PROJECT SUMMARY/ABSTRACT: AIMS: The enclosed proposal outlines a phase III multicenter randomized clinical trial to establish the efficacy of early treatment with an inhaled corticosteroid combined with a beta-agonist vs. usual care for prevention of acute respiratory failure from pneumonia. This trial builds closely upon our recently completed NHLBI-funded Lung Injury Prevention Study with Budesonide and a Beta-agonist (LIPS-B) demonstrating that early treatment with aerosolized budesonide (a corticosteroid) and formoterol (a beta-agonist) improved oxygenation and reduced acute respiratory failure (ARF) in high-risk patients in the emergency department. The current trial will enroll 600 patients across 10 academic centers in U.S. and be conducted within the Discovery Network of the Society of Critical Care Medicine. Secondary aims will explore risk factors for respiratory failure and potential heterogenous treatment effects (HTE) in clinically and biologically defined subgroups. SIGNIFICANCE: Pneumonia is the leading infectious cause of hospitalization and death in the United States. Currently, other than antibiotics and supportive care, no established treatments directly target the lung injury that occurs with severe pneumonia. However, corticosteroids have been shown to reduce inflammation and preserve alveolar barrier function, while beta-agonists increase resorption of pulmonary edema and preserve vascular permeability?potentially crucial functions in preventing ARF in patients with pneumonia. Our recently completed phase IIa clinic trial suggest benefit of inhaled corticosteroids combined a beta-agonist. A trial to establish efficacy of these therapies, and to inform optimal treatment of patients hospitalized for pneumonia, is both timely and of critical importance to the mission of the NHLBI. INNOVATION: This trial will continue the critical innovation of early intervention to prevent disease progression in LIPS-B. Previous trials of beta- agonists and systemic steroids failed to show clinic benefits in mechanically ventilated patients with established ARDS. LIPS-B delivered aerosolized study drug within a median of 9 hours from presentation and prior to ARF, and demonstrated improved oxygenation and lower rates of ARF. We suspect that both early treatment and inhaled delivery are critical innovations responsible for these encouraging results. IMPACT: If we establish efficacy of these safe, inexpensive, and widely available medications, we will dramatically impact treatment of a major cause of hospitalization and death. Regardless of the trial?s results, our exploratory secondary aim will inform design of future trials in a field of special interest to the NHLBI.
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