Ganciclovir to Prevent Reactivation of Cytomegalovirus in Patients With Acute Respiratory Failure and Sepsis (GRAIL^3)

This is a phase 3 study designed to evaluate whether the administration of ganciclovir increases ventilator-free days in immunocompetent patients with sepsis associated acute respiratory failure. Our hypothesis is that IV ganciclovir administered early in critical illness will effectively suppress CMV reactivation in CMV seropositive adults with sepsis-associated acute respiratory failure thereby leading to improved clinical outcomes

Study Overview

• Status: Terminated
• Conditions: Acute Respiratory Failure
• Intervention / Treatment: Drug: IV Ganciclovir; Drug: Normal saline

• Study Type: Interventional
• Enrollment (Actual): 205
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Denver, Colorado, United States, 80204
      • University of Colorado Denver
  • Maryland
    • Baltimore, Maryland, United States, 21218
      • Johns Hopkins University
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham & Women's Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-5360
      • University of Michigan
    • Detroit, Michigan, United States, 48202
      • Henry Ford Hospital
  • Missouri
    • St Louis, Missouri, United States, 63130
      • Washington University
  • New York
    • The Bronx, New York, United States, 10467
      • Montefioure Medical Center
  • North Carolina
    • Durham, North Carolina, United States, 27708
      • Duke University
    • Winston-Salem, North Carolina, United States, 27157
      • Wakeforest University, School of Medicine
  • Ohio
    • Cincinnati, Ohio, United States, 45221
      • University of Cincinnati
    • Cleveland, Ohio, United States, 44195
      • The Cleveland Clinic Foundation
    • Columbus, Ohio, United States, 43210
      • Ohio State University Medical Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15261
      • University of Pittsburgh Medical Center
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical College of South Carolina
  • Tennessee
    • Nashville, Tennessee, United States, 37235
      • Vanderbilt University
  • Utah
    • Murray, Utah, United States, 84107
      • Intermountain Medical Center
  • Vermont
    • Burlington, Vermont, United States, 05405
      • University of Vermont College of Medicine
  • Washington
    • Seattle, Washington, United States, 98195
      • University of Washington Medical Center
    • Seattle, Washington, United States, 98104
      • Harborview Medical Center
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin School of Medicine & Public Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Subject/next of kin informed consent
• Age > 18 years
• CMV IgG seropositive by lateral flow assay (LFA) or standard serologic methods
• Receiving care in an ICU
• Acute respiratory failure as defined in Section 4.1.1.
• Expected to require respiratory support for at least 2 more days after randomization
• Infection confirmed or suspected by the treating clinician and felt to be the source of acute respiratory failure (Respiratory failure associated with infection confers at least 2 SOFA points above assumed baseline SOFA score of 0, thereby meeting Sepsis-3 definition).

Exclusion Criteria:

• Known or suspected immunosuppression, including:

  • HIV+ (i.e. prior positive test or clinical signs of suspicion of HIV/AIDS; a negative HIV test is not required for enrollment)

  • stem cell transplantation:

    • within 6 months after autologous transplantation or
    • within 1 years after allogeneic transplantation (regardless of immunosuppression)
    • greater than 1 year of allogeneic transplantation if still taking systemic immunosuppression or prophylactic antibiotics (e.g. for chronic graft versus host disease) Note: if details of stem cell transplantation are unknown, patients who do not take systemic immunosuppression and do not take anti-infective prophylaxis are acceptable for enrollment and randomization.
  • solid organ transplantation with receipt of systemic immunosuppression (any time)
  • cytotoxic anti-cancer chemotherapy within the past three months (Note: next-of-kin estimate is acceptable)
  • congenital immunodeficiency requiring antimicrobial prophylaxis (e.g. TMP-SMX, dapsone, antifungal drugs, intravenous immunoglobulin)

  • receipt of one or more of the following in the indicated time period (see Appendix C):

    • within 6 months: alemtuzumab, antithymocyte/antilymphocyte antibodies, or other immunosuppressive drugs associated with CMV reactivation Note: if no information on these agents is available in the history and no direct or indirect evidence exists from the history that any condition exists that requires treatment with these agents (based on the investigator's assessment), the subject may be enrolled. For all drug information, next-of-kin estimates are acceptable. See Appendix C for commonly prescribed immunosuppressive agents. Information on the use of biologics with moderate immunosuppressive effect but no known effect on CMV are permitted and will be recorded in the CRFs.
• Expected to survive < 72 hours (in the opinion of the investigator)
• Has been hospitalized for > 120 hours (subjects who are transferred from a chronic care ward, such as a rehabilitation unit, with an acute event are acceptable).
• Pregnant or breastfeeding (either currently or expected within one month). Note: for women of childbearing age (18-60 years, unless documentation of surgical sterilization [hysterectomy, tubal ligation, oophorectomy]), if a pregnancy test has not been done as part of initial ICU admission work-up, it will be ordered stat and documented to be negative before randomization. Both urine and blood tests are acceptable.
• Absolute neutrophil count < 1,000/mm3 (if no ANC value is available, the WBC must be > 2500/mm3)
• Use of anti-CMV drugs (cidofovir, letermovir, foscarnet, valganciclovir, ganciclovir) within seven (7) days of patient randomization.
• Currently enrolled in an interventional trial of an investigational therapeutic agent known or suspected to have anti-CMV activity or to be associated with significant known hematologic toxicity (prior approval required).
• At baseline patients who have both a tracheostomy, and have been on continuous 24-hour chronic mechanical ventilation.
• Patients with Child Class C Cirrhosis.
• Patients with severe (requiring home oxygen) pre-existing interstitial lung disease.
• Allergy to ganciclovir
• Incarcerated

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: IV Ganciclovir; 5mg/kg IV twice daily for 5 days, then followed by IV ganciclovir once daily until hospital discharge	Drug: IV Ganciclovir; For first 5 days, dosing of intravenous ganciclovir is 10 mg/kg daily, given as 5 mg/kg every 12 hours (adjusted for renal function). After first 5 days (up to 28 days) IV ganciclovir 5 mg/kg QD ( adjusted for renal function). A minimum interval of 6 hours is required between the first and second dose.; Other Names: Cytovene
Placebo Comparator: Placebo; normal saline IV twice daily for 5 days, then followed by IV normal saline once daily until hospital discharge	Drug: Normal saline; For first 5 days, dosing of intravenous saline is 10 mg/kg daily, given as 5 mg/kg every 12 hours (adjusted for renal function). After first 5 days (up to 28 days) IV saline 5 mg/kg QD ( adjusted for renal function). A minimum interval of 6 hours is required between the first and second dose.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Respiratory-support-free Days in Immunocompetent Patients With Sepsis-associated Acute Respiratory Failure	To evaluate whether administration of ganciclovir increases respiratory-support-free days in immunocompetent patients with sepsis-associated acute respiratory failure. The outcome is the number of days the participant is not on respiratory support in the first 28 study days. This outcome uses the last-off approach to calculate the number of respiratory support days. The number of support days after calculated from the last day the participant was on respiratory support.	up to 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To Evaluate Whether Administration of Ganciclovir Increases Ventilator-free Days in Immunocompetent Patients With Sepsis-associated Acute Respiratory Failure.	During the first 28 study days, the number of days the participants are not on mechanical ventilation using the last off approach is compared between the two treatment arms.	up to 28 study days
To Evaluate Whether Administration of Ganciclovir Increases Total Respiratory-support-free Days (All RSFDS, Instead of Last-off Approach) in Immunocompetent Patients With Sepsis- Associated Acute Respiratory Failure	During the first 28 study days, the number of days the participants are not on any respiratory-support is compared between the two treatment arms. Instead of using last-off approach, we will count all the days during 28 days period.	up to 28 days
To Evaluate Whether Mortality and Time to Death in the 28 Days is Different Among Ganciclovir Recipients Relative to Placebo Recipients, Respectively.	This is a time to event outcome with death as the event and censoring at the time of study termination if the participant is alive at 28 days. The hazard ratio and Cox proportional hazards models are used for this endpoint.	at study day 28
To Evaluate Whether Mortality and Time to Death in the 180 Days is Different Among Ganciclovir Recipients Relative to Placebo Recipients, Respectively.	This is a time to event outcome with death as the event and censoring at the time of study termination if the participant is alive at the end of the study (day 180).	at the final study visit (day 180)
To Evaluate Whether Duration of Mechanical Ventilation Among Survivors in the First 28 Days is Different Among Ganciclovir Recipients Relative to Placebo Recipients.	This endpoint summarizes the days of mechanical ventilation for those participants who survive the first 28 days of the study. Participants who die in the first 28 days are excluded.	up to 28 days
To Evaluate Whether Duration of Respiratory Support Among Survivors in the First 28 Days is Different Among Ganciclovir Recipients Relative to Placebo Recipients.	This endpoint summarizes the days of all types of respiratory support for those participants who survive the first 28 days of the study. Participants who die in the first 28 days are excluded.	up to 28 days
To Evaluate Whether Oxygenation is Different Among Ganciclovir Recipients Relative to Placebo Recipients.	The PaO2/FiO2 (P/F) ratio was used to define oxygenation. The P/F ratio was summarized over the first 7 days of the study. The lowest PaO2 value within each study day was reported and used in the oxygenation calculation. If the PaO2 value was not available, an estimate of PaO2 was calculated from the SpO2 lowest value.	up to 7 days
To Evaluate Whether ICU-free Days in the First 28 Days Are Different Among Ganciclovir Recipients Relative to Placebo Recipients.	During the first 28 study days, the number of days the participants are not in ICU using the last off approach is compared between the two treatment arms.	up to 28 days
To Evaluate Whether CMV DNA Detection in Plasma and Endotracheal Aspirate (ETA) by Day 28 is Different Among Ganciclovir Recipients Relative to Placebo Recipients.	CMV DNA detection in plasma and endotracheal aspirate (ETA) by day 28 is defined as positive CMV PCR result from any ETA, plasma, or serum specimen collected through day 28. CMV reactivation by day 28 will be summarized with number of participants with CMV reactivation in two levels: as any detectable CMV DNA (any level) and as high-level reactivation (>1000 IU/mL) for CMV negative patients at baseline.	up to 28 days
To Assess the Number and Severity of Adverse Events and Serious Adverse Events in the First 28 Days in Both Groups.	During the first 28 days, this endpoint summarizes the number of participants who experienced adverse events (AEs) of severity grade ≥3 and whether any serious adverse events (SAEs) occurred in each study arm.	up to 28 days

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI)
• Investigators: Principal Investigator: Michael Boeckh, MD, Fred Hutchinson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): June 29, 2021
• Primary Completion (Actual): October 25, 2024
• Study Completion (Actual): April 8, 2025

Study Registration Dates

• First Submitted: December 23, 2020
• First Submitted That Met QC Criteria: January 11, 2021
• First Posted (Actual): January 12, 2021

Study Record Updates

• Last Update Posted (Estimated): December 12, 2025
• Last Update Submitted That Met QC Criteria: November 26, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Respiration Disorders; Respiratory Distress Syndrome; Respiratory Insufficiency; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pharmaceutical Preparations; Guanine; Hypoxanthines; Purinones; Purines; Crystalloid Solutions; Isotonic Solutions; Solutions; Acyclovir; Ganciclovir; Saline Solution
• Other Study ID Numbers: RG1121219; 10547 (Other Identifier: Fred Hutch); 1UG3HL147011-01A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes