Relieving exertional dyspnea during the 3-min constant speed shuttle test in patients with COPD with indacaterol/glycopyrronium versus tiotropium: the RED trial

Background: Exertional dyspnea is a cardinal feature of chronic obstructive pulmonary disease (COPD) and a major cause of activity limitation. Although dual bronchodilation is more effective than bronchodilator monotherapy at improving resting pulmonary function, it is unclear to which extent this translates into superior relief of exertional dyspnea. Methods: We conducted a randomized controlled, double-blind, cross-over trial comparing indacaterol 110 µg/glycopyrronium 50 µg once daily (OD) with tiotropium 50 µg OD in patients with moderate to severe COPD and resting hyperinflation (functional residual capacity >120% of predicted value). The primary outcome was Borg dyspnea score at the end of a 3-min constant speed shuttle test after 3 weeks of treatment. Secondary outcomes included changes in Borg dyspnea score after the first dose of study medication, expiratory flows and lung volumes. Statistical analysis was conducted using a cross-over analysis of variance model with repeated measurements. Results: A total of 50 patients with COPD and a mean forced expiratory volume in 1 s of 54 ± 11% (mean ± SEM) predicted participated in the cross-over phase of the trial. Compared with baseline, there was a decrease in dyspnea after the first dose of medication with indacaterol/glycopyrronium [mean −1.00, 95% confidence interval (CI) −1.49 to −0.52] but not with tiotropium alone (mean −0.36, 95% CI −0.81 to 0.08). The reduction in dyspnea after the first dose was statistically significant between the two treatments (mean difference of −0.64, 95% CI −1.11 to −0.17). Despite indacaterol/glycopyrronium providing further bronchodilation and lung deflation throughout the trial, the reduction in dyspnea was not sustained at 3 weeks of treatment (mean between-treatment difference at 3 weeks of 0.09, 95% CI −0.44 to 0.61). Conclusion: In comparison with bronchodilator monotherapy, indacaterol/glycopyrronium provided greater immediate exertional dyspnea relief, although this difference was not sustained after 3 weeks of therapy despite evidence of further bronchodilation and lung deflation. The reviews of this paper are available via the supplemental material section.

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Effects of umeclidinium/vilanterol on exercise endurance in COPD: a randomised study

ERJ Open Research ◽

10.1183/23120541.00073-2017 ◽

2018 ◽

Vol 4 (1) ◽

pp. 00073-2017 ◽

Cited By ~ 1

Author(s):

John H. Riley ◽

Chris J. Kalberg ◽

Alison Donald ◽

David A. Lipson ◽

Muhammad Shoaib ◽

...

Keyword(s):

Forced Expiratory Volume ◽

Chronic Obstructive ◽

Post Dose ◽

Double Blind ◽

Endurance Time ◽

Obstructive Pulmonary Disease ◽

Once Daily ◽

Randomised Study ◽

Residual Capacity ◽

Exercise Endurance

This multicentre, randomised, double-blind, placebo-controlled, two-period crossover study assessed the effect of umeclidinium/vilanterol (UMEC/VI) on exercise capacity in patients with chronic obstructive pulmonary disease (COPD) using the endurance shuttle walk test (ESWT).Patients were randomised 1:1 to one of two treatment sequences: 1) UMEC/VI 62.5/25 µg followed by placebo or 2) placebo followed by UMEC/VI 62.5/25 µg. Each treatment was taken once daily for 12 weeks. The primary end-point was 3-h post-dose exercise endurance time (EET) at week 12. Secondary end-points included trough forced expiratory volume in 1 s (FEV1) and 3-h post-dose functional residual capacity (FRC), both at week 12. COPD Assessment Test (CAT) score at week 12 was also assessed.UMEC/VI treatment did not result in a statistically significant improvement in EET change from baseline at week 12 versus placebo (p=0.790). However, improvements were observed in trough FEV1 (206 mL, 95% CI 167–246), 3-h post-dose FRC (−346 mL, 95% CI −487 to −204) and CAT score (−1.07 units, 95% CI −2.09 to −0.05) versus placebo at week 12.UMEC/VI did not result in improvements in EET at week 12 versus placebo, despite improvements in measures of lung function, hyperinflation and health status.

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Maintained therapeutic effect of revefenacin over 52 weeks in moderate to very severe Chronic Obstructive Pulmonary Disease (COPD)

Respiratory Research ◽

10.1186/s12931-019-1187-7 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 6

Author(s):

James F. Donohue ◽

Edward Kerwin ◽

Sanjay Sethi ◽

Brett Haumann ◽

Srikanth Pendyala ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Health Outcomes ◽

Pulmonary Disease ◽

Inhaled Corticosteroids ◽

Forced Expiratory Volume ◽

Chronic Obstructive ◽

Open Label ◽

Double Blind ◽

Obstructive Pulmonary Disease ◽

Long Acting

Abstract Background Revefenacin is a long-acting muscarinic antagonist that was recently approved for the nebulized treatment of chronic obstructive pulmonary disease (COPD). Although shorter duration studies have documented the efficacy of revefenacin in COPD, longer-term efficacy has not been described. In a recent 52-week safety trial, revefenacin was well tolerated and had a favorable benefit-risk profile. Here we report exploratory efficacy and health outcomes in patients receiving revefenacin 175 μg or 88 μg daily during the 52-week trial. Methods In this randomized, parallel-group, 52-week trial (NCT02518139), 1055 participants with moderate to very severe COPD received revefenacin 175 μg or 88 μg in a double-blind manner, or open-label active control tiotropium. Results Over the 52-week treatment period, both doses of revefenacin, as well as tiotropium, elicited significant (all p < 0.0003) improvements from baseline in trough forced expiratory volume in 1 s (FEV1). The trough FEV1 profile (least squares mean change from baseline) for revefenacin 175 μg ranged from 52.3–124.3 mL and the trough FEV1 profile for tiotropium ranged from 79.7–112.8 mL. In subgroup comparisons, the effect of revefenacin on trough FEV1 was comparable in patients taking concomitant long-acting β-agonists, with or without inhaled corticosteroids, with patients who were not taking these medications. There were statistically significant (p < 0.05) improvements in all measured health status outcomes (evaluated using St. George’s Respiratory Questionnaire, COPD Assessment Test, Clinical COPD Questionnaire and Baseline and Transition Dyspnea Index) from 3 months onward, in all treatment arms. Conclusions Significant sustained improvements from baseline in trough FEV1 and respiratory health outcomes were demonstrated for 175-μg revefenacin over 52 weeks, further supporting its use as a once-daily bronchodilator for the nebulized treatment of patients with COPD. Trial registration NCT02518139; Registered 5 August 2015.

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Tiotropium and olodaterol fixed-dose combinationversusmono-components in COPD (GOLD 2–4)

European Respiratory Journal ◽

10.1183/09031936.00136014 ◽

2015 ◽

Vol 45 (4) ◽

pp. 969-979 ◽

Cited By ~ 182

Author(s):

Roland Buhl ◽

François Maltais ◽

Roger Abrahams ◽

Leif Bjermer ◽

Eric Derom ◽

...

Keyword(s):

Area Under The Curve ◽

Forced Expiratory Volume ◽

Phase Iii ◽

Fixed Dose ◽

Chronic Obstructive ◽

Double Blind ◽

Obstructive Pulmonary Disease ◽

Once Daily ◽

Multicentre Phase ◽

St George's Respiratory Questionnaire

Efficacy and safety of tiotropium+olodaterol fixed-dose combination (FDC) compared with the mono-components was evaluated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in two replicate, randomised, double-blind, parallel-group, multicentre, phase III trials.Patients received tiotropium+olodaterol FDC 2.5/5 μg or 5/5 μg, tiotropium 2.5 μg or 5 μg, or olodaterol 5 μg delivered once-dailyviaRespimat inhaler over 52 weeks. Primary end points were forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0–3) response, trough FEV1 response and St George's Respiratory Questionnaire (SGRQ) total score at 24 weeks.In total, 5162 patients (2624 in Study 1237.5 and 2538 in Study 1237.6) received treatment. Both FDCs significantly improved FEV1 AUC0–3 and trough FEV1 responseversusthe mono-components in both studies. Statistically significant improvements in SGRQ total scoreversusthe mono-components were only seen for tiotropium+olodaterol FDC 5/5 μg. Incidence of adverse events was comparable between the FDCs and the mono-components.These studies demonstrated significant improvements in lung function and health-related quality of life with once-daily tiotropium+olodaterol FDCversusmono-components over 1 year in patients with moderate to very severe COPD.

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Never-smokers with occupational COPD have better exercise capacities and ventilatory efficiency than matched smokers with COPD

Journal of Applied Physiology ◽

10.1152/japplphysiol.00306.2020 ◽

2020 ◽

Vol 129 (6) ◽

pp. 1257-1266

Author(s):

Thibaud Soumagne ◽

Alicia Guillien ◽

Nicolas Roche ◽

Jean-Charles Dalphin ◽

Bruno Degano

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Vital Capacity ◽

Forced Expiratory Volume ◽

Chronic Obstructive ◽

Exertional Dyspnea ◽

Obstructive Pulmonary Disease ◽

Ventilatory Efficiency ◽

Never Smokers ◽

Occupational Copd ◽

Lower Limit Of Normal

It is unknown whether or not never-smokers with chronic obstructive pulmonary disease (COPD) behave like their smoking counterparts during exercise. This is the first study showing that never-smokers with mild to moderate COPD [defined by a postbronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) < lower limit of normal] have preserved exercise capacities. They also have lower exertional dyspnea than patients with smoking-related COPD. This suggests that the two COPD groups should not be managed in the same way.

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Obesity modulates diaphragm curvature in subjects with and without COPD

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00173.2017 ◽

2017 ◽

Vol 313 (5) ◽

pp. R620-R629 ◽

Cited By ~ 6

Author(s):

Aladin M. Boriek ◽

Michael A. Lopez ◽

Cristina Velasco ◽

Azam A. Bakir ◽

Anna Frolov ◽

...

Keyword(s):

Forced Expiratory Volume ◽

Normal Weight ◽

The Body ◽

Diaphragm Muscle ◽

Chronic Obstructive ◽

Quiet Breathing ◽

Obstructive Pulmonary Disease ◽

Copd Patients ◽

Left Hemidiaphragm ◽

Residual Capacity

Obesity is a common comorbidity of chronic obstructive pulmonary disease (COPD) and has been associated with worse outcomes. However, it is unknown whether the interaction between obesity and COPD modulates diaphragm shape and consequently its function. The body mass index (BMI) has been used as a correlate of obesity. We tested the hypothesis that the shape of the diaphragm muscle and size of the ring of its insertion in non-COPD and COPD subjects are modulated by BMI. We recruited 48 COPD patients with postbronchiodilator forced expiratory volume in 1 s (FEV1)-to-forced vital capacity (FVC) < 0.7 and 29 age-matched smoker/exsmoker control (non-COPD) subjects, who underwent chest computed tomography (CT) at lung volumes ranging from functional residual capacity (FRC) to total lung capacity (TLC). We then computed maximum principal diaphragm curvature in the midcostal region of the left hemidiaphragm at the end of inspiration during quiet breathing (EI) and at TLC. The radius of maximum curvature of diaphragm muscle increased with BMI in both COPD and non-COPD subjects. The size of diaphragm ring of insertion on the chest wall also increased significantly with increasing BMI. Surprisingly, COPD severity did not appear to cause significant alteration in diaphragm shape except in normal-weight subjects at TLC. Our data uncovered important factors such as BMI, the size of the diaphragm ring of insertion, and disease severity that modulate the structure of the ventilatory pump in non-COPD and COPD subjects.

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CT of Saber-Sheath Trachea

Acta Radiologica ◽

10.1177/028418519403500310 ◽

1994 ◽

Vol 35 (3) ◽

pp. 247-250 ◽

Cited By ~ 15

Author(s):

J. P. Trigaux ◽

G. Hermes ◽

P. Dubois ◽

B. Van Beers ◽

L. Delaunois ◽

...

Keyword(s):

Forced Expiratory Volume ◽

Chronic Obstructive ◽

Functional Tests ◽

Cross Sectional ◽

Obstructive Pulmonary Disease ◽

Lung Capacity ◽

Significant Difference ◽

Residual Capacity ◽

Cross Sectional Imaging ◽

Sectional Imaging

The diagnosis of saber-sheath trachea is easy at CT due to its cross-sectional imaging, but the significance of this CT sign has not been evaluated in the diagnosis of chronic obstructive pulmonary disease (COPD). Various signs of COPD were compared between a series of 20 patients with a saber-sheath trachea at CT (tracheal index <66%) and a group of 20 pneumologic control patients without saber-sheath trachea (tracheal index ≥70%). These signs included clinical and standard radiographic indices of COPD, sternum-spine distance and 3 functional tests of COPD: forced expiratory volume in one second, carbon monoxide diffusing lung capacity, and functional residual capacity (FRC). A significant difference was found between the 2 groups, concerning the values of FRC (p < 10−4) and of sternum-spine distance (p < 10−2). The tracheal index was significantly correlated with the FRC values (r = −0.611; p < 10−5) and with the sternum-spine distance (r = −0.322; p < 0.05). No other significant difference was observed. It is concluded that saber-sheath trachea is basically a sign of hyperinflation.

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Navafenterol (AZD8871) in patients with COPD: a randomized, double-blind, phase I study evaluating safety and pharmacodynamics of single doses of this novel, inhaled, long-acting, dual-pharmacology bronchodilator

Respiratory Research ◽

10.1186/s12931-020-01347-7 ◽

2020 ◽

Vol 21 (S1) ◽

Cited By ~ 1

Author(s):

Dave Singh ◽

Victor Balaguer ◽

Carol Astbury ◽

Ulrika Wählby-Hamrén ◽

Eulalia Jimenez ◽

...

Keyword(s):

Least Squares ◽

Forced Expiratory Volume ◽

Chronic Obstructive ◽

Trial Registry ◽

Open Label ◽

Double Blind ◽

Obstructive Pulmonary Disease ◽

Link Type ◽

Long Acting ◽

Severe Copd

Abstract Background Navafenterol (AZD8871) is a dual-pharmacology muscarinic antagonist β2−agonist (MABA) molecule in development for the treatment of chronic obstructive pulmonary disease (COPD). The pharmacodynamics, safety and tolerability of single doses of navafenterol were investigated in patients with moderate to severe COPD. Methods This was a randomized, five-way complete cross-over study. Patients received single doses of navafenterol 400 μg, navafenterol 1800 μg and placebo (all double-blind) and indacaterol 150 μg and tiotropium 18 μg (both open-label active comparators). The primary pharmacodynamic endpoint was change from baseline in trough forced expiratory volume in 1 s (FEV1) on day 2. Safety and tolerability were monitored throughout. Results Thirty-eight patients were randomized and 28 (73.7%) completed the study. Navafenterol 400 μg and 1800 μg demonstrated statistically significant improvements vs placebo in change from baseline in trough FEV1 (least squares mean [95% confidence interval]: 0.111 [0.059, 0.163] L and 0.210 [0.156, 0.264] L, respectively, both P < .0001). The changes were significantly greater with navafenterol 1800 μg vs the active comparators (least squares mean treatment difference: 0.065–0.069 L, both P < .05). The frequency of treatment-emergent adverse events was similar for placebo and the active comparators (range 34.4–37.5%), slightly higher for navafenterol 400 μg (52.9%), and lowest for navafenterol 1800 μg (22.6%). Conclusions Both doses of navafenterol demonstrated sustained bronchodilation over 24 h. Navafenterol was well tolerated and no safety concerns were raised. Trial registry ClinicalTrials.gov; No.: NCT02573155; URL: www.clinicaltrials.gov. Registered 9th October, 2015.

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INSTEAD: a randomised switch trial of indacaterol versus salmeterol/fluticasone in moderate COPD

European Respiratory Journal ◽

10.1183/09031936.00126814 ◽

2014 ◽

Vol 44 (6) ◽

pp. 1548-1556 ◽

Cited By ~ 78

Author(s):

Andrea Rossi ◽

Thys van der Molen ◽

Ricardo del Olmo ◽

Alberto Papi ◽

Luis Wehbe ◽

...

Keyword(s):

Forced Expiratory Volume ◽

Primary Objective ◽

Chronic Obstructive ◽

Copd Exacerbation ◽

Inhaled Corticosteroid ◽

Double Blind ◽

Obstructive Pulmonary Disease ◽

Once Daily ◽

Copd Exacerbations ◽

Parallel Group

The Indacaterol: Switching Non-exacerbating Patients with Moderate COPD From Salmeterol/Fluticasone to Indacaterol (INSTEAD) study investigated the effect of switching patients at low risk of chronic obstructive pulmonary disease (COPD) exacerbations from salmeterol/fluticasone (SFC; inhaled corticosteroid (ICS) regimen) to indacaterol monotherapy (non-ICS regimen).This 26-week, double-blind, double-dummy, parallel-group, phase IV study, randomised 581 patients with moderate COPD to indacaterol 150 μg once daily or SFC 50/500 μg twice daily. Patients had been receiving SFC 50/500 μg for ≥3 months, with no COPD exacerbations for more than a year before the study (patients for whom ICS is not recommended). The primary objective was to demonstrate non-inferiority of indacaterol to SFC, measured by trough forced expiratory volume in 1 second (FEV1) after 12 weeks (non-inferiority margin of 0.06 L).The primary objective was met, with a mean treatment difference of 9 mL (95% CI -45–26 mL). There were no significant differences between treatments in terms of breathlessness (transition dyspnoea index) or health status (Saint George’s Respiratory Questionnaire) at weeks 12 or 26, or rescue medication use or COPD exacerbation rates over 26 weeks. Safety profiles of both treatments were as expected.This study demonstrated that patients with moderate COPD and no exacerbations in the previous year can be switched from SFC to indacaterol 150 μg with no efficacy loss.

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Efficacy and safety of aclidinium/formoterol versus salmeterol/fluticasone: a phase 3 COPD study

European Respiratory Journal ◽

10.1183/13993003.00216-2016 ◽

2016 ◽

Vol 48 (4) ◽

pp. 1030-1039 ◽

Cited By ~ 40

Author(s):

Claus Vogelmeier ◽

Pier Luigi Paggiaro ◽

Jordi Dorca ◽

Pawel Sliwinski ◽

Marcel Mallet ◽

...

Keyword(s):

Adverse Events ◽

Symptom Control ◽

Forced Expiratory Volume ◽

Controlled Study ◽

Chronic Obstructive ◽

Efficacy And Safety ◽

Double Blind ◽

Obstructive Pulmonary Disease ◽

St George's Respiratory Questionnaire ◽

Exacerbation Risk

The efficacy and safety of twice-daily aclidinium bromide/formoterol fumarate was compared with that of salmeterol/fluticasone propionate in patients with stable, moderate-to-severe chronic obstructive pulmonary disease (COPD).AFFIRM COPD (Aclidinium and Formoterol Findings in Respiratory Medicine COPD) was a 24-week, double-blind, double-dummy, active-controlled study. Patients were randomised (1:1) to aclidinium/formoterol 400/12 µg twice-daily via Genuair/Pressair or salmeterol/fluticasone 50/500 µg twice-daily via Accuhaler. The primary end-point was peak forced expiratory volume in 1 s (FEV1) at week 24. Other end-points included Transition Dyspnoea Index (TDI) focal score at week 24, TDI and St George's Respiratory Questionnaire (SGRQ) responders, COPD Assessment Test and SGRQ scores, assessment of COPD symptoms and exacerbations, use of reliever medication, and device preference. Adverse events were monitored throughout.In total, 933 patients were eligible (mean age 63.4 years, 65.1% male). Aclidinium/formoterol was superior to salmeterol/fluticasone in peak FEV1 and noninferior in TDI. Health status and reduction in exacerbation risk were similar in both groups. While both treatments were well tolerated, pneumonia occurred less frequently with aclidinium/formoterol than salmeterol/fluticasone.In stable COPD, aclidinium/formoterol significantly improved bronchodilation versus salmeterol/fluticasone, with equivalent benefits in symptom control and reduction in exacerbation risk. Both treatments were well tolerated and treatment-related adverse events were less common with aclidinium/formoterol.

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Mechanisms for isolated volume response to a bronchodilator in patients with COPD

Journal of Applied Physiology ◽

10.1152/jappl.2000.88.6.1989 ◽

2000 ◽

Vol 88 (6) ◽

pp. 1989-1995 ◽

Cited By ~ 46

Author(s):

Isa Cerveri ◽

Riccardo Pellegrino ◽

Roberto Dore ◽

Angelo Corsico ◽

Paola Fulgoni ◽

...

Keyword(s):

Forced Expiratory Volume ◽

Chronic Obstructive ◽

Cube Root ◽

High Resolution Computed Tomography ◽

Obstructive Pulmonary Disease ◽

Lung Inflation ◽

Severe Emphysema ◽

Airway Caliber ◽

Volume Response ◽

Residual Capacity

We hypothesized that an altered effect of lung inflation on airway caliber may in part explain the isolated volume response to bronchodilators, i.e., an increase of forced vital capacity (FVC) without change in 1-s forced expiratory volume (FEV1). Small-airway caliber was measured by high-resolution computed tomography at functional residual capacity and total lung capacity in five chronic obstructive pulmonary disease patients with an isolated increase of FVC (FVC responders) and five with an increase of both FVC and FEV1(FVC-FEV1 responders) after inhalation of salbutamol. In FVC-FEV1 responders, the airway diameter increased with the cube root of increase in lung volume but was unchanged or even decreased in four of five FVC responders. FVC responders had more severe emphysema, as inferred from lung function and imaging studies, than FVC-FEV1 responders. We speculate that longitudinal traction or space competition (Verbeken EK, Cauberghs M, and Van de Woestijne KP, J Appl Physiol 81: 2468–2480, 1996) are possible underlying mechanisms. We conclude that the isolated volume response to bronchodilators is associated with severe emphysema and likely results from an altered effect of lung inflation on airway caliber.

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