Efficacy of umeclidinium/vilanterol versus umeclidinium and salmeterol monotherapies in symptomatic patients with COPD not receiving inhaled corticosteroids: the EMAX randomised trial

Abstract

Background: Prospective evidence is lacking regarding incremental benefits of long-acting dual- versus mono-bronchodilation in improving symptoms and preventing short-term disease worsening/treatment failure in low exacerbation risk patients with chronic obstructive pulmonary disease (COPD) not receiving inhaled corticosteroids.

Methods: The 24-week, double-blind, double-dummy, parallel-group Early MAXimisation of bronchodilation for improving COPD stability (EMAX) trial randomised patients at low exacerbation risk not receiving inhaled corticosteroids, to umeclidinium/vilanterol 62.5/25 μg once-daily, umeclidinium 62.5 μg once-daily or salmeterol 50 μg twice-daily. The primary endpoint was trough forced expiratory volume in 1 s (FEV1) at Week 24. The study was also powered for the secondary endpoint of Transition Dyspnoea Index at Week 24. Other efficacy assessments included spirometry, symptoms, heath status and short-term disease worsening measured by the composite endpoint of clinically important deterioration using three definitions.

Results: Change from baseline in trough FEV1 at Week 24 was 66 mL (95% confidence interval [CI]: 43, 89) and 141 mL (95% CI: 118, 164) greater with umeclidinium/vilanterol versus umeclidinium and salmeterol, respectively (both p < 0.001). Umeclidinium/vilanterol demonstrated consistent improvements in Transition Dyspnoea Index versus both monotherapies at Week 24 (vs umeclidinium: 0.37 [95% CI: 0.06, 0.68], p = 0.018; vs salmeterol: 0.45 [95% CI: 0.15, 0.76], p = 0.004) and all other symptom measures at all time points. Regardless of the clinically important deterioration definition considered, umeclidinium/vilanterol significantly reduced the risk of a first clinically important deterioration compared with umeclidinium (by 16-25% [p < 0.01]) and salmeterol (by 26-41% [p < 0.001]). Safety profiles were similar between treatments.

Conclusions: Umeclidinium/vilanterol consistently provides early and sustained improvements in lung function and symptoms and reduces the risk of deterioration/treatment failure versus umeclidinium or salmeterol in symptomatic patients with low exacerbation risk not receiving inhaled corticosteroids. These findings suggest a potential for early use of dual bronchodilators to help optimise therapy in this patient group.

Keywords: Bronchodilator therapy; COPD; Clinically important deterioration; Dyspnoea; Lung function.

Conflict of interest statement

IHB, DAL, CC, MV-B, and PWJ are employees of GSK and hold stocks and shares in GSK. IPN and MLW were employees of GSK at the time of the study. LT is a contingent worker on assignment at GSK. FM has received research grants for participating in multicentre trials for AstraZeneca, Boehringer Ingelheim, GSK, Sanofi, and Novartis, and has received unrestricted research grants and personal fees from Boehringer Ingelheim, Grifols, and Novartis. LB has received honoraria for giving a lecture or attending an advisory board for Airsonett, ALK-Abello, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Meda, Novartis and Teva. EMK has served on advisory boards, speaker panels or received travel reimbursement from for Amphastar, AstraZeneca, Boehringer Ingelheim, GSK, Mylan, Novartis, Pearl, Sunovion, Teva, and Theravance and has received consulting fees from Cipia and GSK. CFV has received grants from AstraZeneca, Boehringer Ingelheim, GSK, Grifols, Novartis, Bayer-Schering, MSD, and Pfizer, and has received personal fees from AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, CSL Behring, GSK, Grifols, Menarini, Mundipharma, Novartis, and Teva. ELLIPTA and DISKUS are owned by/licensed to the GSK group of companies.

Figures

Fig. 1

Patient disposition. aPatients were considered to have completed the study if they received study treatment at Week 24 and completed the follow-up contact at Week 25 (±3 days). ITT, intent-to-treat; UMEC, umeclidinium; VI, vilanterol

Fig. 2

Lung function outcomes. CI, confidence interval; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; IC, inspiratory capacity; LS, least squares; SAL, salmeterol; UMEC, umeclidinium; VI, vilanterol

Fig. 3

Symptom severity outcomes (SAC-TDI (a), E-RS (b), % rescue salbutamol-free days (c)). CI, confidence interval; COPD, chronic obstructive pulmonary disease; E-RS, Evaluating Respiratory Symptoms-COPD; LS, least squares; SAC-TDI, self-administered computerised Transition Dyspnoea Index; SAL, salmeterol; UMEC, umeclidinium; VI, vilanterol

Fig. 4

Risk of a first CID up to Day 168 across multiple composite definitions. a N, patients with at least 1 post baseline assessment (not including exacerbations) for at least one of the individual components or patients who had an exacerbation; b moderate/severe exacerbation; c assessed using a self-administered computerised version. CAT, COPD Assessment Test; CI, confidence interval; CID, clinically important deterioration; COPD, chronic obstructive pulmonary disease; FEV1 trough forced expiratory volume in 1 s; HR, hazard ratio; n, number of patients with an event; TDI, Transition Dyspnoea Index; SAL, salmeterol; SGRQ, St George’s Respiratory Questionnaire; UMEC, umeclidinium; VI, vilanterol

Fig. 5

Kaplan–Meier plots of time to first CID for three definitionsa. aCID was defined as: a – a first moderate or severe exacerbation, and/or a trough FEV1 decrease from baseline of ≥100 mL, and/or a deterioration in SGRQ ≥4 units from baseline; b – a first moderate or severe exacerbation, and/or a trough FEV1 decrease from baseline of ≥100 mL, and/or a deterioration in CAT ≥2 units from baseline; c – a first moderate or severe exacerbation, and/or a deterioration in SGRQ ≥4 units from baseline and/or a deterioration in CAT ≥2 units from baseline and/or a TDI deterioration ≥1 unit decrease from baseline. CAT, COPD Assessment Test; CID, clinically important deterioration; FEV1, forced expiratory volume in 1 s; SAL, salmeterol; SGRQ, St George’s Respiratory Questionnaire; TDI, transition dyspnoea index; UMEC, umeclidinium; VI, vilanterol