The ARREST Pneumonia Clinical Trial. Rationale and Design

Abstract

Patients hospitalized for pneumonia are at high risk for mortality. Effective therapies are therefore needed. Recent randomized clinical trials suggest that systemic steroids can reduce the length of hospital stays among patients hospitalized for pneumonia. Furthermore, preliminary findings from a feasibility study demonstrated that early treatment with a combination of an inhaled corticosteroid and a bronchodilator can improve oxygenation and reduce risk of respiratory failure in patients at risk of acute respiratory distress syndrome. Whether such a combination administered early is effective in reducing acute respiratory failure (ARF) among patients hospitalized with pneumonia is unknown. Here we describe the ARREST Pneumonia (Arrest Respiratory Failure due to Pneumonia) trial designed to address this question. ARREST Pneumonia is a two-arm, randomized, double-blinded, placebo-controlled trial designed to test the efficacy of a combination of an inhaled corticosteroid and a β-agonist compared with placebo for the prevention of ARF in hospitalized participants with severe pneumonia. The primary outcome is ARF within 7 days of randomization, defined as a composite endpoint of intubation and mechanical ventilation; need for high-flow nasal cannula oxygen therapy or noninvasive ventilation for >36 hours (each alone or combined); or death within 36 hours of being placed on respiratory support. The planned enrollment is 600 adult participants at 10 academic medical centers. In addition, we will measure selected plasma biomarkers to better understand mechanisms of action. The trial is funded by the U.S. National Heart Lung and Blood Institute.Clinical trial registered with www.clinicaltrials.gov (NCT04193878).

Keywords: aerosol drug therapy; pneumonia; prevention; respiratory failure.

Figures

Figure 1.

Key pathways in progression of lung injury. AFC = alveolar fluid clearance; ANG-2 = angiopoietin-2; CRP = C-reactive protein; IBA = inhaled β-agonist; ICS = inhaled corticosteroid; IL-6 = interleukin 6; IL-8 = interleukin 8; RAGE = receptor for advanced glycation end products; SP-D = surfactant protein D; TNF-α = tumor necrosis factor-α.

Figure 2.

Organizational structure. ARREST Pneumonia = Arrest Respiratory Failure due to Pneumonia; CCC = Clinical Coordinating Center; DCC = Data Coordinating Center; DSMB = Data and Safety Monitoring Board; IRB = institutional review board; NHLBI = U.S. National Heart Lung and Blood Institute; PI = principal investigator; UCSF = University of California, San Francisco.

Figure 3.

Study timeline. ARF = acute respiratory failure; ED = emergency department.

Figure 4.

Power analysis. ARF = acute respiratory failure; UC = usual care.

Figure 5.

Shock-adjusted change in S/F per treatment day in LIPS-B (Lung Injury Prevention Study with Budesonide and a β-Agonist). S/F = oxygen saturation as measured by pulse oximetry/fraction of inspired oxygen.