Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials.
BACKGROUND
Combination long-acting bronchodilator treatment might be more effective than long-acting bronchodilator monotherapy for the treatment of chronic obstructive pulmonary disease (COPD). We aimed to compare the efficacy and safety of umeclidinium (UMEC) plus vilanterol (VI) with tiotropium (TIO) monotherapy, UMEC monotherapy, or VI monotherapy in patients with moderate to very severe COPD.


METHODS
In two multicentre, randomised, blinded, double-dummy, parallel-group, active-controlled trials, eligible patients (current or former smokers aged 40 years or older with an established clinical history of COPD) were randomly assigned in 1:1:1:1 ratio to UMEC 125 μg plus VI 25 μg, UMEC 62·5 μg plus VI 25 μg, TIO 18 μg, and either VI 25 μg (study 1) or UMEC 125 μg (study 2). All study drugs were used once daily for 24 weeks. TIO was delivered via the HandiHaler inhaler and all other active treatments were delivered via the ELLIPTA dry powder inhaler. Random assignment (by a validated computer-based system) was done by centre and was not stratified. All patients and physicians were masked to assigned treatment during the studies. The primary efficacy endpoint of both studies was trough forced expiratory volume in 1 s (FEV1) on day 169, which was analysed in the intention-to-treat population. Both studies are registered with ClinicalTrials.gov, numbers NCT01316900 (study 1) and NCT01316913 (study 2).


RESULTS
1141 participants were recruited in study 1, and 1191 in study 2. For study 1, after exclusions, 208, 209, 214, and 212 patients were included in the intention-to-treat analyses for TIO monotherapy, VI monotherapy, UMEC 125 μg plus VI 25 μg, and UMEC 62·5 μg plus VI 25 μg, respectively. For study 2, 215, 222, 215, and 217 patients were included in the intention-to-treat analyses for TIO monotherapy, UMEC monotherapy, UMEC 125 μg plus VI 25 μg, and UMEC 62·5 μg plus VI 25 μg, respectively. In both studies, we noted improvements in trough FEV1 on day 169 for both doses of UMEC plus VI compared with TIO monotherapy (study 1, UMEC 125 μg plus VI 25 μg: 0·088 L [95% CI 0·036 to 0·140; p=0·0010]; study 1, UMEC 62·5 μg plus VI 25 μg: 0·090 L [0·039 to 0·141; p=0·0006]; study 2, UMEC 125 μg plus VI 25 μg: 0·074 L [0·025 to 0·123; p=0·0031]; study 2, UMEC 62·5 μg plus VI 25 μg: 0·060 L [0·010 to 0·109; nominal p=0·0182]). Both doses of UMEC plus VI also improved trough FEV1 compared with VI monotherapy (UMEC 125 μg plus VI 25 μg: 0·088 L [0·036 to 0·140; p=0·0010]; UMEC 62·5 μg plus VI 25 μg: 0·090 L [0·039 to 0·142; p=0·0006], but not compared with UMEC 125 μg monotherapy (UMEC 125 μg plus VI 25 μg: 0·037 L [-0·012 to 0·087; p=0·14]; UMEC 62·5 μg plus VI 25 μg: 0·022 L [-0·027 to 0·072; p=0·38]). All treatments produced improvements in dyspnoea and health-related quality of life; we noted no significant differences in symptoms, health status, or risk of exacerbation between UMEC plus VI and TIO. The most common on-treatment, severe-intensity adverse event in both studies was acute exacerbation of COPD (1-4 [<1-2%] patients across treatment groups in study 1 and 1-6 [<1-3%] patients in study 2). We recorded five to 15 (2-7%) on-treatment serious adverse events across treatment groups in study 1, and nine to 22 (4-10%) in study 2. We noted no substantial changes from baseline in vital signs, clinical laboratory findings, or electrocardiography findings in any of the treatment groups.


CONCLUSIONS
Combination treatment with once-daily UMEC plus VI improved lung function compared with VI monotherapy and TIO monotherapy in patients with COPD. Overall our results suggest that the combination of UMEC plus VI could be beneficial for the treatment of moderate to very severe COPD.


BACKGROUND
GlaxoSmithKline.
Respiratory Division, University Hospital, University of Leuven, Leuven, Belgium. Electronic address: marc.decramer@uzleuven.be.
Marc
M
Decramer
University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TX, USA.
Antonio
A
Anzueto
Clinical Research Institute of Southern Oregon, Medford, OR, USA.
Edward
E
Kerwin
Lowcountry Lung and Critical Care, Charleston, SC, USA.
Thomas
T
Kaelin
GlaxoSmithKline, Respiratory and Immuno-Inflammation, Research Triangle Park, NC, USA.
Nathalie
N
Richard
Clinical Development, Aerocrine, Morrisville, NC, USA.
Glenn
G
Crater
GlaxoSmithKline, Stockley Park, Uxbridge, UK.
Maggie
M
Tabberer
GlaxoSmithKline, Respiratory and Immuno-Inflammation, Research Triangle Park, NC, USA.
Stephanie
S
Harris
GlaxoSmithKline, Respiratory and Immuno-Inflammation, Research Triangle Park, NC, USA.
Alison
A
Church
D000280:Administration, Inhalation; D000368:Aged; D001592:Benzyl Alcohols / Q000008:administration & dosage*; D001993:Bronchodilator Agents / Q000008:administration & dosage; D002722:Chlorobenzenes / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D005500:Follow-Up Studies; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy* / Q000503:physiopathology; D011812:Quinuclidines / Q000008:administration & dosage*; D012602:Scopolamine Derivatives / Q000008:administration & dosage*; D013997:Time Factors; D000069447:Tiotropium Bromide; D016896:Treatment Outcome
D001592:Benzyl Alcohols; D001993:Bronchodilator Agents; D002722:Chlorobenzenes; D004338:Drug Combinations; C573971:GSK573719; D011812:Quinuclidines; D012602:Scopolamine Derivatives; C550468:vilanterol; D000069447:Tiotropium Bromide