Reduced All-Cause Mortality in the ETHOS Trial of Budesonide/Glycopyrrolate/Formoterol for Chronic Obstructive Pulmonary Disease. A Randomized, Double-Blind, Multicenter, Parallel-Group Study

Abstract

Rationale: In the phase III, 52-week ETHOS (Efficacy and Safety of Triple Therapy in Obstructive Lung Disease) trial in chronic obstructive pulmonary disease (COPD) (NCT02465567), triple therapy with budesonide/glycopyrrolate/formoterol fumarate (BGF) significantly reduced all-cause mortality compared with glycopyrrolate/formoterol fumarate (GFF). However, 384 of 8,509 patients were missing vital status at Week 52 in the original analyses.Objectives: To assess the robustness of the ETHOS mortality findings after additional data retrieval for patients missing Week 52 vital status in the original analyses.Methods: Patients with moderate to very severe COPD and prior history of exacerbation received twice-daily dosing with 320/18/9.6 μg of BGF (BGF 320), 160/18/9.6 μg of BGF (BGF 160), 18/9.6 μg of GFF, or 320/9.6 μg of budesonide/formoterol fumarate (BFF) (all delivered via a single metered-dose Aerosphere inhaler). Time to death (all-cause) was a prespecified secondary endpoint.Measurements and Main Results: In the final retrieved dataset, which included Week 52 vital status for 99.6% of the intent-to-treat population, risk of death with BGF 320 was significantly lower than GFF (hazard ratio, 0.51; 95% confidence interval, 0.33-0.80; unadjusted P = 0.0035). There were no significant differences in mortality when comparing BGF 320 with BFF (hazard ratio, 0.72; 95% confidence interval, 0.44-1.16; P = 0.1721), nor were significant differences observed when comparing BGF 160 against either dual comparator. Results were similar when the first 30, 60, or 90 days of treatment were excluded from the analysis. Deaths from cardiovascular causes occurred in 0.5%, 0.8%, 1.4%, and 0.5% of patients in the BGF 320, BGF 160, GFF, and BFF groups, respectively.Conclusions: Using final retrieved vital status data, triple therapy with BGF 320 reduced the risk of death compared with GFF, but was not shown to significantly reduce the risk of death compared with BFF, in patients with COPD. Triple therapy containing a lower dose of inhaled corticosteroid (BGF 160) was not shown to significantly reduce the risk of death compared with the dual therapy comparators.

Keywords: BGF metered-dose inhaler; chronic obstructive pulmonary disease; inhaled corticosteroids/long-acting muscarinic antagonist/long-acting β2-agonist; mortality; triple therapy.

Figure 1.

Forest plots for time to death (all-cause) for (A) 320/18/9.6 μg budesonide/glycopyrrolate/formoterol fumarate (BGF) versus glycopyrrolate/formoterol fumarate (GFF), (B) 160/18/9.6 μg BGF versus GFF, (C) 320/18/9.6 μg BGF versus budesonide/formoterol fumarate (BFF), and (D) 160/18/9.6 μg BGF versus BFF (intent-to-treat population). Results for the original dataset are from Reference . Significant P values (i.e., <0.046) in the original dataset are unadjusted because of an endpoint in the type I error control testing hierarchy not reaching significance. The on-treatment analysis includes deaths that occurred within 30 days of the last day of treatment. The intent-to-treat population included all patients who were randomized to treatment and received any amount of study drug. CI = confidence interval; HR = hazard ratio.

Figure 2.

Kaplan-Meier plot for time to all-cause death (final retrieved dataset; intent-to-treat population). BFF = budesonide/formoterol fumarate; BGF = budesonide/glycopyrrolate/formoterol fumarate; GFF = glycopyrrolate/formoterol fumarate.

Figure 3.

Forest plots for subgroup analyses of time to death (all-cause) for (A) 320/18/9.6 μg budesonide/glycopyrrolate/formoterol fumarate (BGF) versus glycopyrrolate/formoterol fumarate (GFF) and (B) 160/18/9.6 μg BGF versus GFF (final retrieved dataset; intent-to-treat population). CI = confidence interval; HR = hazard ratio; ICS = inhaled corticosteroid.

Figure 4.

Forest plots for subgroup analyses of time to death (all-cause) for (A) 320/18/9.6 μg budesonide/glycopyrrolate/formoterol fumarate (BGF) versus budesonide/formoterol fumarate (BFF) and (B) 160/18/9.6 μg BGF versus BFF (final retrieved dataset; intent-to-treat population). CI = confidence interval; HR = hazard ratio; ICS = inhaled corticosteroid.

Figure 5.

Incidence of death by baseline blood eosinophil count for 320/18/9.6 μg BGF versus GFF (final retrieved dataset; intent-to-treat population). Data are from a generalized additive model. Banded areas indicate 95% CIs that reflect the skewed distribution of eosinophil counts, (i.e., 17.3% of patients had counts <100 cells/mm³, 67.9% had 100–300 cells/mm³, and 14.7% had >300 cells/mm³). BGF = budesonide/glycopyrrolate/formoterol fumarate; CI = confidence interval; GFF = glycopyrrolate/formoterol fumarate.

Figure 6.

Hazard ratio for time to all-cause death for 320/18/9.6 μg BGF versus GFF over the study period, excluding all previous data, in patients using inhaled corticosteroids at study entry (final retrieved dataset; intent-to-treat population). BGF = budesonide/glycopyrrolate/formoterol fumarate; CI = confidence interval; GFF = glycopyrrolate/formoterol fumarate.