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.
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.