Effect of budesonide/glycopyrronium/formoterol fumarate dihydrate on cardiopulmonary outcomes in COPD: rationale and design of the THARROS trial

Background Chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) are leading causes of death with overlapping and syndemic pathophysiological interactions. Inhaled triple therapies containing inhaled corticosteroids (ICS), long-acting muscarinic antagonists (LAMA) and long-acting β2-agonists (LABA) reduce COPD exacerbation rates and improve lung function versus dual LAMA/LABA therapy. The effect of inhaled triple therapies on combined cardiac and pulmonary (i.e., cardiopulmonary) events in people with COPD and elevated cardiopulmonary risk has not been prospectively tested in randomised clinical trials. Methods THARROS is a multinational, event-driven cardiopulmonary outcomes trial evaluating budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) triple therapy versus glycopyrronium/formoterol fumarate dihydrate dual therapy in patients with COPD and elevated cardiopulmonary risk not using ICS-containing maintenance therapy. Eligibility requirements include: symptomatic COPD (COPD Assessment Test scores ≥10) without a requirement for prior COPD exacerbations, blood eosinophils ≥100 cells·mm−3 , established CVD or CVD risk based on clinical characteristics, clinical risk scores or imaging-based risk criteria. The composite primary endpoint is time to first severe cardiac or COPD event and includes 3 event types: severe cardiac events (heart failure acute healthcare visit/hospitalisation, myocardial infarction hospitalisation), severe COPD exacerbations and cardiopulmonary death. Approximately 5000 patients will be randomised to achieve 632 participants with ≥1 primary severe adjudicated cardiopulmonary event. Conclusion This first-of-its-kind cardiopulmonary outcomes trial will determine the effect of BGF on a novel composite endpoint comprising severe cardiopulmonary events in a broad COPD population with elevated cardiopulmonary risk not currently using ICS-containing maintenance therapy (see supplement for plain language summary infographic).