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Tiotropium and olodaterol in the prevention of chronic obstructive pulmonary disease exacerbations (DYNAGITO): a double-blind, randomised, parallel-group, active-controlled trial

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Summary

Background

Combinations of long-acting bronchodilators are recommended to reduce the rate of chronic obstructive pulmonary disease (COPD) exacerbations. It is unclear whether combining olodaterol, a long-acting beta-agonist, with tiotropium, a long-acting anti-muscarinic, reduces the rate of exacerbations compared with tiotropium alone.

Methods

This 52-week, double-blind, randomised, parallel-group, active-controlled trial randomly assigned (1:1) patients with COPD with a history of exacerbations using a randomised block design to receive tiotropium–olodaterol 5 μg–5 μg or tiotropium 5 μg once daily. Patients using inhaled corticosteroids continued this therapy. Treatment was masked to patients, investigators, and those involved in analysing the data. The primary endpoint was the rate of moderate and severe COPD exacerbations from the first dose of medication until 1 day after last drug administration. The primary analysis included all randomly assigned patients who received any dose of study medication but were not from a site excluded due to on-site protocol violations. The trial is registered with ClinicalTrials.gov, number NCT02296138.

Findings

Overall, 9009 patients were screened from 818 centres in 51 countries. We recruited 7880 patients between Jan 22, 2015 and March 7, 2016 (mean age 66·4 years [SD 8·5], 5626 [71%] were men, mean FEV1 percent predicted 44·5% [SD 27·7]): 3939 received tiotropium–olodaterol and 3941 tiotropium. The rate of moderate and severe exacerbations was lower with tiotropium–olodaterol than tiotropium (rate ratio [RR] 0·93, 99% CI 0·85–1·02; p=0·0498), not meeting the targeted 0·01 significance level. The proportion of patients reporting adverse events was similar between treatments.

Interpretation

Combining tiotropium and olodaterol did not reduce exacerbation rate as much as expected compared with tiotropium alone.

Funding

Boehringer Ingelheim International GmbH.

Introduction

Symptomatic exacerbations are frequently reported by patients with chronic obstructive pulmonary disease (COPD), and contribute to poor health status, increased risk of death, and increased health-care costs, especially when hospitalisation is necessary.1 Exacerbation frequency is used by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) to assess COPD severity and guide treatment choice.2 Although several non-pharmacological interventions reduce exacerbation risk, there has been a greater focus on pharmacotherapy, since there is evidence that agents such as long-acting bronchodilators, inhaled corticosteroids (ICS), oral antibiotics, and mucolytic drugs can reduce exacerbation frequency.1

Recently, fixed-dose combinations of a long-acting beta-agonist (LABA) and an inhaled long-acting anti-muscarinic (LAMA) drug have been proposed as the initial choice in preventing COPD exacerbations.2 However, the evidence supporting this approach remains limited. The LAMA tiotropium has proven to be more effective than LABA monotherapy,3, 4 and was equivalent to a LABA–ICS combination in preventing exacerbations.5 Although exacerbations were less frequent with LAMA–LABA than LABA–ICS treatment,6 it remains unclear how well LAMA–LABAs perform against tiotropium alone. A combination of indacaterol and glycopyrronium was more effective than glycopyrronium in exacerbation prevention, but was not statistically significantly better than open-label tiotropium, although the study was not powered for the comparison with tiotropium.7 To date, no study has investigated whether adding a LABA to tiotropium in a fixed-dose combination offers additional benefits over tiotropium in exacerbation prevention. Given that tiotropium alone is effective at reducing risk of exacerbation,8 this question is of considerable clinical significance.

Combining the LABA olodaterol with tiotropium in a soft mist inhaler has produced statistically significantly greater improvements in lung function and health status than either drug alone over 52 weeks.9 To determine whether tiotropium–olodaterol reduces the annual rate of exacerbations more than tiotropium alone, we did a double-blind, randomised, parallel-group, active-controlled, 52-week study (designated the DYNAGITO trial).

Research in context

Evidence before this study

We searched PubMed up to Jan 16, 2018, for published articles in English addressing the question of long-acting anti-muscarinic (LAMA)–long-acting beta-agonist (LABA) versus LAMA for exacerbations in patients with chronic obstructive pulmonary disease (COPD), using the search terms “COPD”, “chronic obstructive pulmonary disease”, “exacerbation”, “bronchodilator”, “LAMA”, and “LABA”. Previous studies have shown that tiotropium reduces the risk of exacerbation compared with placebo. Although there were several COPD exacerbation trials investigating combinations of bronchodilators, including the SPARK trial (which compared another LAMA–LABA combination with a LAMA and open-label tiotropium), there was no study comparing a combination of a LABA and tiotropium with tiotropium alone that was powered to detect a difference in exacerbations between treatments.

Added value of this study

It has previously been shown that adding olodaterol to tiotropium offers improvements in lung function, symptoms, and quality of life compared with tiotropium alone, without additional safety or tolerability concerns. This large trial is the first of its kind to address the question of whether adding a LABA to tiotropium can offer further benefits in terms of reducing exacerbations in patients with COPD. The findings showed that the reduction in exacerbation rate was smaller than anticipated and did not reach the planned level of significance. However, there were larger improvements in some subgroups of patients, such as those receiving triple therapy at baseline, and in exacerbations that required oral corticosteroids.

Implications of all of the available evidence

Tiotropium–olodaterol offers benefits for patients with COPD beyond those provided by tiotropium alone, which extend to a small reduction in the risk of exacerbations requiring treatment with corticosteroids. This reduction might be larger in certain subgroups of patients.

Section snippets

Study design and participants

This study was a 52-week, randomised, double-blind, active-controlled, parallel-group trial. Patients with COPD were randomly assigned (1:1) to receive either tiotropium–olodaterol 5 μg–5 μg or tiotropium 5 μg, both delivered once daily (in the morning) via two puffs of the Respimat device (Boehringer Ingelheim, Ingelheim am Rhein, Germany). Patients taking ICS at baseline continued this treatment; those receiving ICS in a fixed-dose combination with a LABA were switched to an equivalent

Results

Patients were recruited from Jan 22, 2015, to March 7, 2016, and the study completed on March 30, 2017. In total, 9009 patients were screened from 818 centres in 51 countries. Of these, 7903 were randomly assigned to treatment and 7880 were treated (figure 1). Mean post-bronchodilator FEV1 at baseline was 1·187 (SD 0·381) L (44·5% predicted). 3132 (40%) patients were receiving LAMA–LABA–ICS, 2036 (26%) were receiving LABA–ICS, and 939 (12%) were receiving LAMA–LABA (table 1). Patients were more

Discussion

In this adequately powered study, there was no significant reduction in the moderate and severe exacerbation rate in patients taking tiotropium–olodaterol compared with tiotropium alone. There was a small difference between treatment groups that met the conventional 5% significance level, but this was below the 1% significance level we targeted. There was no difference in the time to first moderate or severe event between the groups, but patients using ICS during the trial experienced

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