received research support from Bio-Pharm Solutions. The institution of Dr. Nickels has received research support from Pediatric Epilepsy Research Foundation. Dr. Nickels has received personal compensation in the range of $500-$4,999 for serving as a Faculty with J. Kiffin Penry Educational Programs. Dr. Lagae has nothing to disclose. Renzo Guerrini has nothing to disclose. Prof. Zuberi has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Encoded Therapeutics. Prof. Zuberi has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Zogenix. Prof. Zuberi has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for GW Pharma. Prof. Zuberi has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. Prof. Zuberi has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Scottish Central Legal Office. Prof. Zuberi has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for Balfour & Manson Solicitors. The institution of Prof. Zuberi has received research support from Epilepsy Research UK. The institution of Prof. Zuberi has received research support from Scottish Government Digital Health & Care. Rima Nabbout has nothing to disclose. Kate Riney, MB BCh BAO, PhD has nothing to disclose. Shikha Polega has received personal compensation for serving as an employee of UCB. Shikha Polega has stock in UCB. Shikha Polega has stock in Zogenix. Dr. Lothe has received personal compensation for serving as an employee of UCB. Dr. Lothe has received personal compensation for serving as an employee of Zogenix International Limited. Dr. Lothe has stock in Zogenix . Dr. Davis has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for eisai. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biocodex. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EISAI . Dr. Gil-Nagel has received personal compensation in the range of $0-$499 for serving as a Consultant for GW Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Angelini Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EISAI. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for GW Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for PTC Therapeutics . Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Stoke . Dr. Gil-Nagel has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Zogenix . Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Angelini Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for BIAL . Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for EISAI . Dr. Gil-Nagel has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for GW Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Jazz Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for PTC Therapeutics . Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for UCB Pharma. Dr. Gil-Nagel has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Zogenix . The institution of Dr. Gil-Nagel has received research support from Jazz Pharmaceuticals. The institution of Dr. Gil-Nagel has received research support from PTC Therapeutics. The institution of Dr. Gil-Nagel has received research support from Zogenix. The institution of Dr. Gil-Nagel has received research support from Agencia Estatal Innovacion.
IMPORTANCE New treatment options are needed for patients with Lennox-Gastaut syndrome (LGS), a profoundly impairing, treatment-resistant, developmental and epileptic encephalopathy. OBJECTIVE To evaluate the efficacy and safety of fenfluramine in patients with LGS. DESIGN, SETTING. AND PARTICIPANTS This multicenter, double-blind, placebo-controlled, parallel-group randomized clinical trial was conducted from November 27, 2017, to October 25, 2019, and had a 20-week trial duration. Patients were enrolled at 65 study sites in North America, Europe, and Australia. Included patients were aged 2 to 35 years with confirmed diagnosis of LGS and experienced 2 or more drop seizures per week during the 4-week baseline. Using a modified intent-to-treat method, data analysis was performed from November 27, 2017, to October 25, 2019. The database lock date was January 30, 2020, and the date of final report was September 11, 2021. INTERVENTIONS Patients were randomized to receive either a 0.7-mg/kg/d or 0.2-mg/kg/d (maximum 26 mg/d) dose of fenfluramine or placebo. After titration (2-week period), patients were taking their randomized dose for 12 additional weeks. MAIN OUTCOMES AND MEASURES Primary efficacy end point was percentage change from baseline in drop seizure frequency in patients who received 0.7 mg/kg/d of fenfluramine vs placebo. RESULTS A total of 263 patients (median [range] age, 13 [2-35) years; 146 male patients [56%]) were randomized to the 0.7-mg/kg/d fenfluramine group (n = 87), 0.2-mg/kg/d fenfluramine group (n = 89), or placebo group (n = 87). The median percentage reduction in frequency of drop seizures was 26.5 percentage points in the 0.7-mg/kg/d fenfluramine group, 14.2 percentage points in the 0.2-mg/kg/d fenfluramine group, and 7.6 percentage points in the placebo group. The trial met its primary efficacy end point: patients in the 0.7-mg/kg/d fenfluramine group achieved a -19.9 percentage points (95% CI, -31.0 to -8.7 percentage points; P = .001) estimated median difference in drop seizures from baseline vs placebo. More patients in the 0.7-mg/kg/d fenfluramine group achieved a 50% or greater response (22 of 87 [25%]; P = .02) vs placebo (9 of 87 [10%]). Site investigators and caregivers gave a much improved or very much improved rating on the Clinical Global Impression of Improvement scale to more patients in the 0.7-mg/kg/d fenfluramine group than patients in the placebo group (21[26%] vs 5 [6%); P = 001). The seizure subtype that appeared most responsive to fenfluramine was generalized tonic-clonic seizure (120 of 263 [46%)), with a decrease infrequency of 45.7% in the 0.7-mg/kg/d fenfluramine group and 58.2% in the 0,2-mg/kg/d fenfluramine group compared with an increase of 3.7% in the placebo group. Most common treatment-emergent adverse events included decreased appetite (59 [22%]), somnolence (33 [13%]), and fatigue (33 [13%]). No cases of valvular heart disease or pulmonary arterial hypertension were observed. CONCLUSIONS AND RELEVANCE Results of this trial showed that, in patients with LGS, fenfluramine compared with placebo provided a significantly greater reduction in drop seizures and may be a particularly advantageous choice in patients who experience generalized tonic-clonic seizures.
