Triple inhaled therapy reduces moderate, severe COPD exacerbations: ETHOS

Triple inhaled therapy with twice-daily budesonide, at two doses, glycopyrrolate and formoterol reduced the rate of moderate or severe COPD exacerbations compared with two dual-combination therapies, according to data from the ETHOS trial.

“For the first time, triple therapy with half the dose of inhaled corticosteroid was shown to have greater efficacy than higher-dose inhaled corticosteroid/long-acting beta agonist therapy,” Klaus F. Rabe, MD, PhD, professor of pulmonary medicine at the University of Kiel and director of the department of pulmonology at Clinic Grosshandorf, Germany, said during the American Thoracic Society’s Breaking News: Clinical Trial Results in Pulmonary Medicine virtual session.

The phase 3, randomized, double-blind, multicenter, parallel-group ETHOS trial examined the safety and efficacy of triple therapy at two dose levels of inhaled glucocorticoid in patients with moderate to very severe COPD. A total of 8,509 patients (mean age, 64 years) with symptomatic COPD who were receiving at least two inhaled maintenance therapies and had a postbronchodilator FEV₁/FVC ratio of 0.70 or less, postbronchodilator FEV₁ of 25% to 65% of the predicted normal value, smoking history and at least one moderate to severe COPD exacerbation in the previous year were included in the trial.

Patients were randomly assigned to receive twice-daily inhaled triple combination therapy (PT010, AstraZeneca) — consisting of an inhaled glucocorticoid (320 µg or 160 µg budesonide), a long-acting muscarinic antagonist (18 µg glycopyrrolate) and a long-acting beta agonist (9.6 µg formoterol) — or one of two dual-combination therapies, consisting of 18 µg glycopyrrolate plus 9.6 µg formoterol or 320 µg budesonide plus 9.6 µg formoterol.

The primary endpoint, annual rate of moderate of severe COPD exacerbations, was 1.08 in the 320 µg budesonide triple-therapy group, 1.07 in the 160 µg budesonide triple-therapy group), 1.42 in the glycopyrrolate-formoterol group and 1.24 in the budesonide-formoterol group in the intention-to-treat population, according to results presented during the ATS briefing and simultaneously published in The New England Journal of Medicine.

The 320 µg budesonide triple-therapy group had a 24% lower rate of COPD exacerbations compared with glycopyrrolate-formoterol (RR = 0.76; 95% CI, 0.69-0.83; P <.001) and a 13% lower rate of exacerbations compared with budesonide-formoterol (RR = 0.87; 95% CI, 0.79-0.95; P = .003).

With 160 µg budesonide triple therapy, the rate of COPD exacerbations was 25% lower compared with glycopyrrolate-formoterol (RR = 0.75; 95% CI, 0.69-0.83; P < .001) and 14% lower compared with budesonide-formoterol (RR = 0.86; 95% CI, 0.79-0.95; P = .002).

The 320 µg budesonide triple-therapy group had a 46% reduction in all-cause mortality compared with glycopyrrolate-formoterol (HR = 0.54; 95% CI, 0.34-0.87; P = .78) and 22% reduction compared with budesonide-formoterol (HR = 0.78; 95% CI, 0.47-1.3; P = .34). In the 160 µg budesonide triple therapy group, risk for all-cause mortality was lower compared with glycopyrrolate-formoterol (HR = 0.79; 95% CI, 0.52-1.2; P = .26), but higher compared with budesonide-formoterol (HR = 1.13; 95% CI, 0.72-1.8; P = .59).

Incidence of adverse events was similar among all treatment groups. Confirmed pneumonia ranging from 3.5% to 4.5% in groups with inhaled glucocorticoid use and 2.3% in the glycopyrrolate-formoterol group. The most frequently reported adverse events with triple inhaled therapy were nasopharyngitis, COPD and upper respiratory tract infection.

ETHOS is part of the ATHENA phase 3 clinical trial program, which included more than 15,000 patients around the world in 11 trials, according to AstraZeneca. Results of the earlier pivotal phase 3 KRONOS trial were published in Lancet Respiratory Medicine.

References:

• Rabe K, et al. Inhaled Triple Therapy at Two Glucocorticoid Doses in Moderate-to-Very-Severe COPD: The ETHOS Study. Presented at: American Thoracic Society’s Breaking News: Clinical Trial Results in Pulmonary Medicine; June 24, 2020; virtual.
• Press Release.