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

Sponsor

Fred Hutchinson Cancer Center (Other)

Overall Status

Recruiting

CT.gov ID

NCT04706507

Collaborator

National Heart, Lung, and Blood Institute (NHLBI) (NIH)

500

Enrollment

Locations

Arms

74.1

Anticipated Duration (Months)

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief 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

Condition or Disease	Intervention/Treatment	Phase
Acute Respiratory Failure	Drug: IV Ganciclovir	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

500 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jun 29, 2021

Anticipated Primary Completion Date :

May 31, 2026

Anticipated Study Completion Date :

Aug 31, 2027

Arms and Interventions

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: 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

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: IV Ganciclovir

Other Names:

Cytovene

Outcome Measures

Primary Outcome Measures

Respiratory-support-free days in immunocompetent patients with sepsis-associated acute respiratory failure [up to 28 days]
To evaluate whether administration of ganciclovir increases respiratory-support-free days in immunocompetent patients with sepsis-associated acute respiratory failure

Secondary Outcome Measures

To evaluate whether administration of ganciclovir increases ventilator-free days in immunocompetent patients with sepsis-associated acute respiratory failure. [up to 28 days]
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]
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]
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]
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]
To evaluate whether oxygenation is different among ganciclovir recipients relative to placebo recipients. [up to 28 days]
To evaluate whether ICU-free days in the first 28 days are different among ganciclovir recipients relative to placebo recipients. [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. [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. [up to 28 days]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 85 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Colorado Denver	Denver	Colorado	United States	80204
2	Johns Hopkins University	Baltimore	Maryland	United States	21218
3	Brigham & Women's Hospital	Boston	Massachusetts	United States	02115
4	University of Michigan	Ann Arbor	Michigan	United States	48109-5360
5	Henry Ford Hospital	Detroit	Michigan	United States	48202
6	Washington University	Saint Louis	Missouri	United States	63130
7	Montefioure Medical Center	Bronx	New York	United States	10467
8	Duke University	Durham	North Carolina	United States	27708
9	Wakeforest University, School of Medicine	Winston-Salem	North Carolina	United States	27157
10	University of Cincinnati	Cincinnati	Ohio	United States	45221
11	The Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
12	Ohio State University Medical Center	Columbus	Ohio	United States	43210
13	University of Pittsburgh Medical Center	Pittsburgh	Pennsylvania	United States	15261
14	Medical College of South Carolina	Charleston	South Carolina	United States	29425
15	Vanderbilt University	Nashville	Tennessee	United States	37235
16	Intermountain Medical Center	Murray	Utah	United States	84107
17	University of Vermont College of Medicine	Burlington	Vermont	United States	05405
18	Harborview Medical Center	Seattle	Washington	United States	98104
19	University of Washington Medical Center	Seattle	Washington	United States	98195
20	University of Wisconsin School of Medicine & Public Health	Madison	Wisconsin	United States	53792

Sponsors and Collaborators

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

Investigators

Principal Investigator: Michael Boeckh, MD, Fred Hutchinson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Michael Boeckh, Professor, Vaccine and Infectious Disease Division, Fred Hutch, Fred Hutchinson Cancer Center

ClinicalTrials.gov Identifier:

NCT04706507

Other Study ID Numbers:

RG1121219
1UG3HL147011-01A1
10547

First Posted:

Jan 12, 2021

Last Update Posted:

Jul 13, 2022

Last Verified:

Jul 1, 2022

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Studies a U.S. FDA-regulated Drug Product:

Yes

Studies a U.S. FDA-regulated Device Product:

Product Manufactured in and Exported from the U.S.:

Yes

Additional relevant MeSH terms:

Respiratory Insufficiency

Respiratory Distress Syndrome

Ganciclovir

Ganciclovir triphosphate

Study Results

No Results Posted as of Jul 13, 2022