Authors :
Presenting Author: Delphine Breuillard, PhD – Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Université de Paris Cité
Kelly Knupp, MD, MSCS, FAES – University of Colorado, Anschutz Medical Campus
Adam Strzelczyk, MD, MHBA, FEAN – Goethe University Frankfurt, Epilepsy Center Frankfurt Rhine-Main, University Medicine Frankfurt
Danielle Andrade, MD, MSc, FRCPC – Institute of Medical Science, University of Toronto
Patrick Healy, MS – UCB
Jayne Abraham, PhD – UCB
Amélie Lothe, PhD – UCB
Rima Nabbout, MD, PhD – Reference Centre for Rare Epilepsies, Necker Enfants Malades Hospital, APHP, Member of the European Reference Network (ERN) EpiCARE; Institut Imagine; Université Paris Cité
Rationale:
Most adults with Lennox-Gastaut syndrome (LGS) exhibit profound intellectual disabilities; thus, a post hoc analysis of the fenfluramine (FFA) phase 3 randomized controlled trial (RCT; NCT03355209) was performed to evaluate everyday executive function (EEF) by Behavior Rating Inventory of Executive Functioning®—Adult Version (BRIEF®—A) and demonstrated improvement in patients (pts) aged 18-35y with LGS. In this post hoc analysis, we describe FFA-associated changes in EEF by BRIEF®—A scores in pts from this RCT and its open-label extension (OLE; final database lock).
Methods:
In the 14-week RCT, pts with LGS (2–35y) were randomized to FFA 0.2 mg/kg/d (FFA 0.2), FFA 0.7 mg/kg/d (FFA 0.7; max 26 mg/d), or placebo (PBO). Pts could then enter the OLE to receive FFA 0.2 mg/kg/d, flexibly titrated up to 0.7 mg/kg/d (max, 26 mg/d) after Mo1. Pts (18–35y) with caregiver-completed baseline and RCT end-of-study (EOS; Day 99) BRIEF®—A were included in RCT analyses; OLE analyses included pts with BRIEF®—A at RCT baseline and OLE Mo12. Median changes in BRIEF®—A T-scores from baseline for the Behavioral Regulation Index (BRI), Metacognition Index (MI), and Global Executive Composite (GEC) were calculated. The percentage of patients with T≥65 at baseline was compared with that at RCT EOS and OLE Mo12. The Reliable Change Index (RCI) was used to determine clinically meaningful improvement (RCI≥90%) and worsening (RCI≥80%). Associations between change in BRIEF®—A T-scores and seizures associated with a fall were analyzed (Spearman’s correlation).
Results:
Data from 67 adult pts with LGS from the RCT (FFA 0.2, n=24; FFA 0.7, n=18; PBO, n=25) and 41/67 from the OLE were included (Table 1); 19/41 pts in the OLE received a mean daily dose [MDD] < 0.3 mg/kg/d. On GEC, percentage of FFA-treated pts with T≥65 at RCT baseline ranged from 36%–56%. In FFA groups, percentage of pts with T≥65 numerically decreased from baseline to RCT EOS on MI (FFA 0.2: 54%–33%; FFA 0.7: 67%–56%) and GEC (FFA 0.2: 50%–33%; FFA 0.7: 56%–50%) but numerically increased in the PBO group (MI: 44%–52%; GEC: 36%–52%). In the OLE, percentage of pts with T ≥65 treated with FFA MDD < 0.3 mg/kg/d numerically decreased on BRI and GEC (26%–11%; 47%–32%); a decrease in percentage of pts was also observed with FFA MDD ≥0.5 mg/kg/d on GEC (25%–0%). Median changes in T-scores for all BRIEF®—A Indexes/Composite indicated improvement or no change in RCT FFA and OLE groups and worsened in the PBO group (