Validation of a Disease-Specific Instrument for Pediatric Inherited Neuropathy

描述（由申请人提供）：腓骨肌痛病（CMT），或遗传性运动-感觉神经病变，每2500名儿童中就有1名患有此病，通常导致疼痛、抑郁、残疾无力和成年后健康相关生活质量（QOL）显著降低。通过治疗处于疾病早期阶段的儿童来减轻这一巨大的疾病负担至关重要；然而，迄今为止，没有一种治疗方法在临床试验中被证明是有效的。在最近的试验中缺乏治疗效果可能是由于选择了不合适的结果测量。目前缺乏有效、敏感和可靠的主要结局指标作为儿科遗传性神经病变试验的终点，这是该领域进展的一个关键障碍。本应用程序的研究目的是确定一种准确反映儿童CMT疾病进展的结果测量。中心假设是，与以前使用的神经病变试验终点相比，疾病特异性儿童CMT生活质量仪器将作为疾病进展的有效、可靠和更敏感的测量。提出这项研究的基本原理是，确定临床试验的有效结果措施可以增加潜在有效疗法不被不明智地抛弃的可能性。教育目标是获得早期试验方法和监管培训方面的专业知识，将有希望的药物转化为临床试验，从而发展成为该领域的独立研究者和领导者。该项目的具体目标是(a)在儿科CMT的通用和疾病特异性选择之间确定具有更大临床有效性的生活质量工具，以及(b)通过对300名CMT儿童的多中心纵向研究，在复合神经病变评分、电生理学和生活质量数据中确定与CMT儿科患者最相关的结果测量。这一建议意义重大，因为它将确定有效、敏感和可靠的结果指标，这些指标可以(a)作为旨在改善这一人群生活质量的干预措施的计划临床试验的终点，以及(b)协助监测高度脆弱人群的观点：因慢性进行性神经肌肉疾病而残疾的儿童。该研究具有创新性，因为它可能导致选择患者报告的结果作为神经病变试验的主要终点，从而改变目前使用电生理结果测量的范式，这种方法在临床试验中很少显示出有意义的改善。拟议的研究与NIH的使命有关，即帮助减轻人类残疾的负担，因为实现研究目标将积极影响未来确定改善神经肌肉疾病患者生活质量的治疗干预措施的努力。PI的职业发展将由多学科专家指导委员会促进，并直接获得PI导师指导的遗传性神经病变联盟的资源。成功实现所提出的目标将导致确定未来临床试验的有效结果措施，以及PI领导儿科CMT早期临床试验所需的专业知识。

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.