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

Primary Purpose

Acute Respiratory Failure

Status
Recruiting
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
IV Ganciclovir
Sponsored by
Fred Hutchinson Cancer Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Respiratory Failure

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • University of Colorado DenverRecruiting
  • Johns Hopkins UniversityRecruiting
  • Brigham & Women's HospitalRecruiting
  • University of MichiganRecruiting
  • Henry Ford HospitalRecruiting
  • Washington UniversityRecruiting
  • Montefioure Medical CenterRecruiting
  • Duke UniversityRecruiting
  • Wakeforest University, School of MedicineRecruiting
  • University of CincinnatiRecruiting
  • The Cleveland Clinic FoundationRecruiting
  • Ohio State University Medical CenterRecruiting
  • University of Pittsburgh Medical CenterRecruiting
  • Medical College of South CarolinaRecruiting
  • Vanderbilt UniversityRecruiting
  • Intermountain Medical CenterRecruiting
  • University of Vermont College of MedicineRecruiting
  • Harborview Medical CenterRecruiting
  • University of Washington Medical CenterRecruiting
  • University of Wisconsin School of Medicine & Public HealthRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

IV Ganciclovir

Placebo

Arm Description

5mg/kg IV twice daily for 5 days, then followed by IV ganciclovir once daily until hospital discharge

normal saline IV twice daily for 5 days, then followed by IV normal saline once daily until hospital discharge

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

Full Information

First Posted
December 23, 2020
Last Updated
June 29, 2023
Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)
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1. Study Identification

Unique Protocol Identification Number
NCT04706507
Brief Title
Ganciclovir to Prevent Reactivation of Cytomegalovirus in Patients With Acute Respiratory Failure and Sepsis
Acronym
GRAIL^3
Official Title
Ganciclovir to Prevent Reactivation of Cytomegalovirus in Patients With Acute Respiratory Failure and Sepsis
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 29, 2021 (Actual)
Primary Completion Date
May 31, 2026 (Anticipated)
Study Completion Date
August 31, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Fred Hutchinson Cancer Center
Collaborators
National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

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

5. 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

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Respiratory Failure

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
500 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
IV Ganciclovir
Arm Type
Experimental
Arm Description
5mg/kg IV twice daily for 5 days, then followed by IV ganciclovir once daily until hospital discharge
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
normal saline IV twice daily for 5 days, then followed by IV normal saline once daily until hospital discharge
Intervention Type
Drug
Intervention Name(s)
IV Ganciclovir
Other Intervention Name(s)
Cytovene
Intervention Description
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.
Primary Outcome Measure Information:
Title
Respiratory-support-free days in immunocompetent patients with sepsis-associated acute respiratory failure
Description
To evaluate whether administration of ganciclovir increases respiratory-support-free days in immunocompetent patients with sepsis-associated acute respiratory failure
Time Frame
up to 28 days
Secondary Outcome Measure Information:
Title
To evaluate whether administration of ganciclovir increases ventilator-free days in immunocompetent patients with sepsis-associated acute respiratory failure.
Time Frame
up to 28 days
Title
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
Time Frame
up to 28 days
Title
To evaluate whether mortality and time to death in the 28 and 180 days is different among ganciclovir recipients relative to placebo recipients, respectively.
Time Frame
at day 28 and day 180
Title
To evaluate whether duration of mechanical ventilation among survivors in the first 28 days is different among ganciclovir recipients relative to placebo recipients.
Time Frame
up to 28 days
Title
To evaluate whether duration of respiratory support among survivors in the first 28 days is different among ganciclovir recipients relative to placebo recipients.
Time Frame
up to 28 days
Title
To evaluate whether oxygenation is different among ganciclovir recipients relative to placebo recipients.
Time Frame
up to 28 days
Title
To evaluate whether ICU-free days in the first 28 days are different among ganciclovir recipients relative to placebo recipients.
Time Frame
up to 28 days
Title
To evaluate whether CMV DNA detection in plasma and endotracheal aspirate (ETA) by day 28 is different among ganciclovir recipients relative to placebo recipients.
Time Frame
up to 28 days
Title
To assess the number and severity of adverse events and serious adverse events in the first 28 days in both groups.
Time Frame
up to 28 days

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Michael Boeckh, MD
Phone
206 667 6706
Email
mboeckh@fredhutch.org
First Name & Middle Initial & Last Name or Official Title & Degree
Louise Kimball, PhD,RN
Phone
206 667 2904
Email
lkimball@fredhutch.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Michael Boeckh, MD
Organizational Affiliation
Fred Hutchinson Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Colorado Denver
City
Denver
State/Province
Colorado
ZIP/Postal Code
80204
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ellen Burnham, MD
Email
Ellen.Burnham@ucdenver.edu
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21218
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Dale Needham, MD
Facility Name
Brigham & Women's Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Rebecca M Baron, MD
Email
rbaron@bwh.harvard.edu
Facility Name
University of Michigan
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109-5360
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Robert Hyzy, MD
Phone
734-936-5201
Email
rhyzy@umich.edu
Facility Name
Henry Ford Hospital
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mayur Ramesh, MD
Email
Mramesh1@hfhs.org
Facility Name
Washington University
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63130
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Cristina Vazquez Guillamet, MD
Email
m.c.vazquezguillamet@wustl.edu
Facility Name
Montefioure Medical Center
City
Bronx
State/Province
New York
ZIP/Postal Code
10467
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Michelle Gong, MD, MS
Email
MGONG@montefiore.org
Facility Name
Duke University
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27708
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Christopher Cox, MD
Email
christopher.cox@duke.edu
Facility Name
Wakeforest University, School of Medicine
City
Winston-Salem
State/Province
North Carolina
ZIP/Postal Code
27157
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Clark Files, MD
Email
Clark.Files@wakehealth.edu
Facility Name
University of Cincinnati
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45221
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Duncan Hite, MD
Email
hitern@ucmail.uc.edu
Facility Name
The Cleveland Clinic Foundation
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Abhijit Duggal, MD
Email
DUGGALA2@ccf.org
Facility Name
Ohio State University Medical Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Matthew Exline, MD
Phone
614-293-4925
Email
Matthew.Exline@osumc.edu
Facility Name
University of Pittsburgh Medical Center
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15261
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Scott Gunn, MD
Phone
412-958-8398
Email
gunnsr@ccm.upmc.edu
Facility Name
Medical College of South Carolina
City
Charleston
State/Province
South Carolina
ZIP/Postal Code
29425
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Andrew Goodwin
Email
goodwian@musc.edu
Facility Name
Vanderbilt University
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37235
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Todd Rice, MD
Email
todd.rice@Vanderbilt.Edu
Facility Name
Intermountain Medical Center
City
Murray
State/Province
Utah
ZIP/Postal Code
84107
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ithan Peltan, MD
Email
ithan.peltan@imail.org
Facility Name
University of Vermont College of Medicine
City
Burlington
State/Province
Vermont
ZIP/Postal Code
05405
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Renee Stapleton, MD
Email
renee.stapleton@med.uvm.edu
Facility Name
Harborview Medical Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98104
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ajit Limaye, MD
Phone
206-598-1041
Email
ALimaye@u.washington.edu
Facility Name
University of Washington Medical Center
City
Seattle
State/Province
Washington
ZIP/Postal Code
98195
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ajit Limaye, MD
Phone
206-598-1041
Email
ALimaye@medicine.washington.edu
Facility Name
University of Wisconsin School of Medicine & Public Health
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53792
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Loren C Denlinger, MD,PhD
Phone
608-261-1552
Email
cd@medicine.wisc.edu

12. IPD Sharing Statement

Plan to Share IPD
No

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

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