A Controlled Clinical Trial of Regadenoson in Sickle Cell Anemia

描述(由申请人提供)：这项建议支持一项随机、双盲、安慰剂对照、Lib期的瑞格腺苷试验，用于治疗患有镰状细胞病(SCD)的儿童(14岁)和成人的急性血管闭塞发作。在非裔美国人中，SCD是最常见的遗传疾病，在美国大约有7万人受到影响。慢性血管闭塞的急性加重是SCD中两种最常见的疾病的病因，疼痛和急性胸部综合征(ACS)发作。血管闭塞的发病机制是一个涉及镰刀形和非镰形形红细胞、白细胞、血小板、凝血蛋白和激活的内皮细胞的多细胞过程。最近，出现了一种新的研究范式，认为缺血/再灌注(L/R)损伤，尤其是不变的神经激肽转运体(INKT)细胞参与了血管闭塞的发病机制。在SCD小鼠模型中，腺苷2A受体激动剂瑞格腺苷可抑制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一项针对SCD患者的输注瑞格腺苷的I期临床试验。这项试验产生的初步数据表明，低剂量输注的瑞格腺苷是安全的，具有生物活性，可以减少iNKT细胞的激活。扩展我们第一阶段研究的结果，我们设计了一项Lib期试验，以检查瑞格腺苷治疗疼痛和急性冠脉综合征的疗效。在14岁的儿童(&gt；14岁)和成人SCD患者中，我们将：1)确定注射瑞格腺苷是否具有生物化学效果并降低急性血管闭塞事件(疼痛和急性冠脉综合征)的严重性，2)研究瑞格腺苷的剂量和时间依赖性对血液中炎症生物标志物的影响，以及3)评估便携式磁共振成像仪和对比增强超声成像，这两种新的结果指标分别用于评估肺间质水肿和局部血流。在9个机构的多中心试验中，我们将治疗96名患有HbSS/HBS|3-地中海贫血的患者，年龄在14岁到70岁之间，在疼痛或急性冠脉综合征发作期间48小时输注瑞格腺苷。我们的主要结果将是通过核因子-kB的激活来确定iNKT细胞激活的百分比的减少。我们预计，在疼痛和急性冠脉综合征发作期间输注瑞格腺苷将减轻炎症并改善SCD的临床结果，并可能导致进一步研究这种疗法在其他难治性炎症状态下的应用。相关性(见说明)：镰状细胞病是血液的一种遗传性疾病。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瑞格腺苷的药物在镰状细胞疾病患者中的应用，以确定它是否对疼痛或急性胸部综合征发作有效。

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.