Fenfluramine Efficacy Trajectories in Placebo or Treatment Groups from Randomized Controlled Trial to Open-label Extension
Abstract number :
1.408
Submission category :
7. Anti-seizure Medications / 7B. Clinical Trials
Year :
2024
Submission ID :
1125
Source :
www.aesnet.org
Presentation date :
12/7/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Rima Nabbout, MD, PhD – Member of European Reference Network EpiCARE, Reference Centre for Rare Epilepsies, Necker Enfants Malades Hospital, APHP, U 1163 Institut Imagine, Université Paris Cité
Orrin Devinsky, MD – NYU Grossman School of Medicine
Lieven Lagae, MD, PhD, FRCP – Member of the European Reference Network EpiCARE, University of Leuven
Ingrid Scheffer, MBBS, PhD, FRACP, FRS – University of Melbourne, Austin Hospital and Royal Children's Hospital, Florey and Murdoch Children’s Research Institutes
Renzo Guerrini, MD, FRCP, FAES – Meyer Children’s Hospital IRCCS, and University of Florence
Joseph Sullivan, MD – University of California San Francisco Weill Institute for Neurosciences
Antonio Gil-Nagel, MD, PhD – Hospital Ruber Internacional
Sameer Zuberi, MBChB, MD – Paediatric Neurosciences Research Group, Royal Hospital for Children
Kate Riney, MD – Queensland Children's Hospital, South Brisbane, Queensland, Australia
Patrick Healy, MS – UCB, Inc.
Mélanie Langlois, PhD – UCB Pharma S.A.
Jayne Abraham, PhD – UCB Pharma, Inc.
Amélie Lothe, PhD – UCB Pharma S.A.
Kelly Knupp, MD, MSCS, FAES – University of Colorado, Children’s Hospital Colorado
Rationale: Lennox-Gastaut syndrome (LGS) is a developmental and epileptic encephalopathy associated with pharmacoresistant seizures, developmental delay, and cognitive and behavioral deficits that persist into adulthood. LGS is characterized by seizures associated with a fall, including generalized tonic-clonic seizure (GTCS). In the phase 3 randomized controlled trial (RCT; NCT03355209) of fenfluramine (FFA) for management of seizures associated with LGS, both FFA treatment groups (FFA 0.2 and 0.7 mg/kg/day, max = 26 mg/day) experienced a greater change from baseline compared to placebo in frequency of seizures associated with a fall. This reduction was sustained in the open-label extension (OLE) study (NCT03355209). Here, efficacy of FFA, primarily by seizures associated with a fall, is described for patients randomized to placebo or FFA during the RCT and transitioned to FFA in the OLE.
Methods: After completing the 14-week RCT, patients were eligible to enroll in the OLE. After Month 1 (transition to FFA 0.2 mg/kg/d), FFA dose was flexibly titrated to effect and tolerability. Trajectories of efficacy outcomes were assessed for patients who transitioned from placebo (RCT-placebo) in the RCT and from any FFA dose (RCT-FFA) to the OLE. The primary outcome was median percent change from baseline (RCT: titration and maintenance; OLE: Month 1 to end of study) in frequency of seizures associated with a fall. Median percent change from baseline was also assessed for GTCS and number of days with no seizures associated with a fall. Other outcomes included responder rates (≥50% and ≥75% reduction) for seizures associated with a fall and scores on the Clinical Global Impression—Improvement (CGI-I) scale (investigator and caregiver).
Results: In the RCT (N=263), the placebo group (n=87) maintained a consistent median percent change from baseline in seizures associated with a fall (-12.6% to -7.2%, Figure). Within Month 1 of the OLE (transition to FFA 0.2 mg/kg/d; N=247), the RCT-placebo group (n=85) became numerically comparable to the RCT-FFA group (n=156) in median percent change from baseline (-29.0% vs -25.4%). Both RCT-placebo and RCT-FFA groups maintained similar change from baseline in seizures associated with a fall through the end of the OLE. In all other assessed outcomes in the OLE the RCT-placebo and RCT-FFA groups were numerically comparable in efficacy.
Conclusions: Patients previously randomized to placebo exhibited numerical improvements in all efficacy outcomes analyzed following transition to the OLE and initiating FFA treatment. Regression to the mean was not observed in RCT placebo-treated patients, suggesting that changes were not due to extreme events and could be attributed to FFA treatment. The change in frequency of seizures associated with a fall in the RCT-placebo group occurred during Month 1 of the OLE, confirming rapid onset of efficacy. Further analyses on the time to efficacy in a larger population of patients with LGS who may have been excluded from the RCT/OLE would be beneficial.
Funding: UCB Pharma
Anti-seizure Medications