Clinically Meaningful Outcomes for Duchenne Muscular Dystrophy Therapeutic Trials

描述(申请人提供)：Duchenne肌营养不良症(DMD)是一种X连锁的神经肌肉疾病，由dystrophin基因突变引起，导致进行性肌肉无力，通常导致青壮年死亡。这是最常见的儿童神经肌肉疾病，在所有种族中，每3500名男性中就有一人受到影响。致残、行动不便、丧失自理能力和心肺衰竭，会给患者、照顾者和家人带来巨大的心理和情感压力；管理需要大量的健康、教育和社区资源。疾病的流行率、严重性以及合并的情感和经济成本使DMD成为一个重大的公共卫生问题。虽然目前还没有治疗DMD的有效方法，但有希望的、新的治疗方法已经出现，这需要精心设计的临床试验。这一努力的关键是开发实用、成本效益高和易于管理的结果衡量标准，这些衡量标准具有临床意义，并对疾病进展和治疗引起的变化敏感。此外，需要更详细的自然历史数据来优化临床试验设计。目前，我们由20个国际中心组成的小组正在收集348名2至28岁的男性DMD患者的力量、活动范围、运动功能、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两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])和患者报告的与健康相关的生活质量评估(PedsQL[NMM]的神经肌肉模块和NIH PROMIS网络的神经疾病生活质量[NeuroQL]评估)。该项目的具体目标是：具体目标1：评估DMD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孔挂钩试验(9-HPT)和运动功能测量(MFM)。具体目标2：评估DMD中新的患者报告结果(PRO)测量的可靠性、有效性和响应性：包括神经QL和PedsQL的神经肌肉模块(NMM)。具体目标3：通过评估新的客观结果指标(6MWT、9-HPT和MFM)预测行走能力丧失和自给自足能力丧失的里程碑的能力，评估它们的临床意义。7我们假设，在DMD中，6MWT、9-HPT和MFM将是可靠、有效的，根据患者报告的适当结果域确定，对疾病相关进展的反应，以及根据预测重要疾病相关里程碑的能力确定的临床意义。这项建议对DMD患者和研究界具有重要意义，因为这项研究将记录新开发的结果指标的实用性、临床意义和响应性，这些指标将被工业界和学术界用作未来有希望的新疗法的主要临床终点。

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.