Triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicentre, phase 3 randomised controlled trial

doi:10.1016/S2213-2600(18)30327-8

The Lancet Respiratory Medicine

Volume 6, Issue 10, October 2018, Pages 747-758

https://doi.org/10.1016/S2213-2600(18)30327-8 Get rights and content

Summary

Background

Inhaled corticosteroids have been used in patients with chronic obstructive pulmonary disease (COPD), but the potential benefits of their use in triple therapy are not well known. We aimed to compare the efficacy of a triple therapy with corresponding dual therapies in symptomatic patients with moderate to very severe COPD, without a requirement for a history of exacerbations.

Methods

In this double-blind, parallel-group, multicentre phase 3 randomised controlled trial, we recruited patients from hospitals and care centres in Canada, China, Japan, and the USA. Eligible patients were 40–80 years of age, were current or former smokers (with a smoking history of ≥10 pack-years), had an established clinical history of COPD, and were symptomatic for COPD, despite receiving two or more inhaled maintenance therapies for at least 6 weeks before screening. We randomly assigned patients (2:2:1:1) using an interactive web response system to receive budesonide/glycopyrrolate/formoterol fumarate metered-dose inhaler 320/18/9·6 μg (BGF MDI), glycopyrrolate/ formoterol fumarate metered-dose inhaler 18/9·6 μg (GFF MDI), budesonide/formoterol fumarate metered-dose inhaler 320/9·6 μg (BFF MDI), or open-label budesonide/formoterol fumarate dry-powder inhaler 400/12 μg (BUD/ FORM DPI). Primary endpoints for the Europe/Canada statistical analysis approach were FEV₁ area under the curve from 0–4 h (AUC_0–4) for BGF MDI versus BFF MDI and BGF MDI versus BUD/FORM DPI over 24 weeks; and change from baseline in morning pre-dose trough FEV₁ for BGF MDI versus GFF MDI and non-inferiority of BFF MDI versus BUD/FORM DPI (margin of −50 mL from lower bound of 95% CI) over 24 weeks. Comparisons with BUD/FORM DPI were made for the Europe/Canada statistical analysis approach only. This study is registered with ClinicalTrials.gov, number NCT02497001.

Findings

Between Aug 20, 2015, and Jan 5, 2018, 3047 patients were screened from 215 sites, and 1902 were randomly assigned to receive BGF MDI (n=640), GFF MDI (n=627), BFF MDI (n=316), or BUD/FORM DPI (n=319). Over 24 weeks, BGF MDI significantly improved FEV₁ AUC_0–4 versus BFF MDI (least squares mean difference 104 mL, 95% CI 77 to 131; p<0·0001) and BUD/FORM DPI (91 mL, 64 to 117; p<0·0001). BGF MDI also significantly improved pre-dose trough FEV₁ versus GFF MDI (22 mL, 4 to 39; p=0·0139) and BFF MDI was non-inferior to BUD/FORM DPI (−10 mL, −36 to 16; p=0·4390). At week 24, patients in the BGF MDI group had a significantly improved FEV₁ AUC_0–4 compared with patients receiving BFF MDI (116 mL, 95% CI 80 to 152; p<0·0001); there was a non-significant improvement in the change from baseline in morning pre-dose trough FEV₁ at week 24 versus GFF MDI (13 mL, −9 to 36 mL; p=0·2375). The most common treatment-emergent adverse events were nasopharyngitis (n=49 [8%] in the BGF MDI group; n=41 [7%] in the GFF MDI group; n=26 [8%] in the BFF MDI group; and n=30 [9%] in the BUD/FORM DPI group) and upper respiratory tract infection (n=65 [10%]; n=38 [6%]; n=18 [6%]; and n=22 [7%]). Pneumonia incidence was low (<2%) and similar across treatments. There were two treatment-related deaths, both in the GFF MDI group.

Interpretation

BGF MDI was efficacious, well tolerated, and could be a more appropriate treatment than the corresponding dual therapies for symptomatic patients with moderate to very severe COPD, irrespective of exacerbation history.

Funding

Pearl—a member of the AstraZeneca Group.

Introduction

Long-acting bronchodilators, including long-acting muscarinic antagonists (LAMAs) and long-acting β₂-agonists (LABAs), used alone or in combination, play an important part in the maintenance treatment of chronic obstructive pulmonary disease (COPD) at all stages of disease severity.¹ Triple therapy containing dual bronchodilators and an inhaled corticosteroid is recommended only as a treatment option for patients with high exacerbation risk who continue to have symptoms or exacerbations while receiving treatment, particularly LAMA and LABA, or inhaled corticosteroid and LABA.¹ Despite guidance relating to which patients benefit from the addition of an inhaled corticosteroid to other treatments, real-world evidence suggests that inhaled corticosteroids are commonly prescribed to patients with high or low exacerbation risk,² often as an open triple therapy with a fixed-dose combination of inhaled corticosteroid with a LABA and a LAMA.³

Research in context

Evidence before this study

The benefits of therapies containing inhaled corticosteroids have been shown in patients with chronic obstructive pulmonary disease (COPD), but concern regarding the risk-to-benefit ratio of long-term administration of inhaled corticosteroids has led to their recommended use only as a treatment option in patients with a history of exacerbations who continue to experience disease symptoms or exacerbations. However, real-world evidence suggests that inhaled corticosteroids are prescribed to patients with COPD across the spectrum of symptom severity and exacerbation risk. Potential benefits of fixed-dose combination triple therapy (inhaled corticosteroid, long-acting muscarinic antagonist [LAMA], and long-acting β₂-agonist [LABA]), compared with fixed-dose combination dual therapies (LAMA and LABA or inhaled corticosteroid and LABA), are not well defined in symptomatic patients with COPD, particularly those with low exacerbation risk. Furthermore, the role of blood eosinophil counts as a predictor of patient response to inhaled corticosteroid therapy is unclear and largely based on retrospective analyses.

Added value of this study

To our knowledge, KRONOS is the first phase 3 study of a triple fixed-dose combination inhaled corticosteroid, LAMA, and LABA therapy in which the trial population was not enriched for patients who had COPD exacerbations in the year before study entry. The study population is representative of the majority of patients with moderate to very severe COPD who are seen in a clinical setting. More than 80% of the patients in KRONOS were symptomatic patients with moderate to very severe COPD who were not at high risk of exacerbations, a population that has not previously been the focus of phase 3 studies of triple therapies. We also did a prespecified subgroup analysis to investigate the relationship between blood eosinophil counts and treatment effects on lung function and exacerbation rates.

Implications of all the available evidence

Triple therapy improved lung function and symptoms, and reduced COPD exacerbations compared with dual fixed-dose combination therapies of inhaled corticosteroid and LABA, and LAMA and LABA, and was well tolerated in this patient population. The improvements in pre-dose trough FEV₁ for BGF MDI versus GFF MDI were mainly in patients with baseline eosinophil levels higher than approximately 250 cells/mm³, whereas improvements in pre-dose trough FEV₁ for BGF MDI versus BFF MDI were evident over a broad range of eosinophil levels. There were reductions of approximately 20% in the rate of moderate or severe exacerbations in the BGF MDI group versus the GFF MDI group, associated with eosinophil concentrations that most patients exceeded. This finding suggests that triple therapy with BGF MDI could be more effective in improving lung function and reducing the exacerbation risk than LAMA/LABA dual therapy in most patients with COPD.

Although adding an inhaled corticosteroid to a LABA has repeatedly been shown to improve airflow limitation,4, 5 quality of life,4, 5 and exacerbation rates4, 6, 7 compared with use of a LABA alone, questions remain relating to the long-term use of inhaled corticosteroids in COPD, especially given the pneumonia risk reported in some studies8, 9 and the apparent limited effect of an inhaled corticosteroid and LABA on reducing exacerbations compared with a dual LAMA and LABA combination, as reported in one large study.¹⁰ It continues to be debated whether peripheral eosinophil counts can be used to predict exacerbation risk or to identify patients with COPD who might clinically respond to inhaled corticosteroids.11, 12

Triple fixed-dose combinations of inhaled corticosteroid, LAMA, and LABA have been developed for COPD,13, 14, 15, 16 but the potential benefits of triple versus dual fixed-dose combination therapies (LAMA and LABA, or inhaled corticosteroid and LABA) are not well characterised across the spectrum of patients with COPD, with most studies to date focused on patients with a high frequency of exacerbations or severe or very severe airflow limitation, or both.13, 14, 15, 16, 17 Budesonide/glycopyrrolate/formoterol fumarate metered-dose inhaler (BGF MDI), formulated with co-suspension delivery technology, is a triple fixed-dose combination of inhaled corticosteroid, LAMA, and LABA that is in development as a maintenance therapy for patients with COPD. Co-suspension delivery technology facilitates the formulation of multiple drugs into a single MDI device that provides consistent aerosol performance¹⁸ and drug deposition throughout the lungs.¹⁹

In this study, we aimed to compare triple therapy (BGF MDI) with dual therapies (glycopyrrolate/formoterol fumarate [GFF] MDI and budesonide/formoterol fumarate [BFF] MDI), in symptomatic patients with moderate to very severe COPD, irrespective of exacerbation history, measuring lung function, exacerbations, symptoms, and quality of life, and analysing the potential effect of peripheral eosinophil counts on treatment outcomes.

Section snippets

Study design and participants

KRONOS was a randomised, double-blind, parallel-group, phase 3 randomised controlled trial done in 215 sites across four countries (Canada, China, Japan, and the USA). Study sites included hospitals (n=108) and other care centres (n=107; mainly primary care and specialty centres).

Eligible patients were aged 40–80 years; were current or former smokers (with a smoking history of ≥10 pack-years); had an established clinical history of COPD, as defined by the American Thoracic Society

Results

Between Aug 20, 2015, and Jan 5, 2018, 3047 patients were screened, of whom 1902 were randomly assigned to receive BGF MDI (n=640), GFF MDI (n=627), BFF MDI (n=316), or BUD/FORM DPI (n=319; figure 1).

Overall, 1411 (74%) of 1896 patients in the modified intention-to-treat population had no exacerbations in the preceding 12 months, and 88% had no severe exacerbations and 1 or 0 moderate exacerbations in the preceding 12 months, 71·8% were receiving inhaled corticosteroids at screening, and 51·8%

Discussion

BGF MDI provided clinically meaningful improvements in lung function versus BFF MDI and BUD/FORM DPI, with modest improvements reported for BGF MDI versus GFF MDI. However, the primary reason for inhaled corticosteroid use in COPD is to control exacerbations, and there were significant reductions in exacerbation rates for BGF MDI versus GFF MDI. BFF MDI was non-inferior to BUD/FORM DPI for the primary and most secondary endpoints.

Unlike previous phase 3 trials of triple therapies (fixed-dose

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ArticlesTriple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicentre, phase 3 randomised controlled trial

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Respir Med

Respir Med

Lancet Respir Med

Respir Med

Lancet

Lancet

Lancet

Eur J Pharm Sci

Chest

Lancet Respir Med

Pulm Pharmacol Ther

Global strategy for the diagnosis, management and prevention of COPD

A cross-sectional survey of current treatment and symptom burden of patients with COPD consulting for routine care according to GOLD 2014 classifications

Int J Chron Obstruct Pulmon Dis

The inevitable drift to triple therapy in COPD: an analysis of prescribing pathways in the UK

Int J Chron Obstruct Pulmon Dis

Efficacy and tolerability of budesonide/formoterol in one hydrofluoroalkane pressurized metered-dose inhaler in patients with chronic obstructive pulmonary disease: results from a 1-year randomized controlled clinical trial

Drugs

Articles
Triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicentre, phase 3 randomised controlled trial