Effect of Co-trimoxazole vs Placebo Among Patients With Moderate and Severe Idiopathic Pulmonary Fibrosis | Cardiothoracic Surgery | JN Learning | AMA Ed Hub [Skip to Content]
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Effect of Co-trimoxazole (Trimethoprim-Sulfamethoxazole) vs Placebo on Death, Lung Transplant, or Hospital Admission in Patients With Moderate and Severe Idiopathic Pulmonary FibrosisThe EME-TIPAC Randomized Clinical Trial

Educational Objective
To learn whether treatment with co-trimoxazole benefits patients with idiopathic pulmonary fibrosis.
1 Credit CME
Key Points

Question  What is the clinical efficacy of co-trimoxazole (trimethoprim-sulfamethoxazole) in idiopathic pulmonary fibrosis (IPF) in terms of time to death (all causes), lung transplant, or first nonelective hospital admission?

Findings  In this randomized clinical trial, which included 343 patients with moderate or severe IPF, the incidence of the composite outcome among those treated with oral co-trimoxazole, 960 mg twice daily, vs those treated with placebo was 0.45 vs 0.38 per person-year after a median follow-up of 1.02 years; the hazard ratio was not statistically significant.

Meaning  Co-trimoxazole compared with placebo did not improve a composite clinical outcome among patients with moderate or severe IPF.

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

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Article Information

Corresponding Author: Andrew M. Wilson, MD, University of East Anglia, James Watson Road, Norwich Research Park, Bob Champion Research and Education Building, Floor 2, Norwich, Norfolk NR4 7TJ, United Kingdom (a.m.wilson@uea.ac.uk).

Accepted for Publication: November 6, 2020.

Author Contributions: Dr Wilson had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Wilson, Clark, Cahn, Chilvers, Hammond, Livermore, Maher, Parfrey, Swart, Thickett, Whyte, Spencer, Gibbons.

Acquisition, analysis, or interpretation of data: Wilson, Clark, Fraser, Hammond, Maher, Parfrey, Swart, Stirling, Thickett, Whyte, Chaudhuri, Spencer, Adamali, Hart, Stone, Forrest, Simpson, Goudie, Amsha, Hope-Gill, Bianchi, Hoyles, Fletcher, Gatheral, Haider, Dempsey, Woodhead, Kelly, Walters, Allcock, Saini, Bongers, Fahim, Aul, Parr, Fuller, Coker, Chalmers, Heinink, Naseer, Porter, O'Hickey, Spears.

Drafting of the manuscript: Wilson, Clark, Chilvers, Hammond, Stirling, Thickett, Forrest, Haider, Dempsey, Kelly, Saini, Gibbons.

Critical revision of the manuscript for important intellectual content: Wilson, Clark, Cahn, Chilvers, Fraser, Hammond, Livermore, Maher, Parfrey, Swart, Thickett, Whyte, Chaudhuri, Spencer, Adamali, Hart, Stone, Forrest, Simpson, Goudie, Amsha, Hope-Gill, Bianchi, Hoyles, Fletcher, Gatheral, Woodhead, Walters, Allcock, Bongers, Fahim, Aul, Parr, Fuller, Coker, Chalmers, Heinink, Naseer, Porter, O'Hickey, Spears.

Statistical analysis: Clark, Stirling.

Obtained funding: Wilson, Clark, Chilvers, Fraser, Maher, Parfrey, Swart, Thickett, Whyte.

Administrative, technical, or material support: Cahn, Fraser, Hammond, Livermore, Swart, Thickett, Chaudhuri, Spencer, Hart, Forrest, Simpson, Hoyles, Haider, Dempsey, Allcock, Fahim, Aul, Naseer.

Supervision: Wilson, Hammond, Maher, Swart, Goudie, Kelly, Aul, Porter.

Other - principal investigator for patients attending my center: Woodhead.

Other - principal investigator: Parr.

Other - recruitment to trial: Spears.

Conflict of Interest Disclosures: Dr Wilson reported receiving grants from the National Institute for Health Research Efficacy and Mechanism Evaluation Programme during the conduct of the study and grants from Roche outside the submitted work. Dr Clark reported receiving grants from the National Institute for Health Research during the conduct of the study. Dr Cahn reported being an employee of and holding stock options for GlaxoSmithKline outside the submitted work. Dr Hammond reported receiving grants from the National Institute for Health Research during the conduct of the study. Dr Livermore reported receiving personal fees from Antabio, Allecra, Accelerate, Centauri, Entasis, Zambon, Qpex, Shionogi, Menarini, Centauri, Meiji, Melinta, Intergra Holdings, Mutabilis, Nordic, Parapharm, Tetraphase, VenatoRx, Wockhardt, Astellas, Cardiome, Cepheid, Eumedica, and Beckman-Coulter; receiving personal fees from and being a shareholder in Merck, GlaxoSmithKline, and Pfizer; being a shareholder in Perkin-Elmer and Dechra; receiving personal fees from and having stock options in T.A.Z Corporation; and receiving personal fees and nonfinancial support from bioMerieux outside the submitted work. Dr Maher reported receiving grants from the National Institute for Health Research during the conduct of the study and personal fees from Boehringer Ingelheim, Roche, Galapagos, Blade, Respivant, Galecto, Pliant, Bristol Myers Squibb, and Indalo and grants and personal fees from AstraZeneca and GlaxoSmithKline outside the submitted work. Dr Parfrey reported receiving an educational grant, personal fees, and nonfinancial support from Boehringer Ingelheim and Roche. Dr Whyte reported receiving grants from GlaxoSmithKline outside the submitted work. Dr Hart reported receiving grants, personal fees, and nonfinancial support from Boehringer Ingelheim and personal fees from Chiesi outside the submitted work and being a trustee of the charity Action for Pulmonary Fibrosis. Dr Forrest reported receiving personal fees and travel bursary from Boehringer Ingelheim and Roche outside the submitted work. Dr Aul reported receiving personal fees from Pfizer and Chiesi outside the submitted work. Dr Gibbons reported receiving personal fees and conference travel expenses from Boehringer Ingelheim and Roche outside the submitted work. Dr Chalmers reported receiving personal fees from Boehringer Ingelheim and Roche outside the submitted work. No other disclosures were reported.

Funding/Support: The EME-TIPAC trial was funded by the National Institute for Health Research Efficacy and Mechanism Evaluation Programme grant number 12/206/09.

Role of the Funder/Sponsor: The funder 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. In addition they had no right to veto publication or to control the decision regarding to which journal the paper was submitted.

EME-TIPAC team: Nazia Chaudhuri, PhD (University Hospital of South Manchester NHS Foundation Trust); Lisa Spencer, MBChB (Aintree University Hospitals NHS Foundation Trust); Huzaifa Adamali, MD (North Bristol NHS Trust); Simon Hart, PhD (Hull and East Yorkshire Hospitals NHS Trust); Helen Stone, MBChB (University Hospitals of North Midlands NHS Trust); Ian Forrest, PhD (The Newcastle Upon Tyne Hospitals NHS Foundation Trust); John Simpson, PhD (Newcastle University); Andrew Goudie, MD (NHS Tayside); Khaled Amsha, MBChB (Sherwood Forest Hospitals NHS Foundation Trust); Ben Hope-Gill, MD (Cardiff and Vale University Health Board); Stephen Bianchi, PhD (Sheffield Teaching Hospitals NHS Foundation Trust); Rachel Hoyles, PhD (Oxford University Hospital NHS Foundation Trust); Sophie Fletcher, MBChB (University Hospital Southampton NHS Foundation Trust); Timothy Gatheral, PhD (University Hospitals of Morecambe Bay NHS Foundation Trust); Yussef Haider, MD (Lancashire Teaching Hospitals NHS Foundation Trust); Owen Dempsey, MD (Aberdeen Royal Infirmary); Felix Woodhead, PhD (University Hospitals of Leicester NHS Trust); Martin Kelly, MD (Western Health and Social Care Trust); Gareth Walters, MD (Heart of England NHS Foundation Trust); Robert Allcock, MBChB (Gateshead Health NHS Foundation Trust); Gauri Saini, PhD (Nottingham University Hospitals NHS Foundation Trust); Thomas Bongers, MD (Blackpool, Fylde and Wyre Hospitals NHS Foundation Trust); Ahmed Fahim, MD (The Royal Wolverhampton NHS Trust); Raminder Aul, MD (St George's University Hospitals NHS Foundation Trust); Liz Fuller, MD (South Tyneside Foundation Trust); David Parr, MD (University Hospitals Coventry and Warwickshire NHS Trust); Robina Coker, PhD (Imperial College Healthcare NHS Trust); Michael Gibbons, PhD (Royal Devon and Exeter NHS Foundation Trust); George Chalmers, MD (NHS Greater Glasgow and Clyde); Richard Heinink, MBChB (The Shrewsbury and Telford Hospital NHS Trust); Rehan Naseer, MBChB (Calderdale and Huddersfield NHS Foundation Trust); Joanna Porter, PhD (University College London Hospitals NHS Foundation Trust); Stephen O'Hickey, MD (Worcestershire Acute Hospitals NHS Trust); Mark Spears, MBChB (NHS Forth Valley). The EME-TIPAC team contributed to the data collection of the study and the editing of the manuscript.

Disclaimer: This report presents independent research funded by the National Institute for Health Research. The views expressed are those of the author(s) and not necessarily those of the National Health Service, the National Institute for Health Research, or the Department of Health and Social Care.

Data Sharing Statement: See Supplement 4.

Additional Contributions: We would like to thank all the participants who took part in the study. We are grateful to all the staff at recruitment sites who facilitated identification, recruitment, and follow-up of study participants, including Ronan O'Driscoll, PhD (Salford Royal NHS Foundation Trust). Local researchers received funding for their work on this study. We thank Martin Pond, MSc; Anthony Colles, BSc (Norwich Clinical Trials Unit); and the Norwich Clinical Trials Unit Data Management team for developing and maintaining the electronic case report forms and study database. We are grateful for the contribution of Mercedes Mills (University of East Anglia) for her contribution to contracting and to Julie Dawson (Norfolk and Norwich University Hospital NHS Foundation Trust) for her role as sponsor representative. These individuals undertook this work as part of their employment. We thank the National Institute for Health Research Imperial Biomedical Research Centre. We are grateful for the members of the trial steering committee and data monitoring committee. These individuals did not receive any compensation. We thank Steve Jones, BSocSci, from Action for Pulmonary Fibrosis and 2 patient representatives who did not receive compensation other than appropriate travel expenses.

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