Plan forTrial to find Optimum Steroid Regimen in Duchenne Muscular Dystrophy

描述（由申请人提供）：本申请拟计划一项皮质类固醇治疗男孩杜氏肌营养不良症的多中心试验。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。由于对副作用和长期风险/收益的考虑，已经制定了许多不同的方案，导致实践极不一致。确定最佳方案是国家卫生研究院的优先事项；该提案是针对PA-05-038（肌营养不良-发病机制和治疗）而提出的。拟议的随机对照试验将比较3种皮质类固醇治疗方案，以解决实际假设，即在功能和患者/家长满意度方面，每日皮质类固醇（强的松或地拉法柯）比间歇性皮质类固醇（强的松）更有益。主要的统计分析将基于多变量（三维）结果（从地板上爬起来的时间，强制肺活量和治疗满意度）和零假设的全局检验，即皮质类固醇方案在三种结果中的任何一种与替代方案（在同一方向上）在至少一种结果上都没有差异。我们还假设每日服用地帕沙柯比每日服用强的松有更好的副作用。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、照顾者负担和不良事件概况。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、行为和库欣样并发症的标准化方案。规划阶段的活动包括建立数据管理/沟通和患者监测战略；测试/重测可靠性评估；编制业务手册；评估工具的翻译；确认招聘目标的可达成性；最后确定药物分配的细节以及数据和安全监测计划。本试验将评估三种方案中哪一种是治疗杜氏营养不良的最佳方案，并提供有关皮质类固醇长期副作用的新信息。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。摘要：本项目将计划一项研究，以确定使用皮质类固醇治疗杜氏肌营养不良症的最佳剂量和治疗计划，并将有助于标准化预防杜氏肌营养不良症并发症及其皮质类固醇治疗的方法。

DESCRIPTION (provided by applicant): This application proposes to plan a multicenter trial 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 different regimens have been developed because of concerns regarding side effects and long-term risk/benefit, resulting in great inconsistency of practice. Defining the optimum regimen is a stated NIH priority; this proposal has been developed in response to PA-05-038 (Muscular Dystrophy- pathogenesis and therapy). The proposed randomized controlled trial will compare 3 corticosteroid regimens to address the pragmatic hypothesis that daily corticosteroid (prednisone or deflazacort) will be of greater benefit in terms of function and patient/parent satisfaction than intermittent corticosteroid (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 a global test 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) with regard to at least one of the outcomes. We also hypothesize 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, caregiver burden, 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, behavioral, and cushingoid complications of Duchenne dystrophy and corticosteroids. Planning phase activities include establishing data management/communication and patient monitoring strategies; test/retest reliability assessment; preparation of operations manual; translation of assessment tools; confirming the achievability of recruitment targets; and finalizing details of drug distribution and plans for data and safety monitoring. This trial will assess which of the 3 regimens is optimum for treatment of Duchenne dystrophy and provide novel information on longer-term corticosteroid side effects. 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. Lay Summary: This project will plan a study to determine the best dosage and schedule of treatment for use of corticosteroids in Duchenne muscular dystrophy and will help to standardize approaches to prevent complications of Duchenne dystrophy and its corticosteroid treatment.