Joseph Sullivan, MD: Scientifically Determining a Clinically Meaningful Change in Seizure Frequency

January 19, 2019

The Director of the Pediatric Epilepsy Center at UCSF Benioff Children's Hospital spoke about what defines a "clinically meaningful change in seizure frequency" using data from a phase 3 clinical trial of ZX008 for the adjunctive treatment of seizures associated with Dravet syndrome.

“Forty-four was kind of the magic number, so you needed to have a seizure reduction of 44% or greater in order to have a high likelihood of giving that score of 1 or 2.”

At the American Epilepsy Society’s annual meeting held in New Orleans, Louisiana, Joseph Sullivan, MD, a pediatric epileptologist and Director of the Pediatric Epilepsy Center at UCSF Benioff Children’s Hospital, spoke with NeurologyLive about a secondary analysis that was conducted to scientifically determine a clinically meaningful change in seizure frequency through data from a phase 3 clinical trial (Study 1) of fenfluramine HCI oral solution (ZX008) for adjunctive treatment of seizures associated with Dravet syndrome. Researchers examined the percentage change in seizure frequency as well as caregiver and investigator ratings of Clinical Global Impression of Improvement (CGI-I).

Participants with Dravet syndrome (N=119) were enrolled in Study 1 and randomized 1:1:1 to placebo, 0.2 mg/kg/day of ZX008, or 0.8 mg/kg/day ZX008, and entered a 2-week titration phase followed by a 12-week maintenance period. The study met its primary endpoint which included participants in the 0.8 mg/kg/day ZX008 arm demonstrating a 63.9% greater reduction in seizure frequency versus placebo. After the 14-week period, caregivers and investigators rated the change in clinical status from baseline using the CGI-I scale where scores of 1 (very much improved) or 2 (much improved) were considered to have achieved a clinically meaningful response, and a score of 3 (minimally improved) was not considered meaningful.

The analysis of the association between percentage change in seizure frequency and CGI-I rated by caregivers or investigators suggests that a 44% reduction from baseline can be considered a clinically meaningful response in patients with Dravet syndrome. Based on these data, 75%, 46%, and 12.5% of participants in the 0.8 mg/kg/day ZX008, 0.2 mg/kg/day ZX008, and placebo groups, respectively, achieved a clinically meaningful reduction in seizure frequency in Study 1. Higher levels of seizure reduction (60%—68%) were associated with ratings of “very much improved.”

Sullivan explained that a 44% reduction reinforces the notion that a 50% reduction in seizures is a clinically meaningful endpoint.