BACKGROUND Triple fixed-dose regimens of an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting β 2-agonist (LABA) for chronic obstructive pulmonary disease (COPD) have been studied at single dose levels of inhaled glucocorticoid, but studies at two dose levels are lacking. METHODS In a 52-week, phase 3, randomized trial to evaluate the efficacy and safety of triple therapy at two dose levels of inhaled glucocorticoid in patients with moderate-tovery-severe COPD and at least one exacerbation in the past year, we assigned patients in a 1:1:1:1 ratio to receive twice-daily inhaled doses of triple therapy (inhaled glucocorticoid [320 μg or 160 μg of budesonide], a LAMA [18 μg of glycopyrrolate], and a LABA [9.6 μg of formoterol]) or one of two dual therapies (18 μg of glycopyrrolate plus 9.6 μg of formoterol or 320 μg of budesonide plus 9.6 μg of formoterol). The primary end point was the annual rate (the estimated mean number per patient per year) of moderate or severe COPD exacerbations, as analyzed in the modified intention-to-treat population with the use of on-treatment data only. RESULTS The modified intention-to-treat population comprised 8509 patients. The annual rates of moderate or severe exacerbations were 1.08 in the 320-μg-budesonide triple-therapy group (2137 patients), 1.07 in the 160-μg-budesonide triple-therapy group (2121 patients), 1.42 in the glycopyrrolate-formoterol group (2120 patients), and 1.24 in the budesonide-formoterol group (2131 patients). The rate was significantly lower with 320-μg-budesonide triple therapy than with glycopyrrolateformoterol (24% lower: rate ratio, 0.76; 95% confidence interval [CI], 0.69 to 0.83; P<0.001) or budesonide-formoterol (13% lower: rate ratio, 0.87; 95% CI, 0.79 to 0.95; P = 0.003). Similarly, the rate was significantly lower with 160-μg-budesonide triple therapy than with glycopyrrolate-formoterol (25% lower: rate ratio, 0.75; 95% CI, 0.69 to 0.83; P<0.001) or budesonide-formoterol (14% lower: rate ratio, 0.86; 95% CI, 0.79 to 0.95; P = 0.002). The incidence of any adverse event was similar across the treatment groups (range, 61.7 to 64.5%); the incidence of confirmed pneumonia ranged from 3.5 to 4.5% in the groups that included inhaled glucocorticoid use and was 2.3% in the glycopyrrolate-formoterol group. CONCLUSIONS Triple therapy with twice-daily budesonide (at either the 160-μg or 320-μg dose), glycopyrrolate, and formoterol resulted in a lower rate of moderate or severe COPD exacerbations than glycopyrrolate-formoterol or budesonide-formoterol. (Funded by AstraZeneca, ETHOS ClinicalTrials.gov number, NCT02465567.

A. were involved in the acquisition of data and data interpretation. S.B. and P.D. were involved in conception/design and data analysis/interpretation. C.R. and P.D. were involved in conception/design, the acquisition of data, and data interpretation.

FF/UMEC may be a viable treatment for patients with asthma symptomatic on ICS; benefit may be most prominent in those with fixed obstruction. The carryover effect suggests future UMEC studies should use an alternative design. ClinicalTrials.gov: NCT01573624.

Efficacy and safety of umeclidinium administered in a dry power inhaler were evaluated in moderate-to-very-severe chronic obstructive pulmonary disease patients.This was a randomised, placebo-controlled study assessing once-daily umeclidinium 62.5 and 125 mg over 12 weeks. The primary end-point was change from baseline in trough forced expiratory volume in 1 s (FEV1) on day 85. Secondary end-points were 0-6-h weighted mean and serial forced expiratory volume in 1 s. Other end-points were transitional dyspnoea index, health outcomes (St George's Respiratory Questionnaire), pharmacokinetics and safety.246 patients were enrolled; 168 completed the study. On day 85, umeclidinium 62.5 and 125 mg significantly improved least squares mean change from baseline in trough FEV1 (127 and 152 mL, respectively; p,0.001) compared with placebo. On day 84, umeclidinium 62.5 and 125 mg significantly improved least squares mean change from baseline in 0-6-h weighted mean (166 and 191 mL, respectively; p,0.001) and serial FEV1 at each time point (pf0.003). Significant improvement in least squares mean transitional dyspnoea index focal score (1.0 and 1.3 units, respectively; pf0.05) and change from baseline St George's Respiratory Questionnaire total score (-7.9 and -10.87 units, respectively; p,0.001) were noted compared with placebo at week 12. The incidence of adverse events was low and similar across treatments.Umeclidinium 62.5 and 125 mg significantly improved lung function, dyspnoea and health status compared with placebo, and were well tolerated in chronic obstructive pulmonary disease patients over 12 weeks. @ERSpublications Umeclidinium significantly improves lung function, dyspnoea and health status and is well tolerated