FINTEPLA (Fenfluramine) Treatment Improves Everyday Executive Functioning in Preschool Children With Dravet Syndrome: Analysis From 2 Pooled Phase 3 Clinical Trials
Abstract number :
2.413
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2021
Submission ID :
1886483
Source :
www.aesnet.org
Presentation date :
12/5/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:56 AM
Authors :
Kim Bishop, PhD - Global Pharma Consultancy, LLC; Peter Isquith, PhD, ABPdN – Boston Children's Hospital, Harvard Medical School; Gerard Gioia, PhD – Children’s National Health System; Kelly Knupp, MD, MSCS, FAES – Children's Hospital Colorado; Ingrid Scheffer, MD – University of Melbourne, Austin Hospital and Royal Children’s Hospital; Joseph Sullivan, MD – University of California San Francisco, Benioff Children’s Hospital; Rima Nabbout, MD – Hôpital Universitaire Necker-Enfants Malades; Gail Farfel, PhD – Zogenix, Inc.; Bradley Galer, MD – Zogenix, Inc.; Svetlana Shore, PhD – Zogenix, Inc.; Arnold Gammaitoni, PharmD – Zogenix, Inc.
Rationale: The mechanism of action of fenfluramine (FFA) includes 5HT4 agonism and positive modulation of Sigma-1 receptors. Preclinical and clinical literature suggests that these actions have positive effects on memory, learning, and cognition. Previous data have demonstrated that treatment with FFA results in significant improvement in executive function (EF) in children and young adults 5-18 years with DS. The purpose of this study was to determine whether FFA improves everyday EF in a preschool subset of children with Dravet syndrome (DS) during early formative years for neurodevelopment.
Methods: Children with DS received placebo or FFA (0.2, 0.4, or 0.7 mg/kg/day) as part of 1 of 2 14-15-week randomized controlled trials (RCTs). EF was evaluated at baseline and at Week 14-15 for children aged 2-4 years with parent ratings on the Behavior Rating Inventory of Executive Function® – Preschool Version (BRIEF®-P); raw scores were transformed to T-scores (X=50, SD=10) based on the normative sample and are summarized in the Inhibitory Self-Control Index (ISCI), the Flexibility Index (FI), the Emergent Metacognition Index (EMI), and the overall Global Executive Composite (GEC). Clinically meaningful improvement was defined using RCI ≥90% and ≥95% certainty. Clinically meaningful worsening in BRIEF®-P index/composite T-scores from baseline to Week 14 or 15 was defined as exceeding a Reliable Change Index (RCI) of ≥80% certainty. The association between active and placebo treatment groups and the likelihood of clinically meaningful improvement or worsening were evaluated via cross-tabulations and Somers’ d statistic.
Results: Data for 61 evaluable children (placebo, n=22; FFA, n=39; median age, 3 years; 54% male) were analyzed. Elevated T-score (T≥65) was reported for 55%-86% of patients at baseline for ISCI, EMI, and GEC, and for ~33% for FI. Treatment with FFA was associated with significant and clinically meaningful improvement (RCI ≥90%) vs placebo in ISCI (31% vs 5%; p <0.01), FI (21% vs 0%; p <0.01), and GEC (21% vs 0%; p <0.01) (Figure). A similar pattern emerged when data were analyzed at a higher confidence level (RCI ≥95%), with significant and clinically meaningful improvements after FFA vs placebo in FI (18% vs 0%; p <0.01) and GEC (21% in the FFA group vs 0% in placebo; p <0.01). Treatment with FFA was associated with no significant worsening (RCI ≥80%) in any of the BRIEF®-P indexes/composite T-scores compared to placebo (
Anti-seizure Medications