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The 3-min constant speed shuttle test (CSST) was used to examine the effect of tiotropium/olodaterol compared with tiotropium at reducing activity-related breathlessness in patients with chronic obstructive pulmonary disease (COPD).This was a randomised, double-blind, two-period crossover study including COPD patients with moderate to severe pulmonary impairment, lung hyperinflation at rest and a Mahler Baseline Dyspnoea Index <8. Patients received 6 weeks of tiotropium/olodaterol 5/5 µg and tiotropium 5 µg in a randomised order with a 3-week washout period. The speed for the 3-min CSST was determined for each patient such that an intensity of breathing discomfort ≥4 ("somewhat severe") on the modified Borg scale was reached at the end of a completed 3-min CSST.After 6 weeks, there was a decrease in the intensity of breathlessness (Borg dyspnoea score) at the end of the 3-min CSST from baseline with both tiotropium (mean -0.968, 95% CI -1.238- -0.698; n=100) and tiotropium/olodaterol (mean -1.325, 95% CI -1.594- -1.056; n=101). The decrease in breathlessness was statistically significantly greater with tiotropium/olodaterol versus tiotropium (treatment difference -0.357, 95% CI -0.661- -0.053; p=0.0217).Tiotropium/olodaterol reduced activity-related breathlessness more than tiotropium in dyspnoeic patients with moderate to severe COPD exhibiting lung hyperinflation., Competing Interests: Conflict of interest: F. Maltais reports research support from Boehringer Ingelheim, GSK, AstraZeneca, Grifols and Novartis, advisory board participation for Boehringer Ingelheim and GSK, and speaking engagements for Boehringer Ingelheim, Grifols and Novartis. Conflict of interest: J-L. Aumann has nothing to disclose. Conflict of interest: A-M. Kirsten reports institutional compensation for clinical trials from Boehringer Ingelheim, during the conduct of the study; has lectured for Boehringer Ingelheim, AstraZeneca and Berlin-Chemie, and reports institutional compensation for clinical trials from AstraZeneca, Boehringer Ingelheim, Roche, GSK, Novartis, Chiesi, Bayer Healthcare and Sanofi, outside the submitted work. Conflict of interest: É. Nadreau has nothing to disclose. Conflict of interest: H. Macesic is an employee of Boehringer Ingelheim. Conflict of interest: X. Jin is an employee of Boehringer Ingelheim. Conflict of interest: A. Hamilton is an employee of Boehringer Ingelheim. Conflict of interest: D.E. O'Donnell reports grants from AstraZeneca, Boehringer Ingelheim and GSK, during the conduct of the study; and personal fees for serving on speaker bureaus, consultation panels and advisory boards from Almirall, AstraZeneca, Boehringer Ingelheim, GSK, Novartis and Pfizer, outside the submitted work., (Copyright ©ERS 2019.)

Background and Purpose: Fixed-dose combinations of a long-acting beta agonist and an inhaled corticosteroid are more effective than the individual components in COPD. The primary study objective was to demonstrate that the combination indacaterol acetate/mometasone furoate (IND/MF [QMF149]) was non-inferior to the twice-daily combination salmeterol xinafoate/fluticasone propionate (Sal/Flu) in terms of trough FEV 1 at week 12 (day 85). Secondary objectives were to compare the efficacy of IND/MF (QMF149) vs Sal/Flu with respect to other lung function parameters, COPD exacerbations, symptoms and dyspnea, health status/health-related quality of life, and rescue medication use., Materials and Methods: This was a 12-week multicenter, randomized, double-blind, double-dummy, parallel-group, Phase II study in patients with moderate-to-very-severe COPD, who were randomized (1:1) to IND/MF (QMF149) (150/160 µg once daily; n=316) or Sal/Flu (50/500 µg twice daily; n=313)., Results: Over 90% of patients completed the study: 94.6% in the IND/MF (QMF149) group and 92.0% in the Sal/Flu group. The primary objective of non-inferiority of IND/MF (QMF149) to Sal/Flu for trough FEV 1 at week 12 (day 85) was met: the lower limit of the CI (95% CI: 27.7, 83.3 mL) was greater than -60 mL. The analysis for superiority of IND/MF (QMF149) to Sal/Flu demonstrated superiority of IND/MF (QMF149), with a difference of 56 mL ( P <0.001). In addition, IND/MF (QMF149) treatment significantly improved COPD exacerbation-related parameters during the 12-week period. Other significant improvements with IND/MF (QMF 149) vs Sal/Flu were noted for dyspnea at week 12 and other COPD symptoms and COPD rescue medication use over the 12 weeks. The safety and tolerability profiles of both the treatments were similar., Conclusion: IND/MF (QMF149) (150/160 µg once daily) offered superior lung function and symptom efficacy and a favorable safety profile compared with Sal/Flu (50/500 µg twice daily) in patients with moderate-to-very severe COPD., Competing Interests: Disclosure AMT, BH and AR are employees of Novartis Pharma AG. WC is an employee of Novartis Pharmaceuticals Corporation. KMB declares that no personal payments were received from any pharmaceutical entity in the past 5 years. KMB and JB are full-time employees of Insaf Respiratory Research Institute. AMK is an employee of the Pulmonary Research Institute at LungClinic Grosshansdorf. AMK received speaking honoraria, honoraria for participation in advisory board meetings, and travel support for attending congresses in respiratory medicine from Boehringer Ingelheim, AstraZeneca, and Novartis. RNVZS has received honoraria for academic work from Novartis, AZ, CIPLA, ASPEN, Pfizer, GSK, and MSD. The authors report no other conflicts of interest in this work.

Background: The TORRACTO ® study evaluated the effects of tiotropium/olodaterol versus placebo on endurance time during constant work-rate cycling and constant speed shuttle walking in patients with chronic obstructive pulmonary disease (COPD) after 12 weeks of treatment., Methods: The effects of once-daily tiotropium/olodaterol (2.5/5 and 5/5 μg) on endurance time during constant work-rate cycle ergometry (CWRCE) after 6 and 12 weeks of treatment were compared with placebo in patients with COPD in a randomized, double-blind, placebo-controlled, parallel-group clinical trial. Endurance time during the endurance shuttle walk test (ESWT) after 6 and 12 weeks of treatment was also evaluated in a subset of patients., Results: A total of 404 patients received treatment, with 165 participating in the ESWT substudy. A statistically significant improvement in endurance time during CWRCE was observed after 12 weeks (primary endpoint) with tiotropium/olodaterol 5/5 µg [14% ( p = 0.02)] but not with tiotropium/olodaterol 2.5/5 µg [9% ( p = 0.14)] versus placebo. In the ESWT substudy, a trend to improvement in endurance time during ESWT after 12 weeks (key secondary endpoint) was observed with tiotropium/olodaterol 5/5 µg [21% ( p = 0.055)] and tiotropium/olodaterol 2.5/5 µg [21% ( p = 0.056)] versus placebo., Conclusion: Tiotropium/olodaterol 5/5 µg improved endurance time during cycle ergometry versus placebo, with a strong tendency to also improve walking endurance time. [ ClinicalTrials.gov identifier: NCT01525615.].

Background: A previous Phase IIIb study (NCT01462929) in patients with moderate to severe COPD demonstrated that 6 weeks of treatment with aclidinium led to improvements in 24-hour bronchodilation comparable to those with tiotropium, and improvement of symptoms versus placebo. This post hoc analysis was performed to assess the effect of treatment in the symptomatic patient group participating in the study., Methods: Symptomatic patients (defined as those with Evaluating Respiratory Symptoms [E-RS™] in COPD baseline score ≥10 units) received aclidinium bromide 400 μg twice daily (BID), tiotropium 18 μg once daily (QD), or placebo, for 6 weeks. Lung function, COPD respiratory symptoms, and incidence of adverse events (AEs) were assessed., Results: In all, 277 symptomatic patients were included in this post hoc analysis. Aclidinium and tiotropium treatment improved forced expiratory volume in 1 second (FEV 1 ) from baseline to week 6 at all time points over 24 hours versus placebo. In addition, improvements in FEV 1 from baseline during the nighttime period were observed for aclidinium versus tiotropium on day 1 (aclidinium 157 mL, tiotropium 67 mL; P <0.001) and week 6 (aclidinium 153 mL, tiotropium 90 mL; P <0.05). Aclidinium improved trough FEV 1 from baseline versus placebo and tiotropium at day 1 (aclidinium 136 mL, tiotropium 68 mL; P <0.05) and week 6 (aclidinium 137 mL, tiotropium 71 mL; P <0.05). Aclidinium also improved early-morning and nighttime symptom severity, limitation of early-morning activities, and E-RS Total and domain scores versus tiotropium (except E-RS Chest Symptoms) and placebo over 6 weeks. Tolerability showed similar incidence of AEs in each arm., Conclusion: In this post hoc analysis of symptomatic patients with moderate to severe COPD, aclidinium 400 μg BID provided additional improvements compared with tiotropium 18 μg QD in: 1) bronchodilation, particularly during the nighttime, 2) daily COPD symptoms (E-RS), 3) early-morning and nighttime symptoms, and 4) early-morning limitation of activity., Competing Interests: Disclosure JB has received consulting fees, speaker’s fees, and travel expenses from AstraZeneca and has also received compensation for organizing or participating in advisory boards for Cytos, Boehringer Ingelheim, Almirall, AstraZeneca, Novartis, and Revotar Biopharmaceuticals. The institution where JB is currently employed has received compensation for the design, performance, or participation in single or multicenter clinical trials in the past 5 years from several companies including Almirall, Altana, AstraZeneca, Boehringer Ingelheim, Cytos, GSK, Meda Pharmaceuticals, Merck Sharp & Dohme, Mundipharma, Novartis, Pfizer, and Revotar Biopharmaceuticals. RM has received consulting fees, speaker’s fees, and travel expenses from Boehringer Ingelheim and has also received compensation for participating in advisory boards for Boehringer Ingelheim, Almirall, AstraZeneca, and Novartis. Furthermore, RM has received compensation for participation in multicenter clinical trials in the past 5 years from several companies including Almirall, AstraZeneca, Boehringer Ingelheim, GSK, Merck Sharp & Dohme, Mundipharma, Novartis, Pearl, Roche, and Takeda. A-MK is a current employee of Pulmonary Research Institute at LungenClinic Grosshansdorf; the institution received compensation for the design of and/or participation in clinical trials from Almirall, AstraZeneca, Boehringer Ingelheim, GSK, Novartis, Pfizer, Infinity Pharmaceuticals, TEVA, Sterna Biologicals, Chiesi, Bayer, and Takeda. Furthermore, A-MK has received consulting fees, and speaker’s fees from AstraZeneca, Boehringer Ingelheim, and Roche. FC and EGG are employees of AstraZeneca PLC, Barcelona, Spain, and former employees of Almirall S.A., Barcelona, Spain.

Background: Long-acting bronchodilators, including anticholinergics glycopyrronium and tiotropium, are central to symptomatic management of chronic obstructive pulmonary disease (COPD). In patients with moderate to severe COPD, glycopyrronium has demonstrated comparable efficacy to open-label and single-blinded tiotropium, but with faster onset of bronchodilation. The FAST study assessed the efficacy of glycopyrronium compared with tiotropium in serial spirometry and body plethysmography assessments to further characterize the earlier onset of action associated with glycopyrronium., Methods: In this German multicentre, randomised, double-blinded, double-dummy, cross-over study, patients with moderate-to-severe COPD received single-dose of glycopyrronium 44 μg and tiotropium 18 μg via the Breezhaler ® and Handihaler ® devices, respectively. Primary objective was to demonstrate superiority of glycopyrronium over tiotropium in terms of improvement in forced expiratory volume in 1 s as assessed by the area under the curve from 0 to 2 h (FEV 1 AUC 0-2h ). Secondary endpoints were functional residual capacity (FRC), residual volume (RV), inspiratory capacity (IC), and specific airway resistance (sR aw ), all measured by body plethysmography., Results: Of the 152 patients randomised, 99.3% completed the study. After inhalation of the single dose, glycopyrronium demonstrated superiority over tiotropium in early bronchodilation as assessed by improvement in FEV 1 AUC 0-2h (least squares mean treatment difference = 37 mL; 95% CI: 16, 59 mL; p < 0.01) and FEV 1 at 15 min post-dose (least square mean treatment difference = 36 mL; 95% CI: 14, 58 mL; p < 0.01). Both treatments showed similar improvements in FRC pleth , RV, and IC. Glycopyrronium showed statistically significant improvement in sR aw compared with tiotropium over the first 90 min after dosing, with the difference of 0.184 kPa × s at 90 min post-dose (95% CI: 0.315,0.054 kPa × s; p < 0.01)., Conclusions: Glycopyrronium was superior to tiotropium in terms of early bronchodilation. Although both glycopyrronium and tiotropium showed similar improvements in static lung volume parameters, glycopyrronium reduced specific airway resistance faster than tiotropium, which could in part explain the earlier FEV 1 response seen with glycopyrronium., Trial Registration: ClinicalTrials.govNCT01922271., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Two replicate, double-blind, placebo-controlled, 6-week crossover studies assessed the effect of the once-daily long-acting β2-agonist olodaterol 5 μg and 10 μg on constant work-rate cycle endurance in patients with moderate to very severe chronic obstructive pulmonary disease., Methods: Patients received placebo, olodaterol 5 μg once daily (QD) and olodaterol 10 μg QD in a randomised order for 6 weeks each, with a 2-week washout period in between. The primary end point was change in endurance time during constant work-rate cycle ergometry to symptom limitation at 75 % maximal work capacity after 6 weeks of treatment (2 h post-dose), based on log10-transformed data. Key secondary end points were inspiratory capacity at isotime and intensity of breathing discomfort at isotime., Results: 151 and 157 patients were randomised and treated in Studies 1222.37 and 1222.38, respectively, with 147 and 154 being included in the full analysis sets. Mean endurance time at week 6 was increased compared to placebo by 14.0 % (Study 1222.37; p < 0.001) and 11.8 % (Study 1222.38; p < 0.01) with olodaterol 5 μg, and by 13.8 % (Study 1222.37; p < 0.001) and 10.5 % (Study 1222.38; p < 0.01) with olodaterol 10 μg. Inspiratory capacity at isotime increased with olodaterol 5 μg (Study 1222.37, 0.182 L, p < 0.0001; Study 1222.38, 0.084 L, p < 0.05) and 10 μg (Study 1222.37, 0.174 L; Study 1222.38, 0.166 L; both studies, p < 0.0001), and breathing discomfort was significantly reduced in Study 1222.37 (olodaterol 5 μg, 0.77 Borg units, p < 0.001; olodaterol 10 μg, 0.63 Borg units, p < 0.01) but not Study 1222.38., Conclusions: These studies provide further characterisation of the efficacy of olodaterol, showing that improvements in airflow (forced expiratory volume in 1 s) are associated with increases in inspiratory capacity and improvements in exercise endurance time., Trial Registrations: NCT01040130 (1222.37) and NCT01040793 (1222.38).

Background: This study investigated the effects on 24-h lung function and lung volume of a once-daily fixed-dose combination (FDC) of the long-acting muscarinic antagonist tiotropium and the long-acting β2-agonist olodaterol in patients with chronic obstructive pulmonary disease., Methods: This was a randomised, double-blind, placebo-controlled, Phase III trial with an incomplete crossover design. Patients received four of the following six treatment options for 6 weeks each: placebo, olodaterol 5 μg, tiotropium 2.5 μg, tiotropium 5 μg, tiotropium + olodaterol FDC 2.5/5 μg and tiotropium + olodaterol FDC 5/5 μg, all delivered via the Respimat(®) inhaler. The primary end point was forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 24 h (AUC0-24) response after 6 weeks of treatment; key secondary end points were FEV1 AUC from 0 to 12 h and AUC from 12 to 24 h, and further end points included lung-volume parameters measured using body plethysmography (subset of patients), measures of peak and trough FEV1, and incidence of adverse events., Results: A significant improvement in FEV1 AUC0-24 response was observed with tiotropium + olodaterol 5/5 μg and 2.5/5 μg versus placebo and monotherapies after 6 weeks of treatment; mean response with tiotropium + olodaterol 5/5 μg versus placebo was 0.280 L (p < 0.0001). Differences to monotherapies with tiotropium + olodaterol 5/5 μg were 0.115 L versus olodaterol 5 μg, 0.127 L versus tiotropium 2.5 μg and 0.110 L versus tiotropium 5 μg (p < 0.0001 for all comparisons). Secondary end points supported these data. No safety concerns were identified., Conclusions: Overall, this study demonstrated improvements in lung function over 24 h with an FDC of tiotropium + olodaterol over tiotropium or olodaterol alone, with no observed difference in tolerability. ClinicalTrials.gov number: NCT01559116., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: This randomized, double-blind, Phase IIIb study evaluated the 24-hour bronchodilatory efficacy of aclidinium bromide versus placebo and tiotropium in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD)., Methods: Patients received aclidinium 400 μg twice daily (morning and evening), tiotropium 18 μg once daily (morning), or placebo for 6 weeks. The primary endpoint was change from baseline in forced expiratory volume in 1 second area under the curve for the 24-hour period post-morning dose (FEV1 AUC0-24) at week 6. Secondary and additional endpoints included FEV1 AUC12-24, COPD symptoms (EXAcerbations of chronic pulmonary disease Tool-Respiratory Symptoms [E-RS] total score and additional symptoms questionnaire), and safety., Results: Overall, 414 patients were randomized and treated (FEV1 1.63 L [55.8% predicted]). Compared with placebo, FEV1 AUC0-24 and FEV1 AUC12-24 were significantly increased from baseline with aclidinium (∆ = 150 mL and 160 mL, respectively; p < 0.0001) and tiotropium (∆ = 140 mL and 123 mL, respectively; p < 0.0001) at week 6. Significant improvements in E-RS total scores over 6 weeks were numerically greater with aclidinium (p < 0.0001) than tiotropium (p < 0.05) versus placebo. Only aclidinium significantly reduced the severity of early-morning cough, wheeze, shortness of breath, and phlegm, and of nighttime symptoms versus placebo (p < 0.05). Adverse-event (AE) incidence (28%) was similar between treatments. Few anticholinergic AEs (<1.5%) or serious AEs (<3%) occurred in any group., Conclusions: Aclidinium provided significant 24-hour bronchodilation versus placebo from day 1 with comparable efficacy to tiotropium after 6 weeks. Improvements in COPD symptoms were consistently numerically greater with aclidinium versus tiotropium. Aclidinium was generally well tolerated.

BACKGROUND:The TORRACTO® study evaluated the effects of tiotropium/olodaterol versus placebo on endurance time during constant work-rate cycling and constant speed shuttle walking in patients with chronic obstructive pulmonary disease (COPD) after 12 weeks of treatment. METHODS:The effects of once-daily tiotropium/olodaterol (2.5/5 and 5/5 μg) on endurance time during constant work-rate cycle ergometry (CWRCE) after 6 and 12 weeks of treatment were compared with placebo in patients with COPD in a randomized, double-blind, placebo-controlled, parallel-group clinical trial. Endurance time during the endurance shuttle walk test (ESWT) after 6 and 12 weeks of treatment was also evaluated in a subset of patients. RESULTS:A total of 404 patients received treatment, with 165 participating in the ESWT substudy. A statistically significant improvement in endurance time during CWRCE was observed after 12 weeks (primary endpoint) with tiotropium/olodaterol 5/5 µg [14% ( p = 0.02)] but not with tiotropium/olodaterol 2.5/5 µg [9% ( p = 0.14)] versus placebo. In the ESWT substudy, a trend to improvement in endurance time during ESWT after 12 weeks (key secondary endpoint) was observed with tiotropium/olodaterol 5/5 µg [21% ( p = 0.055)] and tiotropium/olodaterol 2.5/5 µg [21% ( p = 0.056)] versus placebo. CONCLUSION:Tiotropium/olodaterol 5/5 µg improved endurance time during cycle ergometry versus placebo, with a strong tendency to also improve walking endurance time. [ ClinicalTrials.gov identifier: NCT01525615.].

Background: This study was conducted to confirm the 24-hour bronchodilator efficacy and pharmacokinetic profile of once-daily tiotropium Respimat® 5 μg add-on to inhaled corticosteroids (ICS) in adults with symptomatic asthma. It used a trial protocol designed to minimize the risk of pharmacokinetic sample contamination resulting from improper sampling procedure, sample handling, or device handling during priming and subsequent inhalation procedure. Methods: A Phase II, randomized, double-blind, two-way crossover study (NCT01696071) comparing two daily dosing regimens of tiotropium for 4 weeks, once-daily 5 μg (evening dosing) or twice-daily 2.5 μg (morning and evening dosing), as add-on to maintenance therapy with ICS (400-800 μg budesonide or equivalent) as controller medication. There was no washout between treatment periods. Results: An increase in the area under the curve of the 24-hour forced expiratory volume in 1 second profile from study baseline was observed following once-daily tiotropium 5 μg (217 mL) and twice-daily 2.5 μg (219 mL), with no difference between the two regimens (−2 mL [95% confidence interval: −38, 34]). In a subset of the study population, total tiotropium exposure, expressed as area under the plasma concentration versus time curve over 24 hours, was comparable between dosing regimens. Unexpected tiotropium plasma levels were observed in two patients, possibly because of contamination. Conclusions: The observed bronchodilator efficacy over 24 hours was similar with once-daily tiotropium 5 μg and twice-daily 2.5 μg as add-on to ICS therapy, supporting the suitability of once-daily dosing to provide sustained improvements in lung function in adults with symptomatic asthma. [ABSTRACT FROM AUTHOR]