Triple-Therapy Combo Decreases COPD Exacerbations

Neil Osterweil

July 20, 2020

Phase 3 trial findings compared outcomes for COPD patients who had triple fixed-dose inhaled corticosteroid, long-acting muscarinic antagonist, and long-acting beta₂ agonist with patients who received one of two dual-therapy combinations. The results were presented at the American Thoracic Society's virtual clinical trial session.

A total of 8,509 patients were randomized on a 1:1:1:1 basis to receive twice daily:

  • Single-inhaler combinations of the inhaled corticosteroid (ICS) budesonide at one of two doses, the long-acting muscarinic antagonist (LAMA) glycopyrrolate, and the long-acting beta₂ agonist (LABA) formoterol.

  • Dual-therapy combination glycopyrrolate and formoterol.

  • Dual-therapy combination budesonide and formoterol.

The annual rate of moderate or severe COPD exacerbations was 1.08 and 1.07 for the triple combinations with 320 mcg and 180 mcg doses of budesonide, respectively, compared with 1.42 for glycopyrrolate-formoterol, and 1.24 for budesonide-formoterol.

Both triple combinations were significantly superior to the dual therapies for controlling exacerbations, reported Klaus F. Rabe, MD, PhD, from LungenClinic Grosshansdorf and Christian-Albrechts University Kiel (Germany), and colleagues in the ETHOS (Efficacy and Safety of Triple Therapy in Obstructive Lung Disease) trial (NCT02465567).

"Our findings show the benefits of triple therapy with a budesonide-glycopyrrolate-formoterol combination over dual therapy with a LAMA-LABA or an inhaled glucocorticoid-LABA combination with respect to the annual rate of moderate or severe COPD exacerbations, symptoms, and health-related quality of life in patients with moderate to very-severe COPD who are at risk of exacerbations," they wrote in a study published online in the New England Journal of Medicine.

The trial showed for the first time that "triple therapy that has half the dose of steroid compared to a standard ICS/LABA combination has had greater efficacy for the exacerbation endpoint," Dr. Rabe said during his presentation.

Triple-therapy combinations with an ICS, LAMA, and LABA are recommended for patients with COPD who remain symptomatic or experience further exacerbations on dual–ICS/LABA or –LAMA/LABA combinations. The triple combinations have been shown in several studies to lower risk of exacerbations and are associated with both better lung function and health-related quality of life, compared with dual therapies, the investigators noted.

However, concerns about adverse events associated with long-term ICS use — including pneumonia, cataracts, and increased fracture risk, possibly related to treatment duration, dose level, or type of corticosteroid used — spurred the ETHOS investigators to compare triple and dual fixed-dose combinations for efficacy and safety over 1 year.

Large Study

They enrolled 8,509 adults aged 40-80 years with symptomatic COPD (defined as score of 10 or higher on the 40-point COPD Assessment Test). All patients were receiving at least two inhaled maintenance therapies at the time of screening, and had a postbronchodilator ratio of forced expiratory volume in 1 second (FEV₁) to forced vital capacity of less than 0.7, with a postbronchodilator FEV₁ of 25%-65% of the predicted normal value. The patients all had a smoking history of at least 10 pack-years and a documented history of at least one moderate or severe COPD exacerbation in the year before screening.

The patients were randomized in equal proportions to receive triple therapy with budesonide at 320- or 160-mcg doses plus glycopyrrolate 18 mcg, and formoterol 9.6 mcg twice daily, or to dual therapy with either glycopyrrolate plus formoterol at the same doses, or 320 mcg budesonide plus 9.6 mcg formoterol.

As noted, for the primary endpoint of the estimated annual rate of moderate or severe exacerbations, the triple combinations were associated with significantly lower rates, with a 24% lower rate (rate ratio, 0.76) with 320 mcg budesonide triple therapy, compared with glycopyrrolate-formoterol, and a 13% lower rate (RR, 0.87), compared with budesonide formoterol (P < .001 and P = .003, respectively).

The triple combination with the 160-mcg budesonide dose was associated with a 25% lower annual rate of exacerbations (RR, 0.75) vs. glycopyrrolate-formoterol, and a 14% lower rate (RR, 0.86) vs. budesonide-formoterol (P < .001 and P = .002, respectively).

Secondary efficacy endpoints also favored the triple combination, including a 20% lower rate ratio of severe exacerbations over 52 weeks for the 320-mcg budesonide group, compared with the budesonide-formoterol group (P = .02).

The 320-mcg dose combination was also associated with a 46% lower risk for all-cause mortality, compared with glycopyrrolate-formoterol (hazard ratio, 0.54; P = .0111).

Confirmed pneumonia was seen in 4.2% of patients on the 320-mcg budesonide dose, 3.5% of those in the 160-mcg group, and 4.5% of patients treated with budesonide-formoterol. The incidence of any adverse effect was similar across the treatment groups, ranging from 61.7% to 64.5%.

Balance Exacerbation, Pneumonia Risk

In the question-and-answer session following his online presentation, Dr. Rabe was asked how the investigators reconciled their data showing increased incidence of pneumonia in budenoside-containing formulations with claims by the maker of the budesonide-formoterol (Symbicort, AstraZeneca) that budesonide is not associated with increased risk of pneumonia.

"We have to say that there are individuals that we have to balance the benefit of [less] exacerbation against the risk of pneumonia," he replied, but noted that the size of the effect, observed both in ETHOS and in the KRONOS trial, was relatively small.

"This definitely adds some information for us to think about when we're trying to do risk-benefit analysis," commented MeiLan K. Han, MD, MS, from the University of Michigan, who moderated the session but was not involved in the study.

The ETHOS trial was funded by AstraZeneca. Dr. Rabe disclosed consulting/advisory board activity with that company and others. Dr. Han has previously disclosed consulting/advising and research funding relationships with other companies.

N Engl J Med. 2020;383:35-48. Abstract

American Thoracic Society (ATS) 2020 International Conference.

This article originally appeared on

Follow Medscape on Facebook, Twitter, Instagram, and YouTube


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.