Elsevier

The Lancet

Volume 388, Issue 10048, 3–9 September 2016, Pages 963-973
The Lancet

Articles
Single inhaler triple therapy versus inhaled corticosteroid plus long-acting β2-agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomised controlled trial

https://doi.org/10.1016/S0140-6736(16)31354-XGet rights and content

Summary

Background

Few 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 designed this study to assess efficacy of single-inhaler combination of an extra fine formulation of beclometasone dipropionate, formoterol fumarate, and glycopyrronium bromide (BDP/FF/GB) in COPD compared with beclometasone dipropionate and formoterol fumarate (BDP/FF) treatment.

Methods

TRILOGY was a randomised, parallel group, double-blind, active-controlled study done in 159 sites across 14 countries. The sites were a mixture of primary, secondary, and tertiary care providers, and specialist investigation units. Eligible patients with COPD had post-bronchodilator forced expiratory volume in 1 s (FEV1) of lower than 50%, one or more moderate-to-severe COPD exacerbation in the previous 12 months, COPD Assessment Test total score of 10 or more, and a Baseline Dyspnea Index focal score of 10 or less. Patients who met the inclusion and exclusion criteria at screening entered a 2-week open-label run-in period where they received beclometasone dipropionate (100 μg) and formoterol fumarate (6 μg) in two actuations twice daily. Patients were then randomly assigned (1:1) with an interactive response technology system to either continue BDP (100 μg) and FF (6 μg) or step-up to BDP (100 μg), FF (6 μg), and GB (12·5 μg) in two actuations twice daily for 52 weeks via pressurised metered-dose inhaler. The three co-primary endpoints were pre-dose FEV1, 2-h post-dose FEV1, and Transition Dyspnea Index (TDI) focal score, all measured at week 26 in the intention-to-treat population (all patients who were randomly assigned and received at least one dose of study drug and had at least one post-baseline efficacy assessment). Safety outcomes were measured in the safety population (all patients who were randomly assigned and received at least one dose of study drug). Secondary endpoints included moderate-to-severe COPD exacerbation rate over 52 weeks. This study is registered with ClinicalTrials.gov, number NCT01917331.

Findings

Between March 21, 2014, and Jan 14, 2016, 1368 patients received either BDP/FF/GB (n=687) or BDP/FF (n=681). At week 26, BDP/FF/GB improved pre-dose FEV1 by 0·081 L (95% CI 0·052–0·109; p<0·001) and 2-h post-dose FEV1 by 0·117 L (0·086–0·147; p<0·001) compared with BDP/FF. Mean TDI focal scores at week 26 were 1·71 for BDP/FF/GB and 1·50 for BDP/FF, with a difference of 0·21 (95% CI −0·08 to 0·51; p=0·160). Adjusted annual moderate-to-severe exacerbation frequencies were 0·41 for BDP/FF/GB and 0·53 for BDP/FF (rate ratio 0·77 [95% CI 0·65–0·92]; p=0·005), corresponding to a 23% reduction in exacerbations with BDP/FF/GB compared with BDP/FF. Adverse events were reported by 368 (54%) patients with BDP/FF/GB and 379 (56%) with BDP/FF. One serious treatment-related adverse event occurred (atrial fibrillation) in a patient in the BDP/FF/GB group.

Interpretation

We provide evidence for the clinical benefits of stepping up patients with COPD from an inhaled corticosteroid/long-acting β2-agonist combination treatment to triple therapy using a single inhaler.

Funding

Chiesi Farmaceutici SpA.

Introduction

The goals of pharmacological treatment of chronic obstructive pulmonary disease (COPD) are to reduce symptoms and the risk of future exacerbations.1 Patients with COPD with a history of exacerbations are at an increased risk of future exacerbations,2, 3 and are more likely to have a reduced quality of life,4 more rapid lung function decline,5, 6 and increased mortality.7 To reduce the risk of future events, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) has specific recommendations for these patients; the first choice treatment is a long-acting muscarinic antagonist, or an inhaled corticosteroid plus a long-acting β2 agonist.1 Both of these options have been shown to improve lung function, alleviate symptoms, and reduce exacerbation rates.8, 9

Many patients with COPD continue to have exacerbations despite treatment with either a long-acting muscarinic antagonist or an inhaled corticosteroid plus a long-acting β2-agonist combination. In clinical practice, treatment is often stepped up to “triple therapy” when this occurs, combining an inhaled corticosteroid, a long-acting β2 agonist, and a long-acting muscarinic antagonist.10 Short-term clinical trials have shown that this step up improves lung function and reduces symptoms.11, 12, 13, 14, 15, 16 However, GOLD recognises that there is little evidence for this approach regarding exacerbation reduction.1

Research in context

Evidence before this study

We searched PubMed for articles published before June 9, 2016, using the search term “Drug Therapy, Combination”[MeSH Terms] AND COPD limited to clinical trials with no language restrictions applied. Of the 312 results from this search, 13 presented data from clinical trials assessing the efficacy of triple therapy with an inhaled corticosteroid plus a long-acting β2 agonist plus a long-acting muscarinic antagonist, with one further manuscript presenting data from a retrospective cohort analysis. Of these, four studies compared triple therapy with inhaled corticosteroid/long-acting β2-agonist therapy; three compared triple therapy with both a long-acting muscarinic antagonist and inhaled corticosteroid/long-acting β2-agonist therapy. Triple therapy consistently provided improved bronchodilation (assessed using forced expiratory volume in 1 s; FEV1) compared with inhaled corticosteroid/long-acting β2-agonist therapy. However, results were more variable for the other endpoints, including health-related quality of life, breathlessness, and exacerbations. Most studies were of short duration and had insufficient sample size to assess exacerbations.

Added value of this study

To our knowledge, this is the first large, long-term study to compare a triple inhaled corticosteroid/long-acting β2-agonist/long-acting muscarinic antagonist combination in a single inhaler with an inhaled corticosteroid/long-acting β2-agonist combination. All patients received inhaled corticosteroid/long-acting β2-agonist therapy during the run-in period, and so the study provides an indication of the benefits of stepping up treatment in patients with COPD with both an exacerbation history and symptoms.

Implications of all the available evidence

Compared with inhaled corticosteroid/long-acting β2-agonist therapy, triple therapy with an inhaled corticosteroid/long-acting β2-agonist/long-acting muscarinic antagonist combination provides additive bronchodilation. This study also shows that a reduction in exacerbations can be achieved through this approach with the use of a single inhaler.

Patients with COPD receiving triple therapy currently use at least two inhalers, typically an inhaled corticosteroid plus a long-acting β2-agonist combination in one inhaler and a long-acting muscarinic antagonist in a second, and often these inhalers are of different types and designs. A single inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β2-agonist inhaler combining extra fine formulations of beclometasone dipropionate, formoterol fumarate, and glycopyrronium bromide (BDP/FF/GB) has been developed to simplify this regimen. In the TRILOGY study, we aimed to compare the efficacy and safety of single inhaler triple therapy comprising BDP/FF/GB to that of beclometasone dipropionate and formoterol fumarate (BDP/FF) in patients with COPD who have severe or very severe airflow limitation, symptoms, and an exacerbation history. The recruitment of this patient group allowed us to assess treatment effects on lung function, symptoms, and exacerbations.

Section snippets

Study design and patients

TRILOGY was a randomised, parallel group, double-blind, active-controlled study done in 159 sites across 14 countries. The sites were a mixture of primary (n=18), secondary (n=99), and tertiary care (n=28) providers, and specialist investigation units (n=14). The main inclusion criteria were being aged 40 years or older; having a diagnosis of COPD, with a post-bronchodilator forced expiratory volume in 1 s (FEV1) of less than 50% and a ratio of FEV1 to forced vital capacity (FVC) of less than

Results

The study ran between March 21, 2014, and Jan 14, 2016. We recruited 1812 patients to this study, of whom, 1368 were randomly assigned to one of the treatment groups (687 to BDP/FF/GB and 681 to BDP/FF; figure 1), with 602 (87·6%) completing the study in the BDP/FF/GB group and 579 (85·0%) in the BDP/FF group. Compliance to treatment was high, with a median of 95·6% of doses taken in the BDP/FF/GB group and 95·0% of doses taken in the BDP/FF group. Median exposure in both groups was 365·0 days

Discussion

This study shows that in patients with COPD who have severe or very severe airflow limitation, symptoms, and an exacerbation history, triple therapy with BDP/FF/GB had a greater effect on pre-dose and 2-h post-dose FEV1 than BDP/FF. For the co-primary endpoint measuring breathlessness (TDI), superiority of BDP/FF/GB over BDP/FF was not shown. The rate of moderate-to-severe COPD exacerbations was 23% lower with BDP/FF/GB compared with BDP/FF, with the time to first exacerbation significantly

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