Planning a Multicenter Trial of PDE5A Inhibition for Duchenne Muscular Dystrophy

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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.