The Efficacy and Mechanism Evaluation of Treating Idiopathic Pulmonary fibrosis with the Addition of Co-trimoxazole (EME-TIPAC)

We hypothesise that the addition of co-trimoxazole to standard therapy is beneficial to patients with moderate to severe idiopathic pulmonary fibrosis (IPF), based upon the findings from our previous study (Thorax 2013;68:155). We aim to investigate this by assessing the time until death (all causes), lung transplant or first non-elective hospital admission, and to determine whether any effect relates to changes in infection and/or markers of disease and neutrophil activity. Design: This will be a double-blind placebo-controlled randomised multicentre clinical trial. Assessments will be undertaken at baseline, after 3 & 6 months then every 6 months and at study exit, which is defined as non-elective hospital admission and at the end of the study (12 months following the last patient enrolment), for a median of 27 months (12 to 42 months). Population: 330 symptomatic (MRC dyspnoea score >1) patients older than 40 years with IPF diagnosed by a multi-disciplinary team at specialist centres according to international guidelines and a FVC<=70% predicted will be enrolled. Patients may receive licensed medication for IPF and anti-oxidants but will be excluded if they have significant co-morbidities, are receiving immunosuppression (other than low dose prednisolone) or unlicensed medication. Intervention: Patients will be randomised to receive 2 tablets of co-trimoxazole 480mg or 2 placebo tablets twice daily. All patients will receive folic acid 5mg daily. Treatment will be reduced to 2 tablets plus 5mg folic acid three times weekly in patients developing gastrointestinal adverse effects or rash. This is a tolerated regime used for long term Pneumocystis jiroveci (PJ) prophylaxis. Primary outcome: Time until death (all causes), lung transplant or first non-elective hospital admission will be determined from adverse event reporting, hospital databases and the Office of National Statistics with active tracing of patients missing appointments. Secondary outcomes: respiratory-related hospital admission, death, health-related quality of life (King’s Brief Interstitial Lung Disease questionnaire), quality of life adjusted years, cough score and quality of life, lung function and oxygen saturations, routine sputum microbiology results. Blood (0, 3, 6 and 12 months and study exit) will be taken for cell count, biochemistry and stored for analysis of biomarkers including C-reactive protein and markers of disease (e.g. surfactant protein-D, and matrix metalloproteinase-7) and neutrophil activity (e.g. myeloperoxidase) at the end of the study, if appropriate. In addition, a subset of 50 patients will undergo bronchoscopy at baseline and after 3 months to evaluate the lower airway microbiota using high-throughput sequencing of bacterial 16S rRNA genes, quantitative microbiological culture, polymerase chain reaction (PCR) for PJ, differential cell count, neutrophil elastase, PIIINP and biomarkers (above). Statistical analysis: With 264 patients randomised over a period of 30 months and an additional 12 months follow-up after the last patient is recruited, the trial will have 80% power to show a change in hospitalisation free survival from a median of 28.8 months in the control arm to 51.1 months in the co-trimoxazole arm (hazard ratio of 0.56). The primary analysis will be on an ITT basis with adjustment for all variables used in the minimisation algorithm, with sensitivity analysis including only patients adhering to the high-dose regime. Analyses will be based on a proportional hazards regression model. The study will last for 4 years. Recruitment will take place in our established network of 21 sites. We expect set-up to take 2 months, recruitment for 30 months, follow-up for 12 months and study analysis and reporting to take 4 months, with a recruitment rate of 0.5 patients/centre/month or <15% of eligible patients.