Effect of Co-trimoxazole (Trimethoprim-Sulfamethoxazole) vs Placebo on Death, Lung Transplant, or Hospital Admission in Patients With Moderate and Severe Idiopathic Pulmonary Fibrosis: The EME-TIPAC Randomized Clinical Trial

Abstract

Importance: Idiopathic pulmonary fibrosis (IPF) has a poor prognosis and limited treatment options. Patients with IPF have altered lung microbiota, with bacterial burden within the lungs associated with mortality; previous studies have suggested benefit with co-trimoxazole (trimethoprim-sulfamethoxazole).

Objective: To determine the efficacy of co-trimoxazole in patients with moderate and severe IPF.

Design, setting, and participants: Double-blind, placebo-controlled, parallel randomized trial of 342 patients with IPF, breathlessness (Medical Research Council dyspnea scale score >1), and impaired lung function (forced vital capacity ≤75% predicted) conducted in 39 UK specialist interstitial lung disease centers between April 2015 (first patient visit) and April 2019 (last patient follow-up).

Interventions: Study participants were randomized to receive 960 mg of oral co-trimoxazole twice daily (n = 170) or matched placebo (n = 172) for between 12 and 42 months. All patients received 5 mg of folic acid orally once daily.

Main outcomes and measures: The primary outcome was time to death (all causes), lung transplant, or first nonelective hospital admission. There were 15 secondary outcomes, including the individual components of the primary end point respiratory-related events, lung function (forced vital capacity and gas transfer), and patient-reported outcomes (Medical Research Council dyspnea scale, 5-level EuroQol 5-dimension questionnaire, cough severity, Leicester Cough Questionnaire, and King's Brief Interstitial Lung Disease questionnaire scores).

Results: Among 342 individuals who were randomized (mean age, 71.3 years; 46 [13%] women), 283 (83%) completed the trial. The median (interquartile range) duration of follow-up was 1.02 (0.35-1.73) years. Events per person-year of follow-up among participants randomized to the co-trimoxazole and placebo groups were 0.45 (84/186) and 0.38 (80/209), respectively, with a hazard ratio of 1.2 ([95% CI, 0.9-1.6]; P = .32). There were no statistically significant differences in other event outcomes, lung function, or patient-reported outcomes. Patients in the co-trimoxazole group had 696 adverse events (nausea [n = 89], diarrhea [n = 52], vomiting [n = 28], and rash [n = 31]) and patients in the placebo group had 640 adverse events (nausea [n = 67], diarrhea [n = 84], vomiting [n = 20], and rash [n = 20]).

Conclusions and relevance: Among patients with moderate or severe IPF, treatment with oral co-trimoxazole did not reduce a composite outcome of time to death, transplant, or nonelective hospitalization compared with placebo.

Trial registration: ISRCTN Identifier: ISRCTN17464641.

Figure 1.. Flow of Participants in a Study of the Effect of Co-trimoxazole vs Placebo on Death, Lung Transplant, or Hospital Admission in Patients With Idiopathic Pulmonary Fibrosis

^aIn a 1:1 ratio, with minimization for site and baseline fibrotic therapy. ^bFive patients in the co-trimoxazole group and 8 in the control group previously had their dose reduced by the investigator. ^cA reduction of the dose to 2 tablets (ie, 960 mg co-trimoxazole or 2 placebo tablets daily) plus 5 mg of folic acid 3 times weekly was permitted if a participant developed gastrointestinal adverse effects or rash, grade 1 hyperkalemia (potassium >5.0 mmol/L), or any other adverse event requiring dose reduction in the view of the principal investigator. ^dA total of 32 individuals from the co-trimoxazole and 26 from the placebo group withdrew during the study, and their data are included until the point of withdrawal. ^eThe secondary outcome data illustrate that of lung function.

Figure 2.. Primary End Point in a Study of the Effect of Co-trimoxazole vs Placebo on Death, Lung Transplant, or Hospital Admission in Patients With Idiopathic Pulmonary Fibrosis

Kaplan-Meier estimates for time to event for the primary end point (death [all causes], lung transplant, or first nonelective hospital admission), analyzed according to the group to which participants were randomized. There was no significant difference between the co-trimoxazole and placebo groups. Median (interquartile range) follow-up was 12.0 (4.4-21.0) months.