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

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ClinicalTrials.gov Identifier: NCT04706507
Recruitment Status : Recruiting
First Posted : January 12, 2021
Last Update Posted : July 20, 2021
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Michael Boeckh, Fred Hutchinson Cancer Research Center

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 485 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 : June 29, 2021
Estimated Primary Completion Date : May 31, 2026
Estimated Study Completion Date : August 31, 2027


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 Name: 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 Name: Cytovene




Primary Outcome Measures :
  1. Ventilator-free days in immunocompetent patients with sepsis-associated acute respiratory failure [ Time Frame: up to 28 days ]
    To evaluate whether administration of ganciclovir increases ventilator-free days in immunocompetent patients with sepsis-associated acute respiratory failure



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Subject/next of kin informed consent
  • Age > 18 years
  • CMV IgG seropositive by standard serologic methods
  • Intubated and requiring mechanical positive pressure ventilation with positive end-expiratory pressure (PEEP) > 5 cmH2O; PaO2/FiO2 < 300mmHg; and new, or if no prior imaging, presumed new unilateral or bilateral infiltrates on chest radiography occurring in the setting of sepsis from any source
  • Meets criteria for sepsis within a 24-hour time period within the 120-hour screening window after hospitalization). Sepsis will be defined according to the recent Sepsis-3 consensus definition (outlined briefly below and in more detail in Appendix G) [70]:

    • Infection suspected or confirmed by the treating physician and
    • Organ dysfunction measured as an acute change in total SOFA score >2 points after the infection (baseline SOFA score assumed 0 unless known pre-existing organ dysfunction).
  • On the day of randomization (by local criteria):

    • Not eligible for SBT (Spontaneous Breathing Trial. Use of sedation and/or vasopressor does not specifically contraindicate SBT) Or
    • Failed SBT

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04706507


Contacts
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Contact: Michael Boeckh, MD 206 667 6706 mboeckh@fredhutch.org
Contact: Louise Kimball, PhD,RN 206 667 2904 lkimball@fredhutch.org

Locations
Show Show 20 study locations
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
National Heart, Lung, and Blood Institute (NHLBI)
Investigators
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Principal Investigator: Michael Boeckh, MD Fred Hutchinson Cancer Research Center
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Responsible Party: Michael Boeckh, Professor, Vaccine and Infectious Disease Division, Fred Hutch, Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT04706507    
Other Study ID Numbers: RG1121219
1UG3HL147011-01A1 ( U.S. NIH Grant/Contract )
10547 ( Other Identifier: Fred Hutch )
First Posted: January 12, 2021    Key Record Dates
Last Update Posted: July 20, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
Additional relevant MeSH terms:
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Respiratory Insufficiency
Respiratory Distress Syndrome, Adult
Respiration Disorders
Respiratory Tract Diseases
Lung Diseases
Ganciclovir
Ganciclovir triphosphate
Antiviral Agents
Anti-Infective Agents
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action