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

• 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
• 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

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）：该提案支持雷鬼核子的随机，双盲，安慰剂对照的LIB试验，用于治疗儿童（> 14岁）和镰状细胞病（SCD）的急性血管熟悉发作（> 14岁）。在非裔美国人中，SCD是影响美国约70,000名个人的最常见遗传疾病。慢性血管咬合的急性加重是SCD，疼痛和急性胸部综合征（ACS）发作的两种最常见病因的病因。血管阻塞的发病机理是一种多细胞过程，涉及镰状和非sick颗红细胞，白细胞，血小板，凝结蛋白和活化的内皮细胞。最近，已经出现了一种修改的范式，这与缺血/再灌注（L/R）损伤有关，尤其是不变的NKT（INKT）细胞在血管闭塞的发病机理中。在SCD的鼠模型中，用腺苷2a受体激动剂雷加纳森（Regadenoson）治疗抑制inkt细胞活性，从而中断L/R损伤并抑制肺部炎症和水肿的严重程度。我们的调查团队在SCD患者中进行了I型雷加氏菌的I期临床试验。该试验产生的初步数据表明，低剂量输液性雷达尼森是安全的并且具有生物学活性，从而减少了inkt细胞的激活。扩展了I阶段研究中的发现，我们设计了一项LIB试验，以检查雷加纳斯森对疼痛和AC的治疗的功效。 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,分别评估肺间隙水肿和区域血流的新型结果措施。在9个机构的一项多中心试验中，我们将对96名参与者进行HBSS/HBS | 3-甲性疾病，年龄在14至70岁之间，并在疼痛或ACS发作期间对Regadenoson进行了48小时的注入。我们的主要结果度量将是通过NF-KB激活确定的激活INKT细胞百分比的百分比。我们预计在疼痛和ACS发作过程中给予输液性雷达森氏菌会减轻炎症并改善SCD的临床结果，并可能导致对其他难治性炎症状态的这种疗法进一步研究。相关性（请参阅说明）：镰状细胞疾病是血液的遗传状况。疼痛和急性胸部综合征发作可能是镰状细胞疾病的致命并发症。我们将研究一种在患有镰状细胞疾病患者中的称为雷加纳斯森的药物，以确定它是否是疼痛或急性胸部综合征发作的有效治疗方法。