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）患者死亡的主要原因。目前对ACS的治疗是输血，这是复杂的同种异体免疫，反应和感染。迫切需要ACS的其他治疗方法。本申请的目的是确定进行临床试验的可行性，检查一种新的药物，regadenoson，用于治疗患有SCD的个体中的ACS。我们在小鼠模型和SCD患者中有大量的初步数据表明，regadenoson，一种腺苷2A受体激动剂，可能通过靶向不变的NKT细胞来中断缺血/再灌注损伤（IRI），并降低ACS发作的严重程度。我们目前正在进行一项I期剂量发现和安全性研究regadenoson在儿童和成人SCD。我们的最终目标是将I期研究的结果扩展到ACS的治疗。我们计划进行一项多中心、随机化IIb期临床试验，以住院时间作为主要结局，比较瑞伽腺苷加标准治疗与单独标准治疗对ACS的疗效。我们组建了一个由经验丰富的SCD研究者领导的由7家机构组成的联盟，参与这项多中心试验。该规划补助金将用于生成适当设计IIb期研究所需的数据。在本申请中，我们将：1）确定我们的研究联盟中是否可以累积足够数量的ACS患者; 2）测量接受regadenoson治疗的SCD和ACS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0的受试者，年龄14至70岁，因轻度至中度ACS发作而入院。参与者将接受48小时的安全和生物有效剂量的regadenoson输注，该剂量将添加到患者医生选择的标准治疗中。我们估计ACS的发病率为每月10例。保守估计，每10次ACS发作将入组1例患者，在24个月的资助期内（每月约入组1例患者），我们将达到我们的累积目标。基于本研究生成的数据，我们计划提交R 01以支持IIb期临床试验。我们预计，regadenoson可能最终被用作输血治疗的辅助治疗，或可能减少某些ACS患者的输血需求。 公共卫生相关性：镰状细胞病是一种遗传性血液疾病。急性胸部综合征是镰状细胞病最致命的并发症。我们将在镰状细胞病和急性胸部综合征患者中进行一项研究，以获得关于一种名为regadenoson的药物的初步信息;这项研究的结果将用于设计一项更大的试验，以确定regadenoson是否是急性胸部综合征的有效治疗方法。! !

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. PUBLIC HEALTH RELEVANCE: Sickle cell disease is a genetic condition of the blood. Acute chest syndrome is the most lethal complication of sickle cell disease. We will conduct a study in people with sickle cel disease and acute chest syndrome in order to obtain preliminary information about a drug called regadenoson; the results of this study will be used to design a larger trial to determine if regadenoson is an effective therapy for acute chest syndrome. ! !