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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
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

Tracking Information
First Submitted Date  ICMJE April 13, 2011
First Posted Date  ICMJE April 15, 2011
Results First Submitted Date  ICMJE June 21, 2017
Results First Posted Date  ICMJE September 13, 2017
Last Update Posted Date August 21, 2018
Actual Study Start Date  ICMJE March 10, 2011
Actual Primary Completion Date June 17, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 15, 2017)
Serum IL-6 Level [ Time Frame: Baseline and Day 14 ]
Change between baseline and 14 days post-randomization between placebo & ganciclovir groups
Original Primary Outcome Measures  ICMJE
 (submitted: April 14, 2011)
Serum IL-6 Level [ Time Frame: at 14 days post-randomization ]
Change between baseline and 14 days post-randomization between placebo & ganciclovir groups
Change History Complete list of historical versions of study NCT01335932 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 24, 2018)
  • 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
  • BAL Levels of IL-6 [ Time Frame: at 7 days post-randomization ]
    Levels of IL-6 from BALs at 7 days post-randomization
  • 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
  • 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
  • CMV Disease [ Time Frame: by 180 days post-randomization ]
    Need to be biopsy-proven
  • 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
  • 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.
  • 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
  • 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
  • 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
  • CMV AUC in Blood [ Time Frame: Day 0 to 28 days post-randomization ]
    CMV AUC in blood from day 0 to day 28
  • CMV AUC in Throat [ Time Frame: Day 0 to 28 days post-randomization ]
    CMV AUC in Throat from day 0 to day 28
  • CMV Peak Viral Load in Blood [ Time Frame: at 28 days post-randomization ]
    CMV Peak Viremia in blood at day 28
  • BAL Levels of IL-8 [ Time Frame: at 7 days post-randomization ]
    Levels of IL-8 in BALs at day 7
  • BAL Levels of TNFa [ Time Frame: at 7 days post-randomization ]
    Levels of TNFa in BALs at day 7
  • Plasma Levels of IL-6 [ Time Frame: at 7 days post-randomization ]
    Plasma levels of IL-6.
  • Plasma Levels of IL-8 [ Time Frame: at 7 days post-randomization ]
    Levels of IL-8 in plasma at day 7
  • 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.
  • 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
  • Plasma Levels of IL-6 [ Time Frame: at 28 days post-randomization ]
    Plasma levels of IL-6 at day 28
  • Plasma Levels of IL-8 [ Time Frame: at 28 days post-randomization ]
    Plasma levels of IL-8 at day 28
  • Plasma Levels of Soluble ICAM-1 [ Time Frame: at 28 days post-randomization ]
    Plasma levels of soluble ICAM-1 at day 28
  • Plasma Levels of Soluble ICAM-1 [ Time Frame: at 7 days post-randomization ]
    Plasma levels of soluble ICAM-1 at day 7
  • 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
  • Peak Plasma Levels of TNF-a [ Time Frame: at 28 days post-randomization ]
    Peak Plasma levels of TNF-a at day 28
  • Peak Plasma Levels of IL-10 [ Time Frame: at 28 days post-randomization ]
    Peak Plasma levels of IL-10 at day 28
  • Peak Plasma Levels of IL-8 [ Time Frame: at 28 days post-randomization ]
    Peak Plasma levels of IL-8 at day 28
  • Peak Plasma Levels of IL-6 [ Time Frame: at 28 days post-randomization ]
    Peak Plasma levels of IL-6 at day 28
  • 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
  • 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
  • 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
  • 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
  • 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
  • Length of Stay [ Time Frame: by 180 days post-randomization ]
    Hospital days alive and not hospitalized by day 180
  • Length of Stay [ Time Frame: by 28 days post-randomization ]
    Hospital days alive and not hospitalized by day 28
  • Organ System Failure at 28 Days [ Time Frame: at 28 days post-randomization ]
    Number of participants with organ system failure at 28 days
  • 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
  • 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
  • Bacteremia and/or Fungemia [ Time Frame: at 28 days post-randomization ]
    Number of participants with bacteremia and/or fungemia
  • Mortality [ Time Frame: at 60 days post-randomization ]
    Mortality at 60 days post randomization
  • Mortality at 180 Days [ Time Frame: at 180 days post-randomization ]
    Mortality at 180 days post-randomization
  • 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
  • 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
  • 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
  • Patients With Serious Adverse Events [ Time Frame: by 35 days post-randomization ]
    Number of patients with Serious Adverse Events by day 35
  • Time to Neutropenia [ Time Frame: by 35 days post-randomization ]
    Time to neutropenia by 35 days post-randomization
  • Use of Granulocyte-colony Stimulating Factor [ Time Frame: by 35 days post-randomization ]
    Number of participants requiring Granulocyte-colony stimulating factor
  • Renal Insufficiency [ Time Frame: by 35 days post-randomization ]
    Number of patients experiencing a glomerular filtration rate < 60mL/min at day 35
  • Red Blood Cell Transfusions Required Per Patients [ Time Frame: by 35 days post-randomization ]
    Red blood cell transfusions required per patients by day 35
  • Platelet Transfusions [ Time Frame: by 35 days post-randomization ]
    Platelet transfusions per patient
  • 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.
  • Bacteremia and Fungemia Outcomes [ Time Frame: at 7 days post-randomization ]
    Bacteremia and fungemia outcomes among subjects who survive at least 7 days
  • 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
  • Overall Mortality [ Time Frame: at 7 days post-randomization ]
    Overall mortality amongst subjects who survive at least 7 days after randomization
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: April 14, 2011)
  • Incidence of CMV reactivation at 28 days (blood, throat, BAL) [ Time Frame: at 28 days post-randomization ]
    The following virologic parameters will be compared between the groups:
    • Time to CMV reactivation at any level
    • Time to > 1,000 copies per mL
    • Time to > 10,000 copies per mL
    • Area under the curve
    • Peak viral load
    • Initial viral load
  • Additional Cytokine Levels [ Time Frame: at 7 and 28 days post-randomization ]
    Additional cytokines with proven association with ALI and CMV will be compared between the groups.
    • BAL levels of IL-6, IL-8, TNF-alpha & TGF-β
    • Plasma IL-6, IL-8, IL-10, TNF-alpha & soluble ICAM-1
    Cytokines will be analyzed at each time point and over time (area under the curve), and peak levels will be compared between randomization and Day 28 (end of treatment).
  • Clinical Outcomes [ Time Frame: at 7, 14, 28, 60, and 180 days post-randomization ]
    • Organ system failure at 14 and 28 days
    • Duration of mechanical ventilation (as assessed by ventilator days and ventilator-free days alive)
    • Lung injury score
    • Bacteremia and/or fungemia
    • Mortality at 60 and 180 days after randomization
    • Composite of survival status, ventilation status, and IL-6 levels
    • Subset analysis of laboratory and clinical outcomes amongst subjects who survive at least 7 days after randomization
    • Subset analysis of laboratory and clinical outcomes amongst subjects who are mechanically ventilated for at least 7 through 14 days after randomization
  • Length of Stay [ Time Frame: by 28 and 180 days post-randomization ]
    • ICU (days alive and not in the ICU by day 28)
    • Hospital (days alive and not hospitalized by day 28 and 180)
  • CMV Disease [ Time Frame: by 180 days post-randomization ]
    Need to be biopsy-proven
  • Safety [ Time Frame: by 35 days post-randomization ]
    • Number and severity of AEs and SAEs as defined in the Adverse Event section of the protocol
    • Time to neutropenia (absolute neutrophil count [ANC] < 1000, <500 per mm3)
    • Use of G-CSF
    • Time to renal insufficiency (creatinine clearance < 60, < 30 ml/min)
    • Time to thrombocytopenia (platelet count < 50,000, < 20,000 per mm3)
    • Number of red cell and platelets products between randomization and day 35 after randomization
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Ganciclovir/Valganciclovir for Prevention of CMV Reactivation in Acute Injury of the Lung and Respiratory Failure
Official Title  ICMJE 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)
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.

Detailed Description

Critical illness due to severe sepsis and trauma are major causes of morbidity and mortality, and a substantial economic burden in the United States and worldwide. Despite advances in clinical care, patients with sepsis and trauma-associated respiratory failure represent specific populations with high rates of adverse outcomes. The etiology of respiratory failure in patients with severe sepsis and trauma is multifactorial, but acute lung injury (ALI) is one of the leading causes, and is associated with prolonged ICU and hospital stays, mortality, and long-term sequelae. Other than general supportive care, few specific interventions other than lung protective ventilation have been shown to improve outcomes in such patients. New approaches for understanding the pathogenesis and developing better therapies are urgently needed.

Acute Lung Injury (ALI) is a syndrome consisting of acute hypoxemic respiratory failure with bilateral pulmonary infiltrates that is associated with both pulmonary and nonpulmonary risk factors (eg. sepsis, trauma) and that is not due primarily to left atrial hypertension. Although a distinction between ALI and a more severe subtype (termed acute respiratory distress syndrome (ARDS) has been made, the pathogenesis, risk factors, and outcomes appear to be similar and for the purposes of this protocol, the term acute lung injury [ALI] will be used to encompass both entities. Accepted consensus definitions of ALI have been introduced and are now widely used for laboratory and clinical investigations of ALI. Acute Lung Injury (ALI) is defined as:

  • PaO2/FiO2 <300
  • Bilateral pulmonary infiltrates on chest x-ray
  • Pulmonary Capillary Wedge Pressure <18mmHg or no clinical evidence of increased left atrial pressure Although a broad range of risk factors for ALI have been described, those that account for the majority of cases include: sepsis, pneumonia, trauma, and aspiration. It is well established that severe trauma is recognized as a precipitating cause of ALI. Recent studies have demonstrated that the incidence of acute lung injury (ALI) is much higher than previously thought, with an estimated age-adjusted incidence of 86 per 100,000 persons per year, resulting in an estimated ~190,000 cases annually in the US. The clinical and health care system impact of ALI is substantial, with an estimated 2,154,000 intensive care unit (ICU) days, 3,622,000 hospital days, and 75,000 deaths in 2000, and is expected to grow significantly given the marked age-related incidence and the aging population. Although general improvements in ICU care over the last 2 decades have led to a trend towards lower mortality due to certain ALI-associated risk factors (trauma, aspiration), the most common causes of ALI, sepsis and pneumonia, remain associated with high mortality rates of ~25-35%. Mortality in ALI is most commonly due to secondary infections/sepsis and multiorgan system failure rather than primary respiratory failure due to hypoxemia, highlighting the systemic nature of ALI. Even among initial survivors of ALI, substantial pulmonary and nonpulmonary functional impairment remains for months to years. Specifically, a proportion of those who survive the initial insult are at risk for prolonged mechanical ventilation and ICU/hospital stay, and the risk factors remain poorly defined. It has been hypothesized that a "2nd hit" may predispose certain patients to greater morbidity in this setting. Despite intensive basic and clinical investigation, only a single intervention (low-tidal volume ["lung protective"] ventilation) is generally accepted to decrease mortality in ALI, while multiple other strategies have failed to improve survival either in early clinical studies or definitive efficacy trials. Thus, given the high incidence and continued substantial clinical impact of ALI despite improvements in general medical/ICU care, and limited proven options other than lung-protective ventilation, new approaches to understanding the pathophysiology and identifying novel targets for intervention in ALI are a high priority.

Overly intense, persistent and dysregulated pulmonary and systemic inflammation has emerged as the leading hypothesis for the pathogenesis of ALI and its complications, but the contributory factors and mechanisms are incompletely defined. Several carefully-conducted prospective human studies have shown an association between specific inflammatory biomarkers in blood and BALF (both the initial levels at onset and changes over time) and important clinical outcomes in ALI. [Animal models have also demonstrated an association between inflammatory cytokines and non-pulmonary organ injury and dysfunction] In addition, one of the most important interventions (low-tidal volume ["lung protective"] ventilation) shown to decrease mortality in ALI is associated with reductions in inflammatory cytokines (IL-6, IL-8) in blood and bronchoalveolar lavage fluid [BALF].

Cytomegalovirus (CMV) is a ubiquitous virus in humans worldwide, and has been linked to adverse clinical outcomes including prolongation of mechanical ventilation, increased length of stay, and mortality in multiple studies of critically-ill, apparently immunocompetent, seropositive adults.

Cytomegalovirus (CMV) is a human herpes virus known to infect more than 50-90% of US adults and is known to be a major cause of morbidity and mortality in immunocompromised patients. CMV infection can be acquired through multiple means, including: mother-to-child (in utero, breast milk), infected body fluids (saliva, genital secretions), blood transfusion or organ transplant. The prevalence of CMV infection increases with age throughout life such that by age 90, ~90% of persons will have acquired CMV infection. In immunocompetent persons, following primary infection by any of the routes noted above, CMV is controlled by the immune system and establishes latency ("dormancy") in multiple organs/cell-types for the life of the host. In particular, the lung represents one of the largest reservoirs of latent CMV in seropositive hosts, and may explain the propensity for CMV-associated pulmonary disease in predisposed hosts. During periods of immunosuppression (or as a result of specific stimuli such as TNF-α, LPS, or catecholamines that are commonly associated with critical illness & sepsis [CMV can reactivate from latency (preferentially in the lung) to produce active infection (viral replication). In persons with impaired cellular immunity, reactivation can progress to high-grade CMV replication and commonly leads to tissue injury and clinically-evident disease such as CMV pneumonia. Lower-grade CMV reactivation that is otherwise clinically silent ("subclinical") can also be detected in apparently immunocompetent persons with critical illness using sensitive techniques such as PCR. In addition, even low-level, otherwise asymptomatic subclinical CMV reactivation can produce significant biologic effects both in vitro and in vivo, such as inflammation, fibrosis and immunosuppression. Each of these biologic effects of subclinical CMV infection has either previously been demonstrated (inflammation, fibrosis) or could theoretically be important (immunosuppression) in sepsis-associated ALI and its complications. These biological effects of CMV have been shown to occur through various mediators and other indirect means [Importantly, several important CMV-associated adverse clinical outcomes in transplant populations [allograft rejection, secondary infections] are not necessarily accompanied by overt CMV disease and can only be detected by relatively sensitive means of virus detection such as PCR.

Reactivation of CMV in apparently immunocompetent patients with critical illness due to a broad range of causes has been documented in multiple prior studies using a variety of virologic techniques. The specific triggers for CMV reactivation from latency have been identified and are known to be elevated in patients with sepsis and acute lung injury [A prospective study in intubated patients with sepsis from Germany reported more than 60% rate of CMV DNA detection in tracheal aspirates.

In addition to CMV reactivation in sepsis, CMV reactivation has also been demonstrated specifically in lung and blood of patients with acute lung injury.

Retrospectively testing samples collected in a prospective observational cohort study of patients at risk of developing ARDS, CMV reactivation (ie. CMV DNA by PCR) was detected in BALF and/or plasma of 2/5 [40%] of subjects who developed ARDS, in sequential samples from 7/20 [35%] patients with ARDS, but not in patients at risk but who did not develop ARDS (0/5) [Limaye 2009 unpublished data]. In a separate study, CMV reactivation was retrospectively assessed by PCR in BALF of 88 subjects enrolled in a randomized trial of fish oil for treatment of ALI. Seropositivity at baseline (ie. evidence of latent CMV infection) in the cohort was 65% (similar to prior age-related estimates), and CMV reactivation (ie. CMV DNA by PCR) was detected in BALF of 12/57 [21%] patients [Limaye unpublished data 2009].

Several lines of evidence have linked CMV reactivation with adverse clinical outcomes in non-immunosuppressed adults with critical illness. In a recent meta-analysis, CMV reactivation (compared to no reactivation) was associated with a 2-fold increased odds of mortality in ICU patients.

In addition to mortality, recent studies have demonstrated a strong and independent association between CMV reactivation and increased hospital and ICU length of stay and duration of mechanical ventilation.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Prevention
Condition  ICMJE
  • Acute Lung Injury
  • Acute Respiratory Distress Syndrome
  • Respiratory Failure
Intervention  ICMJE
  • 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.
  • 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.

Study Arms  ICMJE
  • 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
    Intervention: Drug: IV Ganciclovir
  • 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
    Intervention: Drug: Placebo
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 14, 2011)
160
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE October 28, 2016
Actual Primary Completion Date June 17, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries Canada
 
Administrative Information
NCT Number  ICMJE NCT01335932
Other Study ID Numbers  ICMJE 7217
U01HL102547 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Michael Boeckh, Fred Hutchinson Cancer Research Center
Study Sponsor  ICMJE Fred Hutchinson Cancer Research Center
Collaborators  ICMJE
  • National Heart, Lung, and Blood Institute (NHLBI)
  • Genentech, Inc.
Investigators  ICMJE
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
PRS Account Fred Hutchinson Cancer Research Center
Verification Date July 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP