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。该项目的具体目标是：(A)通过对400名CMT儿童进行前瞻性的多中心纵向临床试验，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400名CMT儿童进行前瞻性多中心纵向临床试验，在综合神经病变评分、电生理学和QOL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。这项研究具有潜在的创新性，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，这种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。拉姆钱德伦博士的长期目标是开发干预措施，改善神经肌肉疾病患者的生活质量，并开发在临床试验中应用结果衡量标准的专业知识。在Michael Shy博士的主要指导下，PI在实现她在韦恩州立大学的目标方面处于独特的有利地位，Michael Shy博士在CMT基因-表型相关性方面拥有广泛的专业知识，并且在评估临床试验结果衡量标准的可靠性和有效性方面也拥有专业知识。导师职业发展奖为PI提供了理想的媒介，使其成为独立的神经肌肉研究人员，并在临床试验中使用结果衡量标准方面的权威。(1)专业的多学科辅导团队，(2)调查方法论的授课研究生讲座和研讨会，这将在该协会之前获得的临床研究设计和统计分析理学硕士的基础上扩展，以及(3)直接访问由该协会的导师指导的由NINDS资助的遗传性神经病联盟的资源，该联盟专门为进行和促进临床研究而设计。

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 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, through a prospective, multicenter longitudinal clinical trial in 400 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 potentially 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. Dr. Ramchandren's long-term goal is to develop interventions that result in improved QOL for patients with neuromuscular diseases, and develop expertise in the application of outcome measures in clinical trials. The PI is uniquely well-positioned to achieve her goals at Wayne State University under the primary mentorship of Dr. Michael Shy, who has extensive expertise in CMT genotypic- phenotypic correlations, and who also has expertise in evaluating the reliability and validity of outcome measures for clinical trials. The mentored career development award provides the ideal medium for the PI to become an independent neuromuscular researcher and authority on outcome measure utilization in clinical trials. The PI's career development will be facilitated by: (1) an expert multidisciplinary mentorship team, (2) didactic graduate lectures and workshops in Survey Methodology, which will expand on the PI's previously acquired Master of Science in Clinical Research Design and Statistical Analysis and (3) direct access to the resources of the NINDS-funded Inherited Neuropathy Consortium directed by the PI's mentor, which is designed specifically to conduct and promote clinical research.