A Controlled Clinical Trial of Regadenoson in Sickle Cell Anemia

Regadenoson 治疗镰状细胞性贫血的对照临床试验

基本信息

批准号：
8511807
负责人：
Joshua Jeffrey Field
金额：
$ 222.08万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-15 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8511807
关键词：
Acceleration Acute Adolescent Adult Affect African American Age Agonist Award Biological Biological Markers Blood Blood Platelets Blood flow CXCL10 gene CXCL11 gene CXCL9 gene Cell physiology Cells Child Chronic Clinical Clinical Trials Clinical Trials Data Monitoring Committees Coagulation Process Collaborations Controlled Clinical Trials Data Data Coordinating Center Dependence Dose Double-Blind Method Drug Targeting Edema Endothelium Erythrocytes Etiology Event FDA approved Grant Hereditary Disease Hospitalization Hour Human Individual Inflammation Inflammatory Infusion procedures Injury Innovative Therapy Institution Instruction Interleukin-1 Interleukin-12 Interleukin-2 Interleukin-4 Investigation Ischemia Laboratories Lead Leukocytes Lung Magnetic Resonance Magnetic Resonance Imaging Maximum Tolerated Dose Measurement Measures Mediating Mediator of activation protein Modeling Monitor Morbidity - disease rate Mus NF-kappa B National Heart, Lung, and Blood Institute Outcome Outcome Measure Pain Participant Pathogenesis Pharmaceutical Preparations Phase Phase I Clinical Trials Placebo Control Placebos Pneumonia Principal Investigator Process Proteins Protocols documentation Pulmonary Edema Purinergic P1 Receptors Randomized Refractory Regional Blood Flow Reperfusion Injury Reperfusion Therapy Request for Proposals Research Infrastructure Research Personnel Safety Severities Sickle Cell Sickle Cell Anemia System Testing Thalassemia Time Ultrasonography United States acute chest syndrome chemokine cytokine design double-blind placebo controlled trial effective therapy experience improved instrument interstitial macrophage novel phase 1 study primary outcome receptor safety study

项目摘要

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.

描述（由申请人提供）：该提案支持一项随机、双盲、安慰剂对照、regadenoson 的 11b 期试验，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 中两种最常见疾病的病因：疼痛和急性胸部综合征 (ACS)。血管闭塞的发病机制是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，出现了一种改进的范例，涉及缺血/再灌注（l/R）损伤，特别是血管闭塞发病机制中的不变 NKT（iNKT）细胞。在 SCD 小鼠模型中，用腺苷 2A 受体激动剂 regadenoson 治疗可抑制 iNKT 细胞活性，从而中断 L/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针对 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，低剂量输注 regadenoson 是安全的，并且具有生物活性，可减少 INKT 细胞的激活。为了扩展我们的 I 期研究结果，我们设计了一项 IIb 期试验来检验 regadenoson 治疗疼痛和 ACS 的功效。对于患有 SCD 的儿童（> 14 岁）和成人，我们将：1) 确定输注热加腺苷是否具有生化效果并可降低急性血管闭塞事件（疼痛和 ACS）的严重程度，2) 研究剂量和时间依赖性热加腺苷影响血液中炎症生物标志物，3) 评估便携式磁共振成像仪器和对比增强超声检查，评估肺间质水肿的新结果措施和局部血流量。在 9 家机构进行的一项多中心试验中，我们将治疗 96 名患有 HbSS/HbS|3-地中海贫血、年龄在 14 至 70 岁之间的参与者，在疼痛或 ACS 发作期间输注 48 小时的 regadenoson。我们的主要结果指标是根据 NF-kB 激活确定的激活 INKT 细胞百分比的减少。我们预计，在疼痛和 ACS 发作期间输注热加腺苷将减少炎症并改善 SCD 的临床结果，并可能导致对该疗法在其他难治性炎症状态中的进一步研究。相关性（参见说明）：镰状细胞病是一种血液遗传病。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。我们将在镰状细胞病患者中研究一种名为 regadenoson 的药物，以确定它是否能有效治疗疼痛或急性胸部综合征发作。