Modulating Innate and Adaptive Immunity in Complicated Abdominal Sepsis

调节复杂性腹部脓毒症的先天性和适应性免疫

基本信息

批准号：
8367057
负责人：
FREDERICK A MOORE
金额：
$ 10.45万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-05 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8367057
关键词：
Abdomen Address Age Anti-Inflammatory Agents Anti-inflammatory Antigen-Presenting Cells Applications Grants Biological Markers Biological Response Modifiers Burn injury CD28 gene CD3 Antigens Caring Cell physiology Clinical Clinical Decision Support Systems Clinical Research Clinical Treatment Clinical Trials Coagulation Process Complication Conduct Clinical Trials Confounding Factors (Epidemiology)Data Databases Development Diagnosis Drug Industry Epidemiology Evaluation Evidence based intervention Failure Functional disorder Funding Generations Genomics Glues Goals Grant Healthcare Heterogeneity Immune Immune response Immune system Immunologic Monitoring Immunosuppression Incidence Individual Infection Inflammation Inflammatory Response Institution Intervention Investments Israel Leadership Measures Mediating Methods Microfluidic Analytical Techniques Modeling Monitor Morbidity - disease rate Multiple Organ Failure Mus National Institute of General Medical Sciences Natural Immunity Operative Surgical Procedures Organ Organ failure Patients Phase Physicians Population Pre-Clinical Model Procedures Property Proteomics Protocols documentation Randomized Controlled Trials Reliance Request for Applications Research Resuscitation Sepsis Septic Shock Site Soft Tissue Infections Source Supportive care Surgical Management T cell response T-Lymphocyte Technology Testing Translations Trauma United States National Institutes of Health Viral Tumor Antigens adaptive immunity analytical method care burden cohort computerized evidence based guidelines immune function improved indexing inflammatory marker insight microbial mortality new technology novel novel therapeutics patient population point of care pre-clinical preclinical study programs prospective response septic standard of care success

项目摘要

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.

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，也是巨大的医疗保健负担。尽管有数十年的有希望的临床前和早期临床研究，但很少有疗法表现出任何成功。我们认为，临床试验未能治疗腹部败血症的失败是由于（1）不屈服的早期，准确地预测谁将受益（2）患者人群的未欣赏异质性和早期支持的变异性，以及3（3））使用靶向多组分败血症响应的单个成分的单等疗法。当前诊断严重败血症或败血性休克的临床标准是炎症和器官衰竭的非特异性指标，复苏和治疗方案的医生和专业中心之间是可变的。生物反应修饰剂（BRMS）具有炎症反应，微生物识别，凝结级联反应或免疫抑制的各个组成部分，并且未能解决败血症反应的现在公认的复杂性。在此临床试验计划中，我们建议使用经过验证的计算机化临床决策支持（CCDS）系统来组织多中心临床试验，该系统最近开发了，快速的基因组和蛋白质组学分析以监控免疫反应，以及新的BRM，新的BRM， CD28拮抗剂（AB103； Atox Bio Ltd，以色列），靶向先天和适应性免疫功能的多个组成部分。计划中的临床试验具有三个具体目的：（1）建立一个临床研究联盟，该联盟将利用经过验证的CCDS系统来实施基于证据的基于证据的指南标准来管理腹部脓毒症的管理，以及一个当前的互补操作研究数据库来表征该数据库腹部败血症的流行病学并记录和分析临床试验数据；（2）使用最近开发，快速，定量，护理基因组和蛋白质组学分析的炎症和适应性免疫功能的标记，以精确测量，并在每个受试者中反复进行分析，以监测对腹部脓毒症和腹部脓毒症和腹部脓毒症的免疫反应的进展到BRM；（3）使用CCD，流行病学数据库，快速，定量基因组和蛋白质组学分析和AB103进行试验前瞻性随机对照试验（PRCT），以及具有独特的抗炎和免疫刺激特性的新型脱肽。长期目标是在良好的且一致支持的患者队列中建立一个稳定的临床平台，并在良好控制的多站点研究中使用基因组和蛋白质组学生物标志物测试新疗法。计划赠款申请要求资金支持这项工作的组织和计划。公共卫生相关性：我们建议使用计算机化的临床决策支持（CCDS）系统在腹部败血症患者中组织和进行多中心临床试验，以管理支持性护理，这是一个临床研究数据库，以表征临床轨迹，精致的蛋白质组学和基因组测量，以监测免疫状态和一种新的干预措施，以靶向败血症反应的多个组成部分。长期目标是在始终支持的化粪池患者队列中建立一个稳定的临床平台，以使用基因组和蛋白质组学生物标志物来监测效果和机制进行新型疗法进行临床试验。该计划赠款申请要求资金支持这项工作的组织和计划。