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Ganciclovir/Valganciclovir for Prevention of CMV Reactivation in Acute Injury of the Lung and Respiratory Failure (GRAIL)

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ClinicalTrials.gov Identifier: NCT01335932
Recruitment Status : Completed
First Posted : April 15, 2011
Results First Posted : September 13, 2017
Last Update Posted : August 21, 2018
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
Genentech, Inc.
Information provided by (Responsible Party):
Michael Boeckh, Fred Hutchinson Cancer Research Center

Brief 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.


Condition or disease Intervention/treatment Phase
Acute Lung Injury Acute Respiratory Distress Syndrome Respiratory Failure Drug: IV Ganciclovir Drug: Placebo Phase 2

  Show Detailed Description

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 160 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Official Title: A Randomized Double-Blind Placebo-Controlled Trial of Ganciclovir/Valganciclovir for Prevention of Cytomegalovirus Reactivation in Acute Injury of the Lung and Respiratory Failure (The GRAIL Study)
Actual Study Start Date : March 10, 2011
Actual Primary Completion Date : June 17, 2016
Actual Study Completion Date : October 28, 2016


Arm Intervention/treatment
Experimental: IV Ganciclovir
5mg/kg IV twice daily for 5 days, then followed by either IV ganciclovir or oral valganciclovir 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.

Placebo Comparator: Placebo
normal saline IV twice daily for 5 days, then followed by either IV normal saline or oral placebo once daily until hospital discharge
Drug: Placebo

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.





Primary Outcome Measures :
  1. Serum IL-6 Level [ Time Frame: Baseline and Day 14 ]
    Change between baseline and 14 days post-randomization between placebo & ganciclovir groups


Secondary Outcome Measures :
  1. Number of Participants With CMV Reactivation at 28 Days in Plasma [ Time Frame: at 28 days post-randomization ]
    Number of participants in baseline negatives with CMV reactivation at any level at day 28

  2. BAL Levels of IL-6 [ Time Frame: at 7 days post-randomization ]
    Levels of IL-6 from BALs at 7 days post-randomization

  3. Number of Participants With Organ System Failure at 14 Days [ Time Frame: at 14 days post-randomization ]
    Number of participants experiencing organ system failure at 14 days

  4. Number of Days Alive and Not in the ICU [ Time Frame: by 28 days post-randomization ]
    Number of ICU days alive and not in the ICU by day 28

  5. CMV Disease [ Time Frame: by 180 days post-randomization ]
    Need to be biopsy-proven

  6. Grade 3 AEs or Higher [ Time Frame: by 35 days post-randomization ]
    Number of patients with greater than one AE of grade 3 or more

  7. SF-36 Health Survey [ Time Frame: at 1 day post-randomization ]
    Physical Component Summary of SF-36. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability.

  8. Incidence of CMV Reactivation >1,000 IU Per mL at Day 28 in Plasma [ Time Frame: at 28 days post-randomization ]
    Number of participants with CMV reactivation >1,000 IU per mL at day 28 in plasma

  9. Incidence of CMV Reactivation at Any Level at 28 Days in Throat [ Time Frame: at 28 days post-randomization ]
    CMV reactivation in baseline negatives at any level at day 28 in throat

  10. Incidence of CMV Reactivation >1,000 IU Per mL at 28 Days in Throat [ Time Frame: at 28 days post-randomization ]
    Number of participants with CMV reactivation >1,000 IU per mL at day 28 in throat

  11. CMV AUC in Blood [ Time Frame: Day 0 to 28 days post-randomization ]
    CMV AUC in blood from day 0 to day 28

  12. CMV AUC in Throat [ Time Frame: Day 0 to 28 days post-randomization ]
    CMV AUC in Throat from day 0 to day 28

  13. CMV Peak Viral Load in Blood [ Time Frame: at 28 days post-randomization ]
    CMV Peak Viremia in blood at day 28

  14. BAL Levels of IL-8 [ Time Frame: at 7 days post-randomization ]
    Levels of IL-8 in BALs at day 7

  15. BAL Levels of TNFa [ Time Frame: at 7 days post-randomization ]
    Levels of TNFa in BALs at day 7

  16. Plasma Levels of IL-6 [ Time Frame: at 7 days post-randomization ]
    Plasma levels of IL-6.

  17. Plasma Levels of IL-8 [ Time Frame: at 7 days post-randomization ]
    Levels of IL-8 in plasma at day 7

  18. Plasma Levels of TNF a [ Time Frame: at 7 days post-randomization ]
    Plasma levels of TNF a at day 7.Cytokines are summarized on log 10 scale. When logged value is negative, the raw value would be less than 1.

  19. Plasma Levels of TNF a [ Time Frame: Day 0 to 28 days post-randomization ]
    Plasma levels of TNF a from day 0 to day 28

  20. Plasma Levels of IL-6 [ Time Frame: at 28 days post-randomization ]
    Plasma levels of IL-6 at day 28

  21. Plasma Levels of IL-8 [ Time Frame: at 28 days post-randomization ]
    Plasma levels of IL-8 at day 28

  22. Plasma Levels of Soluble ICAM-1 [ Time Frame: at 28 days post-randomization ]
    Plasma levels of soluble ICAM-1 at day 28

  23. Plasma Levels of Soluble ICAM-1 [ Time Frame: at 7 days post-randomization ]
    Plasma levels of soluble ICAM-1 at day 7

  24. Peak Plasma Levels of Soluble ICAM-1 [ Time Frame: Day 0 to 28 days post-randomization ]
    Peak Plasma levels of soluble ICAM-1 from day 0 to day 28

  25. Peak Plasma Levels of TNF-a [ Time Frame: at 28 days post-randomization ]
    Peak Plasma levels of TNF-a at day 28

  26. Peak Plasma Levels of IL-10 [ Time Frame: at 28 days post-randomization ]
    Peak Plasma levels of IL-10 at day 28

  27. Peak Plasma Levels of IL-8 [ Time Frame: at 28 days post-randomization ]
    Peak Plasma levels of IL-8 at day 28

  28. Peak Plasma Levels of IL-6 [ Time Frame: at 28 days post-randomization ]
    Peak Plasma levels of IL-6 at day 28

  29. AUC Plasma Levels of IL-6 [ Time Frame: Day 0 to 28 days post-randomization ]
    AUC Plasma levels of IL-6 from day 0 to day 28

  30. AUC Plasma Levels of IL-8 [ Time Frame: Day 0 to 28 days post-randomization ]
    AUC Plasma levels of IL-8 from day 0 to day 28

  31. AUC Plasma Levels of IL-10 [ Time Frame: at 28 days post-randomization ]
    AUC Plasma levels of IL-10 from day 0 to day 28

  32. AUC Plasma Levels of TNF-a [ Time Frame: at 28 days post-randomization ]
    AUC Plasma levels of TNF-a from day 0 to day 28

  33. AUC Plasma Levels of Soluble ICAM-1 [ Time Frame: at 28 days post-randomization ]
    AUC Plasma levels of soluble ICAM-1 from day 0 to day 28

  34. Length of Stay [ Time Frame: by 180 days post-randomization ]
    Hospital days alive and not hospitalized by day 180

  35. Length of Stay [ Time Frame: by 28 days post-randomization ]
    Hospital days alive and not hospitalized by day 28

  36. Organ System Failure at 28 Days [ Time Frame: at 28 days post-randomization ]
    Number of participants with organ system failure at 28 days

  37. Duration of Mechanical Ventilation as Assessed by Ventilator Free Days [ Time Frame: at 28 days post-randomization ]
    Number of days of mechanical ventilation duration as assessed by ventilator free days

  38. Duration of Mechanical Ventilation as Assessed by Ventilator Days [ Time Frame: at 28 days post-randomization ]
    Number of days of mechanical ventilation duration as assessed by ventilator days

  39. Bacteremia and/or Fungemia [ Time Frame: at 28 days post-randomization ]
    Number of participants with bacteremia and/or fungemia

  40. Mortality [ Time Frame: at 60 days post-randomization ]
    Mortality at 60 days post randomization

  41. Mortality at 180 Days [ Time Frame: at 180 days post-randomization ]
    Mortality at 180 days post-randomization

  42. SF-36 Functional Assessment Physical Component [ Time Frame: at 180 days post-randomization ]
    Physical Component Summary at 180 days post- randomization. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability

  43. SF-36 Functional Assessment Mental Component [ Time Frame: at 180 days post-randomization ]
    Mental Component Summary at 180 days post-randomization. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability

  44. SF-36 Functional Assessment Mental Component on Day 1 [ Time Frame: at 1 day post-randomization ]
    SF-36 Mental Component Summary at 1 day post-randomization. The SF-36 consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability

  45. Patients With Serious Adverse Events [ Time Frame: by 35 days post-randomization ]
    Number of patients with Serious Adverse Events by day 35

  46. Time to Neutropenia [ Time Frame: by 35 days post-randomization ]
    Time to neutropenia by 35 days post-randomization

  47. Use of Granulocyte-colony Stimulating Factor [ Time Frame: by 35 days post-randomization ]
    Number of participants requiring Granulocyte-colony stimulating factor

  48. Renal Insufficiency [ Time Frame: by 35 days post-randomization ]
    Number of patients experiencing a glomerular filtration rate < 60mL/min at day 35

  49. Red Blood Cell Transfusions Required Per Patients [ Time Frame: by 35 days post-randomization ]
    Red blood cell transfusions required per patients by day 35

  50. Platelet Transfusions [ Time Frame: by 35 days post-randomization ]
    Platelet transfusions per patient

  51. Clinical Outcomes [ Time Frame: at 14 days post-randomization ]
    Composite of survival status and >7 days ventilation status, and IL-6 levels. In the composite analysis, the endpoint is composed by death, ventilation status and change of cytokine.

  52. Bacteremia and Fungemia Outcomes [ Time Frame: at 7 days post-randomization ]
    Bacteremia and fungemia outcomes among subjects who survive at least 7 days

  53. Bacteremia and Fungemia Outcomes in Mechanically Ventilated Subjets [ Time Frame: at 7 through 14 days post-randomization ]
    Bacteremia and fungemia events among subjects who are mechanically ventilated for at least 7 through 14 days after randomization

  54. Overall Mortality [ Time Frame: at 7 days post-randomization ]
    Overall mortality amongst subjects who survive at least 7 days after randomization

  55. Number of Mechanical Ventilated Days [ Time Frame: at 7 days post-randomization ]
    Number of mechanical ventilated days amongst subjects who survive at least 7 days after randomization

  56. Number of Ventilator-free Days [ Time Frame: at 7 days post-randomization ]
    Number of ventilator-free days amongst subjects who survive at least 7 days after randomization

  57. Number of Days in the ICU [ Time Frame: at 7 days post-randomization ]
    Number of days in the ICU amongst subjects who survive at least 7 days after randomization

  58. Number of ICU-free Days [ Time Frame: at 7 days post-randomization ]
    Number of ICU-free days amongst subjects who survive at least 7 days after randomization

  59. Number of Days in the Hospital [ Time Frame: at 7 days post-randomization ]
    Number of days in the hospital amongst subjects who survive at least 7 days after randomization

  60. Number of Hospital-free Days [ Time Frame: at 7 days post-randomization ]
    Number of hospital-free days amongst subjects who survive at least 7 days after randomization

  61. Mortality Among Subjects Mechanically Ventilated From Day 7 to 14 [ Time Frame: 28 days ]
    Mortality among subjects by day 28 who are mechanically ventilated for at least 7 through 14 days after randomization

  62. Number of Mechanically Ventilated Days Among Subjects by Day 28 [ Time Frame: 28 days ]
    Number of mechanically ventilated days among subjects by day 28 who are mechanically ventilated for at least 7 through 14 days after randomization

  63. Number of Ventilator-free Days Among Subjects by Day 28 [ Time Frame: 28 days ]
    Number of ventilator-free days among subjects by day 28 who are mechanically ventilated for at least 7 through 14 days after randomization

  64. Number of Days in ICU Amongst Subjects by Day 28 [ Time Frame: 28 days ]
    Number of days in ICU amongst subjects by day 28 who are mechanically ventilated for at least 7 through 14 days after randomization

  65. Number of ICU-free Days Amongst Subjects by Day 28 [ Time Frame: 28 days ]
    Number of ICU-free days amongst subjects by day 28 who are mechanically ventilated for at least 7 through 14 days after randomization

  66. Number of Hospital-free Days Among Subjects by Day 28 [ Time Frame: 28 days ]
    Number of hospital-free days among subjects by day 28 who are mechanically ventilated for at least 7 through 14 days after randomization



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

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): NCT01335932


Locations
United States, Colorado
University of Colorado / National Jewish Health / Swedish Medical Center
Denver, Colorado, United States, 80206
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
United States, Massachusetts
Baystate Critical Care Medicine / Tufts University School of Medicine
Springfield, Massachusetts, United States, 01199
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109-5360
United States, North Carolina
Wakeforest University, School of Medicine
Winston-Salem, North Carolina, United States, 27157
United States, Ohio
The Cleveland Clinic Foundation
Cleveland, Ohio, United States, 44195
Ohio State University Medical Center
Columbus, Ohio, United States, 43210
United States, Oregon
The Oregon Clinic
Portland, Oregon, United States, 97220
United States, Pennsylvania
University of Pennsylvania Medical Center
Philadelphia, Pennsylvania, United States, 19104-6160
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States, 15261
United States, Vermont
University of Vermont College of Medicine
Burlington, Vermont, United States, 05405
United States, Virginia
University of Virginia
Charlottesville, Virginia, United States, 22908-0546
United States, Washington
Harborview Medical Center
Seattle, Washington, United States, 98104
University of Washington Medical Center / Harborview Medical Center
Seattle, Washington, United States, 98195
Sponsors and Collaborators
Fred Hutchinson Cancer Research Center
National Heart, Lung, and Blood Institute (NHLBI)
Genentech, Inc.
Investigators
Principal Investigator: Michael Boeckh, MD Fred Hutchinson Cancer Research Center
Principal Investigator: Ajit Limaye, MD University of Washington
Study Director: Louise Kimball, PhD, RN Fred Hutchinson Cancer Research Center

Publications of Results:
Responsible Party: Michael Boeckh, Principal Investigator, Fred Hutchinson Cancer Research Center
ClinicalTrials.gov Identifier: NCT01335932     History of Changes
Other Study ID Numbers: 7217
U01HL102547 ( U.S. NIH Grant/Contract )
First Posted: April 15, 2011    Key Record Dates
Results First Posted: September 13, 2017
Last Update Posted: August 21, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by Michael Boeckh, Fred Hutchinson Cancer Research Center:
Acute Lung Injury
Acute Respiratory Distress Syndrome
Respiratory Failure
Cytomegalovirus seropositive
Infection
Intravenous Ganciclovir
Non-immunocompromised
Valganciclovir

Additional relevant MeSH terms:
Wounds and Injuries
Respiratory Distress Syndrome, Newborn
Respiratory Distress Syndrome, Adult
Respiratory Insufficiency
Acute Lung Injury
Lung Injury
Lung Diseases
Respiratory Tract Diseases
Respiration Disorders
Infant, Premature, Diseases
Infant, Newborn, Diseases
Thoracic Injuries
Ganciclovir
Valganciclovir
Ganciclovir triphosphate
Antiviral Agents
Anti-Infective Agents
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action