A Randomized Trial of GM-CSF in Patients With ALI/ARDS
Condition: Respiratory Distress Syndrome, Adult
MeSH terms: Respiratory Distress Syndrome; Respiratory Distress Syndrome, Newborn; Acute Lung Injury
Study type: Interventional
Phase: Phase 2

Summary: 
      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: 
      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.
    

Intervention name(s): Placebo; GM-CSF
Intervention type(s): Drug; Drug
Intervention description(s): Placebo will be administered by slow intravenous infusion once daily for 14 days.; Recombinant human GM-CSF (250 mcg/M2) will be administered by slow intravenous infusion once daily for 14 days.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment