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Original Investigation
May 11, 2021

Effect of Antimicrobial Therapy on Respiratory Hospitalization or Death in Adults With Idiopathic Pulmonary Fibrosis: The CleanUP-IPF Randomized Clinical Trial

Author Affiliations
  • 1New York Presbyterian Hospital/Weill Cornell Medicine, New York
  • 2Duke Clinical Research Institute, Duke University, Durham, North Carolina
  • 3Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor
  • 4Department of Respiratory Medicine, Oslo University Hospital - Rikshospitalet, Oslo, Norway
  • 5Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 6Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle
  • 7National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland
  • 8Division of Pulmonary and Critical Care Medicine, Loyola University Medical Center, Maywood, Illinois
  • 9Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania
  • 10Division of Pulmonary and Critical Care Medicine, University of Minnesota, Minneapolis
  • 11Division of Pulmonary and Critical Care Medicine, University of Texas Health San Antonio
  • 12Division of Pulmonary and Critical Care Medicine, University of Utah, Salt Lake City
  • 13Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville
JAMA. 2021;325(18):1841-1851. doi:10.1001/jama.2021.4956
Key Points

Question  Does antimicrobial therapy in addition to usual care improve clinical outcomes in patients with idiopathic pulmonary fibrosis?

Findings  In this pragmatic randomized clinical trial that included 513 adults with idiopathic pulmonary fibrosis the addition of co-trimoxazole (trimethoprim-sulfamethoxazole) or doxycycline to usual care compared with usual care alone resulted in a rate of first nonelective respiratory hospitalization or death of 20.4 vs 18.4 events per 100 person-years, a difference that was not statistically significant.

Meaning  Among adults with idiopathic pulmonary fibrosis, addition of co-trimoxazole or doxycycline compared with usual care did not significantly improve the time to nonrespiratory hospitalization or death.

Abstract

Importance  Alteration in lung microbes is associated with disease progression in idiopathic pulmonary fibrosis.

Objective  To assess the effect of antimicrobial therapy on clinical outcomes.

Design, Setting, and Participants  Pragmatic, randomized, unblinded clinical trial conducted across 35 US sites. A total of 513 patients older than 40 years were randomized from August 2017 to June 2019 (final follow-up was January 2020).

Interventions  Patients were randomized in a 1:1 allocation ratio to receive antimicrobials (n = 254) or usual care alone (n = 259). Antimicrobials included co-trimoxazole (trimethoprim 160 mg/sulfamethoxazole 800 mg twice daily plus folic acid 5 mg daily, n = 128) or doxycycline (100 mg once daily if body weight <50 kg or 100 mg twice daily if ≥50 kg, n = 126). No placebo was administered in the usual care alone group.

Main Outcomes and Measures  The primary end point was time to first nonelective respiratory hospitalization or all-cause mortality.

Results  Among the 513 patients who were randomized (mean age, 71 years; 23.6% women), all (100%) were included in the analysis. The study was terminated for futility on December 18, 2019. After a mean follow-up time of 13.1 months (median, 12.7 months), a total of 108 primary end point events occurred: 52 events (20.4 events per 100 patient-years [95% CI, 14.8-25.9]) in the usual care plus antimicrobial therapy group and 56 events (18.4 events per 100 patient-years [95% CI, 13.2-23.6]) in the usual care group, with no significant difference between groups (adjusted HR, 1.04 [95% CI, 0.71-1.53; P = .83]. There was no statistically significant interaction between the effect of the prespecified antimicrobial agent (co-trimoxazole vs doxycycline) on the primary end point (adjusted HR, 1.15 [95% CI 0.68-1.95] in the co-trimoxazole group vs 0.82 [95% CI, 0.46-1.47] in the doxycycline group; P = .66). Serious adverse events occurring at 5% or greater among those treated with usual care plus antimicrobials vs usual care alone included respiratory events (16.5% vs 10.0%) and infections (2.8% vs 6.6%); adverse events of special interest included diarrhea (10.2% vs 3.1%) and rash (6.7% vs 0%).

Conclusions and Relevance  Among adults with idiopathic pulmonary fibrosis, the addition of co-trimoxazole or doxycycline to usual care, compared with usual care alone, did not significantly improve time to nonelective respiratory hospitalization or death. These findings do not support treatment with these antibiotics for the underlying disease.

Trial Registration  ClinicalTrials.gov Identifier: NCT02759120

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