Abstract Details

Title 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?

Topic Epilepsy/Clinical Neurophysiology (EEG)

Presentation(s) S13 - Epilepsy/Clinical Neurophysiology (EEG) 1 (1:00 PM-1:12 PM)

Poster/Presentation
Number 001

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.

Authors/Disclosures
Arnold Gammaitoni, PharmD (Zogenix) PRESENTER	Dr. Gammaitoni has received personal compensation for serving as an employee of Zogenix Inc.. Dr. Gammaitoni has received stock or an ownership interest from Zogenix Inc..
	No disclosure on file
Dennis J. Dlugos, MD	Dr. Dlugos has received research support from NIH. The institution of Dr. Dlugos has received research support from The Epilepsy Study Consortium.
Gail M. Farfel, PhD	Dr. Farfel has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Durect Corp. Dr. Farfel has received personal compensation in the range of $100,000-$499,999 for serving as an officer or member of the Board of Directors for Zogenix. Dr. Farfel has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for AvroBio. Dr. Farfel has received intellectual property interests from a discovery or technology relating to health care.
	No disclosure on file
Glenn Morrison, PhD (Annexon Biosciences)	Dr. Morrison has received personal compensation for serving as an employee of Alector. Dr. Morrison has received personal compensation in the range of $500-$4,999 for serving as a Consultant for GLG . Dr. Morrison has stock in Alector. Dr. Morrison has received intellectual property interests from a discovery or technology relating to health care.
	No disclosure on file
	No disclosure on file

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