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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

Publication date: December 2014 Source:Respiratory Medicine, Volume 108, Issue 12

Author(s): M. Reza Maleki-Yazdi , Thomas Kaelin , Nathalie Richard , Michael Zvarich , Alison Church

Background 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. Clinical trial registration ClinicalTrials.gov: NCT01777334.





Once-daily tiotropium Respimat® 5 μg is an efficacious 24-h bronchodilator in adults with symptomatic asthma

Publication date: Available online 27 December 2014 Source:Respiratory Medicine

Author(s): Wolfgang Timmer , Petra Moroni-Zentgraf , Piet Cornelissen , Anna Unseld , Emilio Pizzichini , Roland Buhl

Introduction Once-daily tiotropium Respimat® 5 μg is an efficacious add-on therapy to inhaled corticosteroids (ICS) with or without long-acting β2-agonists in patients with symptomatic asthma. The objective of this study was to investigate whether the dosing regimen of tiotropium (once- versus twice-daily), delivered via the Respimat® SoftMist™ inhaler, affected 24-h bronchodilator efficacy and safety versus placebo Respimat® in patients with asthma who were symptomatic despite medium-dose ICS therapy. Methods A randomised, double-blind, placebo-controlled, crossover study with 4-week treatment periods of tiotropium 5 μg (once-daily, evening) and 2.5 μg (twice-daily, morning and evening). The primary efficacy end point was forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 24 h (AUC)(0–24h) at the end of each treatment period. Secondary end points included peak forced expiratory volume in 1 s measured within 24 h of the last evening inhalation (peak FEV1(0–24h)), trough FEV1 measured prior to evening dosing, morning and evening peak expiratory flow (PEFam and PEFpm) and pharmacokinetic assessments. Results 94 patients were randomised (mean age 44.3 years; mean asthma duration 21.3 years) and 89 (94.7%) completed the study. Significant and comparable bronchodilation was achieved over a 24-h period with both tiotropium dosing regimens. FEV1 AUC(0–24h) response (mean ± standard error) was significantly greater with both tiotropium dosing regimens (once-daily 5 μg: 158 ± 24 mL; twice-daily 2.5 μg; 149 ± 24 mL; both p < 0.01) when compared with placebo. Improvements in peak FEV1(0–24h), trough FEV1 and pre-dose PEFam/pm with both dosing regimens versus placebo were statistically significant (all p < 0.01), with no statistically significant differences between the tiotropium treatment regimens. Total systemic exposure and tolerability were comparable between treatment regimens. Conclusions Lung function improvements with tiotropium Respimat® add-on to medium-dose ICS were sustained and similar for once-daily 5 μg and twice-daily 2.5 μg, supporting tiotropium Respimat® 5 μg as a once-daily bronchodilator that provides efficacy over the whole 24-h dosing interval in patients with symptomatic asthma. ClinicalTrials.gov identifier: NCT01152450.





A randomized, three-period crossover study of umeclidinium as monotherapy in adult patients with asthma

Publication date: January 2015 Source:Respiratory Medicine, Volume 109, Issue 1

Author(s): Laurie A. Lee , Anne Briggs , Lisa D. Edwards , Shuying Yang , Steven Pascoe

Background To our knowledge, no studies in patients with asthma have assessed a long-acting muscarinic antagonist in the absence of inhaled corticosteroids (ICS). Objective Evaluate the dose–response, efficacy, and safety of umeclidinium (UMEC) in patients with asthma not receiving ICS. Methods In this double-blind, three-period crossover study, 350 subjects were randomized to a sequence of three of eight inhaled treatments: UMEC 15.6, 31.25, 62.5, 125, or 250 mcg once daily (OD), UMEC 15.6 or 31.25 mcg twice daily (BID), or placebo, administered for 14 days (12–14-day washout). Trough forced expiratory volume in one second (FEV1), 0–24-h weighted mean (WM) FEV1, and safety were assessed. Serial spirometry and pharmacokinetic assessments were performed in a subgroup. Results Subjects had a mean baseline pre- and post-bronchodilator FEV1 of 71% and 88% predicted, respectively. Significant improvements in change from baseline trough FEV1 were observed for UMEC 15.6 OD (0.066 L; p = 0.036) and UMEC 125 OD (0.088 L; p = 0.005) versus placebo, but not other OD or BID doses. UMEC increased 0–24-h WM FEV1 versus placebo (0.068–0.121 L [p ≤ 0.017] with no clear dose–response). Treatment differences were similar for corresponding OD and BID doses in serial assessments. UMEC was rapidly absorbed, with evidence of some accumulation. The incidence of on-treatment adverse events was 9–21% for UMEC and 12% for placebo. There were no treatment-related effects on laboratory parameters. Conclusion The modest trough FEV1 improvements did not conclusively support a therapeutic benefit of UMEC in non-ICS treated patients with asthma. ClinicalTrials.gov NCT01641692.





Efficacy and safety of fluticasone furoate 100 μg once-daily in patients with persistent asthma: A 24-week placebo and active-controlled randomised trial

Publication date: January 2014 Source:Respiratory Medicine, Volume 108, Issue 1

Author(s): Jan Lötvall , Eugene R. Bleecker , William W. Busse , Paul M. O'Byrne , Ashley Woodcock , Edward M. Kerwin , Sally Stone , Richard Forth , Loretta Jacques , Eric D. Bateman

Inhaled corticosteroids (ICSs) improve asthma disease control; once-daily ICS administration may have advantages for patients. Our objective was to assess the efficacy and safety of the novel ICS fluticasone furoate (FF) over 24 weeks versus placebo. This was a 24-week double-blind, double-dummy, placebo- and active-controlled study (NCT01159912) of 343 asthma patients (≥12 years) not controlled by their current ICS. Patients were randomised (1:1:1) to FF100 μg, placebo (both administered once-daily [OD] via ELLIPTA™ dry powder inhaler in the evening) or fluticasone propionate (FP) 250 μg (administered twice-daily (BD) via DISKUS™/ACCUHALER™). Primary endpoint was change from baseline in pre-dose evening forced expiratory volume in 1s (FEV1) at Week 24; change from baseline in % rescue-free 24-h periods was a powered secondary endpoint. Adverse events (AEs) were assessed. FF100 μg OD and FP250 μg BD significantly improved pre-dose evening FEV1 compared with placebo at Week 24 (+146 ml [p = 0.009] and +145 ml [p = 0.011], respectively). Percentage of rescue-free 24-h periods was increased with FF100 μg OD (+14.8%) and FP250 μg BD (+17.9%) compared to placebo (both p < 0.001). On-treatment AEs were reported by 53% (FF100 μg OD), 42% (FP250 μg BD) and 40% (placebo) of patients. On-treatment severe asthma exacerbations were lower with FF100 μg OD (3%) and FP250 μg BD (2%) than placebo (7%). There was significant suppression of urinary cortisol at week 24 with FF100 μg OD (p = 0.030) and FP250 μg BD (p = 0.036) relative to placebo. FF100 μg OD, administered in the evening, achieves significant improvements in lung function and rescue inhaler use over 24 weeks, comparable to FP250 μg BD with similar safety profile.





The effect of fluticasone furoate/umeclidinium in adult patients with asthma: A randomized, dose-ranging study

Background We evaluated the dose–response of umeclidinium (UMEC; a long-acting muscarinic antagonist) combined with fluticasone furoate (FF; an inhaled corticosteroid [ICS]) in patients with asthma.

Methods In a double-blind, three-period crossover study, 421 subjects (symptomatic on ICS), were randomized to a sequence of three of seven treatments: FF 100 mcg alone, FF 100 mcg combined with UMEC (15.6, 31.25, 62.5, 125, or 250 mcg), or vilanterol 25 mcg (a long-acting β-agonist), inhaled once-daily for 14 days (12–14-day washout). Trough forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), and safety were assessed.

Results Period baseline was a significant covariate, indicating a potential carryover effect between treatment periods. Across all treatment periods, trough FEV1 improved with FF/UMEC 125 and 250 versus FF (treatment difference 0.055 L [both doses]; p = 0.018). FF/UMEC increased morning (15.9–22.9 L/min) and evening (16.2–28.8 L/min) PEF versus FF. As intended assessments were confounded, post hoc Period 1 data analyses were performed, demonstrating significant increases in trough FEV1 with FF/UMEC 31.25, 62.5, and 250 versus FF. Trough FEV1 improvements with FF/UMEC were greater in subjects with fixed (0.095–0.304 L) versus non-fixed (−0.084 to 0.041 L) obstruction. The incidence of on-treatment adverse events was 13–25% across groups. No treatment-related effects on laboratory parameters were reported.

Conclusion FF/UMEC may be a viable treatment for patients with asthma symptomatic on ICS; benefit may be most prominent in those with fixed obstruction. The carryover effect suggests future UMEC studies should use an alternative design. ClinicalTrials.gov: NCT01573624.

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