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

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.

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