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

Educational Objective
To understand the relationship of lung dysbiosis to idiopathic pulmonary fibrosis.
1 Credit CME
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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CME Disclosure Statement: Unless noted, all individuals in control of content reported no relevant financial relationships. If applicable, all relevant financial relationships have been mitigated.

Article Information

Corresponding Author: Fernando J. Martinez, MD, MS, 1305 York Ave, PO Box 96, Room Y-1059, New York, NY 10021 (fjm2003@med.cornell.edu).

Accepted for Publication: March 16, 2021.

Author Contributions: Drs Martinez and Anstrom had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Anstrom and Noth are co–senior authors.

Concept and design: Martinez, Flaherty, Wisniewski, Sciurba, Raghu, D. Kim, Criner, Scholand, Anstrom, Noth.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Martinez, Yow, H. Kim, Anstrom, Noth.

Critical revision of the manuscript for important intellectual content: Martinez, Flaherty, Snyder, Durheim, Wisniewski, Sciurba, Raghu, Brooks, D. Kim, Dilling, Criner, H. Kim, Belloli, Nambiar, Scholand, Anstrom, Noth.

Statistical analysis: Martinez, Yow, Wisniewski, D. Kim, Anstrom.

Obtained funding: Martinez, Sciurba, Noth.

Administrative, technical, or material support: Martinez, Snyder, Wisniewski, Sciurba, Criner, Nambiar, Scholand, Anstrom, Noth.

Supervision: Martinez, Snyder, Sciurba, Criner, Nambiar, Anstrom, Noth.

Conflict of Interest Disclosures: Dr Martinez reported serving on the COPD advisory boards of AstraZeneca, Bayer, Boehringer Ingelheim, Chiesi, Sunovion, CSL Behring, Gala, GlaxoSmithKline, Novartis, Polarean, ProterrixBio, Sanofi/Regeneron, Teva, and Verona; COPD study steering committees of AstraZeneca, GlaxoSmithKline, Chiesi, and Sanofi; Interstitial Lung Disease advisory boards or consulting for Abbvie, Boehringer Ingelheim, Bristol Myers Squibb, Bridge Biotherapeutics, CSL Behring, DevPro, Genentech, IQVIA, Sanofi, Shionogi, twoXAR, United Therapeutics, Veracyte, and Zambon. Interstitial Lung Disease study steering committees for Afferent/Merck, Bayer, Biogen, Boehringer Ingelheim, Gilead, Patara/Respivant, ProMedior/Roche, and Veracyte; the data and safety monitoring boards for Biogen, Boehringer Ingelheim, Genentech, GlaxoSmithKline, and Medtronic; advisory boards/consultation on COVID-19 related topics for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, and Raziel; receiving personal fees for continuing medical education from the Academy for Continuing Healthcare Learning, CME Outfitters, Dartmouth University, Integritas, Integrity Communications, MedScape, Methodist Hospital Brooklyn, Miller Communications, National Association for Continuing Education/Haymarket, PeerView Communications, Physicians Education Resource Program, Projects in Knowledge, UpToDate, Vindico, and WebMD; grants from the National Institutes of Health (NIH); and personal fees for serving as deputy editor of the American Journal of Respiratory and Critical Care Medicine. Dr Durheim reported receiving grants from the National Heart, Lung, and Blood Institute (NHLBI) and personal fees from Boehringer Ingelheim and Roche. Dr Sciurba reported receiving institutional grants from the NIH. Dr Raghu reported receiving institutional grants from the NIH and consulting fees from Boehringer Ingelheim and Roche-Genentech. Dr Brooks reported receiving grants from NIH. Dr Dilling reported receiving grants from University of Pittsburgh Pulmonary Trials Cooperative (PTC), personal fees from the Genentech and Boehringer Ingelheim, grant support from Boehringer Ingelheim, Nitto Denko Corp, Galapagos NV, Gilead Sciences, Bellerophon Pulse Technologies, and Duke Clinical Research Institute. Dr Criner reported receiving grants from Boehringer Ingelheim, personal fees from Boehringer Ingelheim, grants from Galapagos and Patara. Dr Belloli reported receiving grants from the NIH. Dr Nambiar reported receiving grants from the University of Pittsburgh, the NHLBI, Roche/Genentech, Pulmonary Fibrosis Foundation, Nitto Denko, FibroGen, and Galapagos; and personal fees from Boehringer Ingelheim, Roche/Genentech, and Veracyte. Dr Scholand reported receiving personal fees from Genentech, Boerhinger Ingelheim, Veracyte, and United Therapeutics. Dr Anstrom reported receiving grants from Merck, Bayer, and the NIH. Dr Noth reported receiving grants from the NIH, Veracyte, and Three Lakes Foundation; personal fees from Boerhinger Ingelheim, Genentech, and Confo and having a patent for TOLLIP in IPF pending. No other disclosures were reported.

Funding/Support: This work was supported by grants U01HL128964 from the NIH/NHLBI, Three Lakes Foundation, IPF Foundation, and Veracyte Inc.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information: A listing of the CleanUP-IPF Investigators of the Pulmonary Trials Cooperative appears in Supplement 5.

Data Sharing Statement: See Supplement 6.

Additional Contributions: We thank Michelle LoPiccolo, MHA, BS, NewYork-Presbyterian Hospital/Weill Cornell Medicine, for editorial assistance.

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