Changes in effectiveness and safety in patients with Lennox–Gastaut syndrome transitioning from the fenfluramine randomized controlled trial to open‐label extension study

In the phase 3 randomized controlled trial (RCT; NCT03355209) of fenfluramine in Lennox–Gastaut syndrome (LGS), patients in fenfluramine treatment groups (0.2 mg/kg/day, 0.7 mg/kg/day) experienced greater reduction from baseline in frequency of seizures associated with a fall versus placebo, which was sustained in the open‐label extension (OLE) study (NCT03355209). In this post hoc analysis, trajectories of fenfluramine effectiveness and safety, along with dose changes over time, are described for patients with LGS randomized to placebo in RCT who switched to fenfluramine in OLE (PBO‐FFA) and those who received fenfluramine in both RCT/OLE (FFA‐FFA). Among patients who completed 12 months in OLE ( N  = 151), numerical improvements in effectiveness outcomes were seen in the PBO‐FFA group ( n  = 59) after initiating fenfluramine and were similar to those in the FFA‐FFA group ( n  = 92). Regression to the mean was not observed in the PBO‐FFA group, suggesting that changes were due to fenfluramine. Incidence of the most commonly reported treatment‐emergent adverse events increased in the PBO‐FFA group after fenfluramine initiation but decreased in the FFA‐FFA group in OLE. These data demonstrate rapid improvement in seizure frequency and global functioning in both groups with continued clinical improvement as the mean fenfluramine dose was increased. These results confirm that sustained fenfluramine treatment is effective and tolerable.

Plain Language Summary

This study assessed the change over time in the number of seizures, overall improvement, and side effects in patients with LGS receiving placebo (no active medicine) or fenfluramine in a 14‐week study; all patients later received fenfluramine in the extension study. Overall, the number of seizures (associated with a fall) decreased once patients initially receiving placebo changed to fenfluramine (optimal effect around Month 4 while receiving a higher dose), but as expected, common side effects were reported more frequently once patients began fenfluramine treatment. Patients, parents, and doctors should be aware of this time course to allow fenfluramine enough time to work.