Ganciclovir to Prevent Reactivation of Cytomegalovirus in patients with Acute Respiratory Failure and Sepsis

Principal Investigators: Abhijit (Ajit) P Limaye, MD and Cynthia Fisher, MD MPH

Sponsor: Fred Hutchinson Cancer Center

Study Design: Phase 3 Multicenter randomized placebo-controlled double-blind trial

ClinicalTrials.gov ID: NCT04706507

Cytomegalovirus (CMV) is a major cause of morbidity and mortality in immunosuppressed populations. In this NIH sponsored study, we will assess the safety, immunogenicity, and efficacy of the drug Ganciclovir in patients with respiratory failure due to sepsis to suppress CMV reactivation with respiratory -support-free days as the primary outcome measure.

Status: Enrollment is ongoing. At the University of Washington, there are more than 9 patients enrolled in this study.

Background/ Rationale

Cytomegalovirus is a human herpesvirus that is known to infect more than half the US adult population. If infected, while generally harmless for healthy individuals, it can be fatal for those with a compromised immune system as the virus stays in the body and can reactivate at a later time. In patients who are critically ill, CMV tends to be reactivated in the lungs and blood. This may cause further lung problems in those with sepsis resulting in longer hospital or intensive care unit (ICU) stays. Reactivation is associated with worse clinical outcomes, but it is unknown whether suppressing CMV reactivation in this setting would lead to improved clinical outcomes.

Ganciclovir is an FDA-approved antiviral agent that is used to treat or prevent CMV infections in solid organ and bone marrow transplant patients, and in people with AIDS. In this phase 3 multicenter NIH sponsored RCT being conducted at 19 sites, we will assess the efficacy and safety of IV GCV to suppress CMV reactivation and reduce the need for respiratory support among patients with sepsis associated respiratory failure.

Study Design

The study is a phase 3 randomized, double-blind, placebo-controlled multicenter clinical trial with respiratory-support-free days (RSFD) as the primary outcome measure. The study takes a prophylaxis approach with the study population being patients with past exposure to cmv, with respiratory failure due to sepsis, requiring respiratory support, and in the ICU. These patients will have a five day window from their admission to the hospital to be enrolled in the study. The participants will be administered IV Ganciclovir until death, hospital discharge, or 28 days (whichever occurs first). Blood and sputum samples will be collected every three to four days. Patients are contacted on Day 28 (if discharged earlier) and on Day 180 to assess vital status, pregnancy, and adverse events.

Primary Objectives

  1. To evaluate whether administration of ganciclovir increases respiratory-support-free days in immunocompetent patients with sepsis-associated acute respiratory failure

Secondary Objectives

  1. To evaluate whether administration of ganciclovir increases ventilator-free days in immunocompetent patients with sepsis-associated acute respiratory failure.

  2. To evaluate whether administration of ganciclovir increases total respiratory-support-free days (all RSDS, instead of last-off approach) in immunocompetent patients with sepsis-associated acute respiratory failure

  3. To evaluate whether mortality and time to death in the 28 and 180 days is different among ganciclovir recipients relative to placebo recipients, respectively.

  4. To evaluate whether duration of mechanical ventilation among survivors in the first 28 days is different among ganciclovir recipients relative to placebo recipients.

  5. To evaluate whether duration of respiratory support among survivors in the first 28 days is different among ganciclovir recipients relative to placebo recipients.

  6. To evaluate whether oxygenation is different among ganciclovir recipients relative to placebo recipients.

  7. To evaluate whether ICU-free days in the first 28 days are different among ganciclovir recipients relative to placebo recipients.

  8. To evaluate whether CMV DNA detection in plasma and endotracheal aspirate (ETA) by day 28 is different among ganciclovir recipients relative to placebo recipients.

  9. To assess the number and severity of adverse events and serious adverse events in the first 28 days in both groups.

Study Sites:

  • Henry Ford Hospital

  • Ohio State University

  • Cleveland Clinic

  • Bringham & Women’s Hospital

  • Harborview & University of Washington Medical Center

  • University of Vermont

  • University of Pittsburgh Medical Center

  • University of Maryland

  • Washington University, St. Louis

  • Wake Forest

  • Johns Hopkins University

  • University of Michigan

  • University of Colorado Denver

  • University of Cincinnati

  • Duke University

  • Medical University of South Carolina

  • Intermountain Medical Center

  • Vanderbilt University

  • Montefiore Medical Center