A Controlled Clinical Trial of Regadenoson in Sickle Cell Anemia

描述（由申请人提供）：本提案支持一项随机、双盲、安慰剂对照、利腺苷松治疗镰状细胞病（SCD）儿童（bb0 - 14岁）和成人急性血管闭塞发作的lIb期试验。在非裔美国人中，SCD是最常见的遗传疾病，在美国影响了大约7万人。慢性血管阻塞的急性加重是SCD中两种最常见的发病原因，疼痛和急性胸综合征（ACS）发作。血管闭塞的发病机制是一个涉及镰状和非镰状红细胞、白细胞、血小板、凝血蛋白和活化内皮的多细胞过程。最近，一种修正的范式出现，涉及缺血/再灌注（l/R）损伤，特别是不变性NKT （iNKT）细胞在血管闭塞的发病机制中。在小鼠SCD模型中，用regadenoson（一种腺苷2a受体激动剂）治疗可抑制iNKT细胞活性，从而阻断l/R损伤，减轻肺部炎症和水肿的严重程度。我们的研究团队正在进行SCD患者输注regadenoson的I期临床试验。该试验产生的初步数据表明，低剂量滴注regadenoson是安全的，具有生物活性，可降低INKT细胞的活化。在I期研究的基础上，我们设计了一项lIb期试验，以检验regadenoson治疗疼痛和ACS的疗效。对于患有SCD的儿童（bb - 14岁）和成人，我们将：1)确定输注regadenoson是否具有生化效果，并降低急性血管闭塞事件（疼痛和ACS）的严重程度；2)研究regadenoson对血液中炎症生物标志物的剂量依赖性和时间依赖性；3)分别评估便携式磁共振成像仪和超声造影这两种评估肺间质水肿和局部血流量的新结果指标。在9个机构的一项多中心试验中，我们将治疗96名14至70岁的HbSS/HbS| - 3-地中海贫血患者，在疼痛或ACS发作期间输注48小时再腺苷松。我们的主要结局指标是通过NF-kB激活来确定INKT细胞活化百分比的减少。我们预计，在疼痛和ACS发作期间输注regadenoson将减少SCD的炎症并改善临床结果，并可能导致对其他难治性炎症状态的进一步研究。相关性（见说明书）：镰状细胞病是一种血液遗传疾病。疼痛和急性胸综合征发作是镰状细胞病潜在的致命并发症。我们将在镰状细胞病患者身上研究一种叫做再腺苷松的药物，以确定它是否能有效治疗疼痛或急性胸综合征发作。

DESCRIPTION (provided by applicant): This proposal supports a randomized, double-blind, placebo-controlled, phase lIb trial of regadenoson for the treatment of acute vaso-occlusive episodes in children (> 14 years) and adults with sickle cell disease (SCD). Among African Americans, SCD is the most common genetic disorder affecting approximately 70,000 individuals in the United States. Acute exacerbation of chronic vaso-occlusion is the etiology for the two most common morbidities in SCD, pain and acute chest syndrome (ACS) episodes. The pathogenesis of vaso- occlusion is a multi-cellular process involving sickle and non-sickle erythrocytes, white blood cells, platelets, coagulation proteins and activated endothelium. Recently, a modified paradigm has emerged implicating ischemia/reperfusion (l/R) injury and, in particular, invariant NKT (iNKT) cells in the pathogenesis of vaso- occlusion. In murine models of SCD, treatment with regadenoson, an adenosine2A receptor agonist, inhibits iNKT cell activity thereby interrupting l/R injury and dampening the severity of pulmonary inflammation and edema. Our investigative team has an ongoing phase I clinical trial of infusional regadenoson in individuals with SCD. Preliminary data generated from this trial suggest that low-dose infusional regadenoson is safe and has biological activity, decreasing activation of INKT cells. Extending the findings in our phase I study, we have designed a phase lIb trial to examine the efficacy of regadenoson for the treatment of pain and ACS. In children (> 14 years) and adults with SCD, we will: 1) determine if infusional regadenoson is biochemically effective and reduces the severity of acute vaso-occlusive events (pain and ACS), 2) investigate the dose- and time-dependence of regadenoson to influence inflammatory biomarkers in blood, and 3) evaluate a portable magnetic resonance imaging instrument and contrast-enhanced ultrasonography, novel outcome measures to assess pulmonary interstitial edema and regional blood flow, respectively. In a multi-center trial at 9 institutions, we will treat 96 participants ith HbSS/HbS|3-thalassemia, ages 14 to 70 years, with a 48 hour infusion of regadenoson during a pain or ACS episode. Our primary outcome measure will be reduction in percentage of activated INKT cells as determined by NF-kB activation. We anticipate that administering infusional regadenoson during pain and ACS episodes will decease inflammation and improve clinical outcomes in SCD, and may lead to further investigations of this therapy in other refractory inflammatory states. RELEVANCE (See instructions): Sickle cell disease is a genetic condition of the blood. Pain and acute chest syndrome episodes are potentially lethal complications of sickle cell disease. We will study a drug called regadenoson in people with sickle cell disease to determine if it is an effective treatment for pain or acute chest syndrome episodes.