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

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.

Figure 1.. Recruitment, Randomization, and Patient Flow

Recruitment of 513 patients with idiopathic pulmonary fibrosis who were randomized to 2 therapeutic strategies in a 1:1 allocation ratio. Prior to randomization eligible patients and their physician were offered a preference for the co-trimoxazole (trimethoprim-sulfamethoxazole) or doxycycline stratum; the protocol specified co-trimoxazole in the absence of a selection. ^aUnable to return to the treatment site in a timely fashion because of either the COVID-19 shutdown or scheduling difficulties.

Figure 2.. Time to the Primary Composite End Point and Its Components

There were no statistically significant differences between the antimicrobial therapy plus usual care group and usual care–only group based on the log-rank test for this end point nor for the components.