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X连锁神经肌肉疾病，由肌营养不良蛋白基因突变引起，导致进行性肌无力，通常在年轻时死亡。它是最常见的儿童神经肌肉疾病，影响所有种族群体中约1/3，500的男性。致残性虚弱、丧失活动能力和自我护理能力以及心肺功能衰竭对患者、护理人员和家庭造成了巨大的心理和情感压力;需要大量的健康、教育和社区资源进行管理。DMD的患病率、严重性以及综合的情感和经济成本使其成为一个重要的公共卫生问题。虽然目前尚无有效的DMD治疗方法，但DMD的有前途的新型治疗方法已经出现，需要精心设计的临床试验。这项工作的关键是开发实用，成本效益高，易于管理的结果措施，这些措施具有临床意义，对疾病进展和治疗引起的变化敏感。此外，需要更详细的自然史数据来优化临床试验设计。目前，我们的20个国际中心正在收集一系列措施的力量，活动范围，运动功能能力，肺功能，和患者报告的健康相关的生活质量在一个队列的348名男性DMD之间的2和28岁。在这项拟议的辅助研究中，我们将在基线和每年进行一次新的客观临床结局测量（6分钟步行试验[6 MWT]、9孔桩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 [NMM]神经肌肉模块和NIH PROMIS网络神经疾病生活质量[NeuroQoL]评估），持续两年。该项目的具体目标是：具体目标1：评估DMD中新型客观临床结局指标的可靠性、有效性和反应性：包括6 MWT、9孔桩试验（9-HPT）和运动功能测量（MFM）。具体目标二：评估DMD患者报告的新型结局（PRO）指标的可靠性、有效性和反应性：包括PedsQL（NMM）的NeuroQoL和神经肌肉模块。具体目标3：通过评估新型客观结局指标（6 MWT、9-HPT和MFM）预测失能和丧失自我进食能力里程碑的能力，评估其临床意义。7我们假设，在DMD中，6 MWT、9-HPT和MFM将是可靠的、有效的，如通过与适当的患者报告的结果域的关联来确定的，对疾病相关进展有反应，并且具有临床意义，如通过预测重要的疾病相关里程碑的能力来确定的。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指标的实用性，临床意义和反应性，这些指标将被行业和学术界用作未来有希望的新治疗方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.