Clinically Meaningful Outcomes for Duchenne Muscular Dystrophy Therapeutic Trials

描述（由申请人提供）：杜氏肌营养不良症（DMD）是一种由肌营养不良蛋白基因突变引起的x连锁神经肌肉疾病，导致进行性肌肉无力，通常在青年期导致死亡。这是最常见的儿童神经肌肉疾病，在所有种族中，每3500名男性中就有1人患有此病。致残性虚弱、丧失行动能力和自我照顾能力以及心肺衰竭，给患者、护理人员和家属造成巨大的心理和情绪压力；管理需要大量的卫生、教育和社区资源。疾病的流行程度、严重性以及综合的情感和经济成本使DMD成为一个重大的公共卫生问题。虽然目前还没有有效的治疗DMD的方法，但有希望的和新的治疗方法已经出现，需要精心设计的临床试验。这项工作的关键是开发实用的、具有成本效益的、易于管理的结果测量，这些结果测量具有临床意义，并且对疾病进展和治疗引起的变化敏感。此外，需要更详细的自然病史数据来优化临床试验设计。目前，我们的20个国际研究中心正在收集348名2至28岁男性DMD患者的力量、活动范围、运动功能能力、肺功能和患者报告的健康相关生活质量的一系列测量数据。在这项拟议的辅助研究中，我们将在基线和每年进行新的客观临床结果测量（6分钟步行试验[6MWT]， 9孔钉试验和运动功能测量[MFM]）和患者报告的健康相关生活质量评估（PedsQL的神经肌肉模块[NMM]和NIH PROMIS网络神经疾病生活质量[NeuroQoL]评估）。该项目的具体目标是：具体目标1：评估DMD中新的客观临床结果测量的可靠性，有效性和反应性：包括6MWT， 9孔钉试验（9-HPT）和运动功能测量（MFM）。具体目标2：评估DMD中新型患者报告结果（PRO）测量的可靠性、有效性和响应性：包括PedsQL （NMM）的神经质量和神经肌肉模块。具体目标3：通过评估新的客观结果测量（6MWT、9-HPT和MFM）预测行走能力丧失和自我进食能力丧失里程碑的能力，评估其临床意义。我们假设在DMD中，6MWT、9-HPT和MFM将是可靠的，通过与适当的患者报告的结果域的关联来确定是有效的，对疾病相关进展有反应，并且通过预测重要疾病相关里程碑的能力来确定是有临床意义的。该提案对DMD患者和研究界具有重要意义，因为该研究将记录新开发的结果测量的效用、临床意义和反应性，这些结果测量将被工业界和学术界用作未来有希望的新疗法的治疗试验的主要临床终点。

DESCRIPTION (provided by applicant): Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder caused by mutation of the dystrophin gene with resultant progressive muscle weakness, leading to death usually by young adulthood. It is the most common childhood neuromuscular disorder affecting about 1 in 3,500 males across all ethnic groups. Disabling weakness, loss of ambulation and self-care, and cardiopulmonary failure, create tremendous psychological and emotional stress on patients, caregivers, and family; and considerable health, education, and community resources are required for management. The disease prevalence, seriousness, and the combined emotional and financial cost make DMD a significant public health concern. Although no effective treatment for DMD is available at this time, promising and novel therapeutic treatments have emerged for DMD that will require well-designed clinical trials. Critical in this effort is the development of practical, cost-effective, and easily administered outcome measures that are clinically meaningful and sensitive to changes due to disease progression and treatment. In addition, a more detailed natural history data is needed to optimize clinical trial design. Currently, our group of twenty international centers is collecting serial measures of strength, range of motion, motor functional ability, pulmonary function, and patient-reported health-related quality of life in a cohort of 348 males with DMD between 2 and 28 years of age. In this proposed ancillary study, we will administer novel objective clinical outcome measures (6-minute walk test [6MWT], 9-hole peg test and Motor Function Measure [MFM]) and assessments of patient-reported health-related quality of life (Neuromuscular Module of the PedsQL [NMM] and NIH PROMIS Network Quality of Life in Neurological Disease [NeuroQoL] assessment) at baseline and annually for two years. Specific aims of the project are: Specific Aim 1: To assess the reliability, validity, and responsiveness of novel objective clinical outcome measures in DMD: including the 6MWT, the 9-hole peg test (9-HPT), and the Motor Function Measure (MFM). Specific Aim 2: To assess the reliability, validity, and responsiveness of novel patient-reported outcome (PRO) measures in DMD: including the NeuroQoL and Neuromuscular module of the PedsQL (NMM). Specific Aim 3: To assess the clinical meaningfulness of novel objective outcome measures (6MWT, 9-HPT, and MFM) by assessing their ability to predict milestones of loss of ambulation and loss of ability to self-feed. 7 We hypothesize that in DMD, the 6MWT, 9-HPT, and MFM will be reliable, valid as determined by association with appropriate patient-reported outcome domains, responsive to disease-related progression, and clinically meaningful as determined by ability to predict important disease-related milestones. The proposal is significant for DMD patients and the research community because the study will document the utility, clinical meaningfulness and responsiveness of newly developed outcome measures that will be used as primary clinical endpoints by industry and academics in future therapeutic trials of promising new treatments. PUBLIC HEALTH RELEVANCE: Duchenne muscular dystrophy (DMD) is the most common neuromuscular disease of childhood and is the neuromuscular disorder with the greatest annual per capita cost for outpatient rehabilitative treatment. The combination of the disease's prevalence, seriousness, cross-cultural presentation, and the combined emotional and financial expense make DMD a significant public health concern. One of the critical issues identified by the DMD research community, industry, and federal agencies is the development of practical, cost-effective, easily administered endpoints that are clinically meaningful and sensitive to changes in disease progression as well as those produced by treatments. Our proposal is significant for DMD patients because we will document the utility, clinical meaningfulness, and responsiveness of newly developed outcome measures that will be used as primary clinical endpoints by industry in future therapeutic trials of promising novel agents.