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

Lancet. 2017 May 13;389(10082):1919-1929. doi: 10.1016/S0140-6736(17)30188-5. Epub 2017 Apr 3.

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 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.

Funding: Chiesi Farmaceutici SpA.

Publication types

  • Comparative Study
  • Randomized Controlled Trial

MeSH terms

  • Administration, Inhalation
  • Adult
  • Aged
  • Beclomethasone / administration & dosage*
  • Bronchodilator Agents / administration & dosage*
  • Double-Blind Method
  • Female
  • Forced Expiratory Volume
  • Formoterol Fumarate / administration & dosage*
  • Glucocorticoids / administration & dosage*
  • Glycopyrrolate / administration & dosage*
  • Humans
  • Male
  • Middle Aged
  • Muscarinic Antagonists / administration & dosage*
  • Nebulizers and Vaporizers
  • Pulmonary Disease, Chronic Obstructive / drug therapy*
  • Tiotropium Bromide / administration & dosage*

Substances

  • Bronchodilator Agents
  • Glucocorticoids
  • Muscarinic Antagonists
  • Beclomethasone
  • Glycopyrrolate
  • Formoterol Fumarate
  • Tiotropium Bromide

Associated data

  • ClinicalTrials.gov/NCT01911364