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
Brief Title
Ganciclovir to Prevent Reactivation of Cytomegalovirus in Patients With Acute Respiratory Failure and Sepsis
Completion Date
Completion Date Type
Actual
Conditions
Acute Respiratory Failure
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
* 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
Inclusion 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).
* 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).
Gender
All
Gender Based
false
Healthy Volunteers
No
Last Update Post Date
Last Update Post Date Type
Estimated
Last Update Submit Date
Maximum Age
85 Years
Minimum Age
18 Years
NCT Id
NCT04706507
Org Class
Other
Org Full Name
Fred Hutchinson Cancer Center
Org Study Id
RG1121219
Overall Status
Terminated
Phases
Phase 3
Primary Completion Date
Primary Completion Date Type
Actual
Official Title
Ganciclovir to Prevent Reactivation of Cytomegalovirus in Patients With Acute Respiratory Failure and Sepsis
Primary Outcomes
Outcome Description
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.
Outcome Measure
Respiratory-support-free Days in Immunocompetent Patients With Sepsis-associated Acute Respiratory Failure
Outcome Time Frame
up to 28 days
Secondary Ids
Secondary Id
1UG3HL147011-01A1
Secondary Id
10547
Secondary Outcomes
Outcome Description
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.
Outcome Time Frame
up to 28 study days
Outcome Measure
To Evaluate Whether Administration of Ganciclovir Increases Ventilator-free Days in Immunocompetent Patients With Sepsis-associated Acute Respiratory Failure.
Outcome Description
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.
Outcome Time Frame
up to 28 days
Outcome Measure
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
Outcome Description
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.
Outcome Time Frame
at study day 28
Outcome Measure
To Evaluate Whether Mortality and Time to Death in the 28 Days is Different Among Ganciclovir Recipients Relative to Placebo Recipients, Respectively.
Outcome Description
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).
Outcome Time Frame
at the final study visit (day 180)
Outcome Measure
To Evaluate Whether Mortality and Time to Death in the 180 Days is Different Among Ganciclovir Recipients Relative to Placebo Recipients, Respectively.
Outcome Description
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.
Outcome Time Frame
up to 28 days
Outcome Measure
To Evaluate Whether Duration of Mechanical Ventilation Among Survivors in the First 28 Days is Different Among Ganciclovir Recipients Relative to Placebo Recipients.
Outcome Description
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.
Outcome Time Frame
up to 28 days
Outcome Measure
To Evaluate Whether Duration of Respiratory Support Among Survivors in the First 28 Days is Different Among Ganciclovir Recipients Relative to Placebo Recipients.
Outcome Description
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.
Outcome Time Frame
up to 7 days
Outcome Measure
To Evaluate Whether Oxygenation is Different Among Ganciclovir Recipients Relative to Placebo Recipients.
Outcome Description
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.
Outcome Time Frame
up to 28 days
Outcome Measure
To Evaluate Whether ICU-free Days in the First 28 Days Are Different Among Ganciclovir Recipients Relative to Placebo Recipients.
Outcome Description
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.
Outcome Time Frame
up to 28 days
Outcome Measure
To Evaluate Whether CMV DNA Detection in Plasma and Endotracheal Aspirate (ETA) by Day 28 is Different Among Ganciclovir Recipients Relative to Placebo Recipients.
Outcome Description
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.
Outcome Time Frame
up to 28 days
Outcome Measure
To Assess the Number and Severity of Adverse Events and Serious Adverse Events in the First 28 Days in Both Groups.
Start Date
Start Date Type
Actual
Status Verified Date
First Post Date
First Post Date Type
Actual
First Submit Date
First Submit QC Date
Std Ages
Adult
Older Adult
Maximum Age Number (converted to Years and rounded down)
85
Minimum Age Number (converted to Years and rounded down)
18
Investigators
Investigator Type
Principal Investigator
Investigator Name
Michelle Gong
Investigator Email
mgong@montefiore.org
Investigator Phone
718-920-5464
MeSH Terms
GANCICLOVIR
SALINE SOLUTION
ACYCLOVIR
GUANINE
HYPOXANTHINES
PURINONES
PURINES
HETEROCYCLIC COMPOUNDS, 2-RING
HETEROCYCLIC COMPOUNDS, FUSED-RING
HETEROCYCLIC COMPOUNDS
CRYSTALLOID SOLUTIONS
ISOTONIC SOLUTIONS
SOLUTIONS
PHARMACEUTICAL PREPARATIONS