A Pilot Study of N-acetylcysteine in Sickle Cell Disease Vaso-Occlusive Crisis

 描述（由申请人提供）：镰状细胞病（SCD）是一种慢性疾病，其特征是疼痛发作、发病率和死亡率增加，在有效治疗方面有许多未满足的需求。虽然SCD的病理生理学是复杂的，但溶血、红细胞（RBC）血管粘附和改变的氧化还原状态都起关键作用。我们小组先前的研究支持这样的假设，即药物N-乙酰半胱氨酸（NAC）可以通过切割血管粘附蛋白--过度活跃的血管性血友病因子来调节SCD。在一项正在进行的对稳定的SCD门诊患者进行NAC输注的研究中，我们发现了对VWF的影响，以及全血、血浆和红细胞（RBC）中抗氧化活性的增加，以及RBC碎片和致密细胞的减少等发现。迄今为止，入组的受试者对该药物耐受良好。我们进一步假设，NAC将是一种有效的治疗SCD血管闭塞性危象（VOC），降低VWF的分泌和改善红细胞功能和活力。为了获得开发成功的NAC治疗VOC的多中心随机安慰剂对照试验所需的数据，我们提出了以下具体目的：1）在华盛顿大学医学中心急诊室或VOC住院部的患者中进行NAC的初步研究，NAC输注持续5天或直至出院。该初步研究的终点是可行性、安全性和临床疗效指标。2)评估在这种情况下NAC活性的研究实验室相关性，包括VWF活性、VWF多聚体组成、RBC碎片和致密细胞、细胞聚集体的测量，以及反映抗氧化活性的测量。这将增加我们对NAC治疗SCD机制的理解，并为多中心试验选择实验室生物标志物提供信息。以及，3）开发一项NAC治疗SCD血管闭塞危象的多中心随机安慰剂对照临床试验，根据该试点试验的结果以及全国镰状细胞医疗提供者/研究者的参与选择临床应答和实验室终点。NAC是VOC的一种有前途的低成本疗法，可以为许多镰状细胞病患者提供益处。

 DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is a chronic disease characterized by painful episodes, increased morbidity and mortality and has many unmet needs in effective treatment. While the pathophysiology of SCD is complex, hemolysis, red blood cell (RBC) vascular adhesion and an altered redox state all play key roles. Prior studies from our group support the hypothesis that the drug N-acetylcysteine (NAC) can modulate SCD by cleaving hyperactive von Willebrand factor, a vascular adhesion protein. In an ongoing study of NAC infusions in stable outpatients with SCD, we have found an effect on VWF, as well as an increase in the antioxidant activity in whole blood, plasma and red blood cells (RBC) and a decrease in RBC fragments and dense cells, among other findings. The drug has been well tolerated by subjects enrolled to date. We further hypothesize that NAC will be an effective treatment for SCD vaso-occlusive crisis (VOC) by decreasing VWF adhesiveness and improving red blood cell function and viability. To obtain the data needed to develop a successful multicenter randomized placebo controlled trial of NAC in VOC, we propose the following Specific Aims: 1) To conduct a pilot study of NAC in patients presenting to the University of Washington Medical Center emergency room or inpatient unit in VOC, with NAC infusions continuing for 5 days or until discharge. Endpoints for this pilot study will be feasibility, safet, and measures of clinical efficacy. 2) To assess research laboratory correlates of NAC activity in this setting, including measures of VWF activity, VWF multimer composition, RBC fragments and dense cells, cellular aggregates, and measures reflective of antioxidant activity. This will increase our understanding of the mechanism(s) of NAC in treatment of SCD and inform the selection of laboratory biomarkers for the multicenter trial. And, 3) To develop a multicenter randomized placebo-controlled clinical trial of NAC in SCD vaso-occlusive crisis, with clinical response and laboratory endpoints chosen based on findings from this pilot trial and with engagement of sickle cell medical providers/investigators across the country. NAC is a promising, low cost therapy for VOC which could provide benefit for many patients with sickle cell disease.