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

描述（由申请人提供）：拟议研究和结构化教育计划的目标是将PI发展成为一名独立的研究者，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，重点是学习创新的试验设计方法，以应对SCD研究的具体挑战。首席研究员将接受先进的个性化和课堂培训，这些培训将建立在候选人作为急诊医生的优势和先前的临床调查培训基础上，以学习过渡到其职业生涯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疾病，在所有器官系统均有表现。青少年和成人SCD患者血管闭塞和死亡的最大危险因素之一是出现呼吸道症状，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，他们没有被医生诊断为哮喘。这项拟议的研究旨在验证一个全球性的假设，即吸入皮质类固醇（ICS）是一种用于治疗哮喘的疗法，可以预防患有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)对不符合哮喘诊断标准但报告复发性咳嗽或喘息的成年SCD患者进行ICS的可行性研究-随机对照试验，2)测量ICS对SCD中肺部炎症（由呼出的一氧化氮确定）和血管损伤（由sVCAM确定）的生物学相关性的影响。3)比较SCD治疗性试验的传统临床试验设计和贝叶斯适应性临床试验设计的特性，为设计ICS的最终试验做准备。这些目标有可能：(1)改变SCD患者反复咳嗽或喘息的护理标准；(2)深入了解SCD患者非喘息性喘息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.