Planning a Multicenter Trial of PDE5A Inhibition for Duchenne Muscular Dystrophy

描述(申请人提供)：Duchenne肌营养不良症(DMD)是一种毁灭性的X连锁肌肉萎缩疾病，目前还没有专门的治疗方法。每3500名男婴中就有一名患有DMD，占所有肌肉营养不良病例的80%。男孩被诊断为蹒跚学步的孩子，大多数人在15岁之前就被轮椅束缚住了。死亡通常发生在20岁之前，死于呼吸肌无力和心肌病。迫切需要在研究方面取得治疗上的突破。自从Dstrophin被发现是DMD的致病基因以来，已经过去了25年。虽然有关DMD的基础科学蓬勃发展，但临床翻译却没有。Victor博士和他的同事在过去20年中对患有DMD的小鼠和男孩进行的平行翻译实验表明，肌膜nNOSm的丢失使病变肌肉纤维易受功能性缺血的影响，并牵涉到骨骼肌源性一氧化氮(NO)，成为治疗这种难治性疾病的新靶点。事实上，磷酸二酯酶(PDE5A)抑制剂延长了血管平滑肌中一氧化氮的下游靶标cGMP的半衰期，迅速改善了运动诱导的DMD小鼠模型的肌肉缺血、肌肉损伤和疲劳。紧迫的问题是：我们能否将这项令人信服的小鼠研究转化为造福于人类患者--患有DMD的男孩？在这里，我们提出了第一个多中心试验，以测试他达拉非对PDE5A的抑制是否会增加DMD(7-15岁，动态、保留的射血分数)男孩6分钟步行试验(主要终点)的步行距离。次要终点包括生活质量和心脏MRI所显示的心肌应变。我们建议一项分层、随机、双盲、安慰剂对照的IIB期试验，两剂他达拉非治疗12周。为了实施这项试验，经验丰富的多学科研究团队需要12个月的U34规划期，以实现下列具体目标：1)制定全面的招募和保留计划，包括为少数群体外联制定新的战略；2)审查研究设计的方方面面并进行权力计算；3)制定试验时间表和预算，与NIAMS一起审查里程碑，并在收到U34后3个月提交UM1申请；然后，在其余9个月中，4)满足所有人类受试者的保护要求；5)制定一份全面的操作程序和培训手册。计划活动将在三个地点进行：锡达斯-西奈医学中心-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。拟议的试验直接涉及NIAMS的目标。对患有较不严重疾病的年轻男孩采取先发制人的方法，比对患有较晚期疾病的老年患者采取抢救性治疗更有可能改善DMD的自然病史。抑制PDE5A可以通过允许DMD患者进行更多的运动而减少对使用的依赖肌肉损伤，从而减缓疾病的进展并提高生活质量。如果是这样的话，这将构成一项治疗突破，可以迅速改变临床实践，因为不需要开发新药。 公共卫生相关性：杜氏肌营养不良症是一种破坏性的肌肉萎缩疾病，每3500名男婴中就有一人受到影响，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，大多数人在15岁时被轮椅束缚，肺炎和心力衰竭的死亡通常在20岁之前发生。这项计划拨款的目的是为一项多中心临床试验做准备，以确定药物他达拉非(Cialis)是否可以作为第一种治疗方法来提高杜氏肌营养不良症男孩的运动耐量。他达拉非已被证明可以改善肌肉营养不良小鼠的血液流动和肌肉疲劳。

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.