The goal of this Translational Program Project Grant is to advance the biologic understanding and therapeutic application of inhaled carbon monoxide (CO) in sepsis-induced ALI. Core B (the Clinical Studies Coordination Core) will provide important resources and support for the Project Investigators in carrying out the proposed Translational Studies. Specifically, this core will provide human samples from well-phenotyped subjects to investigators in Projects 1-4 and serve as the Data Coordinating Center (DCC) for the Phase I safety and proof-of-concept trials in administering inhaled CO to patients with sepsis-induced ALI. Objective 1: To identify patients with the systemic inflammatory response syndrome (SIRS), sepsis, and sepsis-induced acute lung injury (ALI); to collect and store plasma, RNA, and primary cells from subjects in a clinical biorepository; and to provide biostatistical support for Projects 1-4 for the analysis and interpretation of studies performed using these specimens. This Core will provide investigators in Projects 1-4 with uniformly processed clinical samples from well-characterized critically ill patients from the BWH Medical ICU. We anticipate that we will enroll at least 1,000 subjects (over 5 years). Objective 2: To serve as the DCC for the Phase 1 first-in-ALI safety study for inhaled CO in sepsis induced ALI in Project 1 and proof-of-concept study with collection of muscle biopsies after inhaled CO in Project 2. Collection of samples as in Objective 1 will be undertaken pre- and post-CO exposure for distribution to the investigators in Projects 1-4. As the DCC for the clinical trials in Years 3-5, we will provide support to the investigators at BWH, MGH, and DUMC in carrying out these trials. In years 1-2, we will submit the IND and IRB applications and develop the infrastructure for initiating the trials. Once the trial is initiated, we will manage the database, process adverse events, and produce regular reports to the DSMB, FDA, and investigators. We will also collect and analyze data from Project investigators regarding levels of biomarkers in clinical samples. Overall Objective: By centralizing clinical trials oversight, clinical sample collection, and phenotyping by experienced and expert investigators, well-characterized and uniformly processed clinical samples can be provided to investigators from Projects 1-4 to facilitate their translational research aims. Importantly, data from the Phase I safety and proof-of-concept studies will form the basis for a Phase ll/lll clinical trial in the 2nd 5-year cycle of this translational Program Project Grant.
Sepsis-induced ALI is a condition with high morbidity and mortality and with limited available treatment options. This Translational Program Project Grant proposes to advance the understanding and application of a novel therapeutic modality, inhaled carbon monoxide, in these critically ill patients. This Core will play a key role in facilitating the translational aspects of this proposal for all of the proposed projects.
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