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

描述（由申请人提供）：急性胸综合征（ACS）是镰状细胞病（SCD）患者死亡的主要原因。目前治疗ACS的方法是输血，但由于同种异体免疫、反应和感染而复杂化。ACS迫切需要额外的治疗方法。本申请的目的是确定进行一项临床试验的可行性，研究一种新型药物，regadenoson，用于治疗SCD患者的ACS。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regadenoson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。我们目前正在对儿童和成人SCD患者进行regadenoson的I期剂量发现和安全性研究。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IIb期试验，比较regadenoson加标准治疗与单独标准治疗对ACS的影响，以住院时间作为主要结局。我们召集了一个由七个机构组成的联盟，由经验丰富的SCD研究人员领导，参与这项多中心试验。此规划拨款将用于生成适当设计第ii期研究所需的数据。在此申请中，我们将：1)确定是否有足够数量的ACS患者可以累积到我们的研究联盟中；2)测量SCD和ACS患者接受再腺苷松治疗的住院时间差异。我们将治疗20例HbSS/ hbs -地中海贫血患者，年龄14至70岁，因轻中度ACS发作而入院。参与者将接受48小时的输注，输注安全且生物有效的regadenoson剂量，该剂量将添加到由患者医生选择的标准治疗中。我们估计在我们的研究中ACS的发生率为每月10次。保守地说，我们估计每10例ACS发作将有1例患者入组，在24个月的资助期内（每月约入组1例患者），我们将达到我们的应计目标。基于本研究产生的数据，我们计划提交R01以支持IIb期临床试验。我们预计，regadenoson可能最终被用作输血治疗的辅助手段，或者可能在某些ACS病例中消除输血的需要。

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.