UH3HL147011

1/2 Ganciclovir to Prevent Reactivation of Cytomegalovirus in Patients with Acute Respiratory Failure and Sepsis - Project Summary

Sepsis-associated acute respiratory failure is a leading cause of morbidity, mortality, and healthcare expenditure worldwide, and its incidence is increasing. Despite extensive investigation, there are few pharmacologic interventions, and care is primarily supportive. Cytomegalovirus (CMV) is a human herpesvirus that infects 50-80% of healthy adults and establishes lifelong latency in the lung. It generally causes overt disease only in severely immunosuppressed patients. However, CMV reactivation (viral replication) from latency occurs in approximately 40% of CMV seropositive, otherwise immunocompetent individuals during critical illness. This reactivation 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, ganciclovir effectively suppressed CMV replication, had an acceptable safety profile, and was associated with improved clinical outcomes. These outcomes included 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 intravenous ganciclovir administered early in critical illness will effectively suppress CMV reactivation in CMV seropositive adults with sepsis-associated acute respiratory failure. This suppression will reduce lung damage, accelerate recovery, and lead to improved clinical outcomes. Therefore, 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.

The study intervention's effect 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) will be measured. In exploratory analyses, we will assess baseline factors as predictors for CMV reactivation and characterize the relationship between CMV viral load kinetics and 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 a proven ability to recruit patients into RCTs. If effective, this inexpensive and feasible intervention has the potential to significantly improve the care of patients with sepsis-associated respiratory failure, substantially change clinical practice, and offer new insights into the sepsis-CMV reactivation relationship.

Fred Hutchinson Cancer Center

THE DIVISION OF LUNG DISEASES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE CAUSES, DIAGNOSIS, PREVENTION, AND TREATMENT OF LUNG DISEASES AND SLEEP DISORDERS. RESEARCH IS FUNDED THROUGH INVESTIGATOR-INITIATED AND INSTITUTE-INITIATED GRANT PROGRAMS AND THROUGH CONTRACT PROGRAMS IN AREAS INCLUDING ASTHMA, BRONCHOPULMONARY DYSPLASIA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CYSTIC FIBROSIS, RESPIRATORY NEUROBIOLOGY, SLEEP AND CIRCADIAN BIOLOGY, SLEEP-DISORDERED BREATHING, CRITICAL CARE AND ACUTE LUNG INJURY, DEVELOPMENTAL BIOLOGY AND PEDIATRIC PULMONARY DISEASES, IMMUNOLOGIC AND FIBROTIC PULMONARY DISEASE, RARE LUNG DISORDERS, PULMONARY VASCULAR DISEASE, AND PULMONARY COMPLICATIONS OF AIDS AND TUBERCULOSIS. THE DIVISION IS RESPONSIBLE FOR MONITORING THE LATEST RESEARCH DEVELOPMENTS IN THE EXTRAMURAL SCIENTIFIC COMMUNITY AS WELL AS IDENTIFYING RESEARCH GAPS AND NEEDS, OBTAINING ADVICE FROM EXPERTS IN THE FIELD, AND IMPLEMENTING PROGRAMS TO ADDRESS NEW OPPORTUNITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS, FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS, AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION, FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

Washington United States

State-Wide

Clinical Coordinating Center for Multi-Site Investigator-Initiated Clinical Trials (Collaborative UG3/UH3) - Clinical Trial Required (PAR-18-407)

Amendment Since initial award the End Date has been shortened from 08/31/27 to 08/31/25 and the total obligations have increased 342% from $2,216,945 to $9,788,465.