A Feasibility Study of Regadenoson for the Treatment of Acute Chest Syndrome

描述(由申请人提供)：急性胸部综合征(ACS)是镰状细胞病(SCD)患者的主要死亡原因。目前治疗急性冠脉综合征的方法是输血，其复杂性包括同种异体免疫、反应和感染。目前迫切需要针对急性冠脉综合征的其他治疗方法。这项申请的目的是确定进行一项临床试验的可行性，以检验一种新的药物瑞格腺苷，用于治疗患有SCD的患者的急性冠脉综合征。我们在小鼠模型和SCD患者中有大量的初步数据表明，腺苷2A受体激动剂瑞格腺苷可能通过靶向不变的NKT细胞来阻断缺血/再灌注损伤(IRI)，并降低ACS发作的严重程度。我们目前正在对患有SCD的儿童和成人进行瑞格腺苷的I期剂量发现和安全性研究。我们的最终目标是将第一阶段研究的结果扩展到急性冠脉综合征的治疗。我们计划进行一项多中心、随机的IIb期试验，以住院时间为主要结果，比较瑞格腺苷加标准疗法和单纯标准疗法治疗急性冠脉综合征的疗效。我们组建了一个由七家机构组成的财团，由经验丰富的SCD调查人员领导，参与这项多中心试验。这笔规划赠款将用于生成适当设计第二阶段研究所需的数据。在这项应用中，我们将：1)确定在我们的研究联盟中是否可以积累足够数量的急性冠脉综合征患者；以及2)测量正在接受瑞格腺苷治疗的SCD患者和急性冠脉综合征患者的住院时间差异。我们将治疗20名患有HbSS/HBS-地中海贫血的患者，年龄在14岁到70岁之间，他们因轻到中度的急性冠脉综合征而入院。参与者将接受48小时的安全和生物有效剂量的瑞格腺苷输注，该剂量将被添加到患者医生选择的标准治疗中。我们估计，在我们的联盟中，急性冠脉综合征的发病率为每月10例。保守地说，我们估计每10个急性冠脉综合征发作将有1名患者入选，在24个月的资助期内(每月入选约1名患者)，我们将达到我们的应计目标。基于这项研究产生的数据，我们计划提交R01以支持IIb期临床试验。我们预计，在某些急性冠脉综合征病例中，瑞格腺苷可能最终被用作输血治疗的辅助手段，或者可能不再需要输血。

DESCRIPTION (provided by applicant): Acute chest syndrome (ACS) is the leading cause of death for individuals with sickle cell disease (SCD). Current treatment for ACS is transfusion, which is complicated by alloimmunization, reactions, and infection. Additional therapies for ACS are desperately needed. The objective of this application is to determine the feasibility of conducting a clinical trial examining a novel agent, regadenoson, for the treatment of ACS in individuals with SCD. We have abundant preliminary data in murine models and patients with SCD to suggest that regadenoson, an adenosine2A receptor agonist, may interrupt ischemia/reperfusion injury (IRI) by targeting invariant NKT cells and decrease the severity of ACS episodes. We are currently performing a phase I dose finding and safety study of regadenoson in children and adults with SCD. Our ultimate goal is to extend the findings of the phase I study to the treatment of ACS. We plan to perform a multi-center, randomized phase IIb trial comparing regadenoson plus standard therapy versus standard therapy alone for ACS using length of stay as the primary outcome. We have assembled a consortium of seven institutions led by experienced SCD investigators to participate in this multi-center trial. This planning grant will be used to generate the data necessary to appropriately design the phase IIb study. In this application, we will: 1) determine whether sufficient numbers of patients with ACS can be accrued in our study consortium; and 2) measure the variance in length of stay among individuals with SCD and ACS who are receiving regadenoson. We will treat 20 participants with HbSS/HbS-thalassemia0, ages 14 to 70 years, who are admitted to the hospital for mild to moderate ACS episodes. Participants will receive a 48 hour infusion of a safe and biologically effective dose of regadenoson that will be added to standard therapy elected by the patients' physicians. We estimate that the incidence of ACS episodes in our consortium is 10 per month. Conservatively, we estimate that 1 patient will be enrolled for every 10 ACS episodes and over the 24 month funding period (enrolling about 1 patient per month) we will meet our accrual goal. Based on the data generated from this study, we plan to submit an R01 to support the phase IIb clinical trial. We anticipate that regadenoson may ultimately be used as an adjunct to transfusion therapy or may obviate the need for transfusion in some cases of ACS.