It was our Specific Aim in Phase I to: 1) develop a clinically relevant indirect sepsis-induced acute respiratory distress syndrome (ARDS) model and 2) utilize this model to determine the efficacy of prophylactic COL-3 in preventing the onset of ARDS. Both goals of our Phase I study were achieved and the results are as follows: 1) we successfully developed an injury consisting of a fecal clot (FC) placed in the peritoneal cavity plus clamping of the superior mesenteric artery (SMA) which resulted in ARDS within 48 hours of the insult, and 2) we found that prophylactic COL-3 treatment COMPLETELY prevented the development of ARDS in this model. COL-3 prevented lung injury so effectively that the primary end points including lung function, oxygenation, serum and alveolar cytokine concentration, lung water and histologic pathology were not significantly different from the non-septic Control Group. In addition to preventing ARDS, COL-3 also precluded the development of septic shock, an unexpected effect that was not originally hypothesized.
Our SPECIFIC AIMS for Phase II are: I) - Transfer manufacture of COL-3 to a cGMP facility and scale up batch size, reduce the level of impurities, and refine analytical methods. This cGMP material will then be used to accomplish Specific Aims II and III. II) - Establish the """"""""treatment window"""""""" following injury during which COL-3 will remain effective at preventing ARDS and septic shock. COL-3 will be given: a) concomitant with injury but before the onset of the systemic inflammatory response syndrome (SIRS), b) following the development of SIRS (SIRS will be confirmed by an increase in plasma IL-6) but before sepsis development, c) during sepsis (positive blood culture), and d) after lung injury (significant fall in PaO2/FiO2ratio). These data will be crucial in refining the objectives for the final stage of COL-3 development - a multi-center clinical trial. III) - Determine that COL-3 improves 10-day survival in a smoke inhalation plus burn sheep model of ARDS. Can COL-3 improve survival in a clinically applicable non-septic model of ARDS? This Aim will establish that COL-3 is effective in: a) treating ARDS caused by direct (smoke inhalation) pulmonary injury and b) that COL-3 reduces not only morbidity but also mortality.
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