New England Journal of Medicine July 02, 2020

Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very-Severe COPD

Klaus F. Rabe, Fernando J. Martinez, Gary T. Ferguson, Chen Wang, Dave Singh, Jadwiga A. Wedzicha, Roopa Trivedi, Earl St. Rose, Shaila Ballal, Julie McLaren, Patrick Darken, Magnus Aurivillius, Colin Reisner, Paul Dorinsky

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Bottom Line

In the Phase 3 ETHOS trial, single-inhaler triple therapy containing budesonide, glycopyrrolate, and formoterol significantly reduced moderate-to-severe exacerbations and lowered all-cause mortality compared with dual therapies in patients with advanced COPD.

Key Findings

1. The annual rate of moderate or severe exacerbations was 1.08 for the 320-μg budesonide triple-therapy arm (BGF-320), 1.07 for the 160-μg budesonide triple-therapy arm (BGF-160), 1.42 for the glycopyrrolate-formoterol arm (GFF), and 1.24 for the budesonide-formoterol arm (BFF).

2. BGF-320 reduced the rate of moderate or severe exacerbations by 24% compared to GFF (Rate Ratio [RR], 0.76; 95% CI, 0.69 to 0.83; P<0.001) and by 13% compared to BFF (RR, 0.87; 95% CI, 0.79 to 0.95; P=0.003).

3. BGF-160 demonstrated a similar reduction in exacerbations, achieving a 25% decrease versus GFF (RR, 0.75; 95% CI, 0.69 to 0.83; P<0.001) and a 14% decrease versus BFF (RR, 0.86; 95% CI, 0.79 to 0.95; P=0.002).

4. All-cause mortality (a key secondary endpoint) over 52 weeks was significantly lower in the BGF-320 arm compared with the GFF arm, demonstrating an unadjusted 46% risk reduction (HR, 0.54; 95% CI, 0.34 to 0.87) in the primary NEJM analysis, which was later corroborated as a 49% risk reduction (HR, 0.51; 95% CI, 0.33 to 0.80) in the final retrieved data set published in 2021.

5. The incidence of confirmed pneumonia was higher in the arms containing inhaled corticosteroids (3.5% to 4.5%) compared to the LAMA/LABA dual therapy arm (2.3%).

Study Design

Design

RCT

Double-Blind

Sample

8,509

Patients

Duration

52 wk

Median

Setting

Multicenter, multinational

Population Patients aged 40 to 80 years with symptomatic (CAT score ≥10), moderate-to-very-severe COPD (FEV1 25-65% of predicted) receiving ≥2 inhaled maintenance therapies, with a smoking history of ≥10 pack-years, and ≥1 moderate-to-severe exacerbation in the past year.

Intervention Single-inhaler triple therapy with budesonide, glycopyrrolate, and formoterol fumarate (BGF) twice daily, administered at either a standard budesonide dose (320/18/9.6 μg) or a lower dose (160/18/9.6 μg).

Comparator Single-inhaler dual therapies: a LAMA/LABA combination (glycopyrrolate/formoterol fumarate 18/9.6 μg [GFF]) or an ICS/LABA combination (budesonide/formoterol fumarate 320/9.6 μg [BFF]) twice daily.

Outcome The annual rate of moderate or severe COPD exacerbations over 52 weeks.

Study Limitations

• The trial was 52 weeks in duration, which may not be long enough to definitively capture the long-term safety profile and long-term trajectory of mortality benefits of triple therapy.

• A large proportion of enrolled patients were already receiving inhaled corticosteroids (ICS) prior to trial entry. Randomizing these patients to a LAMA/LABA arm involves abrupt ICS withdrawal, which can precipitate exacerbations and artificially inflate the comparative benefit of the triple therapy arms.

• Patients with a current asthma diagnosis were excluded, but patients with asthma-COPD overlap or simply elevated blood eosinophils were included, which could mean the ICS-driven benefits are concentrated in a specific phenotypic subgroup rather than all COPD patients.

• Mortality was analyzed as a secondary endpoint. Although the findings were statistically significant, the relatively low absolute number of deaths requires careful interpretation and prompted subsequent data retrieval efforts to finalize.

Clinical Significance

The ETHOS trial is a landmark study establishing single-inhaler triple therapy as standard-of-care for patients with severe, exacerbation-prone COPD. Alongside the IMPACT trial, it proved that combining an inhaled corticosteroid with dual bronchodilators not only minimizes the burden of acute exacerbations but confers a rare, highly sought-after mortality benefit in a disease previously thought resistant to disease-modifying therapies. The study further clarified that both standard and lower doses of budesonide mitigate exacerbations, although the mortality benefit was most definitive with the standard (320-μg) dose.

Historical Context

Historically, mortality in COPD was notoriously difficult to impact pharmacologically; benefits were largely confined to smoking cessation, long-term oxygen therapy, and lung volume reduction surgery. Earlier monumental trials, like TORCH (2007), failed to show a statistically significant mortality benefit for ICS/LABA versus placebo and raised alarms regarding an increased risk of pneumonia. The IMPACT trial (2018) changed the paradigm by showing a mortality benefit with triple therapy, but generated controversy regarding ICS withdrawal effects in its control arms. ETHOS (2020) validated the IMPACT findings using a different medication combination (budesonide/glycopyrrolate/formoterol), firmly entrenching triple therapy in the GOLD guidelines for patients with frequent exacerbations and elevated eosinophils.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the pharmacological rationale for combining an inhaled corticosteroid (ICS), a long-acting muscarinic antagonist (LAMA), and a long-acting beta-agonist (LABA) in the management of severe COPD, and how do their mechanisms synergize?

Key Response

LABAs stimulate beta-2 receptors for bronchodilation, LAMAs block M3 receptors to prevent bronchoconstriction and reduce mucus hypersecretion, and ICS reduces airway inflammation. Synergistically, corticosteroids upregulate beta-2 receptor expression, preventing LABA tachyphylaxis, while the bronchodilators improve the peripheral deposition of the ICS.

Resident

In light of the ETHOS trial demonstrating mortality benefits with triple therapy, which specific patient profiles in the clinic should be escalated from dual therapy (LAMA/LABA) to triple therapy, and what key biomarker should guide this decision?

Key Response

Patients with frequent exacerbations (2 or more moderate, or 1 or more leading to hospitalization in the past year) despite optimal dual bronchodilation should be escalated. Blood eosinophil count (typically >100 or >300 cells/mcL) is the key biomarker; higher eosinophils strongly predict a better response to the addition of an ICS, balancing the exacerbation and mortality benefit against the increased risk of pneumonia.

Fellow

The ETHOS trial showed a significant reduction in all-cause mortality with the 320-mcg budesonide triple therapy compared to LAMA/LABA. How does the withdrawal effect of prior ICS use in the run-in period potentially confound this mortality benefit, and how should we interpret the results for ICS-naive patients?

Key Response

Many patients entering COPD trials are already on ICS. Discontinuing ICS during the run-in period to randomize them to LAMA/LABA can precipitate exacerbations in steroid-dependent patients, artificially inflating the apparent benefit of the ICS-containing triple therapy arm. Fellows must recognize that while the mortality benefit is groundbreaking, its magnitude might be most applicable to patients already exhibiting an eosinophilic phenotype that warrants ICS, rather than being an automatic starting point for ICS-naive patients.

Attending

Considering the ETHOS trial evaluated two different doses of budesonide (160 mcg and 320 mcg), how do we balance the mortality and exacerbation benefits of the higher ICS dose against the long-term cumulative risks of ICS in an aging COPD population?

Key Response

While the 320-mcg dose showed a statistically significant all-cause mortality benefit compared to LAMA/LABA, attendings must weigh this against the dose-dependent risks of ICS like pneumonia, osteoporosis, and cataracts. The choice between 160 mcg and 320 mcg must be personalized: the higher dose may be reserved for patients with severe frequent exacerbations and high eosinophils who prioritize mortality reduction, while stepping down to the 160 mcg dose could be considered in patients stabilizing over time to mitigate long-term risks.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The ETHOS trial assessed all-cause mortality as a secondary endpoint. What are the statistical implications of hierarchical testing procedures in this context, and how does the handling of informative censoring for patients who discontinued the trial drug impact the robustness of the mortality findings?

Key Response

In severe COPD trials, differential dropout rates are common, often higher in the LAMA/LABA arm due to exacerbations. If mortality vital status is not rigorously retrieved for patients who drop out (informative censoring), survival curves can be biased. Researchers must scrutinize the estimands and sensitivity analyses used to handle this missingness, as well as ensure that Type I error is controlled when testing secondary endpoints like mortality after primary exacerbation outcomes.

Journal Editor

As a peer reviewer analyzing the ETHOS trial, what concerns arise from the choice of the specific dual therapy comparators (Budesonide/Formoterol and Glycopyrrolate/Formoterol) rather than an existing standard-of-care single-inhaler triple therapy, and how does this affect the study's external validity?

Key Response

A critical reviewer would flag that comparing a new single-inhaler triple therapy to dual therapies proves it is better than step-down care for severe exacerbators, but it does not establish superiority or non-inferiority against existing triple therapies (e.g., fluticasone/umeclidinium/vilanterol). Additionally, the specific dual therapies used may have different pharmacokinetic profiles than those currently favored, raising questions about whether the observed effect size is purely a class effect or specific to this formulation.

Guideline Committee

Current GOLD guidelines recommend escalating to triple therapy for Group E patients with elevated eosinophils. Based on the ETHOS mortality data, should the guidelines shift to recommend triple therapy as the initial standard of care for all Group E patients, or should the blood eosinophil threshold remain a strict gateway?

Key Response

Current GOLD guidelines recommend considering triple therapy strongly when eosinophils are >300 cells/mcL, or >100 with frequent exacerbations. Despite ETHOS showing a mortality benefit, the committee must consider that the ICS benefit is highly correlated with eosinophil levels, while the risk of pneumonia remains. Therefore, guidelines should likely maintain eosinophils as a critical biomarker for phenotyping, reserving triple therapy as an initial step only for those with the appropriate biomarker profile to avoid over-treating low-eosinophil patients with ICS.

Clinical Landscape

Noteworthy Related Trials

2018

IMPACT Trial

n = 10,355 · NEJM

Tested

Fluticasone furoate, umeclidinium, and vilanterol

Population

Patients with symptomatic COPD and a history of exacerbations

Comparator

Fluticasone furoate/vilanterol or umeclidinium/vilanterol

Endpoint

Annual rate of moderate or severe COPD exacerbations

Key result: Triple therapy resulted in a significantly lower rate of moderate or severe COPD exacerbations and lower all-cause mortality than dual therapies.

2018

TRIBUTE Trial

n = 1,532 · Lancet

Tested

Beclometasone, formoterol, and glycopyrronium

Population

Patients with symptomatic COPD and severe airflow limitation

Comparator

Indacaterol and glycopyrronium

Endpoint

Rate of moderate-to-severe COPD exacerbations

Key result: Triple therapy significantly reduced the rate of moderate-to-severe exacerbations compared to dual bronchodilator therapy without inhaled corticosteroids.

2018

KRONOS Trial

n = 1,902 · Lancet Respir Med

Tested

Budesonide, glycopyrronium, and formoterol

Population

Patients with moderate-to-very-severe COPD

Comparator

Glycopyrronium/formoterol or budesonide/formoterol

Endpoint

Lung function assessed by FEV1 AUC0-4 and trough FEV1

Key result: Triple therapy significantly improved lung function and reduced exacerbation rates compared with dual therapies.

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