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

NCT01335932 | Completed Phase 2 Results DMC

• 2 other identifiers: 7217U01HL102547
• Study Type: interventional
• Target: 160
• Locations: 1 country
• Sites: 14

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.

Conditions

Acute Lung Injury; Acute Respiratory Distress Syndrome; Respiratory Failure

Keywords

Acute Lung Injury; Acute Respiratory Distress Syndrome; Respiratory Failure; Cytomegalovirus seropositive; Infection; Intravenous Ganciclovir; Non-immunocompromised; Valganciclovir

Outcome Measures

Primary Outcomes (1)

• Serum IL-6 Level

  Change between baseline and 14 days post-randomization between placebo \& ganciclovir groups

  Baseline and Day 14

Secondary Outcomes (66)

• Number of Participants With CMV Reactivation at 28 Days in Plasma

  at 28 days post-randomization

• BAL Levels of IL-6

  at 7 days post-randomization

• Number of Participants With Organ System Failure at 14 Days

  at 14 days post-randomization

• Number of Days Alive and Not in the ICU

  by 28 days post-randomization

• CMV Disease

  by 180 days post-randomization

Study Arms (2)

IV Ganciclovir

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

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

Interventions

IV Ganciclovir DRUG

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.

IV Ganciclovir

Placebo DRUG

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.

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subject/next of kin informed consent
• Age \>= 18 years
• 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)
• Intubated and requiring mechanical positive pressure ventilation (including Acute Lung Injury/ARDS (EA Consensus Definition))
• Meets criteria for either:
• Severe sepsis criteria (as defined in appendix G) within a 24-hour time period within the 120 hour window
• 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)
• 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

You may not qualify if:

• BMI \> 60 (1st weight during hospital admission)
• 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:

Sponsors & Collaborators

• Fred Hutchinson Cancer Center: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator
• Genentech, Inc.: collaborator

Study Sites (14)

University of Colorado / National Jewish Health / Swedish Medical Center

Denver, Colorado, 80206, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Baystate Critical Care Medicine / Tufts University School of Medicine

Springfield, Massachusetts, 01199, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109-5360, United States

Location

Wakeforest University, School of Medicine

Winston-Salem, North Carolina, 27157, United States

Location

The Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

Ohio State University Medical Center

Columbus, Ohio, 43210, United States

Location

The Oregon Clinic

Portland, Oregon, 97220, United States

Location

University of Pennsylvania Medical Center

Philadelphia, Pennsylvania, 19104-6160, United States

Location

University of Pittsburgh Medical Center

Pittsburgh, Pennsylvania, 15261, United States

Location

University of Vermont College of Medicine

Burlington, Vermont, 05405, United States

Location

University of Virginia

Charlottesville, Virginia, 22908-0546, United States

Location

Harborview Medical Center

Seattle, Washington, 98104, United States

Location

University of Washington Medical Center / Harborview Medical Center

Seattle, Washington, 98195, United States

Location

Related Publications (1)

• 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.

  PMID: 28829877 RESULT

MeSH Terms

Conditions

Acute Lung Injury; Respiratory Distress Syndrome; Respiratory Insufficiency; Infections

Interventions

Ganciclovir

Condition Hierarchy (Ancestors)

Lung Injury; Lung Diseases; Respiratory Tract Diseases; Respiration Disorders

Intervention Hierarchy (Ancestors)

Acyclovir; Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

Inclusion of too few trauma patients to assess treatment effects, a long enrollment window length, discontinuation of BAL sampling due to feasibility and changes in oral drug availability (later part of the study)

Results Point of Contact

• Title: Dr.Michael Boeckh
• Organization: FHCRC

mboeckh@fredhutch.org

206 667-6706

Study Officials

• Michael Boeckh, MD

  Fred Hutchinson Cancer Center

  PRINCIPAL INVESTIGATOR

• Ajit Limaye, MD

  University of Washington

  PRINCIPAL INVESTIGATOR

• Louise Kimball, PhD, RN

  Fred Hutchinson Cancer Center

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: April 13, 2011
• First Posted: April 15, 2011
• Study Start: March 10, 2011
• Primary Completion: June 17, 2016
• Study Completion: October 28, 2016
• Last Updated: August 21, 2018
• Results First Posted: September 13, 2017

Record last verified: 2018-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (14)