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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Randomized Trial of GM-CSF in Patients With ALI/ARDS

Conditions
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Respiratory Distress Syndrome, Adult

Intervention / Treatment
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* Drug: Placebo
* Drug: GM-CSF


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>Participants will be randomized to receive recombinant human GM-CSF (250 mcg/M2). | Drug: GM-CSF<br>* Recombinant human GM-CSF (250 mcg/M2) will be administered by slow intravenous infusion once daily for 14 days.<br>|
| Placebo Comparator: 2<br>Participants will be randomized to receive placebo. | Drug: Placebo<br>* Placebo will be administered by slow intravenous infusion once daily for 14 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ventilator-free Days During Days 1-28 |  | Measured at Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxygenation Index Change at Day 15 From Day 1 | The oxygenation index is a calculation used in intensive care medicine to measure the fraction of inspired oxygen (FiO2) and its usage within the body. It is calculated as the fraction of inspired oxygen times Mean airway pressure)/Partial pressure of oxygen in arterial blood Day 15 minus first day drug or placebo administered (Day 1). | Day 1, Day 15 | 
| Days Without Organ Failure | Non-respiratory | Measured at Day 28 |