Validation of a Disease-Specific Instrument for Pediatric Inherited Neuropathy

描述(申请人提供)：Charcot-Marie-Tooth病(CMT)，或遗传性运动感觉神经病，每2500名儿童中就有一名患有此病，成年后通常会导致疼痛、抑郁、致残虚弱和与健康相关的生活质量(QOL)显著下降。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，到目前为止，还没有一种疗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适当的结果衡量标准。目前，在儿科遗传性神经病试验中，缺乏有效、敏感和可靠的主要结果指标作为终点，这是这一领域取得进展的关键障碍。这项应用的研究目标是确定一种准确反映儿童CMT疾病进展的结果衡量标准。中心假设是，与以前使用的神经病试验终点相比，特定疾病的儿科CMT生活质量量表将作为疾病进展的有效、可靠和更敏感的衡量标准。这项拟议研究的基本原理是，为临床试验确定有效的结果衡量标准，增加了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学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)通过对300名CMT儿童进行多中心纵向研究，确定在儿童CMT的一般选择和疾病特异性选择之间具有更高临床有效性的QOL工具，以及(B)通过对300名CMT儿童进行多中心纵向研究，在综合神经病变评分、电生理学和生活质量数据中确定与儿童CMT患者最相关的结果衡量标准。这项提议意义重大，因为它将确定有效、敏感和可靠的结果衡量标准，这些措施可以(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)协助监测高度脆弱群体的观点：因慢性进行性神经肌肉疾病而致残的儿童。这项研究具有创新性，因为它可能导致在神经病变试验中选择患者报告的结果作为主要终点，从而改变目前利用电生理结果测量的范式，这些测量方法在临床试验中很少显示出有意义的改善。这项拟议的研究与NIH帮助减轻人类残疾负担的使命相关，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的努力产生积极影响。私教的职业发展将由专家多学科指导委员会推动，并直接获得由私教导师指导的遗传性神经病联盟的资源。成功实现拟议目标将导致为未来的临床试验确定有效的结果衡量标准，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：为儿童遗传性神经病试验确定有效的结果衡量标准，为开发最终可能广泛适用于所有神经疾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。这项拟议的研究与公共卫生相关，因为使研究人员能够通过可靠、有效和敏感的结果衡量遗传神经病儿童的治疗反应，可以导致干预措施，帮助减轻这一脆弱人群的疾病负担。

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.