Planning a Multicenter Trial of PDE5A Inhibition for Duchenne Muscular Dystrophy

计划开展 PDE5A 抑制治疗杜氏肌营养不良症的多中心试验

• 批准号: 8295579
• 负责人: Ronald G Victor
• 金额: $ 44.32万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8295579
• 关键词: Accounting; Address; Affect; Age; Agreement; Basic Science; Bees; Binding; Birth; Blood flow; Budgets; Cardiac; Cardiomyopathies; Case Report Form; Cessation of life; Cialis; Clinical; Clinical Trials; Computer software; Consent; Cyclic GMP; Data; Databases; Development; Diagnosis; Disease; Disease Progression; Dose; Double-Blind Method; Duchenne muscular dystrophy; Dystrophin; EFRAC; Echocardiography; Exercise; Exercise Tolerance; Fatigue; Florida; Functional disorder; Genes; Goals; Grant; Half-Life; Heart failure; Human; Industry; Injury; Institutional Review Boards; Interdisciplinary Study; Ischemia; Letters; Link; Magnetic Resonance Imaging; Manuals; Mediation; Medical center; Minority; Modeling; Monitor; Multicenter Trials; Mus; Muscle; Muscle Fatigue; Muscle Fibers; Muscle Weakness; Muscular Dystrophies; Myocardial; Myocardial dysfunction; National Institute of Arthritis and Musculoskeletal and Skin Diseases; Natural History; Nitric Oxide; Pamphlets; Patients; Pediatric Hospitals; Pennsylvania; Pharmaceutical Preparations; Phase; Philadelphia; Placebo Control; Pneumonia; Procedures; Protocols documentation; Quality of life; Randomized; Refractory Disease; Research; Research Design; Research Personnel; Research Subjects; Resources; Respiratory Muscles; Safety; Sample Size; Site; Skeletal Muscle; Testing; Therapeutic; TimeLine; Toddler; Training; Translating; Translations; Universities; Vascular Smooth Muscle; Walking; Wasting Syndrome; Wheelchairs; Writing; Zebrafish; advanced disease; boys; clinical practice; drug development; experience; human subject protection; improved; indexing; inhibitor/antagonist; male; mdx mouse; mouse model; new therapeutic target; novel strategies; older patient; outreach; phosphoric diester hydrolase; research study; tadalafil

DESCRIPTION (provided by applicant): Duchenne muscular dystrophy (DMD) is a devastating X-linked muscle-wasting disease for which there is as yet no specific treatment. Affecting one in 3,500 male births, DMD accounts for 80% of all cases of muscular dystrophy. Boys are diagnosed as toddlers and most are wheelchair bound by age 15. Death often occurs by age 20 from respiratory muscle weakness and cardiomyopathy. A therapeutic breakthrough in research is urgently needed. Twenty-five years have passed since dystrophin was discovered to be the disease gene in DMD. Although basic science on DMD has flourished, clinical translation has not. Parallel translational experiments in mouse models and boys with DMD by Dr. Victor and co-workers during the past two decades have shown that loss of sarcolemmal nNOSm renders the diseased muscle fibers susceptible to functional ischemia and implicated skeletal muscle-derived nitric oxide (NO) as a novel therapeutic target for this refractory disease. Indeed, phosphodiesterase (PDE5A) inhibitors, which prolong the half-life of cGMP-the downstream target of NO in vascular smooth muscle-rapidly ameliorated exercise-induced muscle ischemia, muscle injury, and fatigue in the mdx mouse model of DMD. The burning question is: Can we translate this compelling mouse research to benefit human patients-boys with DMD? Here we propose the first multicenter trial to test if PDE5A inhibition with tadalafil increases the distance walked on a 6-minute walk test (primary end point) in boys with DMD (ages 7-15, ambulatory, preserved ejection fraction). Secondary end points include quality of life and myocardial strain by cardiac MRI. We propose a stratified, randomized, double-blind, placebo-controlled Phase IIB trial of two doses of tadalafil treatment for 12 weeks. To implement this trial, a 12- month U34 planning period is essential for an experienced multidisciplinary research team to achieve the following specific aims: 1) develop a comprehensive recruitment and retention plan, including development of novel strategies for minority outreach; 2) vet every aspect of the study design and conduct power calculations; 3) develop trial timeline and budget, review milestones with NIAMS, and submit the UM1 application three months after receiving the U34; then, in the remaining nine months, 4) address all human subjects' protection requirements; and 5) develop a comprehensive manual of operating procedures and training manual. Planning activities will be conducted at three sites: Cedars-Sinai Medical Center-UCLA, Children's Hospital of Philadelphia-University of Pennsylvania, and University of Florida. The proposed trial directly addresses the goals of NIAMS. A preemptive approach in younger boys with less advanced disease has a far better chance of improving the natural history of DMD than rescue therapy in older patients with far advanced disease. PDE5A inhibition could slow disease progression and improve quality of life by allowing patients with DMD to perform more exercise with less use-dependent muscle injury. If so, this would constitute a therapeutic breakthrough that could quickly transform clinical practice, as no new drug development is required. PUBLIC HEALTH RELEVANCE: Affecting one in 3,500 male births, Duchenne muscular dystrophy is a devastating muscle-wasting disease for which there is as yet no specific treatment. Boys are diagnosed as toddlers, most are wheelchair bound by age 15, and death from pneumonia and heart failure often occurs by age 20. The aim of this planning grant is to prepare for a multicenter clinical trial to determine if the drug tadalafil (Cialis), which has bee shown to improve blood flow and muscle fatigue in mice with muscular dystrophy, could be the first ever treatment to improve exercise tolerance in boys with Duchenne muscular dystrophy.

描述（由申请人提供）：杜氏肌营养不良症（DMD）是一种毁灭性的X连锁肌肉萎缩性疾病，目前还没有特异性治疗方法。DMD影响每3，500名男婴中的一名，占所有肌肉萎缩症病例的80%。男孩被诊断为蹒跚学步的孩子，大多数在15岁时坐轮椅。死亡通常发生在20岁之前，死于呼吸肌无力和心肌病。迫切需要在研究中取得治疗性突破。自从肌营养不良蛋白被发现是DMD的致病基因以来，已经过去了25年。尽管DMD的基础科学已经蓬勃发展，但临床翻译却没有。维克托博士及其同事在过去二十年中在小鼠模型和DMD男孩中进行的平行翻译实验表明，肌膜nNOSm的缺失使患病的肌纤维对功能性缺血敏感，并暗示骨骼肌源性一氧化氮（NO）作为这种难治性疾病的新治疗靶点。事实上，磷酸二酯酶（PDE 5A）抑制剂，延长cGMP的半衰期-血管平滑肌中NO的下游靶点-迅速改善运动诱导的肌肉缺血，肌肉损伤，并在DMD的mdx小鼠模型疲劳。最紧迫的问题是：我们能否将这一引人注目的小鼠研究转化为有益于人类患者（DMD男孩）的研究？在这里，我们提出了第一个多中心试验，以测试是否PDE 5A抑制与他达拉非增加步行距离6分钟步行试验（主要终点）的DMD男孩（7-15岁，走动，保留射血分数）。次要终点包括生活质量和心脏MRI心肌应变。我们提出了一个分层，随机，双盲，安慰剂对照的IIB期试验的两个剂量的他达拉非治疗12周。为了实施这项试验，12个月的U34规划期对于经验丰富的多学科研究团队实现以下具体目标至关重要：1）制定全面的招募和保留计划，包括制定少数民族外展的新策略; 2）审查研究设计的各个方面并进行功效计算; 3）制定试验时间轴和预算，与NIAMS一起审查里程碑，并在收到U34后三个月提交UM 1申请;然后，在剩余的九个月内，4）解决所有人类受试者的保护要求; 5）制定全面的操作程序手册和培训手册。计划活动将在三个地点进行：雪松西奈医疗中心-加州大学洛杉矶分校，费城儿童医院-宾夕法尼亚大学和佛罗里达大学。拟议的试验直接解决了NIAMS的目标。在病情较轻的年轻男孩中采用先发制人的方法比在病情严重的老年患者中采用补救治疗更有可能改善DMD的自然病史。PDE 5A抑制可以通过允许DMD患者进行更多的运动，减少使用依赖性肌肉损伤，从而减缓疾病进展并改善生活质量。如果是这样的话，这将构成一个治疗上的突破，可以迅速改变临床实践，因为不需要新药开发。 公共卫生关系：杜氏肌营养不良症是一种毁灭性的肌肉消耗性疾病，每3,500名男婴中就有一名受到影响，目前还没有具体的治疗方法。男孩被诊断为蹒跚学步的孩子，大多数在15岁时坐轮椅，死于肺炎和心力衰竭的人往往在20岁时死亡。这项计划拨款的目的是为一项多中心临床试验做准备，以确定他达拉非（Cialis）是否可以成为首个改善Duchenne肌营养不良症男孩运动耐量的治疗方法。