Describe everyday executive function (EEF) changes associated with fenfluramine treatment in adults with Lennox-Gastaut syndrome (LGS) using the Behavior Rating Inventory of Executive Functioning®—Adult Version (BRIEF®—A).

Previous post hoc analysis of a fenfluramine LGS randomized clinical trial (RCT) demonstrated EEF improvements in adults treated with fenfluramine (combined doses) versus placebo.

Patients with LGS (2–35y) were randomized (14-week RCT, NCT03355209) to fenfluramine 0.7mg/kg/d (maximum 26mg/d), 0.2mg/kg/d, or placebo; then, could enter the open-label extension (OLE; fenfluramine 0.2mg/kg/d flexibly titrated up to 0.7mg/kg/d).

Baseline and RCT end-of-study (Day 99) or OLE Month 12 caregiver-completed BRIEF®—A were required for data inclusion. Clinically meaningful improvement/worsening (Reliable Change Index≥90%/≥80%) in median BRIEF®—A T-scores (Behavioral Regulation Index [BRI], Metacognition Index [MI], Global Executive Composite [GEC]), changes in T≥65 patient frequency, and Spearman’s correlations between change in seizures associated with a fall and T-scores were analyzed.

RCT and OLE data from 67 (fenfluramine [0.7mg/kg/d, n=18; 0.2mg/kg/d, n=24]; placebo, n=25) and 41 adults with LGS, respectively, were included.

A greater percentage of RCT fenfluramine-treated and OLE patients had median T-score improvements versus placebo (BRI: 17%–33%, 26%–39% versus 12%; MI: 33%, 39%–47% versus 4%; GEC: 28%–38%, 42%–44% versus 8%).

Baseline BRI, MI, and GEC T≥65 frequencies were 25%–33%, 44%–67%, and 36%–56%. MI and GEC T≥65 frequencies decreased with fenfluramine treatment and increased in the placebo group. In OLE, all BRIEF®—A Indexes/Composite frequencies decreased.

Correlations between change in frequency of seizures associated with a fall and BRIEF®—A Indexes/Composite were negligible to weak (RCT: −0.232 to 0.024; OLE: −0.239 to −0.206).

Adults with LGS treated with fenfluramine had clinically meaningful EEF improvements during a 14-week RCT and its 12-month OLE. Reductions in seizures associated with a fall and EEF improvements were partially independent of each other.