Clinically Meaningful Outcomes for Duchenne Muscular Dystrophy Therapeutic Trials

杜氏肌营养不良症治疗试验具有临床意义的结果

• 批准号: 8735608
• 负责人: Craig M. McDonald
• 金额: $ 34.6万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8735608
• 关键词: Activities of Daily Living; Adrenal Cortex Hormones; Affect; Age; Age-Years; Ancillary Study; Articular Range of Motion; Cardiopulmonary; Caring; Cessation of life; Characteristics; Child; Childhood; Clinical; Clinical Trials; Clinical Trials Design; Communities; Community Health Education; Data; Data Collection; Development; Disease; Disease Progression; Duchenne muscular dystrophy; Dystrophin; Effectiveness; Emotional; Emotional Stress; Ethnic group; Failure; Family Caregiver; Financial cost; Future; Genes; Industry; International; Link; Measures; Motor; Muscle Weakness; Muscular Dystrophies; Mutation; Natural History; Neuromuscular Diseases; Outcome; Outcome Measure; Outpatients; Parents; Patient Outcomes Assessments; Patients; Personal Satisfaction; Persons; Prevalence; Proxy; Psychological Stress; Public Health; Pulmonary function tests; Quality of life; Rehabilitation therapy; Reporting; Research; Resources; Self Care; Severity of illness; Staging; Testing; Therapeutic Agents; Therapy Clinical Trials; Time; United States National Institutes of Health; Upper Extremity; Validity and Reliability; Walking; base; cohort; cost; cost effective; design; effective therapy; feeding; health related quality of life; international center; male; nervous system disorder; neuromuscular; new therapeutic target; novel; novel therapeutics; prospective; pulmonary function; response; young adult

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.

描述（由申请人提供）：Duchenne肌肉营养不良（DMD）是由肌营养不良蛋白基因突变引起的X连锁神经肌肉疾病，导致渐进性肌肉无力，通常导致年轻成年。它是最常见的儿童神经肌肉疾病，影响了所有种族的3500名男性中约1个。禁用弱点，流动和自我保健以及心肺失败，给患者，看护人和家庭带来巨大的心理和情感压力；管理需要大量健康，教育和社区资源。疾病的患病率，严重性以及情绪和财务成本的综合使DMD成为一个重大的公共健康问题。尽管目前尚无对DMD的有效治疗方法，但是对于需要精心设计的临床试验的DMD出现了有希望的新型治疗方法。这项工作中至关重要的是开发实用，具有成本效益且易于执行的结果指标，这些措施在临床上有意义且对由于疾病进展和治疗而变化敏感。此外，还需要更详细的自然历史数据来优化临床试验设计。目前，我们的二十个国际中心集团正在收集强度，运动功能范围，运动功能范围，肺功能和患者报告的与健康相关的生活质量的序列度量，其中348名DMD男性在2至28岁之间。 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 年。该项目的具体目的是：具体目标1：评估DMD中新型客观临床结果度量的可靠性，有效性和反应性：包括6MWT，9孔PEG测试（9-HPT）和运动功能度量（MFM）。具体目的2：评估DMD中新型患者报告结果（PRO）测量的可靠性，有效性和反应性：包括PEDSQL（NMM）的神经QOL和神经肌肉模块。特定目的3：通过评估他们预测他们预测失去行动丧失和自我喂养能力的里程碑的能力，评估新型客观结果度量（6MWT，9-HPT和MFM）的临床意义。 7我们假设在DMD中，6MWT，9-HPT和MFM将是可靠的，有效，可以通过与适当的患者报告的结果领域相关性，对疾病相关的进展有反应，并且在临床上有意义，并取决于预测重要疾病相关的重要里程碑的能力。该提案对DMD患者和研究界非常重要，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，这些措施将在未来有希望的新治疗的治疗试验中用作行业和学者的主要临床终点。

项目成果

Validation of Chemokine Biomarkers in Duchenne Muscular Dystrophy.

• DOI: 10.3390/life11080827
• 发表时间: 2021-08-13
• 期刊: Life (Basel, Switzerland)
• 作者: Ogundele M;Zhang JS;Goswami MV;Barbieri ML;Dang UJ;Novak JS;Hoffman EP;Nagaraju K;Cinrg-Dnhs Investigators;Hathout Y
• 通讯作者: Hathout Y

Genetic modifiers of upper limb function in Duchenne muscular dystrophy.

• DOI: 10.1007/s00415-022-11133-8
• 发表时间: 2022-09
• 期刊: Journal of neurology
• 影响因子: 6

Clinical approach to the diagnostic evaluation of hereditary and acquired neuromuscular diseases.

• DOI: 10.1016/j.pmr.2012.06.011
• 发表时间: 2012-08
• 期刊: PHYSICAL MEDICINE AND REHABILITATION CLINICS OF NORTH AMERICA
• 影响因子: 1.7
• 作者: McDonald, Craig M.

Tandem Mass Tag-Based Serum Proteome Profiling for Biomarker Discovery in Young Duchenne Muscular Dystrophy Boys.

• DOI: 10.1021/acsomega.0c03206
• 发表时间: 2020-10-20
• 期刊: ACS omega
• 影响因子: 4.1
• 作者: Alayi TD;Tawalbeh SM;Ogundele M;Smith HR;Samsel AM;Barbieri ML;Hathout Y
• 通讯作者: Hathout Y

Long-Term Functional Efficacy and Safety of Viltolarsen in Patients with Duchenne Muscular Dystrophy.

• DOI: 10.3233/jnd-220811
• 发表时间: 2022
• 期刊: JOURNAL OF NEUROMUSCULAR DISEASES
• 影响因子: 3.3
• 作者: Clemens, Paula R.;Rao, Vamshi K.;Connolly, Anne M.;Harper, Amy D.;Mah, Jean K.;McDonald, Craig M.;Smith, Edward C.;Zaidman, Craig M.;Nakagawa, Tomoyuki;Hoffman, Eric P.
• 通讯作者: Hoffman, Eric P.