Ganciclovir/Valganciclovir for Prevention of CMV Reactivation in Acute Injury of the Lung and Respiratory Failure
Condition: Acute Lung Injury; Acute Respiratory Distress Syndrome; Respiratory Failure
MeSH terms: Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Respiratory Insufficiency; Acute Lung Injury; Lung Injury; Wounds and Injuries
Intervention: IV Ganciclovir; Placebo
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.; For first 5 days, dosing of intravenous placebo is daily, given every 12 hours. After first 5 days (up to 28 days), IV placebo QD. A minimum interval of 6 hours is required between the first and second dose.
The placebo is an IV solution that does not contain any active medications.
Intervention MeSH terms: Ganciclovir; Ganciclovir triphosphate
Phase: Phase 2
Study type: Interventional
Primary purpose: Prevention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 160.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Acute Lung Injury; Acute Respiratory Distress Syndrome; Respiratory Failure; Cytomegalovirus seropositive; Infection; Intravenous Ganciclovir; Non-immunocompromised; Valganciclovir

Summary:

      To evaluate whether administration of ganciclovir reduces serum IL-6 levels (i.e. reduction
      between baseline and 14 days post-randomization) in immunocompetent adults with severe sepsis
      or trauma associated respiratory failure.

      Primary Hypotheses:

      - In CMV seropositive adults with severe sepsis or trauma , pulmonary and systemic CMV
      reactivation amplifies and perpetuates both lung and systemic inflammation mediated through
      specific cytokines, and contributes to pulmonary injury and multiorgan system failure,

      AND

      - Prevention of CMV reactivation with ganciclovir decreases pulmonary and systemic
      inflammatory cytokines that are important in the pathogenesis of sepsis and trauma related
      complications.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Subject/next of kin informed consent

          2. Age >= 18 years

          3. CMV IgG seropositive. The following tests are acceptable:

               -  FDA licensed test in a local lab approved by the coordinating center (FHCRC,
                  Seattle, WA).

               -  Test in central study lab (ARUP, Salt Lake City, UT)

               -  A report that patient has previously been tested and found to be CMV seropositive
                  at any time (a credible next of kin report is acceptable; confirmatory test will
                  be done but results are not required for randomization)

          4. Intubated and requiring mechanical positive pressure ventilation (including Acute Lung
             Injury/ARDS (EA Consensus Definition))

          5. Meets criteria for either:

               1. Severe sepsis criteria (as defined in appendix G) within a 24-hour time period
                  within the 120 hour window

                  OR

               2. Trauma with respiratory failure and an ISS score > 15 within a 24 hour time
                  period, and within the 120 hour window (where mechanical ventilation is not due
                  solely to a head injury)

          6. On the day of randomization (by local criteria):

               -  Not eligible for SBT (use of sedation and/or vasopressor does not specifically
                  contraindicate SBT),or

               -  Failed SBT

        Exclusion Criteria:

          1. BMI > 60 (1st weight during hospital admission)

          2. 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:

                    -  within 6 months: alemtuzumab, antithymocyte/antilymphocyte antibodies

                    -  within 3 months: immunomodulator therapy (TNF-alpha antagonist, rituximab,
                       tocilizumab, IL1 receptor antagonist and other biologics)

                    -  within 30 days:

                         -  corticosteroids > 10 mg/day (chronic administration, daily average over
                            the time period)

                              -  topical steroids are permissible

                              -  use of hydrocortisone in "stress doses" up to 100 mg four times a
                                 day (400mg/daily) for up to 4 days prior to randomization is
                                 permissible

                              -  use of temporary short-term (up to 2 weeks) increased doses of
                                 systemic steroids (up tp 1 mg/kg) for exacerbation of chronic
                                 conditions are permissible.

                         -  methotrexate (> 10.0 mg/week)

                         -  azathioprine (> 75 mg/day)

             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 D for commonly prescribed immunosuppressive agents.

          3. Expected to survive < 72 hours (in the opinion of the investigator)

          4. 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).

          5. 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.

          6. Absolute neutrophil count < 1,000/mm3 (if no ANC value is available, the WBC must be >
             2500/mm3)

          7. Use of cidofovir within seven (7) days of patient randomization. The use of the
             following antivirals is permitted under the following conditions:

               -  Ganciclovir, foscarnet, high-dose acyclovir, or valacyclovir until the day of
                  randomization

               -  Acyclovir as empiric therapy for central nervous system HSV or VZV infection
                  until the diagnosis can be excluded

               -  For enrolled patients during the active study drug phase, acyclovir, famciclovir,
                  valacyclovir for treatment of HSV or VZV infection as clinically indicated.

          8. 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 (Note: confirm eligibility with one of the study medical
             directors at the coordinating site).

          9. At baseline patients who have both a tracheostomy, and have been on continuous 24-hour
             chronic mechanical ventilation.

         10. Patients with Child Class C Cirrhosis.

         11. Patients with pre-existing interstitial lung disease.