Authors :
Kevin Chapman, MD – Phoenix Children's Hospital
Muhammad Zafar, MD – Duke University School of Medicine
Anthony Fine, MD – Mayo Clinic
Betsy Williams, PhD – IQVIA
Stella Karantzoulis, PhD, ABPP-CN – IQVIA
Nicole Wedick, ScD – Neurocrine Biosciences, Inc.
Dietrich Haubenberger, MD, MHSc, FAAN – Neurocrine Biosciences, Inc.
Svetlana Shore, PhD – Neurocrine Biosciences, Inc.
Presenting Author: Carolyn McMicken, PsyD – Neurocrine Biosciences, Inc.
Rationale:
EE-CSWS is a rare pediatric syndrome associated with cognitive, behavioral and functional impairments. There are no fit-for-purpose clinical outcome assessments (COAs) that assess meaningful changes among patients living with this condition, and an overall lack of syndrome-specific COAs in pediatric epilepsy. We sought to develop novel clinician- and caregiver-reported COAs to measure EE-CSWS concepts of interest in clinical trials. Methods:
Signs, symptoms, and impacts of EE-CSWS were identified through targeted literature and social media intelligence reviews, and concept-elicitation interviews with clinicians and caregivers. This was used to develop a preliminary conceptual model of the disease and evaluate existing instruments for content validity and psychometric properties. None were identified as fit-for-purpose; thus, an expert panel was engaged to prioritize concepts of interest, align on type(s) of COA, and generate novel items. De novo COAs were developed, and cognitive debriefing interviews with clinicians/caregivers were conducted to finalize the conceptual model, evaluate content validity, and refine the COAs. Mock patient vignettes were used to test reliability of the novel COAs and understand clinician/caregiver perspectives on clinically meaningful change. Initial descriptive and psychometric analyses were performed in a Phase 2, double-blind, placebo-controlled study of NBI-827104 in 14 EE-CSWS children. Exit interviews with caregivers and clinicians were used to understand perceptions of meaningful change on the COAs.Results:
Four disease-specific COAs were developed: Global Impression of Severity for caregivers (CSWS-CaGI-S) and clinicians (CSWS-CGI-S), and Global Impression of Change for caregivers (CSWS-CaGI-C) and clinicians (CSWS-CGI-C). Each includes 3 domains: Cognitive/Intellectual, Behavior-Related, and Daily Activities/Self-Care. Test-retest reliability coefficients were generally at least substantial (i.e., 0.6) for all test-retest periods. Item-to-item correlations showed good correspondence between domain scores and overall scores ( >0.5), indicating overall scores captured content assessed by the 3 domains. Sensitivity to change in CSWS-CGI-S and CSWS-CaGI-S showed a fairly consistent pattern between baseline and Week 12. Known-groups validity analysis indicated that those assessed by the clinician as more severe on the generic CGI-S were also assessed by the clinician and caregiver as more severe on the EE-CSWS-specific measure. In general, improvement in both clinician- and caregiver-assessed overall severity of 1.0 point was considered meaningful.Conclusions:
EE-CSWS-specific caregiver and clinician Global Impression scales were developed to fill an unmet need and assess changes in EE-CSWS signs, symptoms, and impacts important to pediatric patients living with this condition. Initial analyses indicate these are reliable measures of clinically relevant concepts for clinical trial use in this target population. Funding:
Neurocrine Biosciences Inc.