Objective: To evaluate whether fenfluramine (FFA) is associated with improvement in everyday executive function (EF)-self-regulation-in preschool-aged children with Dravet syndrome (DS)., Methods: Children with DS received placebo or FFA in one of two phase III studies (first study: placebo, FFA 0.2 mg/kg/day, or FFA 0.7 mg/kg/day added to stiripentol-free standard-of-care regimens; second study: placebo or FFA 0.4 mg/kg/day added to stiripentol-inclusive regimens). Everyday EF was evaluated at baseline and Week 14-15 for children aged 2-4 years with parent ratings on the Behavior Rating Inventory of Executive Function®-Preschool (BRIEF®-P); raw scores were transformed to T-scores and summarized in Inhibitory Self-Control Index (ISCI), Flexibility Index (FI), Emergent Metacognition Index (EMI), and Global Executive Composite (GEC). Clinically meaningful improvement and worsening were defined using RCI ≥ 90% and RCI ≥ 80% certainty, respectively. The associations between placebo vs FFA combined (0.2, 0.4, and 0.7 mg/kg/day) or individual treatment groups and the likelihood of clinically meaningful change in BRIEF®-P indexes/composite T-scores were evaluated using Somers'd; pairwise comparisons were calculated by 2-sided Fisher's Exact tests (p ≤ 0.05) and Cramér's V., Results: Data were analyzed for 61 evaluable children of median age 3 years (placebo, n = 22; FFA 0.2 mg/kg/day, n = 15; 0.4 mg/kg/day [with stiripentol], n = 10; 0.7 mg/kg/day, n = 14 [total FFA, n = 39]). Elevated or problematic T-scores (T ≥ 65) were reported in 55% to 86% of patients at baseline for ISCI, EMI, and GEC, and in ∼33% for FI. Seventeen of the 61 children (28%) showed reliable, clinically meaningful improvement (RCI ≥ 90% certainty) in at least one BRIEF®-P index/composite, including a majority of the children in the FFA 0.7 mg/kg/day group (9/14, 64%). Only 53% of these children (9/17) also experienced clinically meaningful reduction (≥50%) in monthly convulsive seizure frequency, including 6/14 patients in the FFA 0.7 mg/kg/day group. Overall, there were positive associations between the four individual treatment groups and the likelihood of reliable, clinically meaningful improvement in all BRIEF®-P indexes/composite (ISCI, p = 0.001; FI, p = 0.005; EMI, p = 0.040; GEC, p = 0.002). The FFA 0.7 mg/kg/day group showed a greater likelihood of reliable, clinically meaningful improvement than placebo in ISCI (50% vs 5%; p = 0.003), FI (36% vs 0%; p = 0.005), and GEC (36% vs 0%; p = 0.005). For EMI, the FFA 0.7 mg/kg/day group showed a greater likelihood of reliable, clinically meaningful improvement than the FFA 0.2 mg/kg/day group (29% vs 0%; p = 0.040), but did not meet the significance threshold compared with placebo (29% vs 5%; p = 0.064). There were no significant associations between treatment and the likelihood of reliable, clinically meaningful worsening (p > 0.05)., Significance: In this preschool-aged DS population with high baseline everyday EF impairment, FFA treatment for 14-15 weeks was associated with dose-dependent, clinically meaningful improvements in regulating behavior, emotion, cognition, and overall everyday EF. These clinically meaningful improvements in everyday EF were not entirely due to seizure frequency reduction, suggesting that FFA may have direct effects on everyday EF during the early formative years of neurodevelopment., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Bishop is Principal Consultant for Global Pharma Consultancy, LLC, which has received consultancy fees from Zogenix for research support; Dr. Isquith and Dr. Gioia are Associate Consultants for Global Pharma Consultancy, LLC, which has received consultancy fees from Zogenix for research support, and have received royalties from Psychological Assessment Resources (PAR, Inc.) for sale of the BRIEF® instruments; Dr. Knupp received research grants during the conduct of the study from Zogenix and the Pediatric Epilepsy Research Foundation, and outside the submitted work received research grants from the Colorado Department of Public Health and West Therapeutics and was a DSMB member for Greenwich Pharmaceuticals; Dr. Scheffer received compensation from Zogenix during the conduct of the study; personal fees from GlaxoSmithKline, Eisai, BioMarin, Nutricia, and Xenon Pharmaceuticals outside the submitted work; research funding from the National Health and Medical Research Council, Health Research Council of New Zealand, and National Institutes of Health; personal fees and other compensation from UCB; and other compensation with Zynerba Pharmaceuticals, GW Pharmaceuticals, Ovid Therapeutics, Marinus, and Ultragenyx; Dr. Nabbout received research support from Eisai, GW Pharma, UCB, and Zogenix; served as a consultant/advisor for Eisai, Biogen, GW Pharma, Novartis, Shire, and Zogenix; and served in a speaker role for Advicenne, Eisai, BioMarin, GW Pharma, Novartis, and Zogenix; Dr. Specchio has received consulting fees from Zogenix and support from LivaNova, BioMarin; she has served as a paid consultant for LivaNova; Dr. Sullivan received research grants from Zogenix (with travel support), Stoke, Marinus, and Biopharm; has served as a consultant/advisor for the Dravet Syndrome Foundation, Epygenix, Encoded, GW Pharma, Asceneuron, Longboard Pharmaceuticals, Knopp Biosciences, and Neurocrine; as a reviewer for the Epilepsy Study Consortium; and has stock options in Epygenix; Dr. Auvin has received personal fees from Arvelle, Biocodex, GW Pharma, and Xenon; personal fees and nonfinancial support from Biomarin, GW Pharma, and Nutricia; personal fees/grants from Eisai and UCB Pharma for work as an investigator; and research support from Zogenix; Dr. Cross received grants from Zogenix, Marinus, GW Pharma, Vitaflo, the National Institute of Health Research (NIHR), EPSRC, GOSH Charity, ERUK, the Waterloo Foundation, and the Great Ormond Street Hospital Biomedical Research Centre; she has been a consultant/advisor for Zogenix and GW Pharma, for which remuneration was made to the department outside of the submitted work; chair of the Medical Board for DravetUK, Hope for Hypothalamic Hamartoma, and Matthew’s Friends; supported by the NIHR Biomedical Research Centre at Great Ormond Street Hospital; endowed chair at UCL Great Ormond Street Institute of Child Health; Dr. Guerrini received research grants from Zogenix during the conduct of the study and received personal fees as a speaker or consultant from Zogenix outside the submitted work; he has served as an investigator for studies with Biocodex, UCB, Angelini, and Eisai Inc, and as a speaker/advisory board member for Biocodex, Novartis, Biomarin, and GW Pharma outside the submitted work; Dr. Gammaitoni, Dr. Galer, and Dr. Farfel were employees of and had ownership interest in Zogenix at the time of the study., (Copyright © 2022 UCB. Published by Elsevier Inc. All rights reserved.)