A phase IIb, randomised, parallel-group study: the efficacy, safety and tolerability of once-daily umeclidinium in patients with asthma receiving inhaled corticosteroids

Abstract

Background: Patients with asthma uncontrolled on inhaled corticosteroids may benefit from umeclidinium (UMEC), a long-acting muscarinic antagonist.

Methods: This Phase IIb, double-blind study included patients with reversible, uncontrolled/partially-controlled asthma for ≥6 months, receiving ≥100 mcg/day fluticasone propionate (or equivalent) for ≥12 weeks. Following a 2-week run-in on open-label fluticasone furoate (FF) 100 mcg, patients were randomised (1:1:1) to receive UMEC 31.25 mcg, UMEC 62.5 mcg or placebo on top of FF 100 mcg once-daily for 24 weeks. As-needed salbutamol was provided. Primary and secondary endpoints were change from baseline in clinic trough forced expiratory volume in 1 s (FEV1) and clinic FEV1 3 h post-dose, respectively, at Week 24. Other endpoints included change from baseline in home daily spirometry (trough FEV1, evening FEV1, morning [pre-dose] and evening peak expiratory flow) over 24 weeks. Safety was assessed throughout the study.

Results: The intent-to-treat population comprised 421 patients (UMEC 31.25 mcg: n =139, UMEC 62.5 mcg: n =139, placebo: n =143). UMEC 31.25 mcg and 62.5 mcg demonstrated significantly greater improvements from baseline in clinic trough FEV1 at Week 24 (difference [95% CI]: 0.176 L [0.092, 0.260; p<0.001] and 0.184 L [0.101, 0.268; p<0.001], respectively), clinic FEV1 3 h post-dose at Week 24 (0.190 L [0.100, 0.279; p<0.001] and 0.198 L [0.109, 0.287; p<0.001], respectively) and mean change from baseline in daily home spirometry over 24 weeks versus placebo. No new safety signals were identified.

Conclusions: UMEC is a highly effective bronchodilator that leads to improved lung function when administered as a single bronchodilator on top of FF in subjects with fully reversible, uncontrolled/partially-controlled moderate asthma. These data support a favourable benefit/risk profile for UMEC (31.25 mcg and 62.5 mcg).

Trial registration: GSK study ID: 205832; Clinicaltrials.gov ID: NCT03012061.

Keywords: Asthma; Forced expiratory volume in 1 s; Inhaled corticosteroid; Long-acting muscarinic antagonist; Umeclidinium.

Conflict of interest statement

The authors met the criteria for authorship as recommended by the International Committee of Medical Journal Editors. ZB, RvM, KR and AF are employees of GSK and own stock in GSK. SP, RD and LL were employees of GSK at the time of study and own stocks in GSK. EK is an employee of Crisor LLC Research and has served on advisory boards, speaker panels or received travel reimbursement from Amphastar, AstraZeneca, Boehringer Ingelheim, Forest, GSK, Mylan, Novartis, Pearl, Sunovion, Teva and Theravance. EK has conducted multicentre clinical research trials for approximately 40 pharmaceutical companies. RN was an employee of Asthma & Allergy Associates at the time of the study, and receives grant funding or research support from Aimmune, AstraZeneca, Attenua, Biocryst, Chiesi, Dyax, Genentech, GSK, Lupin, Menlo, Novartis, Pearl, Pfizer, Sanofi Aventis, Shire, Spirosure, Teva, 3M and Watson. RN is also a consultant or scientific advisor for Boehringer Ingelheim, GSK, Optinose, Stallergenes Greer and CSL Behring and receives speaker’s fees from Boehringer Ingelheim, CSL Behring, GSK, Stallergenes Greer and Merck. DB is an employee of the University of Cincinnati College of Medicine and Bernstein Clinical Research Center. DB receives grant/research/clinical trial support from GSK, Teva, AstraZeneca, Pearl, Novartis, Genentech, Lupin, Merck, Mylan, Boehringer Ingelheim, Amgen, Aimmune, Menlo, Shire, Biocryst and provides consultancy or contributes towards advisory boards for GSK, ALK America, Gerson-Lehman and Guidepoint Global. No authors were paid for the development of the manuscript. ELLIPTA is owned by or licensed to the GSK group of companies.

Figures

Fig. 1

(a) Study design and (b) patient disposition. aOne patient failed pre-screening and entered screening, and was counted as both a pre-screen failure and in the all patients screened population. bEleven patients failed screening and entered the run-in period, and were counted as both screen failures and in the entered run-in population. cThe study planned to randomise 384 patients. dOne patient had an unknown study completion status. ePatient 954 in the UMEC 62.5 mcg group discontinued study treatment the day prior to Visit 5 (Week 24) and was not dosed at that clinic visit. However, this patient was not reported as prematurely discontinuing study treatment in the eCRF and was counted in the completed study population. On treatment was defined as study treatment start date day (inclusive) to study treatment stop date + 1 (inclusive). Post treatment was defined as study treatment stop date + 1 day (exclusive) to Visit 5/EW Visit date (as applicable) (inclusive). The all patients enrolled population included all patients for whom a record exists in the database. The all patients screened population included all patients who completed ≥1 screening procedure. The randomised population included all patients who were randomised. The ITT population included all patients who were randomised, excluding those who were randomised in error and did not receive study treatment. AE, adverse event; eCRF, electronic Case Report Form; EW, early withdrawal; FF, fluticasone furoate; FU, follow-up; ICS, inhaled corticosteroid; ITT, intent-to-treat, SABA, short-acting β2-agonist; UMEC, umeclidinium; V, visit

Fig. 2

LS mean change from baseline in clinic spirometry measures (ITT population). LS mean (95% CI) change from baseline in clinic (a) trough FEV1 at Week 24, (b) FEV1 (L) at 3 h post dose at Week 24 and (c) trough FEV1 at Weeks 4, 12 and 24 (ITT population). Error bars represent 95% CI. ***p<0.001, treatment difference from placebo. CI, confidence interval; FEV1, forced expiratory volume in 1 s; ITT, intent-to-treat; LS, least squares; UMEC, umeclidinium; N, ITT population; n, number of participants with analysable data at Week 24

Fig. 3

LS mean change from baseline in home spirometry measures and E-RS total scores. LS mean (95% CI) change from baseline in (a) home trough FEV1 up to Week 8 by 1-weekly intervals, (b) home trough FEV1 over the 24-week treatment period by 4-weekly intervals, (c) AM PEF over the 24-week treatment period by 4-weekly intervals and (d) E-RS total scores over the 24-week treatment period by 4-weekly intervals (ITT population). Error bars represent 95% CI. *p≤0.05; **p≤0.01; ***p≤0.001, treatment difference from placebo. AM, morning; CI, confidence interval; E-RS, Evaluating Respiratory Symptoms; FEV1, forced expiratory volume in 1 s; ITT, intent-to-treat; LS, least squares, PEF, peak expiratory flow; UMEC, umeclidinium