Inhaled Mometasone to Promote Reduction in Vaso-occlusive Events (IMPROVE)

描述（由申请人提供）：拟定研究和结构化教育计划的目标是将PI培养为独立研究者，其职业目标是预防急性并发症和改善镰状细胞病（SCD）的紧急管理，重点是学习试验设计的创新方法，以应对SCD研究特有的挑战。主要研究者将接受高级个性化和课堂培训，这些培训将建立在候选人作为急诊医生的优势和临床研究的先前培训基础上，以学习过渡到其职业生涯的下一阶段所需的特定定量技能，包括适应性试验设计方法，贝叶斯分析和纵向建模技术。SCD是一种遗传性血红蛋白紊乱，表现在所有器官系统中。在患有SCD的青少年和成人中，血管闭塞和死亡的最大风险因素之一是存在呼吸道症状，如咳嗽或喘息。初步数据表明，复发性咳嗽或喘息发生在近一半的SCD患者中，他们没有进行哮喘的医生诊断。这项拟议的研究旨在验证一个全球性假设，即吸入性皮质类固醇（ICS），一种治疗哮喘的疗法，将预防患有SCD的成人喘息但不符合哮喘诊断标准的血管闭塞性疼痛发作。本提案的具体目的是：1）进行可行性研究-一项ICS治疗不符合哮喘诊断标准但报告反复咳嗽或喘息的成人SCD患者的随机对照试验，2）测量ICS对肺部炎症生物学相关因素的影响（通过呼出的一氧化氮测定）和血管损伤（如通过sVCAM测定），和3）比较SCD治疗试验的传统和贝叶斯适应性临床试验设计的性质，为设计确定的ICS的试验。这些目标有可能：1）改变SCD和复发性咳嗽或喘鸣患者的护理标准，2）深入了解SCD中非哮喘性喘鸣的发病机制及其对治疗的反应，3）探索创新临床试验设计的适用性，以克服阻碍SCD治疗创新的挑战。

DESCRIPTION (provided by applicant): The goal of the proposed studies and structured educational plan is to develop the PI into an independent investigator with the career goal of preventing acute complications and improving emergent management of sickle cell disease (SCD), with focus on learning innovative approaches to trial design to meet challenges specific to SCD research. The Principal Investigator will receive advanced individualized and classroom training that will build upon the candidate's strengths as an emergency physician and prior training in clinical investigation to learn specific quantitative skills necessary to transition ito the next phase of his career, including adaptive trial design methods, Bayesian analysis and longitudinal modeling techniques. SCD is an inherited disorder of hemoglobin with manifestations in all organ systems. One of the greatest risk factors for vaso-occlusion and death in adolescents and adults with SCD is the presence of respiratory symptoms such as cough or wheeze. Preliminary data indicate that recurrent cough or wheeze occurs in nearly half of individuals with SCD who do not carry a physician diagnosis of asthma. The proposed research is designed to test the global hypothesis that inhaled corticosteroids (ICS), a therapy developed to treat asthma, will prevent vaso-occlusive painful episodes in adults with SCD who wheeze, but do not meet criteria for a diagnosis of asthma. The specific aims of this proposal are 1) Conduct a feasibility study - a randomized controlled trial of ICS for adults with SCD who do not meet criteria for a diagnosis of asthma but report recurrent cough or wheezing, 2) Measure the effects of ICS on biological correlates of pulmonary inflammation (as determined by exhaled nitric oxide) and vascular injury (as determined by sVCAM) in SCD, and 3) Compare properties of traditional and Bayesian adaptive clinical trial design for therapeutic trials in SCD in preparation for designing a definitive trial of ICS. These aims have the potentia to 1) change the standard of care for individuals with SCD and recurrent cough or wheeze, 2) provide insight into the pathogenesis of non-asthmatic wheezing in SCD and its response to treatment, 3) explore the suitability of innovative clinical trial designs to overcome the challenges that have hindered therapeutic innovation for SCD.