Quantifying “Clinically Meaningful Changes” in Seizure Frequency - Data from Three Phase 3 Studies of ZX008 (Fenfluramine Hydrochloride Oral Solution) in Dravet Syndrome: Do Expectations and Views Change Over Time? (2247)

Objective: To examine the degree of seizure frequency reduction associated with caregiver and investigator Clinical Global Impression of Improvement (CGI-I) ratings of “Much improved” or “Very much improved” in randomized controlled trials (RCTs) of fenfluramine for the treatment of Dravet syndrome. Background: A ≥50% reduction in monthly convulsive seizure frequency (MCSF) is traditionally accepted as being clinically meaningful, although this threshold has largely been empirically derived. We employed a robust, anchor-based method for calculating a clinically meaningful change in MCSF using investigator and caregiver CGI-I ratings as the dependent variable. Design/Methods: This analysis used data from two 14–15-week phase 3 RCTs (n=206) and a long-term open-label extension (OLE) study (n=330; median treatment duration, 63.5 weeks; range, 1.0–128.4). Patients in the phase 3 studies received placebo or add-on fenfluramine (0.2–0.7 mg/kg/day). Receiver operating characteristic (ROC) analysis compared change in MCSF with binary versions of investigator and caregiver CGI-I Likert scale ratings. The cutpoint for a clinically meaningful change equaled the change in MCSF at which sensitivity≈specificity. Results: In both RCTs, a linear positive relationship between MCSF reduction and caregiver/investigator CGI-I scores emerged. In the RCTs, ROC analysis identified cutpoints of ≥44% and ≥37.5% reductions in MCSF being associated with CGI-I ratings of “Much Improved” or “Very Much Improved.” In the OLE a different pattern emerged: these same CGI-I ratings corresponded to ≥78%–80% cutpoints. Conclusions: Major differences were found in the cutpoints between the two RCTs and the OLE. These unexpected results suggest that both caregiver and investigator views regarding MCSF reduction and rating a patient “Much improved” or “Very much improved” may change over long periods of time, possibly related to changing expectations of drug effect. Other factors may include non-seizure effects, tolerability, and OLE vs RCT study design. Disclosure: Dr. Gammaitoni has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Zogenix, Inc. Dr. Gammaitoni has received compensation for serving on the Board of Directors of Zogenix, Inc. Dr. Gammaitoni holds stock and/or stock options in Zogenix, Inc.Dr. Sullivan has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Dravet Syndrome Foundation, Epygenix (Consultant/Advisor); Epilepsy Study Consortium (Reviewer). Dr. Sullivan has received research support from Zogenix (with travel support). Dr. Dlugos has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with NIH, Commonwealth of Pennsylvania Department of Health, Pediatric Epilepsy Research Foundation, and The Epilepsy Study Consortium. He has received travel expenses for protocol development conferences or investigator meetings from Marinus, Ovid/Takeda, Ult. Dr. Dlugos has received research support from Zogenix; Greenwich Biosciences; UCB, Brain Sentinel, Neurelis, Inc.; Q-State; USL; Aquestive; Bio-Pharm; Insys; SK Life Sciences; and Encoded Therapeutics. Dr. Farfel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Zogenix. Dr. Farfel holds stock and/or stock options in Zogenix. Dr. Galer has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Zogenix, Inc. Dr. Galer has received compensation for serving on the Board of Directors of Zogenix, Inc. Dr. Morrison has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee: Zogenix, Inc.. Dr. Morrison has received compensation for serving on the Board of Directors of Ownership interest: Zogenix, Inc.. Dr. Morrison holds stock and/or stock options in Ownership interest: Zogenix, Inc.. Dr. Haney has received research support from Zogenix.Dr. Nabbout has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consultant/advisor, Eisai, GW Pharma, Novartis, Shire, Zogenix; Speaker, Advicenne, BioMarin, GW Pharma, Novartis, Zogenix. Dr. Nabbout has received research support from Eisai, GW Pharma, UCB, Zogenix.