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

• 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: Fred Hutchinson Cancer Research Center
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Genentech, Inc.
• Information provided by (Responsible Party): Michael Boeckh, Fred Hutchinson Cancer Research Center

Study Description

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 Design

• 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

Arms and Interventions

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.

Outcome Measures

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

Eligibility Criteria

• 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.

Contacts and Locations

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

More Information

Publications of Results:

Limaye AP, Stapleton RD, Peng L, Gunn SR, Kimball LE, Hyzy R, Exline MC, Files DC, Morris PE, Frankel SK, Mikkelsen ME, Hite D, Enfield KB, Steingrub J, O'Brien J, Parsons PE, Cuschieri J, Wunderink RG, Hotchkin DL, Chen YQ, Rubenfeld GD, Boeckh M. Effect of Ganciclovir on IL-6 Levels Among Cytomegalovirus-Seropositive Adults With Critical Illness: A Randomized Clinical Trial. JAMA. 2017 Aug 22;318(8):731-740. doi: 10.1001/jama.2017.10569.

• 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
• 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:

Respiratory Distress Syndrome, Newborn; Respiratory Distress Syndrome, Adult; Respiratory Insufficiency; Acute Lung Injury; Lung Injury; Wounds and Injuries; 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