Validation of a Disease-Specific Instrument for Pediatric Inherited Neuropathy

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DESCRIPTION (provided by applicant): Charcot-Marie-Tooth disease (CMT), or inherited motor-sensory neuropathy, afflicts 1 in 2500 children, often resulting in pain, depression, disabling weakness and significantly reduced health-related quality of life (QOL) by adulthood. Reducing this large disease burden by treating children who are in the early stages of the disease is crucial; however, to date, no therapy has proven effective in clinical trials. The lack of treatment effect in recent trials may have been due to the selection of unsuitable outcome measures. The current lack of valid, sensitive and reliable primary outcome measures to utilize as endpoints in pediatric inherited neuropathy trials represents a critical barrier to progression in this field. The research objective of this application is to identify an outcome measure that accurately reflects CMT disease progression in children. The central hypothesis is that a disease-specific pediatric CMT QOL instrument will serve as a valid, reliable, and more sensitive measure of disease progression, than previously utilized neuropathy trial endpoints. The rationale for the proposed research is that identifying validated outcome measures for a clinical trial increases the likelihood that potentially efficacious therapies are not discarded injudiciously. The educational objective is to achieve expertise in early phase trial methodology and regulatory training, to translate promising drugs to clinical trials and thereby develop into an independent investigator and leader in this field. The specific aims of the project are to (a) identify the QOL instrument of greater clinical validity between generic and disease-specific options in pediatric CMT, and (b) identify the outcome measure that is most relevant to the pediatric patient with CMT, among composite neuropathy scores, electrophysiology, and QOL data, via a multicenter, longitudinal study of 300 children with CMT. This proposal is significant because it would identify valid, sensitive and reliable outcome measures that could (a) serve as endpoints in planned clinical trials of interventions designed to improve the quality of life of this population, and (b) assist in monitoring the perspective of a highly vulnerable population: children with disability due to a chronic, progressive neuromuscular disease. The study is innovative because it may lead to the selection of patient-reported outcomes as primary endpoints in neuropathy trials, thus shifting the current paradigm of utilizing electrophysiologic outcome measures, which have rarely shown meaningful improvement in clinical trials. The proposed research is relevant to the NIH's mission to help reduce the burdens of human disability, as achieving study aims will positively impact future efforts to identify therapeutic interventions that improve the QOL of patients with neuromuscular diseases. The PI's career development will be facilitated by an expert multidisciplinary Mentoring Committee, and direct access to the resources of an Inherited Neuropathy Consortium directed by the PI's mentor. Success in achieving the proposed aims would lead to the identification of validated outcome measures for future clinical trials as well as the expertise needed by the PI to lead early phase clinical trials in pediatric CMT.