Ganciclovir to Prevent Reactivation of Cytomegalovirus in Patients With Acute Respiratory Failure and Sepsis

Acute Respiratory Failure Clinical Trial

— GRAIL^3  

Official title:

Ganciclovir to Prevent Reactivation of Cytomegalovirus in Patients With Acute Respiratory Failure and Sepsis

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04706507
• Other study ID #: RG1121219
• Secondary ID: 1UG3HL147011-01A
• Status: Recruiting
• Phase: Phase 3
• Start date: June 29, 2021
• Est. completion date: August 31, 2027

Study information

• Verified date: February 2024
• Source: Fred Hutchinson Cancer Center
• Contact: Michael Boeckh, MD
• Phone: 206 667 6706
• Email: mboeckh[@]fredhutch.org
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 500
• Est. completion date: August 31, 2027
• Est. primary completion date: May 31, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 85 Years

Eligibility

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

Related Conditions & MeSH terms

• Acute Respiratory Failure
• Respiratory Distress Syndrome
• Respiratory Insufficiency

Intervention

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.

Locations

Country	Name	City	State
United States	University of Michigan	Ann Arbor	Michigan
United States	Johns Hopkins University	Baltimore	Maryland
United States	Brigham & Women's Hospital	Boston	Massachusetts
United States	Montefioure Medical Center	Bronx	New York
United States	University of Vermont College of Medicine	Burlington	Vermont
United States	Medical College of South Carolina	Charleston	South Carolina
United States	University of Cincinnati	Cincinnati	Ohio
United States	The Cleveland Clinic Foundation	Cleveland	Ohio
United States	Ohio State University Medical Center	Columbus	Ohio
United States	University of Colorado Denver	Denver	Colorado
United States	Henry Ford Hospital	Detroit	Michigan
United States	Duke University	Durham	North Carolina
United States	University of Wisconsin School of Medicine & Public Health	Madison	Wisconsin
United States	Intermountain Medical Center	Murray	Utah
United States	Vanderbilt University	Nashville	Tennessee
United States	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania
United States	Washington University	Saint Louis	Missouri
United States	Harborview Medical Center	Seattle	Washington
United States	University of Washington Medical Center	Seattle	Washington
United States	Wakeforest University, School of Medicine	Winston-Salem	North Carolina

Sponsors (2)

Lead Sponsor	Collaborator
Fred Hutchinson Cancer Center	National Heart, Lung, and Blood Institute (NHLBI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	up to 28 days
Secondary	To evaluate whether administration of ganciclovir increases ventilator-free days in immunocompetent patients with sepsis-associated acute respiratory failure.		up to 28 days
Secondary	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		up to 28 days
Secondary	To evaluate whether mortality and time to death in the 28 and 180 days is different among ganciclovir recipients relative to placebo recipients, respectively.		at day 28 and day 180
Secondary	To evaluate whether duration of mechanical ventilation among survivors in the first 28 days is different among ganciclovir recipients relative to placebo recipients.		up to 28 days
Secondary	To evaluate whether duration of respiratory support among survivors in the first 28 days is different among ganciclovir recipients relative to placebo recipients.		up to 28 days
Secondary	To evaluate whether oxygenation is different among ganciclovir recipients relative to placebo recipients.		up to 28 days
Secondary	To evaluate whether ICU-free days in the first 28 days are different among ganciclovir recipients relative to placebo recipients.		up to 28 days
Secondary	To evaluate whether CMV DNA detection in plasma and endotracheal aspirate (ETA) by day 28 is different among ganciclovir recipients relative to placebo recipients.		up to 28 days
Secondary	To assess the number and severity of adverse events and serious adverse events in the first 28 days in both groups.		up to 28 days