Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomised controlled trial

Background Limited data are available for the efficacy of triple therapy with two long-acting bronchodilators and an inhaled corticosteroid in chronic obstructive pulmonary disease (COPD). We compared treatment with extrafine beclometasone dipropionate, formoterol fumarate, and glycopyrronium bromide (BDP/FF/GB; fixed triple) with tiotropium, and BDP/FF plus tiotropium (open triple). Methods For this double-blind, parallel-group, randomised, controlled trial, eligible patients had COPD, postbronchodilator forced expiratory volume in 1 s (FEV1) of less than 50%, at least one moderate-to-severe COPD exacerbation in the previous 12 months, and a COPD Assessment Test total score of at least 10. After a 2-week run-in period receiving one inhalation per day via single-dose dry-powder inhaler of open-label 18 mu g tiotropium, patients were randomised (2: 2: 1) using a interactive response technology system to 52 weeks treatment with tiotropium, fixed triple, or open triple. Randomisation was stratified by country and severity of airflow limitation. The primary endpoint was moderate-to-severe COPD exacerbation rate. The key secondary endpoint was change from baseline in pre-dose FEV1 at week 52. The trial is registered with ClinicalTrials.gov, number NCT01911364. Findings Between Jan 21, 2014, and March 18, 2016, 2691 patients received fixed triple (n=1078), tiotropium (n=1075), or open triple (n=538). Moderate-to-severe exacerbation rates were 0.46 (95% CI 0.41-0.51) for fixed triple, 0.57 (0.52-0.63) for tiotropium, and 0.45 (0.39-0.52) for open triple; fixed triple was superior to tiotropium (rate ratio 0.80 [95% CI 0.69-0.92]; p=0.0025). For week 52 pre-dose FEV1, fixed triple was superior to tiotropium (mean difference 0.061 L [0.037 to 0.086]; p< 0.0001) and non-inferior to open triple (-0.003L [-0.033 to 0.027]; p=0.85). Adverse events were reported by 594 (55%) patients with fixed triple, 622 (58%) with tiotropium, and 309 (58%) with open triple. Interpretation In our TRINITY study, treatment with extrafine fixed triple therapy had clinical benefits compared with tiotropium in patients with symptomatic COPD, FEV1 of less than 50%, and a history of exacerbations.