What Magnitude of Reduction Is a “Clinically Meaningful” Change in Seizure Frequency? Analysis of Long-Term Fenfluramine Phase 3 Dravet Syndrome Data

Background/Purpose: A 50% reduction in monthly convulsive seizure frequency (MCSF) is traditionally accepted as clinically meaningful, although this threshold is largely empirically derived. Here, we used a robust, anchor-based method in a long-term open-label extension (OLE) study of fenfluramine for the treatment of Dravet syndrome to quantify the degree of MCSF reduction associated with various parents/caregiver/investigator Clinical Global Impression of Improvement (CGI-I) ratings.

Methods: MCSF and CGI-I data were derived from an OLE interim analysis (N = 330; October 19, 2020). Correlations between MCSF and CGI-I were analyzed by Spearman's rho. Receiver operating characteristic (ROC) analysis compared change in MCSF with binary versions of investigator and caregiver CGI-I Likert scale ratings. The cut point for a clinically meaningful change, defined by ratings of “much improved” or “very much improved” on CGI-I, was defined as the change in MCSF where sensitivity was approximately equal to specificity.

Results: Caregiver or investigator CGI data at last visit were available from 299 and 313 patients, respectively. MCSF reduction was positively correlated with improvement in caregiver/investigator CGI-I scores (Spearman's rho, 0.530–0.545; p < 0.0001). ROC analysis identified a 60.5% reduction in MCSF as the clinically meaningful cutoff for subjects rated as “Much Improved” or “Very Much Improved.” Additionally, a 72% reduction in MCSF was associated with caregiver/investigator CGI-I ratings of “Very Much Improved.”

Conclusion: This analysis of the association between percent reduction in MCSF and CGI-I suggests that a sustained 60.5% reduction from baseline in convulsive seizure frequency can be considered a clinically meaningful response.

The data were first presented at IEC 2021 Virtual Congress.

No conflict of interest has been declared by the author(s).

Publication History

Article published online:
28 October 2021