Modulating Innate and Adaptive Immunity in Complicated Abdominal Sepsis

描述(由申请人提供)：腹部败血症是发病率和死亡率的主要原因，也是相当大的卫生保健负担。尽管几十年来有希望的临床前和早期临床研究，但很少有治疗方法显示出任何成功。我们认为，腹部脓毒症临床试验的失败是由于(1)不能早期和准确地预测谁将受益，(2)患者群体的未被认识到的异质性及其早期支持治疗的多样性，以及(3)针对多组分脓毒症反应的单个成分的单一疗法的使用。目前诊断严重脓毒症或感染性休克的临床标准是炎症和器官衰竭的非特异性指标，复苏和治疗方案因医生和专业中心而异。生物反应调节剂(BRM)针对炎症反应、微生物识别、凝血级联或免疫抑制的个别成分，未能解决目前公认的脓毒症反应的复杂性。在这项临床试验规划应用中，我们建议组织进行一项多中心临床试验，使用经过验证的用于脓毒症管理的计算机化临床决策支持(CCDS)系统，最近开发的用于监测免疫反应的快速基因组和蛋白质组分析，以及一种新的BRM，一种CD28拮抗剂(AB103；Atox Bio Ltd，以色列)，针对天然和适应性免疫功能的多种成分。计划中的临床试验有三个具体目标：(1)建立一个临床研究联合体，将利用成熟的CCDS系统来执行当前基于证据的腹部脓毒症治疗指南标准，以及一个补充的目前可操作的研究数据库，以确定腹部脓毒症的流行病学特征，并记录和分析临床试验数据；(2)利用最近发展的快速、定量、护理点基因组和蛋白质组分析来确定炎症和适应性免疫功能的标志物，以精确测量，并在每个受试者重复分析的情况下，监测对腹部脓毒症和BRM的免疫反应的进展；以及(3)使用流行病学数据库CCDS、快速定量基因组和蛋白质组分析以及具有独特抗炎和免疫刺激特性的新型十肽AB103进行前瞻性随机对照试验(PRCT)。长期目标是在具有良好特征和持续支持的患者队列中建立一个稳定的临床平台，并在受控良好的多点研究中使用基因组和蛋白质组生物标记物测试新疗法。规划赠款申请要求提供资金，以支持组织和规划这项工作。 公共卫生相关性：我们建议在腹部败血症患者中组织和进行一项多中心临床试验，使用计算机化的临床决策支持(CCDS)系统来管理支持性护理，使用临床研究数据库来表征临床轨迹，使用复杂的蛋白质组和基因组学方法来监测免疫状态，以及一种新的干预措施来针对脓毒症反应的多种成分。长期目标是在持续支持的脓毒症患者队列中建立一个稳定的临床平台，使用基因组和蛋白质组生物标志物进行新疗法的临床试验，以监测疗效和机制。这项规划拨款申请要求提供资金，以支持这项工作的组织和规划。

DESCRIPTION (provided by applicant): Abdominal sepsis is a leading cause of morbidity and mortality, and a substantial health care burden. Despite decades of promising preclinical and early clinical investigations, few therapies have shown any success. We believe that the failure of clinical trials for the treatment of abdominal sepsis has been due to (1) inabiity to predict early and accurately who will benefit (2) unappreciated heterogeneity of the patient population and variability of their early supportive management, and (3) use of monotherapies that target individual components of the multicomponent sepsis response. Current clinical criteria to diagnose severe sepsis or septic shock are nonspecific indices of inflammation and organ failure, and protocols for resuscitation and therapy are variable among physicians and centers of expertise. Biological response modifiers (BRMs) have targeted individual components of the inflammatory response, microbial recognition, coagulation cascade or immune suppression, and have failed to address the now recognized complexity of the sepsis response. In this clinical trial planning application, we propose to organize conduct of a multicenter clinical trial using a proven computerized clinical decision support (CCDS) system for sepsis management, recently developed, rapid genomic and proteomic analyses to monitor immune response, and a new BRM, a CD28 antagonist (AB103; Atox Bio Ltd, Israel) that targets multiple components of innate and adaptive immune function. The planned clinical trial has three specific aims: (1) to establish a clinical research consortium that will utilize a proven CCDS system to implement current evidence based guideline standard of care for management of abdominal sepsis, and a complementary currently operational research database to characterize the epidemiology of abdominal sepsis and record and analyze clinical trial data; (2) to identify markers of inflammation and adaptive immune function using recently developed, rapid, quantitative, point of care genomic and proteomic analyses to precisely measure, and, with repeated analyses in each subject, to monitor progression of immune response to abdominal sepsis and to the BRM; and (3) to conduct a pilot prospective randomized controlled trial (PRCT) using CCDS, an epidemiology database, rapid, quantitative genomic and proteomic analyses, and AB103, a novel decapeptide that has unique anti-inflammatory and immune stimulant properties. The long-term goal is to establish a stable clinical platform in a well characterized and consistently supported cohort of patients, and to test novel therapies using genomic and proteomic biomarkers in well controlled multi-site studies. The planning grant application requests funds to support the organization and planning of this endeavor. PUBLIC HEALTH RELEVANCE: We propose to organize and conduct a multicenter clinical trial in patients with abdominal sepsis using a computerized clinical decision support (CCDS) system to manage supportive care, a clinical research database to characterize clinical trajectories, sophisticated proteomic and genomic measures to monitor immune status, and a novel intervention to target multiple components of the sepsis response. The long-term goal is to establish a stable clinical platform in a consistently supported cohort of septic patients to conduct clinical trials with novel therapies using genomic and proteomic biomarkers to monitor effect and mechanism. This planning grant application requests funds to support the organization and planning of this endeavor.