Once-Daily Umeclidinium/Vilanterol 125/25 μg Therapy in COPD: A Randomized, Controlled Study

doi:10.1378/chest.13-1579

Chest

Volume 145, Issue 5, May 2014, Pages 981-991

https://doi.org/10.1378/chest.13-1579 Get rights and content

Background

Combination long-acting bronchodilator therapy may be more effective than long-acting bronchodilator monotherapy in COPD. Our objectives were to compare the efficacy and safety of once-daily umeclidinium bromide (UMEC)/vilanterol (VI) 125/25 μg with placebo and UMEC or VI monotherapy in COPD.

Methods

This was a double-blind, placebo-controlled, parallel-group study. A total of 1,493 patients were randomized (3:3:3:2) to 24 weeks of treatment with UMEC/VI 125/25 μg, UMEC 125 μg, VI 25 μg, or placebo once daily via dry powder inhaler.

Results

Primary efficacy end point was trough FEV₁ on day 169 (23-24 h postdose). Additional lung-function, symptomatic, and health-related quality-of-life end points were also assessed. Safety evaluations included adverse events, vital signs, ECG, and clinical laboratory measurements. All active treatments significantly improved trough FEV₁ vs placebo (0.124-0.238 L, all P < .001). Improvements with UMEC/VI 125/25 μg were significantly greater than for UMEC 125 μg or VI 25 μg (0.079 L and 0.114 L, both P ≤ .001). Improvements for UMEC/VI 125/25 μg vs placebo were observed for the Transition Dyspnea Index (1.0 unit, P < .001), rescue albuterol use at weeks 1 to 24 (−1.5 puffs/d), and St. George's Respiratory Questionnaire (−3.60 units, P < .001). No safety signals were observed.

Conclusions

Once-daily UMEC/VI 125/25 μg was well tolerated and provided greater improvements in lung function, health status, and dyspnea scores compared with monotherapy components and placebo over 24 weeks. This study supports the use of UMEC/VI 125/25 μg for the maintenance treatment of COPD.

Trial registry

ClinicalTrials.gov; No.: NCT01313637; URL: www.clinicaltrials.gov.

Section snippets

Study Design, Treatments, and Assessments

This was a 24-week, multicenter, randomized, placebo-controlled, parallel-group study in patients with COPD conducted in 153 centers in 14 countries from March 22, 2011, to April 19, 2012. Patients were randomized 3:2 to active treatments and placebo to provide additional safety data for the active treatment arms. Patients were assigned to receive one of four double-blind treatments: UMEC/VI 125/25 μg (delivering 113/22 μg, respectively), UMEC 125 μg (delivering 113 μg), VI 25 μg (delivering 22

Patients

Of the 2,114 patients enrolled in the study, 1,489 were included in the intent-to-treat population (Fig 1). The majority of patients completed the study (74% to 81% active treatment groups; 67% placebo). Patient disposition and reasons for discontinuation are shown in Figure 1. Across the groups, 54% to 58% of patients reported having a cardiovascular-related current medical condition, and 44% to 50% of patients used inhaled corticosteroids. Patient demographics and baseline characteristics

Discussion

This long-term study of patients with moderate to severe COPD treated with the once-daily combination bronchodilator UMEC/VI 125/25 μg revealed three important findings. First, UMEC/VI 125/25 μg provides significant improvements in measures of lung function compared with placebo, UMEC 125 μg, and VI 25 μg throughout the 24-week treatment period. Second, the improvement in lung function is associated with improvements in patient-reported dyspnea and HRQoL health status compared with placebo.

Conclusions

In summary, the combination therapy UMEC 125/25 μg was well tolerated in patients with moderate to severe COPD and produced improvements in lung function, dyspnea, and HRQoL compared with placebo, UMEC 125 μg, and VI 25 μg over 24 weeks of treatment. Both UMEC 125 μg and VI 25 μg were shown to be efficacious compared with placebo. The clinical benefits over monotherapy components, together with the convenience of a once-daily dosing regimen, support the use of UMEC/VI 125/25 μg as a long-term

Acknowledgments

Author contributions: As guarantor of this manuscript, Dr Celli had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.

Dr Celli: contributed to the design of the study, analysis of the data, and preparation of the manuscript; reviewed the manuscript and provided final approval of the submitted version; and agreed to be listed as an author.

Dr Crater: contributed to the study design and conduct,

References (41)

M Cazzola et al.
The scientific rationale for combining long-acting beta2-agonists and muscarinic antagonists in COPD
Pulm Pharmacol Ther
(2010)
JA van Noord et al.
Effects of tiotropium with and without formoterol on airflow obstruction and resting hyperinflation in patients with COPD
Chest
(2006)
JF Donohue et al.
A randomized, double-blind dose-ranging study of the novel LAMA GSK573719 in patients with COPD
Respir Med
(2012)
NA Hanania et al.
The efficacy and safety of the novel long-acting β2 agonist vilanterol in patients with COPD: a randomized placebo-controlled trial
Chest
(2012)
DA Mahler et al.
The measurement of dyspnea: contents, interobserver agreement, and physiologic correlates of two new clinical indexes
Chest
(1984)
K Howard et al.
Development of the shortness of breath with daily activities questionnaire (SOBDA)
Value Health
(2012)
G Feldman et al.
28-Day safety and tolerability of umeclidinium in combination with vilanterol in COPD: a randomized placebo-controlled trial
Pulm Pharmacol Ther
(2012)
EM Kerwin et al.
Efficacy and tolerability of indacaterol 75 μg once daily in patients aged ≥40 years with chronic obstructive pulmonary disease: results from 2 double-blind, placebo-controlled 12-week studies
Clin Ther
(2011)
EL Toy et al.
Treatment of COPD: relationships between daily dosing frequency, adherence, resource use, and costs
Respir Med
(2011)
D Tashkin et al.
Effect of tiotropium in men and women with COPD: results of the 4-year UPLIFT trial
Respir Med
(2010)

BR Celli et al.

Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper

Eur Respir J

(2004)

V Brusasco

Reducing cholinergic constriction: the major reversible mechanism in COPD

Eur Respri Rev

(2006)

PJ Barnes

The role of anticholinergics in chronic obstructive pulmonary disease

Am J Med

(2004)

DA Mahler et al.

Concurrent use of indacaterol plus tiotropium in patients with COPD provides superior bronchodilation compared with tiotropium alone: a randomised, double-blind comparison

Thorax

(2012)

F Maltais et al.

Four weeks once daily treatment with tiotropium+olodaterol (BI 1744) fixed dose combination compared with tiotropium in COPD patients

Eur Respir J

(2010)

C Reisner et al.

Pearl Therapeutics' combination LAMA/LABA MDI (GFF-MDI, PT003) provides a significant benefit on home peak expiratory flow rate (PEFR) and reduces the need for rescue albuterol use compared to its components administered alone, Spiriva(R) Handihaler(R), And Foradil(R) Aerolizer(R) in a randomized, double-blind, placebo-controlled phase 2B study in patients with COPD

Am J Respir Crit Care Med

(2012)

C Reisner et al.

Fixed combination of glycopyrrolate and formoterol mdi (GFF-MDI) demonstrates superior inspiratory capacity (IC) compared to tiotropium dpi (TIO) following 7 days dosing, in a randomized, double-blind, placebo-controlled phase 2b study in patients with COPD

Eur Respir J

(2011)

T van der Molen et al.

Beyond lung function in COPD management: effectiveness of LABA/LAMA combination therapy on patient-centred outcomes

Prim Care Respir J

(2012)

JA van Noord et al.

QVA149 demonstrates superior bronchodilation compared with indacaterol or placebo in patients with chronic obstructive pulmonary disease

Thorax

(2010)

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Researchers have yet to obtain conclusive evidence differentiating among fixed-dose combinations (FDCs) of long-acting muscarinic antagonists (LAMAs) and long-acting β₂-agonists (LABAs) for COPD in terms of real-world clinical outcomes.
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Among the 44,498 patients identified and included, 15,586 received GLY/IND, 20,460 received UMEC/VI, and 8,452 received TIO/OLO. Baseline characteristics were well balanced after 1:1 matching of UMEC/VI and GLY/IND, 2:1 matching of UMEC/VI and TIO/OLO, and 2:1 matching of GLY/IND and TIO/OLO. Risk of severe AE was lower among patients treated with UMEC/VI or GLY/IND than among those who received TIO/OLO (UMEC/VI vs TIO/OLO: 17.85 vs 29.32 per 100 person-years; hazard ratio, 0.76; 95% CI, 0.68-0.84; GLY/IND vs TIO/OLO: 15.54 vs 25.53 per 100 person-years; hazard ratio, 0.77; 95% CI, 0.67-0.88). In addition, GLY/IND users tended to have a lower risk of cardiovascular events than TIO/OLO users, but the difference dissipated when restricting follow up to a shorter duration.
Our results revealed that the risk of severe AE was lower among patients with COPD receiving UMEC/VI or GLY/IND than among those receiving TIO/OLO, whereas the incidence of cardiovascular events was similar across groups but was slightly lower in GLY/IND users when compared with TIO/OLO users. Further research will be required to confirm these findings.
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In this double-blind randomized study (NCT02343458), patients received GFF MDI (18/9.6 μg), glycopyrrolate (GP) MDI (18 μg), formoterol fumarate (FF) MDI (9.6 μg), or placebo MDI twice daily for 24 weeks. The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV₁) over Weeks 12–24. Secondary lung function endpoints, patient-reported outcomes, and safety were assessed. The Japanese subpopulation (n = 150) analyses were exploratory.
GFF MDI improved change from baseline in morning pre-dose trough FEV₁ over Weeks 12–24 versus GP MDI, FF MDI, and placebo MDI (least squares mean [LSM] differences [95% confidence interval]: 69 [8–131], 60 [–1 to 121], and 275 [180–370] mL, respectively). GFF MDI numerically improved Transition Dyspnea Index focal score and change from baseline in St George's Respiratory Questionnaire total score versus placebo MDI (LSM differences 0.19 and −3.78, respectively). Treatment-related adverse events occurred in ≤4.5% of patients in any treatment group.
GFF MDI improved lung function versus monocomponents and placebo MDI in the Japan subpopulation of PINNACLE-4. The efficacy and safety results were generally consistent with those of the global study population, supporting the use of GFF MDI in Japanese patients with moderate-to-very severe COPD.
Dual bronchodilators in chronic obstructive pulmonary disease: Evidence from randomized controlled trials and real-world studies
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Dual bronchodilator therapy with a long-acting muscarinic antagonist (LAMA) and a long-acting β₂-agonist (LABA) is recommended in the pharmacological management of chronic obstructive pulmonary disease (COPD) according to the Global Initiative for Chronic Obstructive Lung Disease. To better understand the evidence supporting use of LAMA+LABA therapy in COPD and evaluate consistency within and across clinical research study types, we systematically reviewed and analyzed data from both randomized controlled trials (RCTs) and real-world studies.
We searched PubMed from inception until April 4, 2019, for phase 2/3/4 RCTs of ≥24 weeks’ duration and real-world studies in which the efficacy and/or safety of LAMA+LABAs were compared with monotherapies, other LAMA+LABAs, LABA+inhaled corticosteroid (ICS), or triple therapy (LAMA+LABA+ICS). We extracted primary and key secondary outcomes data from relevant articles for descriptive purposes.
Overall, 24 RCTs and 8 real-world studies were included in the analysis based on predefined inclusion criteria. LAMA+LABAs improved lung function and health-related quality of life, and reduced exacerbation rates and dyspnea when compared with monotherapies, LABA+ICS, or triple therapy in both RCTs and real-world studies. Importantly, all LAMA+LABAs were well tolerated, with their safety profiles comparable to those of respective monotherapies, and had lower incidences of pneumonia than ICS-containing regimens.
Results of RCTs and real-world studies are largely consistent; demonstrate that LAMA+LABAs improve lung function and health-related quality of life and reduce exacerbation rates and dyspnea relative to other available pharmacotherapies; and reinforce the position of LAMA+LABAs in the pharmacological management of COPD.
Fixed-dose combination of three drugs, i.e. LABA/LAMA/ICS for COPD: Results of a real-world study from India
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The use of triple therapy with inhaled corticosteroids, long-acting beta-agonist and long-acting antimuscarinics has been shown to be beneficial in COPD patients who continue to have symptoms and exacerbations, despite receiving dual bronchodilator combinations. This study assessed the real-world effectiveness and safety of once-daily, fixed-dose combination of Tiotropium/Formoterol/Ciclesonide (TFC) (18 mcg/12 mcg/400 mcg) via dry powder inhaler (DPI) or metered dose inhaler (MDI) in patients with COPD.
In this 24-week, open-label, prospective, non-comparative, multicentre, real-world study, COPD patients requiring triple therapy as judged by their physician, were enrolled. The primary endpoint was mean change from baseline in pre-dose Forced Expiratory Volume in 1 s (FEV₁) at week 24. Pre and post-dose (30 min) FEV₁, Forced Vital capacity (FVC), COPD Assessment Test (CAT), modified Medical Research Council (mMRC) score and safety were also evaluated. A post-hoc analysis was conducted to evaluate the efficacy of the triple drug combination among smoker and non-smoker COPD patients.
Out of the 297 patients enrolled [mean age 61 ± 10 years; 84.8% males; 55.2% smokers and post-dose FEV₁ (% predicted) 39 ± 16%], 253 completed the study. Mean change in pre-dose FEV₁ from baseline to week 24 increased significantly after administering the triple drug combination [580 ± 600 mL, 95% CI (510, 650 mL), p < 0.0001]. The increase in the pre-dose FEV₁ was significant at all time points (p < 0.0001). Similar improvements were seen in pre-dose FVC, post-dose FEV₁ and post-dose FVC across all time points. CAT scores and the proportion of patients with improved mMRC score improved at all visits. The post-hoc analysis showed that TFC significantly increased pre-dose FEV₁ both among smokers [mean change 200 ± 430 mL, 95% CI (130, 270 mL), p < 0.0001] as well as non-smokers [990 ± 470 mL, 95% CI (900, 1070 mL), p < 0.0001] at week 24. This difference was significant from week 12 onwards. Mean change in pre and post-dose FEV₁ and FVC was significant across all visits between the two groups. At week 24, CAT score reduced significantly from baseline (overall: -6.6 ± 6.07; smokers: -5.17 + 6.96; non-smokers: 8.06 ± 4.44; all p < 0.0001). The mean difference between the two groups was 2.88 (p < 0.0001) at week 24. TFC was well tolerated.
In this real world, multicentre study in India, TFC significantly improved lung function, symptoms and quality of life among all patients with COPD, but the effect was more pronounced among non-smoker COPD patients.
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Inhaled long-acting bronchodilators, including long-acting β₂ agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are the mainstay therapy in the treatment of chronic obstructive pulmonary disease (COPD), a disease that poses a heavy burden on morbidity and mortality worldwide. Use of LABAs and LAMAs in patients with COPD, however, has been concerned about an increased risk of adverse cardiovascular events, despite inconsistent findings reported from randomized controlled trials (RCTs) and observational studies. In this review, we detailed the relevant evidence generated from RCTs and observational studies with respect to the risk of cardiovascular disease with use of LABAs and LAMAs in management of COPD, and analyzed the contradictory findings in the literature, as well as recommended future research directions to clear the air regarding the cardiovascular safety of inhaled long-acting bronchodilators.
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View all citing articles on Scopus

Dr Crater is currently at Clinical Development, Aerocrine (Morrisville, NC).

Funding/Support: GlaxoSmithKline funded the design/concept/conduct of the study and manuscript development.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.

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Chest

Original ResearchOnce-Daily Umeclidinium/Vilanterol 125/25 μg Therapy in COPD: A Randomized, Controlled Study

Background

Methods

Results

Conclusions

Trial registry

Section snippets

Study Design, Treatments, and Assessments

Patients

Discussion

Conclusions

Acknowledgments

Pulm Pharmacol Ther

Chest

Respir Med

Chest

Chest

Value Health

Pulm Pharmacol Ther

Clin Ther

Respir Med

Respir Med

Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper

Eur Respir J

Reducing cholinergic constriction: the major reversible mechanism in COPD

Eur Respri Rev

The role of anticholinergics in chronic obstructive pulmonary disease

Am J Med

Concurrent use of indacaterol plus tiotropium in patients with COPD provides superior bronchodilation compared with tiotropium alone: a randomised, double-blind comparison

Thorax

Four weeks once daily treatment with tiotropium+olodaterol (BI 1744) fixed dose combination compared with tiotropium in COPD patients

Eur Respir J

Am J Respir Crit Care Med

Fixed combination of glycopyrrolate and formoterol mdi (GFF-MDI) demonstrates superior inspiratory capacity (IC) compared to tiotropium dpi (TIO) following 7 days dosing, in a randomized, double-blind, placebo-controlled phase 2b study in patients with COPD

Eur Respir J

Beyond lung function in COPD management: effectiveness of LABA/LAMA combination therapy on patient-centred outcomes

Prim Care Respir J

QVA149 demonstrates superior bronchodilation compared with indacaterol or placebo in patients with chronic obstructive pulmonary disease

Thorax

Original Research
Once-Daily Umeclidinium/Vilanterol 125/25 μg Therapy in COPD: A Randomized, Controlled Study