Effect Of Antimicrobial Therapy On Respiratory Hospitalization Or Death In Adults With Idiopathic Pulmonary Fibrosis: The Cleanup-Ipf Randomized Clinical Trial

Key PointsQuestionDoes antimicrobial therapy in addition to usual care improve clinical outcomes in patients with idiopathic pulmonary fibrosis? FindingsIn 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. MeaningAmong 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.ImportanceAlteration in lung microbes is associated with disease progression in idiopathic pulmonary fibrosis. ObjectiveTo assess the effect of antimicrobial therapy on clinical outcomes. Design, Setting, and ParticipantsPragmatic, 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). InterventionsPatients 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 MeasuresThe primary end point was time to first nonelective respiratory hospitalization or all-cause mortality. ResultsAmong 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 RelevanceAmong 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 RegistrationClinicalTrials.gov Identifier: NCT02759120This clinical trial investigates whether the addition of antimicrobial treatments co-trimoxazole or doxycycline to usual care improves outcomes among patients with idiopathic pulmonary fibrosis better than usual care alone.