Phase 1-2 trial of Gamunex (intravenous gammaglobulin) for Sickle Cell Acute Pain

镰状细胞病是世界上最常见的血红蛋白病， 在美国，大约每360名非洲裔美国人中就有1人受到影响，每1200名拉丁美洲人中就有1人受到影响。小血管 闭塞或血管闭塞是导致这种临床并发症的主要病理学 疾病血管闭塞最常见的表现是急性疼痛发作（危象）， 这往往需要住院治疗和麻醉剂的使用，因此需要一个经济，社会， 精神上的创伤护理标准不足，没有具体的 针对持续急性疼痛发作的治疗。 小鼠模型显示，粘附在血管内皮上的白细胞在血管生成中起着重要作用。 在血管闭塞中起着至关重要的作用，可能是通过它们随后与镰状红细胞的相互作用 细胞进一步的研究表明，静脉注射丙种球蛋白（IVIG）之前或之后， 在诱导血管闭塞后， 内皮和随后的红细胞相互作用，导致生存率显著增加。 基于这项工作，我们建议进行一项随机、双盲、安慰剂- 对照、剂量递增I-II期试验，研究单剂量IVIG的安全性和有效性 与对入院的镰状细胞性贫血患者给予生理盐水安慰剂相比， 医院与一个简单的急性疼痛发作。共入组52例受试者。我们 假设IVIG将迅速起作用以减少血管阻塞，从而减少疼痛评分、麻醉剂使用 和住院时间。我们还将研究IVIG对患者的生理作用 通过测量白细胞粘附受体， 内皮和红细胞-白细胞相互作用、微循环血流和血清 溶血的标志物 这项试验的完成将使我们能够在资助期结束前提交NIH 申请将本试验扩展为III期试验或在I-II期试验中测试新发现的 干扰血管闭塞分子机制的药物。

Sickle cell disease is the most common hemoglobinopathy in the world, and, in the United States, affects approximately 1 in 360 African Americans and 1 in 1200 Latinos. Small vessel occlusion, or vaso-occlusion, is the primary pathology leading to clinical complications of this disease. The most frequent manifestation of vaso-occlusion is the acute pain episode (crisis), which often requires hospitalization and narcotic use, thus exacting an economic, social, and psychological toll on afflicted individuals. Standard of care is inadequate, there being no specific therapies that target ongoing acute pain episodes. Mouse models have shown that leukocytes adherent to blood vessel endothelium play a crucial role in vaso-occlusion, probably through their subsequent interaction with sickle red blood cells. Further work has shown that intravenous gammaglobulin (IVIG) administered either prior to or after the induction of vaso-occlusion rapidly and dramatically reduces leukocyte adhesion to endothelium and subsequent red cell interactions, leading to a marked increase in survival. Based on this work , we propose to conduct a randomized, double-blind, placebo- controlled, dose-escalation Phase I-II trial to study the safety and efficacy of a single dose of IVIG compared to normal saline placebo administered to patients with sickle cell anemia admitted to the hospital with an uncomplicated acute pain episode. A total of 52 subjects will be enrolled. We hypothesize that IVIG will act quickly to reduce vaso-occlusion and thus pain scores, narcotic use, and length of hospitalization. We will also investigate the physiological effects of IVIG in patients with sickle cell disease by measuring the adhesion receptors involved in leukocyte adherence to endothelium and red blood cell-leukocyte interactions, microcirculatory blood flow, and serum markers of hemolysis. Completion of this trial will allow us to submit by the end of the grant period an NIH application to expand this trial into a Phase III trial or to test, in Phase I-II trials, newly identified agents that interfere with the molecular mechanism of vaso-occlusion.