A Randomized Trial of GM-CSF in Patients With ALI/ARDS - Full Text View

Sponsors and Collaborators:	National Heart, Lung, and Blood Institute (NHLBI) University of Michigan Emory University University of Colorado at Denver and Health Sciences Center
Information provided by:	National Heart, Lung, and Blood Institute (NHLBI)
ClinicalTrials.gov Identifier:	NCT00201409

Purpose

This study will test the hypothesis that administration of granulocyte-macrophage colony stimulating factor (GM-CSF) to patients with acute lung injury/acute respiratory distress syndrome (ALI/ARDS) will improve the clinical course and outcome by shortening the duration of mechanical ventilation for these patients.

Condition	Intervention	Phase
Respiratory Distress Syndrome, Adult	Drug: Placebo Drug: GM-CSF	Phase II

Drug Information available for: Granulocyte-macrophage colony-stimulating factor Sargramostim

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study
Official Title:	A Randomized Trial of GM-CSF in Patients With ALI/ARDS

Further study details as provided by National Heart, Lung, and Blood Institute (NHLBI):

Primary Outcome Measures:

Ventilator-free days during Days 1-28 [ Time Frame: Measured at Day 28 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Lung epithelial cell integrity [ Time Frame: Measured at Day 28 ] [ Designated as safety issue: No ]
Alveolar macrophage function [ Time Frame: Measured at Day 28 ] [ Designated as safety issue: No ]
Changes in severity of physiologic derangements of respiratory gas exchange [ Time Frame: Measured at Day 28 ] [ Designated as safety issue: Yes ]
Non-respiratory organ failure [ Time Frame: Measured at Day 28 ] [ Designated as safety issue: Yes ]
Incidence of ventilator-associated pneumonia [ Time Frame: Measured at Day 28 ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	200
Study Start Date:	July 2004
Estimated Study Completion Date:	July 2009
Estimated Primary Completion Date:	May 2009 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental Participants will be randomized to receive recombinant human GM-CSF (250 mcg/M2).	Drug: GM-CSF Recombinant human GM-CSF (250 mcg/M2) will be administered by slow intravenous infusion once daily for 14 days.
2: Placebo Comparator Participants will be randomized to receive placebo.	Drug: Placebo Placebo will be administered by slow intravenous infusion once daily for 14 days.

Detailed Description:

BACKGROUND:

Respiratory failure due to ALI/ARDS remains a major health problem, despite significant progress in intensive care unit care and ventilator management. ALI/ARDS is characterized by unacceptably high mortality despite enormous expenditure of health care resources. Survivors face long-term consequences that may affect their quality of life. New therapies are needed to improve early survival and to decrease long-term sequelae of this syndrome. GM-CSF is a naturally occurring cytokine that is present in the normal lung, with important roles in pulmonary homeostasis. GM-CSF is essential for normal maturation and function of alveolar macrophages (resident inflammatory cells that are responsible for initial defense against pneumonia).

Alveolar epithelial cells line the gas exchange surface of the lung. Acute lung injury and subsequent abnormal healing is linked to delayed repair of damage to the epithelium following initial injury. This can then lead to pulmonary fibrosis. GM-CSF has potent effects on alveolar epithelial cells, promoting proliferation and limiting epithelial cell death. Thus, GM-CSF has a distinctive combination of activities that make it an excellent candidate for a therapeutic intervention in ALI/ARDS. Preliminary studies for this project demonstrate that GM-CSF can protect experimental animals against acute lung injury, can decrease susceptibility to pneumonia, and is protective against pulmonary fibrosis following acute lung injury. There is extensive experience with the administration of recombinant human GM-CSF to human patients (this biological is approved by the FDA and has been well-tolerated in trials involving critically ill patients). This project is based on the hypothesis that administration of GM-CSF will improve clinical outcomes for patients with ALI/ARDS.

DESIGN NARRATIVE:

With the assent of the attending physician, informed consent will be obtained from the patient or next of kin as soon as possible after case identification. Physiologic measurements and specimen collection will begin at the time of entry into the study. Three days after the patient has met criteria for ALI/ARDS or at entry into the study (whichever is later), he/she will be randomized to receive recombinant human GM-CSF (250 mcg/M2) or placebo, administered by slow intravenous infusion once daily for 14 days.

This study will allow entry of patients who have fulfilled criteria for ALI/ARDS for up to 7 days. Treatment will be initiated after patients have met criteria for at least 3 days. Treatment with GM-CSF may prove both safe and effective within the first 1-2 days of lung injury. However, the present study will not address that question. It is unlikely that the opportunity for improved outcome will be lost by delaying therapy for up to 3 days (based on the proposed mechanisms by which GM-CSF might benefit this patient population). Similarly, the decision to treat for 14 days will allow for improved outcome in patients with non-resolving ARDS by reducing the incidence of ventilator-associated pneumonia and by decreasing pathologic fibroproliferation.

The primary endpoint for this study will be the duration of mechanical ventilation. Additional important endpoints will include changes in the severity of physiologic derangements of respiratory gas exchange, non-respiratory organ failure, and incidence of ventilator-associated pneumonia. Additional assessments designed to determine the mechanism of benefit of GM-CSF treatment will include measures of lung epithelial cell integrity and measures of alveolar macrophage (lung inflammatory cell) function.

Eligibility

Ages Eligible for Study:	18 Years to 90 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Acute onset of illness with:

PaO2/FiO2 ratio of less than 300 (ALI) or PaO2/FiO2 ratio of less than 200 (ARDS)
Bilateral infiltrates consistent with pulmonary edema on frontal chest radiograph (infiltrates may be patchy, diffuse, homogeneous, or asymmetric)
Requirement for positive pressure ventilation via an endotracheal tube
No clinical evidence of left atrial hypertension (pulmonary arterial wedge pressure measure up to 18 mm Hg)
First three criteria must occur together within a 24-hour interval

Exclusion criteria:

Greater than 7 days elapsed following institution of mechanical ventilation
Pregnancy
Chronic respiratory failure as defined by any of the following: 1) FEV1 less than 20 ml/kg of PBW; or 2) FEV1/FVC less than 50%
Chronic hypercapnia or hypoxemia
Hospitalization within the past 6 months for acute respiratory failure
Chronic home use of oxygen or mechanical ventilation
Left ventricular failure as defined by New York Heart Association (NYHA) class IV status
Neutropenia (absolute neutrophil count less than 1000 cells/mm3)
History of hematological malignancy or bone marrow transplant
Entry into other intervention clinical trials
Decision of the patient or attending physician to forego aggressive care
Expected survival rate of less than 6 months (based solely on pre-existing medical problems [i.e., poorly controlled neoplasm or other end-stage disease])
AIDS or known history of HIV infection
Prednisone (or equivalent) therapy greater than or equal to 20 mg/day for a period of not less than 2 months with treatment continuing within 3 weeks prior to screening
Cytotoxic therapy within 3 weeks of screening
Morbid obesity defined as greater than 1 kg/c, body weight
At risk for increased intracranial pressure that may result from permissive hypercapnia or in whom permissive hypercapnia may be otherwise contraindicated
Neuromuscular disease that would potentially impact ability to wean from mechanical ventilation
Receiving extracorporeal membrane oxygenation when meeting screening criteria

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00201409

Contacts

Contact: Robert C. Hyzy, M.D.	734-936-5201	rhyzy@umich.edu
Contact: Ronald E. Dechert, Ph.D.	734 936-5860	rdechert@umich.edu

Locations

United States, Colorado
University of Colorado Health Sciences Center	Recruiting
Denver, Colorado, United States, 80262
Contact: Marc Moss 720-848-0748 Marc.Moss@UCHSC.edu
Principal Investigator: Marc Moss, MD
United States, Georgia
Emory University	Completed
Atlanta, Georgia, United States, 30303
United States, Michigan
University of Michigan	Recruiting
Ann Arbor, Michigan, United States, 48109
Contact: Ronald E. Dechert, PhD 734-936-5237 rdechert@umich.edu
Sub-Investigator: Robert Paine, MD
Principal Investigator: Robert Hyzy, M.D.

Sponsors and Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

University of Michigan

Emory University

University of Colorado at Denver and Health Sciences Center

Investigators

Study Director:	Robert Paine, MD	University of Utah and University of Michigan
Principal Investigator:	Robert C. Hyzy, M.D.	University of Michigan

More Information

Publications:

Paine R 3rd, Wilcoxen SE, Morris SB, Sartori C, Baleeiro CE, Matthay MA, Christensen PJ. Transgenic overexpression of granulocyte macrophage-colony stimulating factor in the lung prevents hyperoxic lung injury. Am J Pathol. 2003 Dec;163(6):2397-406.

Paine R 3rd, Morris SB, Jin H, Wilcoxen SE, Phare SM, Moore BB, Coffey MJ, Toews GB. Impaired functional activity of alveolar macrophages from GM-CSF-deficient mice. Am J Physiol Lung Cell Mol Physiol. 2001 Nov;281(5):L1210-8.

Baleeiro CE, Wilcoxen SE, Morris SB, Standiford TJ, Paine R 3rd. Sublethal hyperoxia impairs pulmonary innate immunity. J Immunol. 2003 Jul 15;171(2):955-63.

Presneill JJ, Harris T, Stewart AG, Cade JF, Wilson JW. A randomized phase II trial of granulocyte-macrophage colony-stimulating factor therapy in severe sepsis with respiratory dysfunction. Am J Respir Crit Care Med. 2002 Jul 15;166(2):138-43.

Matute-Bello G, Liles WC, Radella F 2nd, Steinberg KP, Ruzinski JT, Hudson LD, Martin TR. Modulation of neutrophil apoptosis by granulocyte colony-stimulating factor and granulocyte/macrophage colony-stimulating factor during the course of acute respiratory distress syndrome. Crit Care Med. 2000 Jan;28(1):1-7.

Responsible Party:	University of Michigan ( Robert C. Hyzy, M.D. )
Study ID Numbers:	258, P50 HL074024
Study First Received:	September 12, 2005
Last Updated:	March 13, 2009
ClinicalTrials.gov Identifier:	NCT00201409 History of Changes
Health Authority:	United States: Food and Drug Administration

Study placed in the following topic categories:

Respiratory Tract Diseases
Lung Diseases
Respiration Disorders
Respiratory Distress Syndrome, Adult
Acute Respiratory Distress Syndrome

Additional relevant MeSH terms:

Respiratory Tract Diseases
Lung Diseases
Respiration Disorders
Respiratory Distress Syndrome, Adult

ClinicalTrials.gov processed this record on May 07, 2009