Validation of a Disease-Specific Instrument for Pediatric Inherited Neuropathy

描述（由申请人提供）：腓骨肌萎缩症（CMT）或遗传性运动感觉神经病，每2500名儿童中就有1名患病，通常导致疼痛、抑郁、致残性虚弱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少这种巨大的疾病负担至关重要;然而，迄今为止，没有任何治疗方法在临床试验中被证明是有效的。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局指标。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试验的终点，这是该领域进展的关键障碍。本申请的研究目的是确定一种准确反映儿童CMT疾病进展的结局指标。中心假设是疾病特异性儿科CMT QOL工具将作为一种有效、可靠且比先前使用的神经病变试验终点更敏感的疾病进展指标。这项研究的基本原理是，确定临床试验的有效结果指标，增加了潜在有效疗法不会被不明智地丢弃的可能性。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，将有前途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。该项目的具体目的是：（a）通过对300名CMT儿童进行的多中心纵向研究，确定儿科CMT中通用和疾病特异性选项之间临床有效性更高的QOL工具，以及（B）在复合神经病变评分、电生理学和QOL数据中，确定与CMT儿科患者最相关的结局指标。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）作为计划的旨在改善这一人群生活质量的干预措施临床试验的终点，（B）协助监测高度脆弱人群的前景：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局作为神经病试验的主要终点，从而改变了目前使用电生理结局指标的范式，这些指标在临床试验中很少显示有意义的改善。拟议的研究与NIH的使命有关，以帮助减轻人类残疾的负担，因为实现研究目标将对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产生积极影响。PI的职业发展将由专家多学科指导委员会促进，并直接访问PI导师指导的遗传性神经病联盟的资源。成功实现拟定目标将导致确定未来临床试验的有效结局指标以及PI领导儿科CMT早期临床试验所需的专业知识。 公共卫生相关性：儿童遗传性神经病试验的有效结局指标的确定为开发最终可能广泛适用于所有神经病的靶向治疗提供了机会。因此，研究结果将对未来改善神经肌肉疾病患者生活质量的努力产生积极影响。拟议的研究与公共卫生有关，因为使研究人员能够通过可靠，有效和敏感的结果措施来衡量遗传性神经病儿童的治疗反应，可以导致有助于减少这一弱势群体疾病负担的干预措施。

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. PUBLIC HEALTH RELEVANCE: Identification of validated outcome measures for pediatric inherited neuropathy trials offers the opportunity to develop targeted therapies that may eventually be broadly applicable to all neuropathies. Thus, study outcomes will positively impact future efforts to improve the quality of life of patients with neuromuscular diseases. The proposed research has relevance to public health, because enabling researchers to measure treatment responses in children with inherited neuropathy via reliable, valid and sensitive outcome measures can lead to interventions that help reduce the disease burden in this vulnerable population.