Joseph Levitt, Haley Hedlin, Angela J Rogers, Victoria Ding, Justin Lee, Di Lu, Ken W Mahaffey, Ognjen Gajic, Michael A Matthay, Jennifer W Wilson, Christian Bime, Nina Gentile, Odeyemi Yewande, Rodrigo Cartin-Ceba, William Checkley, David A Kaufman, Joshua L Denson, Kami Hu, Marie-Carmelle Elie, Rosemary Vojnik, Manisha Desai, Emir Festic
BACKGROUND: Pneumonia is a major cause of hospitalization and death. Trials of systemic steroids have yielded mixed results. In a preliminary trial, we found aerosolized budesonide/formoterol improved oxygenation in patients with pneumonia.
METHODS: This phase 3, multicenter, double-blind trial randomized hospitalized patients with pneumonia and hypoxemia to twice daily aerosolized budesonide/formoterol vs. placebo for up to 5 days. The primary endpoint was acute respiratory failure (ARF) defined as need for HFNO, non-invasive, or invasive ventilation for >36 hours. Exclusion criteria included indications for inhaled beta agonists or steroids. The protocol was amended to allow 6 mg of dexamethasone in COVID patients only. Heterogeneous treatment effects (HTE) were explored among pre-specified subgroups at a significance of p<0.10.
RESULTS: We enrolled 465 patients from May 2020 to July 2025. The trial was stopped for futility after 75% enrollment. Median time from ED presentation to first dose of study drug was 20 hours. ARF occurred in 50 of 230 (21.7%) and 47 of 235 patients (20.0%) in placebo and treatment arms (OR 0.9, 95% CI 0.6-1.5, p = 0.7). There was HTE with a trend toward less ARF when first dose was delivered in <20 hours (<20h OR 0.6, 95%CI 0.3-1.2 vs. >20h OR 1.4, 95%CI 0.7-2.7, interaction p = 0.07). No differences occurred in secondary endpoints
CONCLUSIONS: Aerosolized budesonide/formoterol did not reduce rates of acute respiratory failure in hospitalized patients with pneumonia and hypoxemia.