Fenfluramine Treatment Is Associated With Improvement in Everyday Executive Function in Adults With Lennox-Gastaut Syndrome: Post-Hoc Analysis of Dose Effects From a Phase 3 Trial Rationale
Kim Bishop1, Peter Isquith2, Kelly Knupp3, Joseph Sullivan4, Rima Nabbout5, Antonio Gil-Nagel6, Ingrid Scheffer7, Stéphane Auvin8, J Helen Cross9, Renzo Guerrini10, Robert Roth11, Gerard Gioia12, Amélie Lothe13, Shikha Polega14
1Global Pharma Consultancy, LLC, 2Global Pharma Consultancy, LLC; Boston Children’s Hospital, Harvard Medical School, 3Children's Hospital Colorado, 4University of California San Francisco, Benioff Children’s Hospital, 5Reference Centre for Rare Epilepsies, Hôpital Universitaire Necker-Enfants Malades, APHP, Member of EPICARE, Institut Imagine, Université Paris Cité, 6Hospital Ruber Internacional, 7University of Melbourne, Austin Hospital and Royal Children’s Hospital, Florey Institute and Murdoch Children’s Research Institute, 8Robert Debré University Hospital, APHP, Université de Paris, Institut Universitaire de France (IUF), 9UCL NIHR BRC Great Ormond Street Institute of Child Health, 10Anna Meyer Children's Hospital, University of Florence, 11Global Pharma Consultancy, LLC; Dartmouth-Hitchcock Medical Center, 12Global Pharma Consultancy, LLC; Children’s National Health System, 13Zogenix International (now a part of UCB), 14Zogenix, Inc. (now a part of UCB)
Objective:
Examine the associations between placebo and fenfluramine (FFA) treatment groups and the likelihood of clinically meaningful change on everyday executive function (EF) in adults with Lennox-Gastaut syndrome (LGS) over a 14-week phase 3 trial.
Background:
LGS patients have problems with everyday EF. Children and adolescents with LGS showed improvement in everyday EF following FFA treatment. We evaluated whether caregiver-rated everyday EF improved after FFA treatment in adults with LGS.
Design/Methods:
Data were analyzed for 57 adults with LGS aged 19-35 years (placebo, n=23; FFA 0.2mg/kg/day, n=18; FFA 0.7mg/kg/day, n=16). Everyday EF was evaluated using the Behavior Rating Inventory of Executive Function®—Adult Version (BRIEF®-A). Clinically meaningful improvement and worsening were defined using Reliable Change Index ≥90% and ≥80% certainty, respectively, and calculated using cross-tabulations and Somers’ D (p≤0.05); if significant, two-sided Fisher’s Exact tests were performed (p≤0.05).
Results:
Treatment and the likelihood of improvement were associated in the Behavior Regulation Index (BRI), Metacognition Index (MI), and Global Executive Composite (GEC). FFA 0.7 mg/kg/day showed a greater likelihood of improvement than placebo in MI. Treatment and likelihood of improvement were associated in 3 of 4 BRI and 3 of 5 MI scales. FFA 0.7 mg/kg/day showed a greater likelihood of improvement than placebo in the Inhibit, Initiate, Task Monitor, and Organization of Materials scales. FFA 0.2mg/kg/day showed a greater likelihood of improvement than placebo in the Shift scale. No clinically meaningful worsening was detected with treatment.
Conclusions:
FFA was associated with clinically meaningful improvements in everyday EF in adults with LGS over a relatively short treatment period. Higher-dose FFA showed a greater likelihood of improvement in everyday cognitive regulation, driven by amelioration in initiating, task monitoring, and organizing materials. Treatment with FFA initiated in adulthood may confer benefits in everyday EF.