A Controlled Clinical Trial of Regadenoson in Sickle Cell Anemia

描述（由申请人提供）：该提案支持regadenoson治疗儿童（> 14岁）和成人镰状细胞病（SCD）急性血管闭塞发作的随机、双盲、安慰剂对照、IIb期试验。在非裔美国人中，SCD是最常见的遗传性疾病，影响美国约70，000人。慢性血管闭塞的急性加重是SCD中两种最常见的发病率，疼痛和急性胸部综合征（ACS）发作的病因。血管闭塞的发病机制是一个涉及镰状和非镰状红细胞、白色血细胞、血小板、凝血蛋白和活化内皮的多细胞过程。最近，已经出现了一种修改的范例，其涉及缺血/再灌注（I/R）损伤，特别是血管闭塞发病机制中的不变NKT（iNKT）细胞。在SCD的鼠模型中，用regadenoson（一种腺苷2A受体激动剂）治疗抑制iNKT细胞活性，从而中断I/R损伤并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一项在SCD患者中注射regadenoson的I期临床试验。该试验产生的初步数据表明，低剂量的regadenoson是安全的，具有生物活性，可减少INKT细胞的活化。扩展了我们I期研究的发现，我们设计了一项IIb期试验，以检查regadenoson治疗疼痛和ACS的疗效。儿童（> 14岁）和成人SCD，我们将：1）确定注射regadenoson是否在生化上有效并降低急性血管闭塞事件的严重程度（疼痛和ACS），2）研究regadenoson影响血液中炎症生物标志物的剂量和时间依赖性，和3）评估便携式磁共振成像仪器和对比增强超声检查，分别评估肺间质水肿和局部血流量的新结局指标。在9个机构的多中心试验中，我们将用HbSS/HbS治疗96名参与者，|3-地中海贫血，年龄14至70岁，在疼痛或ACS发作期间输注regadenoson 48小时。我们的主要结果测量将是通过NF-kB活化确定的活化INKT细胞百分比的降低。我们预计，在疼痛和ACS发作期间输注regadenoson将减少炎症并改善SCD的临床结局，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）：镰状细胞病是一种遗传性血液疾病。疼痛和急性胸部综合征发作是镰状细胞病的潜在致命并发症。我们将研究一种名为regadenoson的药物用于镰状细胞病患者，以确定它是否是治疗疼痛或急性胸部综合征发作的有效方法。

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.