title: 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.
abstract: 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, post-bronchodilator 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 μg 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 FEV1at week 52. The trial is registered with ClinicalTrials.gov, number NCT01911364.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  In our TRINITY study, treatment with extrafine fixed triple therapy had clinical benefits compared with tiotropium in patients with symptomatic COPD, FEV1of less than 50%, and a history of exacerbations.
  
  
  BACKGROUND
  Chiesi Farmaceutici SpA.
authors.affiliation: Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, UK; University Hospital South Manchester NHS Foundation Trust, Manchester, UK; Medicines Evaluation Unit, Manchester, UK. Electronic address: jorgen.vestbo@manchester.ac.uk.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Vestbo
authors.affiliation: Research Centre on Asthma and COPD, University of Ferrara, Ferrara, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Papi
authors.affiliation: Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Corradi
authors.affiliation: Pulmonology Department No 2, Kharkiv City Clinical Hospital No 13, Kharkiv, Ukraine.
authors.forename: Viktor
authors.initials: V
authors.lastname: Blazhko
authors.affiliation: Global Clinical Development, Chiesi Farmaceutici SpA, Parma, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Montagna
authors.affiliation: Global Clinical Development, Chiesi SAS, Courbevoie, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Francisco
authors.affiliation: Global Clinical Development, Chiesi SAS, Courbevoie, France.
authors.forename: Géraldine
authors.initials: G
authors.lastname: Cohuet
authors.affiliation: Global Clinical Development, Chiesi Farmaceutici SpA, Parma, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Vezzoli
authors.affiliation: Global Clinical Development, Chiesi Farmaceutici SpA, Parma, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Scuri
authors.affiliation: Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, UK; University Hospital South Manchester NHS Foundation Trust, Manchester, UK; Medicines Evaluation Unit, Manchester, UK.
authors.forename: Dave
authors.initials: D
authors.lastname: Singh
mesh_terms: D000280:Administration, Inhalation; D000328:Adult; D000368:Aged; D001507:Beclomethasone / Q000008:administration & dosage*; D001993:Bronchodilator Agents / Q000008:administration & dosage*; D004311:Double-Blind Method; D005260:Female; D005541:Forced Expiratory Volume; D000068759:Formoterol Fumarate / Q000008:administration & dosage*; D005938:Glucocorticoids / Q000008:administration & dosage*; D006024:Glycopyrrolate / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage*; D009330:Nebulizers and Vaporizers; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*; D000069447:Tiotropium Bromide / Q000008:administration & dosage*
chemical_list: D001993:Bronchodilator Agents; D005938:Glucocorticoids; D018727:Muscarinic Antagonists; D001507:Beclomethasone; D006024:Glycopyrrolate; D000068759:Formoterol Fumarate; D000069447:Tiotropium Bromide