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

描述(由申请人提供)： 镰状细胞病是世界上最常见的血红蛋白疾病，在美国，大约每360名非洲裔美国人和每1200名拉丁裔美国人中就有一人受到影响。小血管闭塞或血管闭塞是导致本病临床并发症的主要病理因素。血管闭塞最常见的表现是急性疼痛发作(危象)，通常需要住院和使用麻醉剂，从而给患者带来经济、社会和心理上的损失。护理标准不足，没有针对持续急性疼痛发作的具体治疗。 小鼠模型表明，白细胞与血管内皮细胞的黏附可能通过随后与镰刀状红细胞的相互作用在血管闭塞中发挥关键作用。进一步的研究表明，在血管闭塞诱导之前或之后静脉注射LVlG可以迅速和显著地减少白细胞与内皮细胞的黏附和随后的红细胞相互作用，从而显著增加存活率。 基于这项工作，研究人员建议进行一项随机、双盲、安慰剂对照、剂量递增的1/2阶段试验，以研究单剂IVIG与生理盐水安慰剂对入院并无并发症的急性疼痛发作的SCD患者的安全性和有效性。共录取52个科目。研究人员假设，IVIG将迅速起作用，从而减少血管闭塞，从而减少疼痛评分、麻醉药物使用和住院时间。他们还将通过测量参与白细胞与内皮细胞黏附和红细胞-白细胞相互作用的黏附受体、微循环血流量和血清溶血标志物来研究IVIG对SCD患者的生理影响。 研究人员预计，这项试验的完成将使他们能够在授权期结束前提交一份国立卫生研究院的申请，将这项试验扩大到3期试验，或在1/2期试验中测试新发现的干扰血管闭塞分子机制的药物。

DESCRIPTION (provided by applicant): 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 lVlG 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, the investigators propose to conduct a randomized, double-blind, placebo-controlled, dose-escalation Phase 1/2 trial to study the safety and efficacy of a single dose of IVIG compared to normal saline placebo administered to patients with SCD admitted to the hospital with an uncomplicated acute pain episode. A total of 52 subjects will be enrolled. The investigators hypothesize that IVIG will act quickly to reduce vaso-occlusion and thus pain scores, narcotic use, and length of hospitalization. They will also investigate the physiological effects of IVIG in patients with SCD 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. The investigators expect that completion of this trial will allow them to submit by the end of the grant period a National Institutes of Health application to expand this trial into a Phase 3 trial or to test, in Phase 1/2 trials, newly identified agents that interfere with the molecular mechanism of vaso-occlusion.