Elsevier

The Lancet

Volume 391, Issue 10125, 17–23 March 2018, Pages 1076-1084
The Lancet

Articles
Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial

https://doi.org/10.1016/S0140-6736(18)30206-XGet rights and content

Summary

Background

Evidence is scarce on the relative risk-benefit of inhaled triple therapy, consisting of inhaled corticosteroid, long-acting muscarinic antagonist, and long-acting β2-agonist, versus dual bronchodilation for chronic obstructive pulmonary disease (COPD). We aimed to compare a single-inhaler triple combination of beclometasone dipropionate, formoterol fumarate, and glycopyrronium (BDP/FF/G) versus a single-inhaler dual bronchodilator combination of indacaterol plus glycopyrronium (IND/GLY) in terms of the rate of moderate-to-severe COPD exacerbations over 52 weeks of treatment.

Methods

This randomised, parallel-group, double-blind, double-dummy study was done at 187 sites across 17 countries. Eligible patients had symptomatic COPD, severe or very severe airflow limitation, at least one moderate or severe exacerbation in the previous year, and were receiving inhaled maintenance medication. After a 2 week run-in period with one inhalation per day of IND/GLY (85 μg/43 μg), patients were randomly assigned (1:1), via an interactive response technology system, to receive 52 weeks of treatment with two inhalations of extrafine BDP/FF/G (87 μg/5 μg/9 μg) twice per day or one inhalation of IND/GLY (85 μg/43 μg) per day. Randomisation was stratified by country and severity of airflow limitation. The primary endpoint was the rate of moderate-to-severe COPD exacerbations across 52 weeks of treatment in all randomised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment. Safety was assessed in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02579850.

Findings

Between May, 29 2015, and July 10, 2017, 1532 patients received BDP/FF/G (n=764) or IND/GLY (n=768). Moderate-to-severe exacerbation rates were 0·50 per patient per year (95% CI 0·45–0·57) for BDP/FF/G and 0·59 per patient per year (0·53–0·67) for IND/GLY, giving a rate ratio of 0·848 (0·723–0·995, p=0·043) in favour of BDP/FF/G. Adverse events were reported by 490 (64%) of 764 patients receiving BDP/FF/G and 516 (67%) of 768 patients receiving IND/GLY. Pneumonia occurred in 28 (4%) patients receiving BDP/FF/G versus 27 (4%) patients receiving IND/GLY. One treatment-related serious adverse event occurred in each group: dysuria in a patient receiving BDP/FF/G and atrial fibrillation in a patient receiving IND/GLY.

Interpretation

In patients with symptomatic COPD, severe or very severe airflow limitation, and an exacerbation history despite maintenance therapy, extrafine BDP/FF/G significantly reduced the rate of moderate-to-severe exacerbations compared with IND/GLY, without increasing the risk of pneumonia.

Funding

Chiesi Farmaceutici.

Introduction

Chronic obstructive pulmonary disease (COPD) is characterised by persistent respiratory symptoms and airflow limitation that is usually caused by significant exposure to noxious particles or gases.1 Chronic inflammation causes structural changes, narrowing of small airways, and destruction of the lung parenchyma, resulting in persistent airflow limitation, chronic respiratory symptoms, and exacerbations.1 Inhaled triple therapy, consisting of a corticosteroid, a long-acting β2-agonist, and a long-acting muscarinic antagonist, is recommended by the Global Initiative for Obstructive Lung Disease for patients who have further exacerbations despite dual bronchodilation with a long-acting β2-agonist plus a long-acting muscarinic antagonist or a long-acting β2-agonist plus an inhaled corticosteroid.1 Triple therapy is commonly used in clinical practice,2, 3 but there is little evidence to support the risk-benefit of triple therapy versus dual bronchodilation. In particular, no studies have directly compared single-inhaler triple therapy with single-inhaler dual bronchodilator therapy for reducing exacerbations.

A single-inhaler triple therapy is available consisting of an extrafine formulation (ie, with mass median aerodynamic diameter <2 μm) of the inhaled corticosteroid beclometasone dipropionate (BDP), the long-acting β2-agonist formoterol fumarate (FF), and the long-acting muscarinic antagonist glycopyrronium (G). Two previous 52 week studies have already assessed the efficacy and safety of this combination: in the TRILOGY study,4 BDP/FF/G reduced the rate of COPD exacerbations by 23% compared with BDP/FF, whereas in TRINITY,5 BDP/FF/G reduced the rate of COPD exacerbations by 20% compared with the long-acting muscarinic antagonist tiotropium.5 In the present study, TRIBUTE, we compared the effects of BDP/FF/G with those of a single-inhaler combination of the long-acting β2-agonist indacaterol plus glycopyrronium (IND/GLY). We chose IND/GLY as the comparator in this study because this combination has shown greater efficacy than both long-acting muscarinic antagonist monotherapy and the combination of an inhaled corticosteroid plus long-acting β2-agonist in terms of the rate of moderate-to-severe exacerbations.6, 7 We aimed to compare BDP/FF/G with IND/GLY in terms of the rate of moderate-to-severe COPD exacerbations over 52 weeks of treatment.

Research in context

Evidence before this study

We searched PubMed for articles published before Jan 4, 2018, using the search term “Drug Therapy, Combination”[MeSH Terms] OR triple AND COPD AND trial, with no limits applied. Of the 565 search results, 30 presented data from clinical trials investigating the efficacy of triple therapy consisting of an inhaled corticosteroid plus a long-acting β2-agonist plus a long-acting muscarinic antagonist. Only two of these studies included a group receiving a long-acting β2-agonist plus a long-acting muscarinic antagonist. One study compared the efficacy of triple therapy or dual bronchodilation with that of long-acting muscarinic antagonist monotherapy; although there were no formal statistical comparisons between triple therapy and dual bronchodilation, compared with patients receiving dual bronchodilation fewer patients receiving triple therapy had an exacerbation during the 1 year follow-up. The second study recruited patients who were newly diagnosed with COPD following referral for a surgical intervention for lung cancer, and who were then randomised to 1 week of treatment with triple therapy or dual bronchodilation.

Added value of this study

TRIBUTE is, to our knowledge, the first long-term study to specifically compare the effects of triple therapy in a single inhaler with those of dual bronchodilation on the rate of exacerbations.

Implications of all the available evidence

Compared with dual bronchodilator therapy, 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 patients with symptomatic COPD, an FEV1 of less than 50%, and an exacerbation history, despite maintenance therapy.

Section snippets

Study design

TRIBUTE was a randomised, parallel-group, double-blind, double-dummy, active-controlled phase 3b study, done at 187 sites across 17 countries (appendix). The sites were a mixture of primary (n=37), secondary (n=104) and tertiary care centres (n=1), and specialised investigation units (n=45).

Patients who met the inclusion and exclusion criteria at screening (visit 1) had their COPD maintenance therapy switched to one inhalation of IND/GLY per day for a 2 week open-label run-in period (appendix).

Results

The study took place between May 29, 2015, and July 10, 2017. We recruited 2103 patients, of whom 1532 were eligible to be randomly assigned to one of the treatment groups. The study was completed by 666 (87%) of 764 patients assigned to the BDP/FF/G group and 648 (84%) of 768 patients in the IND/GLY group (figure 1). Compliance to treatment was high; the median of percentage of doses taken was 98·6% in the BDP/FF/G group and 98·4% in the IND/GLY group. Baseline characteristics of the recruited

Discussion

Our results showed that the inhaled corticosteroid-containing triple combination of extrafine BDP/FF/G in a single inhaler was associated with a significantly larger reduction in rate of moderate-to-severe COPD exacerbations than the dual bronchodilator combination of IND/GLY over 52 weeks of treatment, without differences in adverse effects, particularly pneumonia.

This study is, to our knowledge, the first to specifically compare single-inhaler triple therapy with a fixed single-inhaler dual

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