FOR-DMD:Double-blind randomized trial to optimize steroid regimen in Duchenne MD

描述（由申请人提供）：本申请提出了一项多中心试验，比较皮质类固醇治疗男孩杜氏肌营养不良症的长期方案。皮质类固醇强的松对治疗杜氏营养不良有18个月的疗效，另一种皮质类固醇地拉法柯也可能有疗效。由于担心副作用和长期风险/收益，许多皮质类固醇治疗方案一直在使用，导致实践中存在很大差异。鉴于“2008年比较有效性研究法案”，这项研究尤其及时。拟议的随机对照试验将比较3种最广泛使用的皮质类固醇治疗方案，以解决实用性假设，即每日强的松和每日地帕沙柯在功能和父母满意度方面比间歇（强的松）更有益。主要统计分析将基于多变量（三维）结果（从地面上升的时间、强制肺活量和治疗满意度）和零假设的整体检验，即皮质类固醇方案在三种结果变量中的任何一种结果与在所有三种结果变量中不同的替代方案（在相同方向上）都没有差异，三种皮质类固醇方案之间的三种两两比较分别进行。另一个假设是每日服用地帕沙柯比每日服用强的松副作用更小。该试验将随机抽取300名4-7岁的男孩服用0.75 mg/kg/d的强的松；氟扎柯0.9 mg/kg/d；或0.75 mg/kg/d强的松，10天交替服用，休息10天。次要结果变量包括方案耐受性、其他定时功能测试；心功能、生活质量和不良事件概况。参与者将在2年的时间内被招募，并至少随访3年。研究方案包括治疗和预防杜氏营养不良和皮质类固醇的骨骼、心脏、呼吸、行为和库欣样并发症的标准化方案。该试验将通过评估在患者/家长对治疗满意度的背景下肌肉力量的益处来评估三种方案中哪一种是治疗杜氏营养不良症的最佳方案。它将为长期（8-10年）研究皮质类固醇治疗方案的相对疗效和耐受性提供基础，主要结果变量为失去活动能力的时间。辅助研究将探索研究对象中不同表型和对皮质类固醇治疗反应的分子基础。

DESCRIPTION (provided by applicant): This application proposes a multicenter trial comparing long-term regimens of corticosteroids in boys with Duchenne muscular dystrophy. The corticosteroid prednisone is of established 18 months benefit to strength in Duchenne dystrophy, and another corticosteroid, deflazacort, may also be of benefit. Many corticosteroid regimens have been in use because of concerns regarding side effects and long-term risk/benefit, resulting in great variations in practice. The study is particularly timely in view of the "Comparative Effectiveness Research Act of 2008". The proposed randomized controlled trial will compare the 3 most widely used corticosteroid regimens to address the pragmatic hypothesis that both daily prednisone and daily deflazacort will be of greater benefit in terms of function and parent satisfaction than intermittent (prednisone). The primary statistical analysis will be based on a multivariate (3-dimensional) outcome (time to rise from the floor, forced vital capacity, and treatment satisfaction) and global tests of the null hypothesis that the corticosteroid regimens do not differ with regard to any of the three outcomes vs the alternative that they differ (in the same direction) for all 3 outcome variables, performed separately for each of the three pair-wise comparisons among the three corticosteroid regimens. A secondary hypothesis states that daily deflazacort will have a preferable side effect profile to that of daily prednisone. The trial will randomize 300 boys aged 4-7 years to 0.75 mg/kg/d prednisone; 0.9 mg/kg/d deflazacort; or 0.75 mg/kg/d prednisone for 10 days alternating with 10 days off. Secondary outcome variables will include regimen tolerance, other timed function tests; cardiac function, quality of life, and adverse event profile. Participants will be recruited over a 2 year period and followed for at least 3 years. The study protocol includes standardized regimens for treatment and prevention of bone, cardiac, respiratory, behavioral, and cushingoid complications of Duchenne dystrophy and corticosteroids. This trial will assess which of the 3 regimens is optimum for treatment of Duchenne dystrophy by assessing benefits to muscle strength in the context of patient/parent satisfaction with treatment. It will provide the basis for the long-term (8-10 year) study of the relative efficacy and tolerability of corticosteroid regimens with the primary outcome variable of time to loss of ambulation. Ancillary studies will explore the molecular basis for differing phenotypes and responses to corticosteroid treatment in study subjects. PUBLIC HEALTH RELEVANCE: This project will find the optimum corticosteroid regimen for treatment of boys with Duchenne muscular dystrophy --- the commonest form of muscular dystrophy and the commonest childhood neuromuscular disease. Information from this trial will be of importance to all health care providers treating children and is essential for other novel treatments being explored in Duchenne muscular dystrophy.