PROJECT SUMMARY Sepsis-associated acute respiratory failure is a leading cause of morbidity, mortality and health care expenditure world-wide, and is increasing in incidence. Despite intensive investigation, there are few pharmacologic interventions, and care is largely supportive. Cytomegalovirus (CMV) is a human herpesvirus that infects 50- 80% of healthy adults and establishes lifelong latency in the lung, generally causing overt disease only in severely immunosuppressed patients. CMV reactivation (viral replication) from latency occurs in ~40% of CMV seropositive, otherwise immunocompetent persons during critical illness and is associated with worse clinical outcomes including increased mortality, prolonged mechanical ventilation, and increased ICU length of stay. Compelling evidence implicating CMV reactivation as a causal contributor to morbidity and mortality in sepsis- associated respiratory failure comes from animal models and our recently completed NHLBI-funded phase 2 randomized placebo-controlled trial (RCT) of ganciclovir prophylaxis. In this trial, among CMV seropositive adults with sepsis-associated respiratory failure, ganciclovir effectively suppressed CMV replication, had an acceptable safety profile, and was associated with improved clinical outcomes, including increased ventilator-free days (VFD), shorter duration of mechanical ventilation among survivors, shorter ICU length of stay, and improved PaO2/FiO2 ratio in day-7 survivors. We hypothesize that IV ganciclovir administered early in critical illness will effectively suppress CMV reactivation in CMV seropositive adults with sepsis-associated acute respiratory failure, thereby reducing lung damage, accelerating recovery, and leading to improved clinical outcomes. We propose to conduct a phase 3 RCT to determine whether the antiviral drug ganciclovir given as prophylaxis improves VFDs and other clinically relevant outcomes when administered within 5 days of ICU admission to CMV seropositive immunocompetent adults with sepsis-associated acute respiratory failure. We will measure the effect of the study intervention on the primary trial outcome (VFDs) and secondary outcomes (mortality at 28 days, duration of mechanical ventilation in survivors, oxygenation, static respiratory system compliance, CMV plasma and lung reactivation, and a core set of longer-term outcomes at 6 months). In exploratory analyses, we will assess baseline factors as predictors for CMV reactivation, and characterize the relationship of CMV viral load kinetics with VFDs and other clinical outcomes. Our interdisciplinary team has unique experience in successfully coordinating multi-site multi-PI ICU-based RCTs. We have established a network of 19 clinical sites in the US, all of which have robust infrastructure for ICU clinical trials and proven ability to recruit patients into RCTs. If it is effective, this inexpensive and feasible intervention has the potential to significantly improve care of patients with sepsis-associated respiratory failure, substantially change clinical practice, and offer new insights into the sepsis-CMV reactivation relationship.

PROJECT NARRATIVE This multicenter clinical trial will examine whether the use of an antiviral drug called ganciclovir can safely and effectively prevent reactivation of a common virus called cytomegalovirus and improve clinical outcomes in adults with sepsis-associated acute respiratory failure. If this study shows a clinical benefit, routine use of this antiviral drug could become standard therapy to improve the outcomes of adults with prior exposure to CMV and who have sepsis-associated acute respiratory failure requiring mechanical ventilation.