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Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: Results of a 24-week, randomized, controlled trial
Combinations of inhaled long-acting bronchodilator therapies such as muscarinic antagonists and β2-agonists may be more effective than monotherapy in the treatment of chronic obstructive pulmonary disease (COPD).
Methods
This study was a 24-week, Phase III, multicenter, randomized, blinded, double-dummy, parallel-group study of the once-daily, inhaled, fixed-dose combination of the long-acting muscarinic antagonist umeclidinium bromide and the long-acting β2-agonist vilanterol (UMEC/VI 62.5/25 mcg) versus tiotropium (TIO, 18 mcg). The primary endpoint was trough forced expiratory volume in 1 s (FEV1) at Day 169. The secondary endpoint was weighted mean FEV1 over 0–6 h post-dose at Day 168. For key endpoints, a step-down closed testing hierarchy was applied to account for multiplicity. Other efficacy and safety endpoints were assessed.
Results
Statistically significant improvements in trough FEV1 at Day 169 (0.112 L, 95% confidence interval [CI]: 0.081, 0.144; p < 0.001) and weighted mean FEV1 over 0–6 h post-dose at Day 168 (0.105 L, 95% CI: 0.071, 0.140; p < 0.001) were observed for UMEC/VI versus TIO. In addition UMEC/VI improved health-related quality of life, and reduced requirement for the use of rescue medication compared with TIO. The incidence of adverse events was similar between treatment groups.
Conclusions
UMEC/VI was associated with statistically significant and clinically meaningful improvements in lung function versus TIO. UMEC/VI was well tolerated. UMEC/VI 62.5/25 mcg could provide an effective new treatment option for patients with moderate-to-very severe COPD.
The pharmacological management of stable chronic obstructive pulmonary disease (COPD) primarily aims to improve symptoms and quality of life (QoL), optimize lung function, and reduce exacerbations. Inhaled bronchodilators such as muscarinic antagonists and β2-adrenoceptor agonists are central to this approach [
GOLD, Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease, http://www.goldcopd.org/ [accessed March 2014].
]. In contrast, β2-agonists induce smooth muscle relaxation by stimulating β2-adrenoceptors, leading to increased levels of cyclic adenosine monophosphate and reducing bronchoconstriction [
GOLD, Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease, http://www.goldcopd.org/ [accessed March 2014].
]. These distinct and complementary mechanisms of action provide the opportunity to develop combination bronchodilator therapies that may further improve treatment efficacy in patients with COPD and improve adherence to treatment. Combination therapies may also lower the risk of side effects compared with increasing the dose of a single agent in patients with COPD [
GOLD, Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease, http://www.goldcopd.org/ [accessed March 2014].
Clinical studies of long-acting muscarinic antagonists (LAMA) combined with long-acting β2-agonists (LABA) in patients with COPD support this rationale and have shown greater improvements in lung function compared with monotherapies [
Concurrent use of indacaterol plus tiotropium in patients with COPD provides superior bronchodilation compared with tiotropium alone: a randomised, double-blind comparison.
Combined treatment with formoterol and tiotropium is more efficacious than treatment with tiotropium alone in patients with chronic obstructive pulmonary disease, regardless of smoking status, inhaled corticosteroid use, baseline severity, or gender.
]. In addition, once-daily treatment regimens offer greater convenience for patients compared with more frequent dosing schedules.
A fixed-dose combination of the inhaled LAMA, umeclidinium bromide (UMEC), and the inhaled LABA, vilanterol (VI), is approved in the US and EU for the long-term, once-daily maintenance treatment of COPD. Studies have demonstrated that UMEC and VI improve lung function and are well tolerated in patients with COPD, both as a fixed-dose combination and as monotherapies [
Two large, Phase III, randomized studies recently reported that combination therapy with once-daily UMEC/VI 62.5/25 mcg or UMEC/VI 125/25 mcg (delivering 55/22 mcg and 113/22 mcg, respectively) provided statistically significant and clinically meaningful improvements in lung function measures versus tiotropium bromide (TIO [Boehringer Ingelheim], an approved COPD treatment) in patients with COPD [
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.
]. Here, we report the results of a multicenter, Phase III, randomized study which aims to provide further data on lung function outcomes and health-related QoL (HRQoL) in a larger population of patients receiving UMEC/VI 62.5/25 mcg versus TIO 18 mcg.
Materials and methods
Study design
This was a 24-week, Phase III, multicenter, randomized, double-dummy, parallel-group study of once-daily UMEC/VI 62.5/25 mcg versus once-daily TIO 18 mcg (ClinicalTrials.gov: NCT01777334; GSK study number: ZEP117115). The study was conducted at 71 centers in eight countries (Bulgaria, Canada, Germany, Hungary, Romania, Russia, Spain, and the United States). The study was approved by the relevant local ethics review committees (Supplementary File 1) and conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.
Patients
Patients aged ≥40 years with moderate-to-very severe COPD and an established clinical history of COPD as defined by American Thoracic Society/European Respiratory Society guidelines were eligible for enrollment [
]. Patients were excluded if they were hospitalized for COPD or pneumonia within 12 weeks prior to Visit 1. Full inclusion and exclusion criteria are listed in Supplementary File 2.
All patients gave written, informed consent before study participation.
Treatment
Patients were randomized 1:1 to treatment with once-daily UMEC/VI 62.5/25 mcg (delivering 55/22 mcg) via dry powder inhaler (DPI, ELLIPTA™ DPI) or TIO 18 mcg (via HandiHaler®) for 24 weeks. The randomization code was generated using a GlaxoSmithKline validated computerized system, RandAll version 2.5. Allocation of treatments was controlled using RAMOS (Randomization and Medication Ordering System, GlaxoSmithKline) and the link to the randomization schedule was kept confidential from all staff. Treatments were assigned by a dedicated telephone line, and the system was fully tracked with an audit trail maintained.
A double-dummy design was used for retaining the blinding (Supplementary File 3). UMEC/VI and corresponding placebo were administered once-daily in the morning via the ELLIPTA™ DPI. Blister packaged capsules of TIO or its corresponding placebo were administered once daily in the morning via the HandiHaler® DPI.
The use of albuterol/salbutamol provided by GlaxoSmithKline via metered dose inhaler as relief medication was permitted throughout the study, but was withheld for ≥4 h prior to spirometry testing. Inhaled corticosteroids (ICS) at a consistent dose of up to 1000 mcg/day of fluticasone propionate or equivalent were permitted and recorded. Systemic, oral, or parenteral corticosteroids were prohibited within 6 weeks prior to Visit 1 (12 weeks for depot corticosteroids); ICS dose greater than 1000 mcg/day was prohibited within 30 days of Visit 1. Initiation or discontinuation of ICS within 30 days prior to Visit 1 was not permitted. If a patient was being treated with ICS at screening, it was to be continued to the end of the treatment period unless there was a significant medical reason for discontinuation. Use of combination LABA/ICS, TIO, and LABA monotherapy was prohibited 30 days, 14 days, and 48 h prior to Visit 1, respectively. A full list of prohibited medications and corresponding timeframes are provided in Supplementary File 2.
Outcomes and assessments
The primary endpoint was trough forced expiratory volume in 1 s (FEV1) at Day 169 (defined as mean of FEV1 values obtained 23 and 24 h after the previous day's dosing). The secondary endpoint was weighted mean (WM) FEV1 over 0–6 h post-dose at Day 168. In addition, other lung function endpoints assessed included trough FEV1 at Days 2, 28, 56, 84, 112, 140, and 168, WM FEV1 over 0–6 h post-dose at Days 1 and 84, time to onset of action (defined as an increase of 0.100 L above baseline in FEV1) during 0–6 h post-dose at Day 1, trough forced vital capacity (FVC) at Day 169, percentage of responders achieving an increase in FEV1 of ≥12% and ≥0.200 L above baseline at any time during 0–6 h post-dose at Day 1, percentage of responders achieving an increase in trough FEV1 of ≥0.100 L above baseline at Day 169, peak FEV1 (maximum FEV1 recorded over 0–6 h post-dose time points) at Day 168. Additional efficacy outcomes are described in Supplementary File 4.
Incidence of adverse events (AEs) and AEs of special interest (cardiovascular events, pneumonia, lower respiratory tract infection [LRTI]; Supplementary File 5) were investigated during the treatment period.
Sample size and statistical analyses
Assuming a 2-sided 5% significance level and an estimate of residual standard deviation for trough FEV1 of 0.240 L (based on mixed models repeated measures [MMRM] analysis of previous studies), a study with 337 evaluable patients per arm would have 90% power to detect a 0.060 L difference between treatments in trough FEV1. It was estimated that approximately 25% of patients would withdraw from the study without providing a Week 24/Day 169 assessment. Therefore, it was planned that 450 patients should be randomized to each treatment arm.
Primary analyses were performed on the intent-to-treat (ITT) population, defined as all randomized patients who had received at least one dose of study drug during the treatment period. The primary endpoint, trough FEV1 at Day 169 was analyzed using MMRM analysis [
], including covariates of baseline FEV1, smoking status, Day, center group, treatment, Day by baseline interaction, and Day by treatment interaction, where Day is nominal. The model used all available trough FEV1 values recorded at Days 2, 28, 56, 84, 112, 140, 168, and 169. Missing data were not directly imputed in this analysis. However, all non-missing data for a subject were used within the analysis to estimate the treatment effect for trough FEV1 at Day 169. The secondary endpoint, 0–6 h WM FEV1 was analyzed in a similar fashion. See Supplementary File 6 for more details on statistical analyses.
To account for multiplicity across treatment comparisons and key endpoints, a step-down closed testing procedure was used. Accordingly, if the UMEC/VI 62.5/25 versus TIO comparison for the primary efficacy endpoint of trough FEV1 on Day 169 demonstrated statistical significance at the 5% level then the comparison of the secondary efficacy endpoint (0–6 h WM FEV1) on Day 168 would be tested. Likewise, inferences from all other comparisons with respect to other efficacy endpoints were made if the treatment comparison for the secondary efficacy endpoint was statistically significant at the 5% level. No further multiplicity adjustments were applied.
Exploratory analyses were performed to investigate if the treatment effect on the primary and secondary endpoint was modified by factors of interest. One such factor of interest was ICS use at Screening (eg, present or not present). This analysis was done by fitting a repeated measures model that included the same covariates as in the main analysis, with the addition of terms for ICS Use and ICS Use by treatment interaction (see Supplementary File 6 for additional details).
Results
Patients
The study took place between January 2013 and October 2013. In total, 1191 patients were enrolled in the study and 905 patients were randomized to receive treatment. All 905 patients were included in the ITT population (Fig. 1). The overall subject disposition was similar for each treatment group. Most patients completed the study (88%, UMEC/VI group; 86%, TIO group). The most common reasons for withdrawal were AEs, lack of efficacy, and withdrawn consent (Fig. 1).
Patient demographics were similar between treatment groups (Table 1). Approximately 50% of patients in both treatment groups were taking ICS from 30 days prior to Screening (Visit 1) to the end of the treatment period. A greater percentage of patients were reversible to salbutamol/ipratropium compared with those reversible to salbutamol alone. Greater improvements in FEV1 were also demonstrated post salbutamol/ipratropium compared with salbutamol alone (Table 1).
Table 1Patient demographics and characteristics (ITT population).
Patients are reversible to salbutamol and ipratropium if they have an increase in FEV1 of ≥12% and ≥200 mL following administration of both salbutamol and ipratropium.
n (%)
244 (54)
239 (53)
FEV1, forced expiratory volume in 1 second; FVC, forced vital capacity; GOLD, global initiative for chronic lung disease; ICS, inhaled corticosteroids; ITT, intent-to-treat; SD, standard deviation; TIO, tiotropium bromide; UMEC, umeclidinium bromide; VI, vilanterol.
a Patients were classed as current smokers if they had smoked within 6 months of the screening visit.
b Patients are reversible to salbutamol if they have an increase in FEV1 of ≥12% and ≥200 mL following administration of salbutamol.
c Patients are reversible to salbutamol and ipratropium if they have an increase in FEV1 of ≥12% and ≥200 mL following administration of both salbutamol and ipratropium.
A clinically meaningful and statistically significant improvement of 0.112 L (95% confidence interval [CI]: 0.081, 0.144) in trough FEV1 at Day 169 was observed for UMEC/VI 62.5/25 mcg versus TIO 18 mcg (Table 2).
In addition, a clinically meaningful and statistically significant improvement of 0.105 L (95% CI: 0.071, 0.140) in 0–6 h WM FEV1 at Day 168 was also observed for UMEC/VI 62.5/25 mcg versus TIO 18 mcg. Statistically significant improvements for UMEC/VI 62.5/25 mcg versus TIO were also observed early for both trough FEV1 and WM FEV1, and were maintained at other clinic visits throughout the study (Figure 2, Figure 3, Supplementary Files 7 and 8).
Figure 2LS mean change from baseline in trough FEV1, L (ITT population). CI, confidence interval; FEV1, forced expiratory volume in 1 s; ITT, intent-to-treat; LS, least squares; TIO, tiotropium bromide; UMEC, umeclidinium bromide; VI, vilanterol.
The exploratory analyses suggested that there was no impact of ICS use on treatment effect for trough FEV1 at Day 169 and 0–6 h WM FEV1 at Day 168. Further details of the exploratory analyses of other factors of interest can be found in Supplementary File 9.
Median time to onset of action defined as a post-dose FEV1 ≥0.100 L above baseline, during the 0–6 h post-dose on Day 1 was shorter in UMEC/VI 62.5/25 mcg versus TIO 18 mcg (19 versus 31 min: Table 2). The proportion of patients experiencing: i) an increase in FEV1 of ≥12% and ≥0.200 L above baseline 0–6 h post-dose on Day 1; and ii) an increase in trough FEV1 of ≥0.100 L above baseline at Day 169, was greater with UMEC/VI 62.5/25 mcg versus TIO 18 mcg for both thresholds (Table 2). Similarly, patients receiving UMEC/VI 62.5/25 mcg had statistically significantly higher odds of achieving both thresholds versus TIO 18 mcg (Table 2). Statistically significant improvements in peak FEV1 on Day 168 were observed for UMEC/VI 62.5/25 mcg versus TIO 18 mcg (Table 2).
For trough FVC at Day 169, a statistically significant and clinically meaningful improvement was observed with UMEC/VI 62.5/25 versus TIO 18 mcg (0.124 L [95% CI: 0.073, 0.174]; Table 2). Improvements in FVC were also observed at Day 2 and maintained at other clinic visits in the study (Fig. 4, Supplementary File 10).
Figure 4LS mean change from baseline in trough FVC (L) (ITT population). CI, confidence interval; FVC, forced vital capacity; ITT, intent-to-treat; LS, least squares; TIO, tiotropium; UMEC, umeclidinium bromide; VI, vilanterol. Analysis performed using a repeated measures model with covariates of treatment, baseline (mean of the two FVC assessments made 30 and 5 min pre-dose on Day 1), smoking status, center group, Day, Day by baseline, and Day by treatment interactions. Day axis is not to scale.
A small percentage of patients in each group reported an on-treatment COPD exacerbation (Supplementary File 11).
Health outcomes
Statistically significant improvements in St George's Respiratory Questionnaire (SGRQ) total score were observed for the UMEC/VI 62.5/25 mcg group versus TIO 18 mcg at Day 28, 84, and 168 (Table 3, Fig. 5, Supplementary File 12). The proportion of SGRQ responders at Day 28 and 84 and SGRQ domain scores at Day 168 are summarized in Supplementary Files 13 and 14, respectively.
Table 3HRQoL (SGRQ scores) and rescue use (ITT population).
UMEC/VI 62.5/25 (N = 454)
TIO (N = 451)
SGRQ total score at Day 168, LS mean change from baseline (SE)
−7.27 (0.538)
−5.17 (0.548)
Treatment difference (95% CI)
−2.10 (−3.61, −0.59)
UMEC/VI 62.5/25 versus TIO
0.006
p-value
Proportion of SGRQ responders at Day 168
Responder, n (%)
237 (53)
196 (46)
Treatment difference, OR (95% CI)
UMEC/VI 62.5/25 versus TIO
1.4 (1.0, 1.8)
p-value
0.022
Rescue albuterol/salbutamol use (mean puffs/day over Weeks 1–24),
−1.3 (0.09)
−0.8 (0.09)
LS mean change from baseline (SE)
Treatment difference, (95% CI)
UMEC/VI 62.5/25 versus TIO
−0.5 (−0.7, −0.2)
p-value
<0.001
CI, confidence interval; HRQoL, health-related quality of life; ITT, intent-to-treat; LS, least squares; OR, odds ratio; SGRQ, St George's respiratory questionnaire; SE, standard error; TIO, tiotropium bromide; UMEC, umeclidinium bromide; VI, vilanterol.
The odds of being a responder (defined as a reduction from baseline in SGRQ total score of ≥4 units) were statistically significantly greater for UMEC/VI 62.5/25 mcg versus TIO 18 mcg at Day 28, 84, and 168 (Table 3, Supplementary File 12).
Figure 5LS mean (96% CI) change from baseline in SGRQ total score (ITT population). CI, confidence interval; ITT, intent-to-treat; LS, least squares; SGRQ, St George's Respiratory Questionnaire; TIO, tiotropium; UMEC, umeclidinium bromide; VI, vilanterol. Analysis performed using a repeated measures model with covariates of treatment, baseline (score on Day 1), smoking status, center group, Day, Day by baseline, and Day by treatment interactions.
A statistically significant reduction from baseline in rescue salbutamol use over 24 weeks was observed with UMEC/VI 62.5/25 mcg versus TIO 18 mcg (Table 3).
Safety and tolerability
The overall incidence of on-treatment AEs was similar in both treatment groups (44% UMEC/VI group versus 42%, TIO group) (Table 4).
Table 4Summary of adverse events (ITT population).
UMEC/VI 62.5/25 (N = 454)
TIO (N = 451)
Any on-treatment AEs, n (%)
202 (44)
190 (42)
Most common on-treatment AEs (reported in ≥3% patients in any treatment group, n (%)
Headache
40 (9)
31 (7)
Nasopharyngitis
28 (6)
30 (7)
Cough
13 (3)
15 (3)
Back pain
9 (2)
13 (3)
Any on-treatment SAEs, n (%)
16 (4)
17 (4)
Any drug-related AEs, n (%)
19 (4)
17 (4)
Any AEs related to permanent discontinuation of medication/withdrawal, n (%)
The incidence of on-treatment SAEs was low (4% for both treatment groups), and no on-treatment SAEs were considered related to study drug (Table 4).
Seven deaths occurred during the study comprising two subjects in the UMEC/VI treatment group (cardiac failure and death from unknown reason) and five subjects in the TIO group (sudden death, pancreatic carcinoma, respiratory failure, pulmonary embolism, and cardiac failure acute). None of the deaths were judged to be related to the study drug.
The incidence of any cardiovascular AEs of special interest was equivalent between UMEC/VI 62.5/25 mcg (2%) and TIO 18 mcg (2%). Incidence of pneumonia and LRTI was also similar between UMEC/VI 62.5/25 mcg (<1%) and TIO 18 mcg (1%) (Table 4). The subject in the UMEC/VI 62.5/25 group with an on-treatment pneumonia event had entered screening on an ICS. Of the three TIO subjects that had an on-treatment pneumonia event, one subject was receiving an ICS.
Discussion
The patient population in this study consisted of patients with COPD who had moderate-to-very severe disease and characteristics similar to other studies of LAMAs and LABAs [
]. Results from this study demonstrated statistically significant and clinically meaningful improvements with UMEC/VI 62.5/25 mcg on trough FEV1 at Day 169 and WM FEV1 over 0–6 h post-dose at Day 168 versus TIO 18 mcg. This suggests that UMEC/VI was a more effective bronchodilator than TIO at the beginning and end of the dosing interval. The improvements in trough FEV1 and WM FEV1 were consistent over the 24-week study, and are in line with previous studies of UMEC/VI versus TIO [
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.
Evidence of improvement in QoL with UMEC/VI was observed, with UMEC/VI demonstrating statistically significant improvements in the SGRQ score (a respiratory-related QoL measure) versus TIO, which was further supported by significant reductions in rescue medication use.
Permitted concurrent medications for the duration of the study from screening through to the end of the treatment period included ICS up to a maximum daily dose of 1000 mcg fluticasone propionate or equivalent. An exploratory analysis suggested that ICS use did not impact the treatment effect on trough FEV1 at Day 169. There are limitations to this analysis, including that the study was not powered to detect interactions and treatment randomization was not stratified by ICS use. However, it should be noted that in a pre-specified subgroup analysis conducted using integrated data (N = 4713; ITT population) from four 24-week, multicenter, randomized, double-blind, placebo- and active-controlled studies that enrolled patients with COPD, UMEC/VI at doses of 125/25 mcg and 62.5/25 mcg demonstrated similar magnitudes of improvement in trough FEV1 at Day 169 compared with placebo in the subgroups of ICS users and non-ICS users [
These results add to a growing body of evidence supporting the use of dual bronchodilator therapy over bronchodilator monotherapy in the management of symptomatic patients with COPD. Early studies showed that the free combination of TIO and formoterol produced greater improvements in day-time and night-time FEV1 than either component in patients with COPD [
Combined treatment with formoterol and tiotropium is more efficacious than treatment with tiotropium alone in patients with chronic obstructive pulmonary disease, regardless of smoking status, inhaled corticosteroid use, baseline severity, or gender.
]. More recently, the SHINE study (ClinicalTrials.gov: NCT01202188; in patients with moderate-to-very severe COPD) demonstrated that the fixed-dose LAMA/LABA combination QVA149 (glycopyrronium/indacaterol; Novartis Pharmaceuticals) produced statistically significant improvements in trough FEV1 after 26 weeks, in comparison with indacaterol, glycopyrronium, TIO, and placebo [
]. A fixed-dose combination of aclidinium bromide/formoterol fumarate (Almirall and Forest Laboratories) is also in development, with a large clinical trial program underway in patients with moderate-to-severe COPD [
UMEC/VI 62.5/25 mcg was well tolerated in the present study, and had a safety profile similar to that of TIO. There was a similar overall incidence of AEs in each study group, and a low incidence of SAEs. Both muscarinic antagonists and β2-agonists have previously been associated with adverse effects on the cardiovascular system [
Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis.
], and therefore incidence of these effects were considered to be of interest in this study. Overall, the incidence of cardiovascular AEs of special interest was low: 2% for both UMEC/VI and TIO. Pneumonia is a common event in the COPD population [
]. In this study, the incidence of pneumonia and LRTIs was low in both the UMEC/VI (<1%) and TIO (1%) treatment groups, despite >50% of patients receiving ICS.
Current COPD treatment guidelines recommend a combination of a LAMA/LABA as an option for patients with significant symptoms and a low risk of exacerbations, patients with few symptoms and a high risk of exacerbations, and patients with many symptoms and high risk of exacerbations [
GOLD, Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease, http://www.goldcopd.org/ [accessed March 2014].
]. Additional studies of LABA/LAMA combinations in patients with differing severities of COPD, as well as in combination with ICS, would be useful to expand the experience with UMEC/VI, further characterize the benefit of this combination in clinical practice, and help determine its optimal place in the treatment paradigm of COPD.
Conclusions
The results of the present study demonstrated statistically significant and clinically meaningful improvements in trough FEV1 for UMEC/VI versus TIO, which was supported by a clinically meaningful improvement in 0–6 h WM FEV1. Improvements were also observed in measures considered important to patients, including rescue medication use and HRQoL. Overall, UMEC/VI was well tolerated. These findings show that UMEC/VI 62.5/25 mcg could provide an effective new treatment option for patients with moderate-to-very severe COPD, providing greater efficacy than monotherapy.
Conflict of interest statement
M. Reza Maleki-Yazdi has acted as a consultant to and received research grants from Almirall, AstraZeneca, Boehringer Ingelheim, Forest Laboratories, GlaxoSmithKline, Novartis, Merck, Ono Pharmaceuticals, and Pfizer. Thomas Kaelin has received research grants from Forest Laboratories, GlaxoSmithKline, Boehringer-Ingelheim, Parexel, Novartis, Ikaria, and Pearl. Michael Zvarich, Alison Church, and Nathalie Richard are employees of GlaxoSmithKline and hold stocks/shares in GlaxoSmithKline.
Acknowledgments
The work presented here, including the conduct of the study, data analysis and interpretation, was funded by GlaxoSmithKline. Editorial assistance in the preparation of the manuscript (provided by Joanne Parker at Fishawack Indicia Ltd) was funded by GlaxoSmithKline.
Appendix A. Supplementary data
The following is the supplementary data related to this article:
GOLD, Global strategy for the diagnosis, management and prevention of chronic obstructive pulmonary disease, http://www.goldcopd.org/ [accessed March 2014].
Concurrent use of indacaterol plus tiotropium in patients with COPD provides superior bronchodilation compared with tiotropium alone: a randomised, double-blind comparison.
Combined treatment with formoterol and tiotropium is more efficacious than treatment with tiotropium alone in patients with chronic obstructive pulmonary disease, regardless of smoking status, inhaled corticosteroid use, baseline severity, or gender.
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.
Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis.
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