Elsevier

The Lancet

Volume 389, Issue 10082, 13–19 May 2017, Pages 1919-1929
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(17)30188-5Get rights and content

Summary

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.

Introduction

Chronic obstructive pulmonary disease (COPD) is a progressive disease, characterised by the presence of persistent respiratory symptoms, such as breathlessness, cough, and phlegm, and exacerbations.1 Much of the burden of COPD is due to exacerbations, which are associated with increased disease progression, reduced quality of life, and increased costs (especially from hospitalisation).2, 3, 4, 5 In patients at risk of exacerbations, most current guidelines recommend starting with either a long-acting muscarinic antagonist or a combination of an inhaled corticosteroid and a long-acting β2-agonist.1, 6 Triple therapy with an inhaled corticosteroid, a long-acting β2-agonist, and a long-acting muscarinic antagonist is recommended in patients with exacerbations despite initial treatment,1, 6 and is frequently used for the management of COPD. However, few studies have addressed the added value of triple therapy for preventing exacerbations. Although two 12-week studies7, 8 have suggested that triple therapy can provide a greater reduction in exacerbations compared with a long-acting muscarinic antagonist, longer trials are needed to assess moderate and severe exacerbations, not least because of their marked seasonality.9 One long term study10 compared triple therapy with a long-acting muscarinic antagonist but showed no reduction in exacerbation rate by 12 months. However, this study did not evaluate the clinical efficacy of a triple therapy delivered in a single inhaler.

Currently, patients with COPD receiving triple therapy must use at least two inhalers, typically a combined inhaled corticosteroid plus long-acting β2-agonist in one inhaler and a long-acting muscarinic antagonist in another. Often these inhalers are of different types and designs, which might in turn negatively impact correct inhaler use and treatment adherence. A single inhaler combining extrafine formulations of the inhaled corticosteroid beclometasone dipropionate (BDP), the long-acting β2-agonist formoterol fumarate (FF) and the long-acting muscarinic antagonist glycopyrronium bromide (GB) has been developed to simplify this regimen, with extrafine formulations able to reach and treat not only the large airways but also the small airways.11 In the TRINITY study, we aimed to evaluate the use of extrafine BDP/FF/GB (fixed triple) over a monotherapy long-acting muscarinic antagonist, tiotropium, with a free combination of BDP/FF in one inhaler and tiotropium in a second inhaler (open triple) as a control.

Research in context

Evidence before this study

We searched PubMed for articles published before Sept 13, 2016, with no start date or language restrictions, using the search terms “Drug Therapy, Combination” [MeSH Terms] OR “triple” AND “COPD” AND “trial”, with no limits applied. Of the 524 results, 18 studies presented data from clinical trials evaluating the efficacy of triple therapy with an inhaled corticosteroid plus a long-acting β2-agonist plus a long-acting muscarinic antagonist, with one retrospective cohort analysis. Of these, six studies compared triple therapy with a long-acting muscarinic antagonist therapy; and five compared triple therapy with both a long-acting muscarinic antagonist and an inhaled corticosteroid plus a long-acting β2-agonist. Although most studies were of short duration (mostly 12–24 weeks), a number showed a reduction in the rate of exacerbations for triple therapy versus long-acting muscarinic antagonist, together with a consistent improvement in bronchodilation. However, results were more variable for the other endpoints, including health-related quality of life, and none of these studies used a single inhaler triple combination.

Added value of this study

To our knowledge, this is the first long-term study specifically designed to evaluate the effect of a single inhaler triple therapy versus long-acting muscarinic antagonist therapy on the rate of exacerbations in a population at high exacerbation risk.

Implications of all the available evidence

By comparison with long-acting muscarinic antagonist alone, triple therapy with an inhaled corticosteroid, a long-acting β2-agonist and a long-acting muscarinic antagonist in a single inhaler reduces the rate of COPD exacerbations in this high-risk population, together with improvements in lung function, and in a range of other clinically relevant measures.

Section snippets

Study design

Our study was a randomised, parallel group, double-blind, double-dummy, active-controlled trial, at 224 sites across 15 countries (six in Argentina, five in Belarus, ten in Bulgaria, five in Croatia, 17 in Germany, 14 in Hungary, three in Italy, five in Mexico, 33 in Poland, 16 in Romania, 53 in Russia, six in Slovakia, five in Turkey, three in the UK, and 43 in Ukraine. The sites were a mixture of primary care (17), secondary care (121), tertiary care (48), and specialist investigation units

Results

The study ran between Jan 21, 2014, and March 18, 2016. We recruited 3433 patients of whom 2691 were randomly assigned to one of the treatment groups, with 986 (91%) of 1078 completing the study in the fixed triple group, 914 (85%) of 1075 in the tiotropium group, and 496 (92%) of 538 in the open triple group (figure 1). Patients in the tiotropium group were more likely to prematurely withdraw from the study than either of the other two groups (p<0·0001). Compliance to treatment was high, with

Discussion

The study met the primary and both key secondary endpoints. Extrafine fixed triple resulted in a 20% (95% CI 8–31) reduction in the rate of moderate-to-severe COPD exacerbations compared with tiotropium, together with a 0·061 L mean improvement in pre-dose FEV1. Furthermore, the non-inferiority of fixed triple relative to open triple was shown for pre-dose FEV1. Fixed triple reduced both moderate and severe exacerbation rates, hyperinflation (as measured by inspiratory capacity), and rescue

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