PAR-18-953 (ASCOT-DMD)

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Project Summary The premise of this application is informed by the strategic priorities of the Muscular Dystrophy Coordinating Committee (MDCC) of the National Institutes of Health (NIH), and from our clinical and research experience on cognition in Duchenne Muscular Dystrophy (DMD). Cognitive health is one of the key determinants of quality-of-life (QoL) in DMD. The improvement in life-expectancy, along with the exciting pace of drug development and drug approval in this rare disease space has provided a backdrop to be more inclusive of treating cognitive symptoms in DMD. The preclinical success can be more rapidly translated to clinical trials by establishing sensitive and robust performance-outcome (PerfO) measures of cognition. In this application, we bring a team science approach, leveraging the research expertise of Drs. Thangarajh, Adams and Kaat to investigate the strength of the NIH Toolbox Cognition Battery (NIHTB-CB), as a performance- outcome measure for cognition in DMD. The NIHTB-CB permits continuity of measurement, fulfills the NIH mandate for scientific rigor and reproducibility, and is scalable for multi-site clinical trials, unlike gold-standard neuropsychological tests which cannot be applied with high fidelity in clinical trial settings. The specific aims of the proposal are to establish the (i) test-retest reliability and practice effects of the NIHTB-CB, (ii) to use patient-reported outcome measures (PROMs) to identify participants’ self-reported function, QoL, and symptom burden, and (iii) to longitudinally assess cognitive development using NIHTB-CB. This prospective, longitudinal study will assess 46 participants with NIHTB-CB, cognition-specific PROMs and standardized rating scales. The NIHTB-CB will be administered at baseline, 3 weeks (± 1 week), and at 1 year, to investigate the test-retest reliability and practice effects, an attribute that is critical for FDA’s approval for any PerfO measure. Innovation: This proposal is the first to investigate whether the NIHTB-CB holds promise as a PerfO measure of cognition in DMD. We bring a team science approach to improve the cognitive research footprint in DMD. The completion of our study will provide the scientific rationale to adopt the NIH Toolbox as a PerfO measure of cognition in clinical trials in DMD.