A randomized trial of once-daily fluticasone furoate/vilanterol or vilanterol versus placebo to determine effects on arterial stiffness in COPD Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study A randomized, parallel-group study to evaluate the efficacy of umeclidinium/vilanterol 62.5/25 μg on health-related quality of life in patients with COPD Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2 study Efficacy and safety of once-daily NVA237 in patients with moderate-to-severe COPD: the GLOW1 trial Efficacy and safety of once-daily fluticasone furoate/vilanterol (100/25 mcg) versus twice-daily fluticasone propionate/salmeterol (250/50 mcg) in COPD patients. Tiotropium in patients with moderate COPD naive to maintenance therapy: a randomised placebo-controlled trial A 4-year trial of tiotropium in chronic obstructive pulmonary disease. LANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPD Efficacy and safety of once-daily glycopyrronium in predominantly Chinese patients with moderate-to-severe chronic obstructive pulmonary disease: the GLOW7 study Tiotropium and exercise training in COPD patients: Effects on dyspnea and exercise tolerance Efficacy and Safety of a 12-week Treatment with Twice-daily Aclidinium Bromide in COPD Patients (ACCORD COPD I) Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN study Umeclidinium/vilanterol as step-up therapy from tiotropium in patients with moderate COPD: a randomized, parallel-group, 12-week study A randomized, blinded study to evaluate the efficacy and safety of umeclidinium 62.5 μg compared with tiotropium 18 μg in patients with COPD Absence of electrocardiographic findings and improved function with once-daily tiotropium in patients with chronic obstructive pulmonary disease. Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: the 24-week, randomized, placebo-controlled AUGMENT COPD study Anti-inflammatory effects of salmeterol/fluticasone propionate 50/250 mcg combination therapy in Japanese patients with chronic obstructive pulmonary disease 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. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Inhaled formoterol dry powder versus ipratropium bromide in chronic obstructive pulmonary disease. Tiotropium improves FEV1 in patients with COPD irrespective of smoking status. Efficacy and safety of fluticasone furoate/vilanterol or tiotropium in subjects with COPD at cardiovascular risk A randomised, open-label study of umeclidinium versus glycopyrronium in patients with COPD Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium A randomised trial of fluticasone furoate/vilanterol (50/25 μg; 100/25 μg) on lung function in COPD. Efficacy and safety of tiotropium in COPD patients in primary care – the SPiRiva Usual CarE (SPRUCE) study Umeclidinium/vilanterol versus fluticasone propionate/salmeterol in COPD: a randomised trial Long-acting bronchodilators and arterial stiffness in patients with COPD: a comparison of fluticasone furoate/vilanterol with tiotropium. The Tiotropium Safety and Performance in Respimat® (TIOSPIR®) Trial: Spirometry Outcomes A blinded evaluation of the efficacy and safety of glycopyrronium, a once-daily long-acting muscarinic antagonist, versus tiotropium, in patients with COPD: the GLOW5 study Umeclidinium in patients with COPD: a randomised, placebo-controlled study Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2–4) Anti-inflammatory effects of salmeterol/fluticasone, tiotropium/fluticasone or tiotropium in COPD Efficacy and safety of once-daily inhaled umeclidinium/vilanterol in Asian patients with COPD: results from a randomized, placebo-controlled study A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease The Tiotropium Safety and Performance in Respimat® Trial (TIOSPIR®), a large scale, randomized, controlled, parallel-group trial-design and rationale Efficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study Tiotropium + olodaterol shows clinically meaningful improvements in quality of life. Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. The efficacy and safety of combination salmeterol (50 microg)/fluticasone propionate (500 microg) inhalation twice daily via accuhaler in Chinese patients with COPD. A randomized study of tiotropium Respimat Soft Mist inhaler vs. ipratropium pMDI in COPD. The spirometric efficacy of once-daily dosing with tiotropium in stable COPD: a 13-week multicenter trial. The US Tiotropium Study Group. The efficacy and safety of fluticasone propionate (250 microg)/salmeterol (50 microg) combined in the Diskus inhaler for the treatment of COPD. Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Tiotropium in Early‐Stage Chronic Obstructive Pulmonary Disease A randomized controlled trial to assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary disease. Ipratropium bromide hydrofluoroalkane inhalation aerosol is safe and effective in patients with COPD. 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. The Effect of Tiotropium on Hyperinflation and Exercise Capacity in Chronic Obstructive Pulmonary Disease Long-term general and cardiovascular safety of tiotropium/olodaterol in patients with moderate to very severe chronic obstructive pulmonary disease. Efficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease: results of a 6-month randomized clinical trial. Mortality in the 4-year trial of tiotropium (UPLIFT) in patients with chronic obstructive pulmonary disease. Bronchodilator efficacy of tiotropium in patients with mild to moderate COPD. Efficacy and safety of aclidinium/formoterol versus salmeterol/fluticasone: a phase 3 COPD study Tiotropium Respimat inhaler and the risk of death in COPD. A one-year trial of tiotropium Respimat plus usual therapy in COPD patients. Fluticasone furoate/vilanterol (100/25; 200/25 μg) improves lung function in COPD: a randomised trial. ACCORD COPD II: A Randomized Clinical Trial to Evaluate the 12-Week Efficacy and Safety of Twice-Daily Aclidinium Bromide in Chronic Obstructive Pulmonary Disease Patients A pilot study to assess the effects of combining fluticasone propionate/salmeterol and tiotropium on the airflow obstruction of patients with severe-to-very severe COPD. Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study. A randomised controlled comparison of tiotropium nd ipratropium in the treatment of chronic obstructive pulmonary disease. The Dutch Tiotropium Study Group. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. Prevention of Exacerbations of Chronic Obstructive Pulmonary Disease with Tiotropium, a Once-Daily Inhaled Anticholinergic Bronchodilator Safety and efficacy of dual bronchodilation with QVA149 in COPD patients: the ENLIGHTEN study. Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD. Efficacy and safety of aclidinium bromide in patients with COPD: A phase 3 randomized clinical trial in a Korean population.
Introduction Chronic obstructive pulmonary disease ( COPD ) is associated with increased cardiovascular morbidity and mortality . Elevated arterial stiffness , measured by aortic pulse wave velocity ( aPWV ) , is a cardiovascular risk surrogate and is potentially modifiable by inhaled corticosteroid/long-acting beta2-agonist combinations in patients with COPD . Material s and methods The effects of once-daily inhaled fluticasone furoate/vilanterol ( FF/VI ) 100/25 µg , VI 25 µg , versus placebo on arterial stiffness in patients with COPD and baseline aPWV ≥11.0 m/s were investigated in a 24-week , multicenter , double-blind , r and omized , stratified ( by COPD exacerbation history ) , parallel-group , placebo-controlled trial . Eligible patients were ≥40 years old , with ≥10 pack-year smoking history , forced expiratory volume in 1 s (FEV1)/forced vital capacity ≤0.70 , and post-bronchodilator FEV1 ≤70 % of predicted . Patients with a major cardiovascular event in the previous 6 months/current severe heart failure/uncontrolled hypertension were excluded .  Primary endpoint is change from baseline in aPWV after 24 weeks of treatment . Safety analyses included adverse events ( AEs ) . Results The intent-to-treat population included 430 patients : FF/VI ( n=135 ) , VI ( n=154 ) , and placebo ( n=141 ) . Patients were predominantly male ( 79 % ) and Asian or White ( each 48 % ) , with a mean age of 68.5 years ( st and ard deviation [ SD ] = 7.9 ) , percentage predicted post-bronchodilator FEV1 50.1 % ( SD = 13.3 ) , and aPWV 13.26 m/s ( SD = 2.22 ) at screening . At 24 weeks , mean ( st and ard error [ SE ] ) changes from baseline in aPWV were −1.75 m/s ( SE = 0.26 , FF/VI ) , −1.95 m/s ( SE = 0.24 , VI ) , and −1.97 m/s ( SE = 0.28 , placebo ) . AEs occurred in 57 % ( FF/VI ) , 51 % ( VI ) , and 41 % ( placebo ) of patients . Conclusion No differences were observed in aPWV-adjusted mean change from baseline for FF/VI 100/25 µg , compared with placebo We investigated the efficacy and safety of dual bronchodilation with QVA149 versus its monocomponents indacaterol and glycopyrronium , tiotropium and placebo in patients with moderate-to-severe chronic obstructive pulmonary disease ( COPD ) . This was a multicentre , r and omised , double-blind , placebo- and active-controlled , 26-week trial . Patients ( n = 2144 ) were r and omised ( 2:2:2:2:1 ) to receive once-daily QVA149 ( indacaterol 110 & mgr;g/glycopyrronium 50 & mgr;g ) , indacaterol 150 & mgr;g , glycopyrronium 50 & mgr;g , open-label tiotropium 18 & mgr;g or placebo . The primary end-point was trough forced expiratory volume in 1 s ( FEV1 ) at week 26 for QVA149 versus its monocomponents . Secondary end-points included dyspnoea , health status , rescue medication use and safety . Trough FEV1 at week 26 was significantly improved ( p<0.001 ) with QVA149 compared with indacaterol and glycopyrronium ( least squares mean ( LSM ) differences 0.07 L and 0.09 L , respectively ) , tiotropium and placebo ( LSM differences 0.08 L and 0.20 L , respectively ) ; these beneficial effects were sustained throughout the 26-week study . QVA149 significantly improved dyspnoea and health status versus placebo ( p<0.001 and p = 0.002 , respectively ) and tiotropium ( p = 0.007 and p = 0.009 , respectively ) at week 26 . All treatments were well tolerated . Dual bronchodilation with once-daily QVA149 demonstrated superior and clinical ly meaningful outcomes versus placebo and superiority versus treatment with a single bronchodilator , with a safety and tolerability profile similar to placebo , supporting the concept of fixed-dose long-acting muscarinic antagonist/long-acting & bgr;2-agonist combinations for the treatment of COPD . Dual indacaterol/glycopyrronium therapy was safe and more efficacious than monotherapy in moderate-to-severe COPD Background The combination of the inhaled muscarinic antagonist umeclidinium ( UMEC ) with the long-acting β2-agonist vilanterol ( VI ) has been shown to provide significant improvements in lung function compared with UMEC , VI , or placebo ( PBO ) in patients with chronic obstructive pulmonary disease ( COPD ) . This study was specifically design ed to support these findings by assessing health-related quality of life and symptomatic outcomes in a similar population . Methods This was a 12-week multicenter , r and omized , double-blind , parallel-group , placebo-controlled study . Eligible patients were r and omized 1:1 to receive once-daily UMEC/VI 62.5/25 μg ( via ELLIPTA ® dry powder inhaler ) or PBO for 12 weeks . The primary endpoint was St George ’s Respiratory Question naire ( SGRQ ) total score at day 84 . Secondary efficacy endpoints included rescue albuterol use ( puffs/day ) over weeks 1–12 and trough forced expiratory volume in 1 second on day 84 . Adverse events were also assessed . Results A total of 496 patients were included in the intent-to-treat population in the UMEC/VI ( n=248 ) and PBO ( n=248 ) treatment groups . UMEC/VI 62.5/25 μg provided a significant and clinical ly meaningful improvement in SGRQ total score at day 84 versus PBO ( difference between treatments in SGRQ total score change from baseline : −4.03 [ 95 % confidence interval { CI } : −6.28 , −1.79 ] ; P<0.001 ) . UMEC/VI 62.5/25 μg result ed in a statistically significant reduction in rescue albuterol use versus PBO ( −0.7 puffs/day [ 95 % CI : −1.1 , −0.4 ] ; P<0.001 ) . UMEC/VI 62.5/25 μg provided a significant and clinical ly meaningful improvement in trough forced expiratory volume in 1 second on day 84 versus PBO ( 122 mL [ 95 % CI : 71 , 172 ] ; P<0.001 ) . The incidence of adverse events was similar between treatments ( 32 % and 30 % of patients in the UMEC/VI 62.5/25 μg and PBO groups , respectively ) . Conclusion The results of this study demonstrate that treatment with UMEC/VI 62.5/25 μg provides clinical ly important improvements in SGRQ and rescue medication use  versus PBO in patients with moderate-to-very-severe COPD NVA237 ( glycopyrronium bromide ) is a once-daily long-acting muscarinic antagonist ( LAMA ) in development for chronic obstructive pulmonary disease ( COPD ) . The GLycopyrronium bromide in COPD airWays clinical Study 2 ( GLOW2 ) evaluated the efficacy and safety of NVA237 in moderate-to-severe COPD over 52 weeks . Patients were r and omised 2:1:1 to NVA237 50 μg , placebo or open-label tiotropium 18 μg for 52 weeks . Primary end-point was trough forced expiratory volume in 1 s ( FEV1 ) at 12 weeks . 1,066 patients were r and omised , 810 completed the study . At week 12 , trough FEV1 increased significantly by 97 mL with NVA237 ( 95 % CI 64.6–130.2 ; p<0.001 ) and 83 mL with tiotropium ( 95 % CI 45.6–121.4 ; p<0.001 ) . Compared with placebo , NVA237 produced significant improvements in dyspnoea ( Transition Dyspnoea Index at week 26 ; p=0.002 ) and health status ( St George 's Respiratory Question naire at week 52 ; p<0.001 ) . NVA237 significantly reduced the risk of moderate-to-severe COPD exacerbations by 34 % ( p=0.001 ) and the use of rescue medication ( p=0.039 ) , versus  placebo  . NVA237-placebo and tiotropium-placebo differences were comparable for all outcomes . Safety profiles were similar across groups . NVA237 50 μg provided significant improvements in lung function , dyspnoea , health status , exacerbations and rescue medication use , versus placebo , and was comparable to tiotropium . NVA237 can potentially be an alternative choice of LAMA for COPD patients Background NVA237 is a once-daily dry-powder formulation of the long-acting muscarinic antagonist glycopyrronium bromide in development for the treatment of chronic obstructive pulmonary disease ( COPD ) . The glycopyrronium bromide in COPD airways clinical study 1 ( GLOW1 ) evaluated the efficacy , safety and tolerability of NVA237 in patients with moderate-to-severe COPD . Methods Patients with COPD with a smoking history of ≥ 10 pack-years , post-bronchodilator forced expiratory volume in 1 second ( FEV1 ) < 80 % and ≥ 30 % predicted normal and FEV1/forced vital capacity < 0.70 were enrolled . Patients were r and omized to double-blind treatment with NVA237 50 μg once daily or placebo for 26 weeks with inhaled/intranasal corticosteroids or H1 antagonists permitted in patients stabilized on them prior to study entry . The primary outcome measure was trough FEV1 at Week 12 . Results A total of 822 patients were r and omized to NVA237 ( n = 552 ) or placebo ( n = 270 ) . Least squares mean ( ± st and ard error ) trough FEV1 at Week 12 was significantly higher in patients receiving NVA237 ( 1.408 ± 0.0105 L ) , versus placebo ( 1.301 ± 0.0137 L ; treatment difference 108 ± 14.8 mL , p < 0.001 ) . Significant improvements in trough FEV1 were apparent at the end of Day 1 and sustained through Week 26 . FEV1 was significantly improved in the NVA237 group versus placebo throughout the 24-hour periods on Day 1 and at Weeks 12 and 26 , and at all other visits and timepoints . Transition dyspnoea index focal scores and St. George 's Respiratory Question naire scores were significantly improved with NVA237 versus placebo at Week 26 , with treatment differences of 1.04 ( p < 0.001 ) and -2.81 ( p = 0.004 ) , respectively  . NVA237 significantly reduced the risk of first moderate/severe COPD exacerbation by 31 % ( p = 0.023 ) and use of rescue medication by 0.46 puffs per day ( p = 0.005 ) , versus placebo . NVA237 was well tolerated and had an acceptable safety profile , with a low frequency of cardiac and typical antimuscarinic adverse effects . Conclusions Once-daily NVA237 was safe and well tolerated and provided rapid , sustained improvements in lung function , improvements in dyspnoea , and health-related quality of life , and reduced the risk of exacerbations and the use of rescue medication . Trial registration Clinical Trials.gov : BACKGROUND Fluticasone furoate/vilanterol ( FF/VI ) is an inhaled corticosteroid/long-acting beta2-agonist ( ICS/LABA ) , recently approved as once-daily maintenance therapy for COPD . We compared the lung function effects of FF/VI with those of twice-daily fluticasone propionate/salmeterol ( FP/SAL ) . METHODS Three 12 week studies comparing FF/VI and FP/SAL were conducted . Patients aged ≥40 years with moderate-to-very severe COPD were r and omized to receive double-blind , double-dummy FF/VI 100/25 mcg once-daily , or FP/SAL 250/50 mcg twice-daily for 12 weeks following a 2 week placebo run-in period . The primary endpoint of each study was change from baseline trough in 0 - 24 h weighted mean FEV(1 ) ( wmFEV(1 ) ) on Day 84 . Safety was also assessed . RESULTS In Study 1 ( HZC113109 ) ( intent-to-treat n : FF/VI = 260 ; FP/SAL = 259 ) , the increase from baseline in 0 - 24 h wmFEV(1 ) was significantly greater with FF/VI than FP/SAL ( Δ80 mL , P < 0.001 ) . In Study 2 ( HZC112352 ) ( intent-to-treat n : FF/VI = 259 ; FP/SAL = 252 ) and Study 3 ( RLV116974 ) ( intent-to-treat n : FF/VI = 412 ; FP/SAL = 416 ) , the increase from baseline in 0 - 24 h wmFEV(1 ) was not significantly greater with FF/VI than FP/SAL ( Δ29 mL , P = 0.267 ; Δ25 mL , P = 0.137 ) . The treatment difference was statistically but not clinical ly significant in a pooled analysis ( Δ41 mL , P < 0.001 ) . Pooled adverse events ( FF/VI 27 % ; FP/SAL 28 % ) and serious adverse events ( FF/VI 2 % ; FP/SAL 3 % ) were similar between treatments . CONCLUSIONS Our data suggest that once-daily FF/VI 100/25 mcg provides FEV(1 ) improvement in COPD that is at least comparable with that conferred by twice-daily FP/SAL 250/50 mcg , although interpretation is limited by differences in individual study outcomes . The safety profiles of FF/VI 100/25 mcg and FP/SAL 250/50 mcg are similar . CLINICAL TRIAL REGISTRATION clinical trials.gov : NCT01323634 ; NCT01323621 ; NCT01706328 . GlaxoSmithKline study codes : HZC113109 ; HZC112352 ; RLV116974 Background : The benefits of pharmacotherapy with tiotropium H and iHaler 18 μg for patients with chronic obstructive pulmonary disease ( COPD ) have been previously demonstrated . However , few data exist regarding the treatment of moderate disease ( Global Initiative for Chronic Obstructive Lung Disease ( GOLD ) stage II ) . Aims : To determine whether tiotropium improves lung function/patient-reported outcomes in patients with GOLD stage II COPD naive to maintenance therapy . Methods : A r and omised 24-week double-blind placebo-controlled trial of tiotropium 18 μg once daily ( via H and iHaler ) was performed in maintenance therapy – naive patients with forced expiratory volume in 1 s (FEV1)/forced vital capacity ( FVC ) ratio < 0.7 and post-bronchodilator FEV1 ⩾50 and < 80 % . Results : A total of 457 patients were r and omised ( 238 tiotropium , 219 placebo ; mean age 62 years ; FEV1 1.93 l ( 66 % predicted ) )  . Tiotropium was superior to placebo in mean change from baseline in post-dose FEV1 area under the curve from 0 to 3 h ( AUC0–3h ) at week 24 ( primary endpoint ) : 0.19 vs. −0.03 l ( least-squares mean difference 0.23 l , P<0.001 ) . FVC AUC0–3h , trough and peak FEV1 and FVC were significantly improved with tiotropium versus placebo ( P<0.001 ) . Compared with placebo , tiotropium  provided numerical improvements in physical activity ( P = NS ) . Physician ’s Global Assessment ( health status ) improved ( P=0.045 ) with less impairment on the Work Productivity and Activity Impairment question naire ( P=0.043 ) at week 24 . The incidence of exacerbations , cough , bronchitis and dyspnoea was lower with tiotropium than placebo . Conclusions : Tiotropium  improved lung function and patient-reported outcomes in maintenance therapy – naive patients with GOLD stage II COPD , suggesting benefits in initiating maintenance therapy early BACKGROUND Previous studies showing that tiotropium improves multiple end points in patients with chronic obstructive pulmonary disease ( COPD ) led us to examine the long-term effects of tiotropium therapy . METHODS In this r and omized , double-blind trial , we compared 4 years of therapy with either tiotropium or placebo in patients with COPD who were permitted to use all respiratory medications except inhaled anticholinergic drugs . The patients were at least 40 years of age , with a forced expiratory volume in 1 second ( FEV(1 ) ) of 70 % or less after bronchodilation and a ratio of FEV(1 ) to forced vital capacity ( FVC ) of 70 % or less . Co primary end points were the rate of decline in the mean FEV(1 ) before and after bronchodilation beginning on day 30 . Secondary end points included measures of FVC , changes in response on St. George 's Respiratory Question naire ( SGRQ ) , exacerbations of COPD , and mortality . RESULTS Of a total of 5993 patients ( mean age , 65+/-8 years ) with a mean FEV(1 ) of 1.32+/-0.44 liters after bronchodilation ( 48 % of predicted value ) , we r and omly assigned 2987 to the tiotropium group and 3006 to the placebo group . Mean absolute improvements in FEV(1 ) in the tiotropium group were maintained throughout the trial ( ranging from 87 to 103 ml before bronchodilation and from 47 to 65 ml after bronchodilation ) , as compared with the placebo group ( P<0.001 ) . After day 30 , the differences between the two groups in the rate of decline in the mean FEV(1 ) before and after bronchodilation were not significant . The mean absolute total score on the SGRQ was improved ( lower ) in the tiotropium group , as compared with the placebo group , at each time point throughout the 4-year period ( ranging from 2.3 to 3.3 units , P<0.001 ) . At 4 years and 30 days , tiotropium was associated with a reduction in the risks of exacerbations , related hospitalizations , and respiratory failure . CONCLUSIONS In patients with COPD , therapy with tiotropium was associated with improvements in lung function , quality of life , and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV(1 ) . ( Clinical Trials.gov number , NCT00144339 . Background The current Global initiative for chronic Obstructive Lung Disease ( GOLD ) treatment strategy recommends the use of one or more bronchodilators according to the patient ’s airflow limitation , their history of exacerbations , and symptoms . The LANTERN study evaluated the effect of the long-acting β2-agonist (LABA)/long-acting muscarinic antagonist ( LAMA ) dual bronchodilator , QVA149 ( indacaterol/glycopyrronium ) , as compared with the LABA/inhaled corticosteroid , salmeterol/fluticasone ( SFC ) , in patients with moderate-to-severe COPD with a history of ≤1 exacerbation in the previous year . Methods In this double-blind , double-dummy , parallel-group study , 744 patients with moderate-to-severe COPD with a history of ≤1 exacerbations in the previous year were r and omized ( 1:1 ) to QVA149 110/50 μg once daily or SFC 50/500 μg twice daily for 26 weeks . The primary endpoint was noninferiority of QVA149 versus SFC for trough forced expiratory volume in 1 second ( FEV1 ) at week 26 . Results Overall , 676 patients completed the study . The primary objective of noninferiority between QVA149 and SFC in trough FEV1 at week 26 was met . QVA149 demonstrated statistically significant superiority to SFC for trough FEV1 ( treatment difference [Δ]=75 mL ; P<0.001 ) . QVA149 demonstrated a statistically significant improvement in st and ardized area under the curve ( AUC ) from 0 hours to 4 hours for FEV1 ( FEV1 AUC0–4h ) at week 26 versus SFC ( Δ=122 mL ; P<0.001 ) . QVA149 and SFC had similar improvements in transition dyspnea index focal score , St George Respiratory Question naire total score , and rescue medication use . However , QVA149 significantly reduced the rate of moderate or severe exacerbations by 31 % ( P=0.048 ) over SFC . Overall , the incidence of adverse events was comparable between QVA149 ( 40.1 % ) and SFC ( 47.4 % ) . The incidence of pneumonia was threefold lower with QVA149 ( 0.8 % ) versus SFC ( 2.7 % ) . Conclusion These findings support the use of the LABA/LAMA , QVA149 as an alternative treatment , over LABA/inhaled corticosteroid , in the management of moderate-to-severe COPD patients ( GOLD B and GOLD D ) with a history of ≤1 exacerbation in the previous year Background Glycopyrronium is a once-daily ( od ) long-acting muscarinic antagonist for the maintenance treatment of chronic obstructive pulmonary disease ( COPD ) . The GLOW7 study evaluated the efficacy and safety of od glycopyrronium 50 μg in predominantly Chinese patients with moderate-to-severe COPD . Methods In this 26-week , multi-center , double-blind , placebo-controlled , parallel-group study , men and women ≥40 years with moderate-to-severe COPD were r and omized to glycopyrronium 50 μg od or placebo ( 2:1 ) . The primary objective was to confirm the significant improvement of trough forced expiratory volume in 1 second ( FEV1 ) following 12 weeks of treatment with glycopyrronium compared with placebo . Secondary objectives included the effect of glycopyrronium on health status ( St George ’s Respiratory Question naire ) , breathlessness ( Transition Dyspnea Index ) , other lung function parameters , rescue medication use , and COPD exacerbations . Safety and tolerability were also evaluated . Results Of the 460 patients r and omized , 459 were included in the full analysis set ( glycopyrronium , n=306 ; placebo , n=154 ; mean age 64.7 years ; mean post-bronchodilator FEV1 : 50.8 % predicted ) ; 425 ( 92.4 % ) completed the study . At Week 12 , glycopyrronium signifcantly improved trough FEV1 with a least square means treatment difference of 141 mL ( 95 % confidence interval 111 mL , 171 mL ; P<0.001 ) compared with placebo . The mean treatment effect of glycopyrronium was greater than the minimum clinical ly important difference versus placebo in both St George ’s Respiratory Question naire total score ( −4.92 ; P<0.001 ) and Transition Dyspnea Index focal score ( 1.0 ; P<0.001 ) at week 26 . Glycopyrronium  reduced the risk of exacerbations in terms of time to first moderate or severe exacerbation by 28 % ( P=0.153 ) and rate of moderate or severe COPD exacerbation by 29 % ( P=0.119 ) compared with placebo . Incidence of death was 1.3 % with glycopyrronium and 0 % in placebo during the treatment period . Overall incidence of adverse events ( glycopyrronium 43.6 % ; placebo 47.4 % ) and serious adverse events ( glycopyrronium 5.6 % ; placebo 9.1 % ) were similar . Conclusion In predominantly Chinese patients with moderate-to-severe COPD , od glycopyrronium 50 μg significantly improved lung function , dyspnea , and health status compared with placebo . The safety and tolerability profile  of glycopyrronium was comparable to placebo Background Exercise training improves exercise tolerance in chronic obstructive pulmonary disease ( COPD ) . Tiotropium 18 μg once daily induces sustained bronchodilation throughout the day and reduces hyperinflation , one of the pathophysiological factors contributing to exertional dyspnea in COPD patients . Aim To determine whether tiotropium enhances the effects of exercise training in patients with COPD . Design Multicenter , 25 week r and omized , double-blind , placebo-controlled , parallel-group study . Setting Twelve Italian Pulmonary Units practicing pulmonary rehabilitation . Patients and intervention Two hundred thirty four COPD patients ( 196 males ; mean age : 67.4 ± 7.6 ; forced expiratory volume at 1 second ( FEV1 ) : 41.4 ± 13.0 % predicted ) were r and omised to tiotropium 18 μg or placebo inhalation capsules  taken once daily . Both groups underwent a 8 week pulmonary rehabilitation program ( PR ) consisting of 3 exercise training session per week . Measurements Baseline , at the end of PR and after 12 weeks , patients completed pulmonary function testing , six minute walking test ( 6MWT ) , the Baseline and Transition Dyspnea Index ( BDI and TDI ) , and the St. George ’s Respiratory Question naire ( SGRQ ) . Results Relative to placebo , tiotropium had larger trough and post- study drug FEV1 responses on all test days . At the end of and 12 weeks following PR , patients on tiotropium showed no statistically significant differences in 6MWT compared to patients on placebo . Compared to the period immediately prior to PR , the mean improvement in 6MWT was only 29.7 meters ( 7.1 % ) for the combined cohort . Mean TDI focal scores at the end of PR were 3.60 for tiotropium and 2.25 for placebo ( p < 0.01 ) . At 12 weeks after PR , TDI focal scores were 2.71 for tiotropium and 2.11 for placebo ( p = 0.16 ) . Reduction in all four SGRQ component scores , indicating an improvement in health-related quality of life , was observed for the tiotropium group over the duration of the study compared to placebo but the differences were not statistically significant . During the study period , there were fewer exacerbations and exacerbation days in the tiotropium group . Conclusion Although significant improvements were observed with perceived dyspnea , compared to placebo , the addition of tiotropium to pulmonary rehabilitation did not improve the 6MWT Abstract Background : This Phase III study evaluated the efficacy and safety of twice-daily aclidinium 200 μg and 400 μg versus placebo in the treatment of moderate-to-severe COPD . Methods : In this 12-week , double-blind , multicenter trial , patients were r and omized ( 1:1:1 ) to inhaled twice-daily aclidinium 200 μg , aclidinium 400 μg , or placebo . Primary and secondary endpoints were changes from baseline in trough FEV1 and peak FEV1 at Week 12 , respectively . Health status ( St. George 's Respiratory Question naire [ SGRQ ] ) , COPD symptoms ( Transitional Dyspnea Index [ TDI ] , night and early morning symptoms ) , and safety were also assessed . Results : A total of 561 patients ( mean age , 64 ± 9 years ) with a mean baseline FEV1 of 1.36 ± 0.54 L ( 47.2 % of predicted value ) were r and omized . At Week 12 , aclidinium 200 μg and 400 μg showed significant improvements from baseline in mean ( 95 % CI ) trough FEV1 compared with placebo by 86 ( 45 , 127 ) mL and 124 ( 83,164 ) mL , respectively , and in peak FEV1 by 146 ( 101 , 190 ) mL and 192 ( 148 , 236 ) mL , respectively ( p ≤ 0.0001 for all ) . Both aclidinium doses also provided significant improvements in SGRQ , TDI and almost all COPD symptom scores compared with placebo ( p < 0.05 for all ) . Incidences of adverse events ( AEs ) were similar across treatment groups . The incidence of anticholinergic AEs was low and similar across groups ( dry mouth : 0.5%–1.6 % ; constipation : 0%-1.1 % ) . Conclusions : Treatment of moderate-to-severe COPD patients with twice-daily aclidinium 200 μg and 400 μg was associated with significant improvements in bronchodilation , health status , and COPD symptoms . Both doses were well tolerated and had safety profiles similar to placebo . Trial Registration : This ACCORD I study ( AClidinium in Chronic Obstructive Respiratory Disease I ) was registered on clinical trials.gov ( NCT00891462 ) as “ Efficacy and Safety of Aclidinium Bromide for Treatment of Moderate to Severe Chronic Obstructive Pulmonary Disease ( COPD ) ” The efficacy and safety of two doses of aclidinium bromide were evaluated in patients with moderate to severe chronic obstructive pulmonary disease ( COPD ) . In this 24-week , double-blind trial , patients were r and omised to twice-daily aclidinium ( 200 μg or 400 μg ) or placebo . The primary efficacy end-point was change in trough forced expiratory volume in 1 s ( FEV1 ) at week 24 . Other end-points included peak FEV1 , health status ( St George 's Respiratory Question naire ; SGRQ ) and dyspnoea ( Transitional Dyspnoea Index ; TDI ) . Overall , 828 patients were r and omised . At week 24 , significant improvements from baseline were observed with aclidinium 200 μg and 400 μg versus placebo for trough FEV1 ( 99 and 128 mL ; both p<0.0001 ) and peak FEV1 ( 185 and 209 mL ; both p<0.0001 ) . Peak FEV1 improvements on day 1 were comparable with week 24 . Aclidinium 200 μg and 400 μg produced significant improvements over placebo in baseline-adjusted mean SGRQ total score ( -3.8 and -4.6 units ; p<0.001 and p<0.0001 ) and TDI focal score ( 0.6 and 1.0 units ; p<0.05 and p<0.001 ) at week 24 . With both aclidinium doses , the incidence of anticholinergic adverse events was low , and similar to placebo . Twice-daily aclidinium significantly improved bronchodilation , health status and dyspnoea , and was well tolerated in patients with COPD Introduction Patients with COPD who remain symptomatic on long-acting bronchodilator monotherapy may benefit from step-up therapy to a long-acting bronchodilator combination . This study evaluated the efficacy and safety of umeclidinium (UMEC)/vilanterol ( VI ) in patients with moderate COPD who remained symptomatic on tiotropium ( TIO ) . Methods In this r and omized , blinded , double-dummy , parallel-group study ( NCT01899742 ) , patients ( N=494 ) who were prescribed TIO for ≥3 months at screening ( forced expiratory volume in 1 s [ FEV1 ] : 50%–70 % of predicted ; modified Medical Research Council [ mMRC ] score ≥1 ) and completed a 4-week run-in with TIO were r and omized to UMEC/VI 62.5/25 µg or TIO 18 µg for 12 weeks . Efficacy assessment s included trough FEV1 at Day 85 ( primary end point ) , 0–3 h serial FEV1 , rescue medication use , Transition Dyspnea Index ( TDI ) , St George ’s Respiratory Question naire ( SGRQ ) , and COPD Assessment Test ( CAT ) . Safety evaluations included adverse events ( AEs ) . Results Compared with TIO , UMEC/VI produced greater improvements in trough FEV1 ( least squares [ LS ] mean difference : 88 mL at Day 85 [ 95 % confidence interval { CI } : 45–131 ] ; P<0.001 ) and FEV1 after 5 min on Day 1 ( 50 mL [ 95 % CI : 27–72 ] ; P<0.001 ) . Reductions in rescue medication use over 12 weeks were greater with UMEC/VI versus TIO ( LS mean change : −0.1 puffs/d [ 95 % CI : −0.2–0.0 ] ; P≤0.05 ) . More patients achieved clinical ly meaningful improvements in TDI score ( ≥1 unit ) with UMEC/VI ( 63 % ) versus TIO ( 49 % ; odds ratio at Day 84=1.78 [ 95 % CI : 1.21–2.64 ] ; P≤0.01 ) . Improvements in SGRQ and CAT scores were similar between treatments . The incidence of AEs was similar with UMEC/VI ( 30 % ) and TIO ( 31 % ) . Conclusion UMEC/VI step-up therapy provides clinical benefit over TIO monotherapy in patients with moderate COPD who are symptomatic on TIO alone Background The long-acting muscarinic antagonists umeclidinium ( UMEC ) and tiotropium ( TIO ) are approved once-daily maintenance therapies for COPD . This study investigated the efficacy and safety of UMEC versus TIO in COPD . Methods This was a 12-week , multicenter , r and omized , blinded , double-dummy , parallel-group , non-inferiority study . Patients were r and omized 1:1 to UMEC 62.5 μg plus placebo or TIO 18 μg plus placebo .  The primary end point was trough forced expiratory volume in 1 second ( FEV1 ) at day 85 ( non-inferiority margin −50 mL ; per- protocol [ PP ] population ) . Other end points included weighted mean FEV1 over 0–24 and 12–24 hours post-dose . Patient-reported outcomes comprised Transition Dyspnea Index score , St George ’s Respiratory Question naire total score , and COPD Assessment Test score . Adverse events were also assessed . Results In total , 1,017 patients were r and omized to treatment . In the PP population , 489 and 487 patients received UMEC and TIO , respectively . In the PP population , change from baseline in trough FEV1 was greater with UMEC versus TIO at day 85 , meeting non-inferiority and superiority margins ( difference : 59 mL ; 95 % confidence interval [ CI ] : 29–88 ; P<0.001 ) . Similar results were observed in the intent-to-treat analysis of trough FEV1 at day 85 ( 53 mL , 95 % CI : 25–81 ; P<0.001 ) . Improvements in weighted mean FEV1 over 0–24 hours post-dose at day 84 were similar with UMEC and TIO but significantly greater with UMEC versus TIO over 12–24 hours post-dose ( 70 mL ; P=0.015 ) . Clinical ly meaningful improvements in Transition Dyspnea Index and St George ’s Respiratory Question naire were observed with both treatments at all time points . No differences were observed between UMEC and TIO in patient-reported outcomes . Overall incidences of adverse events were similar for UMEC and TIO . Conclusion UMEC 62.5 μg demonstrated superior efficacy to TIO 18 μg on the primary end point of trough FEV1 at day 85 . Safety profiles were similar for both treatments STUDY OBJECTIVES To examine electrocardiographic findings after short- and long-term tiotropium therapy in patients with chronic obstructive pulmonary disease ( COPD ) , and to establish previously reported symptomatic efficacy . DESIGN R and omized , double-blind , placebo-controlled , parallel-group study . SETTING Twelve outpatient investigational centers in the United States . PATIENTS One hundred ninety-six patients with COPD . INTERVENTIONS Patients received either tiotropium 18 mug once/day or placebo , delivered by the H and iHaler device . MEASUREMENTS AND MAIN RESULTS Electrocardiography ( predose and 5 min postdose ) and 24-hour Holter monitoring were performed at baseline and after 8 and 12 weeks of treatment with tiotropium 18 microg once/day or placebo . Efficacy measures ( spirometry , global COPD ratings , scores on the EuroQol Health Question naire [ EQ-5D ] , albuterol inhaler as needed ) were included to demonstrate that the study population exhibited the characteristic improvements observed in previous tiotropium studies . Mean baseline forced expiratory volume in 1 second ( FEV1 ) was 1.03 L. Mean changes in heart rate from baseline were similar in both groups . No differences were noted in the percentage of patients developing rhythm or conduction abnormalities detected with electrocardiography or Holter monitoring . Frequency of premature beats and mean maximal changes in PR , QRS , QT , QTcB , and QTcF intervals were similar in both groups . No patients developed new-onset QT or QTc intervals greater than 500 msec , and no differences were noted in the percentage of patients developing new QT prolongation less than 30 msec , 30 - 60 msec , or greater than 60 msec . At 12 weeks , predose and postdose improvements in FEV1 were 184 and 265 ml , respectively , with tiotropium versus placebo ( p<0.001 ) . Physician and patient global COPD ratings and the EQ-5D visual analog scale scores were improved with tiotropium ( p<0.05 ) ; as-needed albuterol was reduced by 25 % relative to placebo ( p<0.05 ) . CONCLUSION Tiotropium provided spirometric and symptomatic benefits in patients with COPD and was not associated with evidence of electrocardiographic changes in heart rate , rhythm , QT intervals , or conduction Background Combining two long-acting bronchodilators with complementary mechanisms of action may provide treatment benefits to patients with chronic obstructive pulmonary disease ( COPD ) that are greater than those derived from either treatment alone . The efficacy and safety of a fixed-dose combination ( FDC ) of aclidinium bromide , a long-acting muscarinic antagonist , and formoterol fumarate , a long-acting β2-agonist , in patients with moderate to severe COPD are presented . Methods In this 24-week double-blind study , 1692 patients with stable COPD were equally r and omized to twice-daily treatment with FDC aclidinium 400μg/formoterol 12μg ( ACL400/FOR12 FDC ) , FDC aclidinium 400μg/formoterol 6μg ( ACL400/FOR6 FDC ) , aclidinium 400μg , formoterol 12μg , or placebo administered by a multidose dry powder inhaler (Genuair ® /Pressair ® )*. Co primary endpoints were change from baseline to week 24 in 1-hour morning postdose FEV1 ( FDCs versus aclidinium ) and change from baseline to week 24 in morning predose ( trough ) FEV1 ( FDCs versus formoterol ) . Secondary endpoints were change from baseline in St. George ’s Respiratory Question naire ( SGRQ ) total score and improvement in Transition Dyspnea Index ( TDI ) focal score at week 24 . Safety and tolerability were also assessed . Results At study end , improvements from baseline in 1-hour postdose FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC or ACL400/FOR6 FDC compared with aclidinium ( 108 mL and 87 mL , respectively ; p < 0.0001 ) . Improvements in trough FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC versus formoterol ( 45 mL ; p = 0.0102 ) , a numerical improvement of 26 mL in trough FEV1 over formoterol was observed with ACL400/FOR6 FDC . Significant improvements in both SGRQ total and TDI focal scores were observed in the ACL400/FOR12 FDC group at study end ( p < 0.0001 ) , with differences over placebo exceeding the minimal clinical ly important difference of ≥4 points and ≥1 unit , respectively . All treatments were well tolerated , with safety profiles of the FDCs similar to those of the monotherapies . Conclusions Treatment with twice-daily aclidinium 400μg/formoterol 12μg FDC provided rapid and sustained bronchodilation that was greater than either monotherapy ; clinical ly significant improvements in dyspnea and health status were evident compared with placebo . Aclidinium/formoterol FDC may be an effective and well tolerated new treatment option for patients with COPD .Trial registration Clinical trials.gov NCT01437397.*Registered trademarks of Almirall S.A. , Barcelona , Spain ; for use within the US as Pressair ® and Genuair ® within all other licensed territories Purpose Using sputum neutrophils as the primary measure , and other inflammation biomarkers , this study evaluated the anti-inflammatory effects of the combination salmeterol 50 mcg and fluticasone propionate 250 mcg ( SFC 250 ) in Japanese patients with chronic obstructive pulmonary disease ( COPD ) . Patients and methods Patients were treated in a r and omized , double-blind , parallel group , placebo-controlled trial with SFC 250 twice daily ( n=26 ) or placebo  ( n=26 ) for 12 weeks . At the start and end of treatment , inflammation biomarkers ( sputum and serum ) , lung function , and health status ( COPD Assessment Test [ CAT ] question naire ) were measured . Results Although a numerical decrease in differential neutrophil count was observed from baseline , SFC 250 did not significantly reduce sputum neutrophils compared with placebo , nor were there significant changes from baseline in the other biomarkers ( sputum or serum ) , lung function , or CAT , versus placebo . Squamous epithelial cell contamination in some sputum sample s rendered them unacceptable for analysis , which reduced the sample size to n=19 ( SFC 250 ) and n=10 ( placebo ) . However , inclusion of contaminated sample s did not affect the overall trend of the outcome . Ad hoc bootstrap statistical analysis showed a 27.9 % ( SFC 250 ) and 1.3 % ( placebo ) decrease in sputum neutrophils . Sputum IL-8 decreased by 43.2 % after SFC 250 but increased by 48.3 % with placebo . Responder analyses showed 42 % of patients had ≥20 % decrease in neutrophils from baseline ; and 47 % of patients had a ≥200 pg/mL change in sputum IL-8 following SFC 250 versus 20 % after placebo ; both changes are considered clinical ly relevant . Conclusion This study provides additional information about inflammation in Japanese COPD patients and is the first to study the anti-inflammatory effects of SFC 250 in this context and population . In the primary analysis , SFC 250 did not produce significant changes from baseline in sputum neutrophil levels or other sputum or serum inflammatory markers compared with placebo . Secondary ad hoc statistical analysis showed that SFC 250 reduced the number of sputum neutrophils and IL-8 compared with placebo BACKGROUND Combination long-acting bronchodilator treatment might be more effective than long-acting bronchodilator monotherapy for the treatment of chronic obstructive pulmonary disease ( COPD ) . We aim ed to compare the efficacy and safety of umeclidinium ( UMEC ) plus vilanterol ( VI ) with tiotropium ( TIO ) monotherapy , UMEC monotherapy , or VI monotherapy in patients with moderate to very severe COPD . METHODS In two multicentre , r and omised , blinded , double-dummy , parallel-group , active-controlled trials , eligible patients ( current or former smokers aged 40 years or older with an established clinical history of COPD ) were r and omly assigned in 1:1:1:1 ratio to UMEC 125 μg plus VI 25 μg , UMEC 62·5 μg plus VI 25 μg , TIO 18 μg , and either VI 25 μg ( study 1 ) or UMEC 125 μg ( study 2 ) . All study drugs were used once daily for 24 weeks . TIO was delivered via the H and iHaler inhaler and all other active treatments were delivered via the ELLIPTA dry powder inhaler . R and om assignment ( by a vali date d computer-based system ) was done by centre and was not stratified . All patients and physicians were masked to assigned treatment during the studies . The primary efficacy endpoint of both studies was trough forced expiratory volume in 1 s ( FEV1 ) on day 169 , which was analysed in the intention-to-treat population . Both studies are registered with Clinical Trials.gov , numbers NCT01316900 ( study 1 ) and NCT01316913 ( study 2 ) . FINDINGS 1141 participants were recruited in study 1 , and 1191 in study 2 . For study 1 , after exclusions , 208 , 209 , 214 , and 212 patients were included in the intention-to-treat analyses for TIO monotherapy , VI monotherapy , UMEC 125 μg plus VI 25 μg , and UMEC 62·5 μg plus VI 25 μg , respectively . For study 2 , 215 , 222 , 215 , and 217 patients were included in the intention-to-treat analyses  for TIO monotherapy , UMEC monotherapy , UMEC 125 μg plus VI 25 μg , and UMEC 62·5 μg plus VI 25 μg , respectively . In both studies , we noted improvements in trough FEV1 on day 169 for both doses of UMEC plus VI compared with TIO monotherapy ( study 1 , UMEC 125 μg plus VI 25 μg : 0·088 L [ 95 % CI 0·036 to 0·140 ; p=0·0010 ] ; study 1 , UMEC 62·5 μg plus VI 25 μg : 0·090 L [ 0·039 to 0·141 ; p=0·0006 ] ; study 2 , UMEC 125 μg plus VI 25 μg : 0·074 L [ 0·025 to 0·123 ; p=0·0031 ] ; study 2 , UMEC 62·5 μg plus VI 25 μg : 0·060 L [ 0·010 to 0·109 ; nominal p=0·0182 ] ) . Both doses of UMEC plus VI also improved trough FEV1 compared with VI monotherapy ( UMEC 125 μg plus VI 25 μg : 0·088 L [ 0·036 to 0·140 ; p=0·0010 ] ; UMEC 62·5 μg plus VI 25 μg : 0·090 L [ 0·039 to 0·142 ; p=0·0006 ] , but not compared with UMEC 125 μg monotherapy ( UMEC 125 μg plus VI 25 μg : 0·037 L [ -0·012 to 0·087 ; p=0·14 ] ; UMEC 62·5 μg plus VI 25 μg : 0·022 L [ -0·027 to 0·072 ; p=0·38 ] ) . All treatments produced improvements in dyspnoea and health-related quality of life ; we noted no significant differences in symptoms , health status , or risk of exacerbation between UMEC plus VI and TIO . The most common on-treatment , severe-intensity adverse event in both studies was acute exacerbation of COPD ( 1 - 4 [ < 1 - 2 % ] patients across treatment groups in study 1 and 1 - 6 [ < 1 - 3 % ] patients in study 2 ) . We recorded five to 15 ( 2 - 7 % ) on-treatment serious adverse events across treatment groups in study 1 , and nine to 22 ( 4 - 10 % ) in study 2 . We noted no substantial changes from baseline in vital signs , clinical laboratory findings , or electrocardiography findings in any of the treatment groups . INTERPRETATION Combination treatment with once-daily UMEC plus  VI improved lung function compared with VI monotherapy and TIO monotherapy in patients with COPD . Overall our results suggest that the combination of UMEC plus VI could be beneficial for the treatment of moderate to very severe COPD . FUNDING GlaxoSmithKline Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more We compared the effectiveness of inhaled formoterol with that of ipratropium in the treatment of chronic obstructive pulmonary disease ( COPD ) . After a 2-wk run-in period , 780 patients with COPD were r and omized to receive for 12 wk formoterol dry powder 12 or 24 microg twice daily , ipratropium bromide 40 microg four times daily , or placebo in a multicenter , double-blind , parallel-group study . The primary efficacy variable was the area under the curve for forced expiratory volume in 1 s ( FEV(1 ) ) measured over 12 h after 12 wk of treatment . Secondary variables included diary symptoms and quality of life . Both doses of formoterol and ipratropium significantly increased the area under the curve for FEV(1 ) in comparison with placebo ( all p < 0.001 ) . Both doses of formoterol were also significantly superior to ipratropium ( all p < 0.025 ) . Compared with placebo , both doses of formoterol significantly improved symptoms ( all p < or = 0.007 ) and quality of life ( p < 0.01 for total scores ) whereas ipratropium did not show significant effects ( all p > or = 0.3 ) . All study treatments exhibited a similar safety profile . We conclude that formoterol is more effective than ipratropium bromide in the treatment of COPD , as the efficacy of ipratropium on airflow obstruction does not translate into a clinical benefit that patients can perceive This study evaluated whether the effect of tiotropium on the change in trough forced expiratory volume in 1s ( FEV1 ) , vs. placebo , is affected by smoking status . In a 3-month , double-blind study in 31 centres in Portugal , 311 ( 289 completed ) patients were r and omised to tiotropium 18 microg once daily or placebo .  Baseline mean ( st and ard deviation ( SD ) ) FEV1 was 1.11 ( 0.39 ) l in the tiotropium group and 1.13 ( 0.39 ) l in the placebo group . Patients had an average smoking history of 55 ( 25.7 ) pack-years ; 80 ( 26 % ) were smokers and 224 ( 74 % ) were ex-smokers . The primary end-point was change in morning pre-dose ( i.e. trough ) FEV1 after 12 weeks . Trough FEV1 at 12 weeks was significantly improved with tiotropium vs. placebo : the difference in means was 102 ml , P=0.0011 , 95 % confidence interval ( CI ) ( 41 , 164 ) . The difference in means in smokers was 138 ml , P=0.0105 , CI ( 32 , 244 ) ; in ex-smokers it was 66 ml , P=0.0375 , CI ( 3 , 129 ) . The difference between smokers and ex-smokers was not statistically significant ( P=0.6982 ) and may be due to greater variability and differences in disease severity . The significant improvement in lung function in patients treated with tiotropium vs. placebo in both smokers and ex-smokers suggests that tiotropium is an effective and well-tolerated therapy in chronic obstructive pulmonary disease ( COPD ) , regardless of smoking status Background Fluticasone furoate/vilanterol ( FF/VI ) is a novel , once-daily , inhaled corticosteroid/long-acting β2-agonist combination approved for the treatment of COPD and asthma . We compared the safety and efficacy of FF/VI and tiotropium ( TIO ) in subjects with moderate-to-severe COPD with greater risk for comorbid cardiovascular disease ( CVD ) . Methods This r and omized , blinded , double-dummy , parallel-group study compared a once-daily morning dose of FF/VI 100/25 mcg delivered via ELLIPTA ™ with TIO 18 mcg via H and iHaler ® for 12 weeks in subjects with diagnosed COPD , forced expiratory volume in 1 second ( FEV1 ) 30%–70 % predicted , and CVD or CVD risk . The primary endpoint was change from baseline in 24-hour weighted mean FEV1 on Day 84 . Other efficacy endpoints included time to onset of bronchodilation , trough FEV1 , other spirometry measures , rescue medication use , symptoms , quality of life ( St George ’s Respiratory Question naire- COPD [ SGRQ-C ] ) , and health status ( COPD Assessment Tests [ CAT ] ) measures . Safety endpoints included cardiovascular monitoring , cortisol excretion , COPD exacerbations , and adverse events , including prespecified drug effects . Results Both FF/VI and TIO improved the 24-hour weighted mean FEV1 from baseline after 12 weeks with no significant difference between treatments . Other endpoints favored FF/VI for time to onset of bronchodilation , rescue medication use , dyspnea , SGRQ-C and CAT scores , or favored TIO for change from baseline in forced vital capacity and inspiratory capacity . Pneumonia occurred more frequently in the FF/VI group , and two TIO-treated subjects died following cardiovascular events . Other safety measures were similar between groups , and cardiovascular monitoring did not reveal increased CVD risk . Conclusion Both FF/VI and TIO were efficacious in improving lung function  in subjects with COPD and comorbid CVD or CVD risk factors , with minor differences in efficacy and safety profiles This study compared the efficacy and safety of once-daily umeclidinium 62.5 µg with once-daily glycopyrronium 50 µg in patients with moderate-to-severe chronic obstructive pulmonary disease . This was a 12-week , multicentre , r and omised , open-label , parallel-group study ( Clinical trials.gov : NCT02236611 ) . Patients were r and omised 1:1 to umeclidinium 62.5 µg or glycopyrronium 50 µg administered via Ellipta or Breezhaler dry powder inhaler , respectively . The primary endpoint was trough forced expiratory volume in 1 s ( FEV1 ) at day 85 in the per- protocol population . Other endpoints included : weighted mean FEV1 over 0–24 h and patient-reported outcomes ( transition dyspnoea index score and St George 's Respiratory Question naire total score ) . Adverse events were also assessed . A total of 1037 patients were r and omised to treatment . Umeclidinium was non-inferior ( margin : −50 mL ) to glycopyrronium ( trough FEV1 at day 85 treatment difference : 24 mL , 95 % confidence intervals : −5–54 ) . Improvements in other endpoints were similar between treatments . Adverse event incidences were similar for umeclidinium ( 37 % ) and glycopyrronium ( 36 % ) . Once-daily umeclidinium was non-inferior to once-daily glycopyrronium in patients with chronic obstructive pulmonary disease  in trough FEV1 at day 85 . Patient-reported outcomes and safety profiles were similar for both treatments . Once-daily umeclidinium is non-inferior to once-daily glycopyrronium in patients with COPD by trough FEV1 at day 85 Tiotropium , a novel once-daily inhaled anticholinergic , has been shown to improve lung function over a 24-h period . In order to extend these findings , health- outcomes were evaluated over 1 yr in chronic obstructive pulmonary disease ( COPD ) patients . Spirometric results , peak expiratory flow rate ( PEFR ) , salbutamol use and effects on dyspnoea , health-related quality of life and COPD exacerbations were assessed in two identical 1-yr r and omized double-blind double-dummy studies of tiotropium 18 µg once daily ( n=356 ) compared with ipratropium 40 µg q.i.d . ( n=179 ) . Screening forced expiratory volume in one second ( FEV1 ) were 1.25±0.43 L ( 41.9±12.7 % of the predicted value ) ( tiotropium ) and 1.18±0.37 L ( 39.4±10.7 % pred ) ( ipratropium )  . Trough FEV1 at 1 yr improved by 0.12±0.01 L with tiotropium and declined by 0.03±0.02 L with ipratropium ( p<0.001 ) . Significant improvement in PEFR , salbutamol use , Transition Dyspnea Index focal score , and the St George 's Respiratory Question naire total and impact scores were seen with tiotropium ( p<0.01 ) . Tiotropium  reduced the number of exacerbations ( by 24 % , p<0.01 ) , and increased time to first exacerbation ( p<0.01 ) and time to first hospitalization for a COPD exacerbation ( p<0.05 ) compared with ipratropium . Apart from an increased incidence of dry mouth in the tiotropium group , adverse events were similar between treatments . Tiotropium was effective in improving dyspnoea , exacerbations , health-related quality of life and lung function in patients with chronic obstructive pulmonary disease , and exceeds the benefits seen with ipratropium . The data support the use of tiotropium once-daily as first-line maintenance treatment in patients with chronic obstructive pulmonary disease BACKGROUND Fluticasone furoate (FF)/vilanterol ( VI ) is a novel once-daily inhaled corticosteroid/long-acting β2-agonist combination therapy for COPD . We aim ed to assess the efficacy and safety of two strengths of FF/VI ( 100/25 μg ; 50/25 μg ) vs. individual components ( FF 100 μg , VI 25 μg ) and placebo over 24 weeks . METHODS Multicentre , r and omised , placebo-controlled , double-blind , parallel-group study of patients ( N = 1030 ) with moderate-to-severe COPD . All medication was administered once daily in the morning . Co- primary efficacy endpoints were : ( 1 ) weighted mean ( wm ) FEV1 ( 0 - 4 h post-dose on day 168 ) to assess acute lung function effects ; and ( 2 ) trough FEV1 ( 23 - 24 h post-dose on day 169 ) to assess long-lasting effects . Symptom-related outcomes were analysed and adverse events ( AEs ) assessed . RESULTS Main findings were : ( 1 ) the combination of FF/VI at a strength of 100/25 μg significantly ( p < 0.001 ) improved wm FEV1 ( 173 ml ) and trough FEV1 ( 115 ml ) vs. placebo . Similar effects were observed with FF/VI 50/25 μg ; ( 2 ) no significant difference was seen between FF/VI 100/25 μg and VI 25 μg for trough FEV1 ( 48 ml , p = 0.082 ) , while an effect was observed between FF/VI 100/25 μg and FF 100 μg for wm FEV1 ( 120 ml , p < 0.001 ) ; ( 3 ) VI 25 μg over 24 weeks improved lung function  vs. placebo significantly for wm FEV1 ( 103 ml , p < 0.001 ) and trough FEV1 ( 67 ml , p = 0.017 ) ; and ( 4 ) no safety signal was observed . CONCLUSIONS In subjects with moderate-to-severe COPD , FF/VI 100/25 μg provides rapid and significant sustained bronchodilation at 24 weeks . Lung function is improved to a similar extent with FF/VI 50/25 μg and to a somewhat lesser extent with VI 25 μg . All treatments were well tolerated . GSK study number : HZC112206 . Clinical Trials.gov : NCT01053988 Background Clinical trials of tiotropium have principally recruited patients from secondary care with more severe chronic obstructive pulmonary disease ( COPD ) , and typically had included limitation of concomitant medication . In primary care , which is the most common setting for COPD management , many patients may have milder disease , and also may take a broad range of concomitant medication . Methods This r and omised , placebo-controlled , parallel-group , 12-week , 44-centre study investigated the efficacy ( trough forced expiratory volume in 1 second [ FEV1 ] response ) and safety of additional treatment with once-daily tiotropium 18 μg via the H and iHaler ® in a primary care COPD population ( tiotropium : N = 191 , FEV1 = 1.25 L [ 47.91 % predicted ] ; placebo : N = 183 , FEV1 = 1.32 L [ 49.86 % predicted ] ) . Secondary endpoints included : trough forced vital capacity ( FVC ) response , weekly use of rescue short-acting β-agonist , and exacerbation of COPD ( complex of respiratory symptoms/events of > 3 days in duration requiring a change in treatment ) . Treatment effects were determined using non-parametric analysis . Results At Week 12 , median improvement in trough FEV1 response  with tiotropium versus placebo was 0.06 L ( p = 0.0102 ) . The improvement was consistent across baseline treatment and COPD severity . Median improvement in FVC at 2 , 6 and 12 weeks was 0.12 L ( p < 0.001 ) . The percentage of patients with ≥1 exacerbation was reduced ( tiotropium 9.5 % ; placebo 17.9 % ; p = 0.0147 ) , independent of disease severity . Rescue medication usage was significantly reduced in the tiotropium  group compared with  placebo . Adverse event profile was consistent with previous studies . Conclusion Tiotropium provides additional benefits to usual primary care management in a representative COPD population .Trial registration The identifier is : NCT00274079 Background Umeclidinium ( UMEC ; long-acting muscarinic antagonist ) plus vilanterol ( VI ; long-acting beta2 agonist [ LABA ] ) and the LABA/inhaled corticosteroid fluticasone propionate/salmeterol ( FP/SAL ) are approved maintenance treatments for chronic obstructive pulmonary disease ( COPD ) . This 12-week , multicentre , double-blind , parallel-group , double-dummy study compared the efficacy and safety of these treatments in symptomatic patients with moderate-to-severe COPD with no exacerbations in the year prior to enrolment . Methods Patients ( n = 717 ) were r and omised 1:1 to once-daily UMEC/VI 62.5/25 mcg or twice-daily FP/SAL 500/50 mcg . Endpoints included 0–24 h weighted mean ( wm ) forced expiratory volume in 1 s ( FEV1 ) ( Day 84 ; primary ) , trough FEV1 ( Day 85 ; secondary ) , other lung function endpoints , symptoms , quality of life ( QoL ) and safety . Results Improvements with UMEC/VI versus FP/SAL were 0.080 L ( 95 % confidence interval : 0.046–0.113 ; wmFEV1 ) and 0.090 L ( 0.055–0.125 ; trough FEV1 ) ( both p < 0.001 ) . UMEC/VI statistically significantly improved all other lung function measures versus FP/SAL . Both treatments demonstrated a clinical ly meaningful improvement in symptoms ( Transition Dyspnoea Index ≥1 unit ) and QoL ( St George ’s Respiratory Question naire Total score ≥4 unit decrease from baseline ) over 12 weeks . The incidence of adverse events was 28 % ( UMEC/VI ) and 29 % ( FP/SAL ) ; nasopharyngitis and headache were most common . Conclusions Once-daily UMEC/VI 62.5/25 mcg over 12 weeks result ed in significant and sustained improvements in lung function versus twice-daily FP/SAL 500/50 mcg in patients with moderate-to-severe COPD and with no exacerbations in the year prior to enrolment . Trial Registration NCT01822899 Registration date : March 28 , BACKGROUND Increased arterial stiffness as measured by aortic pulse wave velocity ( aPWV ) predicts cardiovascular events and mortality and is elevated in patients with COPD . Prior investigation suggests that a long-acting β-agonist (LABA)/inhaled corticosteroid ( ICS ) lowers aPWV in patients with baseline aPWV ≥ 11 m/s . This study compared the effect of the ICS/LABA fluticasone furoate/vilanterol ( FF/VI ) , 100/25 μg , delivered via the ELLIPTA dry powder inhaler , with tiotropium bromide ( TIO ) , 18 μg , on aPWV . METHODS This multicenter , r and omized , blinded , double-dummy , parallel-group , 12-week study compared FF/VI and TIO , both administered once daily . The primary end point was aPWV change from baseline at 12 weeks . Safety end points included adverse events ( AEs ) , vital signs , and clinical laboratory tests . RESULTS Two hundred fifty-seven patients with COPD and aPWV ≥ 11 m/s were r and omized ; 87 % had prior cardiovascular events and /or risk . The mean difference in aPWV between FF/VI and TIO at week 12 was not significant ( P = .484 ) . Because the study did not contain a placebo arm , a post hoc analysis was performed to show that both treatments lowered aPWV by an approximate difference of 1 m/s compared with baseline . The proportion of patients reporting AEs was similar with FF/VI ( 24 % ) and TIO ( 18 % ) . There were no changes in clinical concern for vital signs or clinical laboratory tests . CONCLUSIONS No differences on aPWV were observed between FF/VI and TIO . However , further studies with a placebo arm are required to establish definitively whether long-acting bronchodilators lower aPWV . Both treatments demonstrated an acceptable tolerability profile . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT01395888 ; URL : www . clinical trials.gov Background Tiotropium Safety and Performance in Respimat ® ( TIOSPIR ® ) compared the safety and efficacy of tiotropium Respimat ® and tiotropium H and iHaler ® in patients with chronic obstructive pulmonary disease ( COPD ) . A prespecified spirometry sub study compared the lung function efficacy between treatment groups . Methods TIOSPIR ® was a large-scale , long-term ( 2.3-year ) , event-driven , r and omized , double-blind , parallel-group trial of 17,135 patients with COPD . In the spirometry sub study , trough forced expiratory volume in 1 second ( FEV1 ) and forced vital capacity ( FVC ) were measured at baseline and every 24 weeks for the duration of the trial . Results The sub study included 1370 patients who received once-daily tiotropium Respimat ®  5 μg ( n = 461 ) , 2.5 μg ( n = 464 ) , or tiotropium H and iHaler ® 18 μg ( n = 445 ) . Adjusted mean trough FEV1 ( average 24–120 weeks ) was 1.285 , 1.258 , and 1.295 L in the Respimat ® 5 μg , 2.5 μg , and H and iHaler ® 18 μg groups ( difference versus H and iHaler ® [ 95 % CI ] : −10 [ −38 , 18 ] mL for Respimat ® 5 μg and , −37 [ −65 , −9 ] mL for Respimat ® 2.5 μg ) ; achieving noninferiority to tiotropium H and iHaler ® 18 μg for tiotropium Respimat ® 5 but not for 2.5 μg ( prespecified analysis ) . Adjusted mean trough FVC was 2.590 , 2.544 , and 2.593 L in the Respimat ® 5 μg , 2.5 μg , and H and iHaler ® 18 μg groups . The rates of FEV1 decline over 24 to 120 weeks were similar for the three treatment arms ( 26 , 40 , and 34 mL/year for the tiotropium Respimat ® 5-μg , 2.5-μg , and H and iHaler ® 18-μg groups ) . The rate of FEV1 decline in GOLD I + II patients was greater than in GOLD III + IV patients ( 46 vs. 23 mL/year ) ; as well as in current versus ex-smokers , in patients receiving combination therapies at baseline versus not , and in those experiencing an exacerbation during the study versus not . Conclusions The TIOSPIR ® spirometry sub study showed that tiotropium Respimat ® 5 μg was noninferior to tiotropium H and iHaler ® 18 μg for trough FEV1 , but Respimat ® 2.5 μg was not . Tiotropium Respimat ® 5 μg provides similar bronchodilator efficacy  to tiotropium H and iHaler ® 18 μg with comparable rates of FEV1 decline . The rate of FEV1 decline varied based on disease severity , with a steeper rate of decline observed in patients with moderate airway obstruction . Trial registration NCT01126437 Background Two once-daily long-acting muscarinic antagonists ( LAMAs ) are currently available for the treatment of chronic obstructive pulmonary disease ( COPD ) – tiotropium and glycopyrronium . Previous studies have compared glycopyrronium with open-label tiotropium . In the GLOW5 study , we compare glycopyrronium with blinded tiotropium . Methods In this blinded , double-dummy , parallel group , 12-week study , patients with moderate-to-severe COPD were r and omized 1:1 to glycopyrronium 50 μg once daily or tiotropium 18 μg once daily  . The primary objective was to demonstrate the non-inferiority of glycopyrronium versus blinded tiotropium with respect to trough forced expiratory volume in 1 second ( FEV1 ) following 12 weeks of treatment ( non-inferiority margin : –50 mL ) . Secondary objectives were to evaluate glycopyrronium versus tiotropium for other spirometric outcomes , breathlessness ( Transition Dyspnea Index ; TDI ) , health status ( St George ’s Respiratory Question naire ; SGRQ ) , daily rescue medication use , COPD exacerbations and COPD symptoms over 12 weeks of treatment . Results 657 patients were r and omized ( glycopyrronium : 327 ; tiotropium : 330 ) ; 96 % ( 630 patients ) completed the study .  Least squares mean trough FEV1  for both glycopyrronium and tiotropium was 1.405 L at Week 12 , meeting the criterion for non-inferiority ( mean treatment difference : 0 mL , 95 % CI : –32 , 31 mL ) . Glycopyrronium demonstrated rapid bronchodilation following first dose on Day 1 , with significantly higher FEV1 at all time points from 0–4 h post-dose versus tiotropium ( all p < 0.001 ) . FEV1 area under the curve from 0–4 h ( AUC0–4h ) post-dose with glycopyrronium was significantly superior to tiotropium on Day 1 ( p < 0.001 ) and was comparable to tiotropium at Week 12 . Glycopyrronium demonstrated comparable improvements to tiotropium  in TDI focal score , SGRQ total score , rescue medication use and the rate of COPD exacerbations ( all p = not significant ) . Patients on glycopyrronium also had a significantly lower total COPD symptom score versus patients on tiotropium after 12 weeks ( p = 0.035 ) . Adverse events were reported by a similar percentage of patients receiving glycopyrronium ( 40.4 % ) and tiotropium ( 40.6 % ) . Conclusion In patients with moderate-to-severe COPD , 12-week blinded treatment with once-daily glycopyrronium 50 μg or tiotropium 18 μg , provided similar efficacy and safety , with glycopyrronium having a faster onset of action on Day 1 versus tiotropium . Trial registration Clinical Trial.gov , Efficacy and safety of umeclidinium administered in a dry power inhaler were evaluated in moderate-to-very-severe chronic obstructive pulmonary disease patients . This was a r and omised , placebo-controlled study assessing once-daily umeclidinium 62.5 and 125 & mgr;g over 12 weeks . The primary end-point was change from baseline in trough forced expiratory volume in 1 s ( FEV1 ) on day 85 . Secondary end-points were 0–6-h weighted mean and serial forced expiratory volume in 1 s. Other end-points were transitional dyspnoea index , health outcomes ( St George ’s Respiratory Question naire ) , pharmacokinetics and safety . 246 patients were enrolled ; 168 completed the study . On day 85 , umeclidinium 62.5 and 125 & mgr;g significantly improved least squares mean change from baseline in trough FEV1 ( 127 and 152 mL , respectively ; p<0.001 ) compared with placebo . On day 84 , umeclidinium 62.5 and 125 & mgr;g significantly improved least squares mean change from baseline in 0–6-h weighted mean ( 166 and 191 mL , respectively ; p<0.001 ) and serial FEV1 at each time point ( p≤0.003 ) . Significant improvement in least squares mean transitional dyspnoea index focal score ( 1.0 and 1.3 units , respectively ; p≤0.05 ) and change from baseline St George ’s Respiratory Question naire total score ( -7.9 and -10.87 units , respectively ; p<0.001 ) were noted compared with placebo at week 12 . The incidence of adverse events was low and similar across treatments . Umeclidinium 62.5 and 125 & mgr;g significantly improved lung function , dyspnoea and health status compared with placebo , and were well tolerated in chronic obstructive pulmonary disease patients over 12 weeks . Umeclidinium significantly improves lung function , dyspnoea and health status and is well tolerated Efficacy and safety of tiotropium+olo date rol 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 , r and omised , double-blind , parallel-group , multicentre , phase III trials . Patients received tiotropium+olo date rol FDC 2.5/5 μg or 5/5 μg , tiotropium 2.5 μg or 5 μg , or olo date rol 5 μg delivered once-daily via Respimat 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 Question naire ( 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 response versus the mono-components in both studies . Statistically significant improvements in SGRQ total score versus the mono-components were only seen for tiotropium+olo date rol 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+olo date rol FDC versus mono-components over 1 year in patients with moderate to very severe COPD . Lung function/symptomatic benefits of daily tiotropium+olo date rol fixed-dose combination in moderate-very severe COPD The anti-inflammatory effects of salmeterol/fluticasone ( SFP ) , tiotropium/fluticasone ( Tio+FP ) and tiotropium ( Tio ) alone were investigated on the inflammatory cells and mediators in sputum induced from chronic obstructive pulmonary disease patients . Subjects were either newly diagnosed or had not taken any medication for 3 months prior to the study . Subjects ( n = 99 ) were r and omised ( not double blinded ) and received either SFP ( 100/1,000 μg daily ) , Tio+FP ( 18/1,000 μg daily ) or Tio ( 18 μg daily ) for 12 weeks . Induced sputum and serum C-reactive protein ( CRP ) were analysed prior to and at the end of treatment . The results showed that treatment with SFP caused a significant reduction in interleukin (IL)-8 and matrix metalloprotease (MMP)-9 in induced sputum , compared with treatment with Tio alone . There were no treatment differences between the SFP and Tio+FP groups in decreasing IL-8 and MMP-9 levels . The reduction in IL-8 showed significant association with the reduction in MMP-9 . All treatment groups failed to significantly reduce the numbers of total cells , neutrophils , macrophages and eosinophils in induced sputum ; in addition , there were no treatment differences in terms of improvement of forced expiratory volume in one second , forced vital capacity , CRP or quality of life between the three groups . The anti-inflammatory effects of salmeterol/fluticasone probably contribute to the clinical benefits seen in chronic obstructive pulmonary disease patients Background Combination of the inhaled long-acting muscarinic antagonist umeclidinium ( UMEC ; GSK573719 ) with the long-acting β2-agonist vilanterol ( VI ) is an approved maintenance treatment for COPD in the US and EU . We compared the efficacy and safety of UMEC/VI with placebo in patients with COPD of Asian ancestry . Patients and methods In this 24-week , Phase III , multicenter , r and omized , double-blind , placebo-controlled , parallel-group study , patients were r and omized 1:1:1 to UMEC/VI 125/25 μg , UMEC/VI 62.5/25 μg , or placebo . The primary efficacy end point was trough forced expiratory volume in 1 second ( FEV1 ) on day 169 ; secondary end points were Transition Dyspnea Index ( TDI ) focal score at week 24 and weighted mean ( WM ) FEV1 over 0–6 hours postdose on day 1 . Additional end points and safety were also assessed . Results Both UMEC/VI 125/25 μg and UMEC/VI 62.5/25 μg statistically significantly improved trough FEV1 at day 169 versus placebo ( UMEC/VI 125/25 μg , 0.216 L , [ 95 % confidence interval [ CI ] 0.175–0.257 ] ; UMEC/VI 62.5/25 μg , 0.151 L , 95 % CI 0.110–0.191 ; both P<0.001 ) . Statistically significant improvements in TDI score were observed for both UMEC/VI groups versus placebo ( UMEC/VI 125/25 μg , 0.9 , 95 % CI 0.3–1.4 , P=0.002 ; UMEC/VI 62.5/25 μg , 0.7 , 95 % CI 0.1–1.2 , P=0.016 ) . On day 1 , both UMEC/VI groups improved 0–6-hour WM FEV1  versus placebo ( UMEC/VI 125/25 μg , 0.182 L 95 % CI 0.161–0.203 ; UMEC/VI 62.5/25 μg , 0.160 L , 95 % CI 0.139–0.181 ; both P<0.001 ) . Statistically significant improvements for UMEC/VI groups versus placebo were observed for rescue albuterol use at weeks 1–24 ( puffs/day , both P<0.001 ) . The incidence of adverse events was similar across groups . Conclusion In Asian patients with COPD , once-daily UMEC/VI 125/25 μg and UMEC 62.5/25 μg result ed in clinical ly meaningful and statistically significant improvements in lung-function end points versus placebo . Symptomatic and quality of life measures also improved . The safety profile of UMEC/VI was consistent with previous studies Currently available inhaled bronchodilators used as therapy for chronic obstructive pulmonary disease ( COPD ) necessitate multiple daily dosing . The present study evaluates the long-term safety and efficacy of tiotropium , a new once-daily anticholinergic in COPD . Patients with stable COPD ( age 65.2±8.7 yrs ( mean±sd ) , n=921 ) were enrolled in two identical r and omized double-blind placebo-controlled 1-yr studies . Patients inhaled tiotropium 18 µg or placebo ( mean screening forced expiratory volume in one second ( FEV1 ) 1.01 versus 0.99 L , 39.1 and 38.1 % of the predicted value ) once daily as a dry powder . The primary spirometric outcome was trough FEV1 ( i.e. FEV1 prior to dosing ) . Changes in dyspnoea were measured using the Transition Dyspnea Index , and health status with the disease-specific St. George 's Respiratory Question naire and the generic Short Form 36 . Medication use and adverse events were recorded . Tiotropium provided significantly superior bronchodilation relative to placebo for trough FEV1 response ( ∼12 % over baseline ) ( p<0.01 ) and mean response during the 3 h following dosing ( ∼22 % over baseline ) ( p<0.001 ) over the 12-month period . Tiotropium recipients showed less dyspnoea ( p<0.001 ) , superior health status scores , and fewer COPD exacerbations and hospitalizations ( p<0.05 ) . Adverse events were comparable with placebo , except for dry mouth incidence ( tiotropium 16.0 % versus placebo 2.7 % , p<0.05 ) . Tiotropium is an effective , once-daily bronchodilator that reduces dyspnoea and chronic obstructive pulmonary disease exacerbation frequency and improves health status . This suggests that tiotropium will make an important contribution to chronic obstructive pulmonary disease therapy Background Tiotropium bromide is an effective therapy for COPD patients . Comparing across programs tiotropium Respimat ® Soft Mist ™ inhaler was at least as efficacious as tiotropium H and iHaler ® , however , concerns have been raised about tiotropium ’s safety when given via Respimat ® . Methods The TIOSPIR ® trial ( NCT01126437 ) compares the safety and efficacy of tiotropium Respimat ® 5 μg once daily ( marketed ) and 2.5 μg once daily ( investigational ) with tiotropium H and iHaler ® 18 μ once daily ( marketed ) . The hypotheses to be tested are 1 ) . that tiotropium Respimat ® 5 μg once daily and Respimat ® 2.5 μg once daily are non-inferior to H and iHaler ® in terms of all-cause mortality , and 2 ) . that tiotropium Respimat ® 5 μg once daily is superior to H and iHaler ® in terms of time to first exacerbation . A spirometry sub study evaluates the bronchodilator efficacy . The trial is a r and omized , double-blind , double dummy , event-driven , parallel group study . Participants can use any background treatment for COPD except inhaled anticholinergic agents . The study encompasses a wide range of COPD patients , e.g. patients with stable cardiac diseases including arrhythmia can be included . Clinical sites are international and include both primary care as well as specialists . Results To date , over 17,000 participants have been r and omized from over 1200 sites in 50 countries with an anticipated treatment duration of 2–3 years . Conclusion TIOSPIR ® will provide precise estimates of the relative safety and efficacy of the Respimat ® and H and iHaler ® formulations of tiotropium , assess potential dose-dependence of important outcomes and provide information on the clinical epidemiology of COPD in a large international patient cohort Background Aclidinium/formoterol is a twice-daily ( BID ) fixed-dose combination ( FDC ) in development for chronic obstructive pulmonary disease ( COPD ) . The efficacy and safety of aclidinium/formoterol versus monotherapy and placebo in patients with COPD was assessed . Methods In this 24-week double-blind , parallel-group , active- and placebo-controlled , multicentre Phase III study , patients ( ≥40 years , post-bronchodilator forced expiratory volume in 1 second [FEV1]/forced vital capacity < 70 % and FEV1 ≥30 % but < 80 % predicted normal ) were r and omised 2:2:2:2:1 to aclidinium/formoterol 400/12 μg ( n = 385 ) or 400/6 μg ( n = 381 ) , aclidinium 400 μg ( n = 385 ) , formoterol 12 μg ( n = 384 ) or placebo ( n = 194 ) BID via Genuair ® /Pressair ® a . Results At Week 24 , aclidinium/formoterol 400/12 μg and 400/6 μg lead to significant improvements from baseline in 1-hour post-dose FEV1  versus aclidinium ( 125 mL [ 95 % CI : 90 , 160 ; p < 0 · 001 ] and 69 mL [ 95 % CI : 34 , 105 ; p < 0.001 ] , respectively ) and trough FEV1 versus formoterol ( 85 mL [ 95 % CI : 51 , 119 ; p < 0.001 ] and 53 mL [ 95 % CI : 19 , 87 ; p < 0.01 ] , respectively ; co- primary endpoints ) . Additionally , aclidinium/formoterol 400/12 μg and 400/6 μg provided significant improvements in Transition Dyspnoea Index ( TDI ) focal score versus placebo ( 1.29 units [ 95 % CI : 0.73 , 1.86 ; p < 0.001 ] and 1.16 units [ 95 % CI : 0.59 , 1.73 ; p < 0.001 ] , respectively ; secondary endpoint ) . All treatments were well tolerated , with safety profiles of the FDCs similar to those of placebo and monotherapy . Conclusions Both aclidinium/formoterol BID doses significantly improved bronchodilation versus monotherapy , and dyspnoea versus placebo , with no increase in safety risk . Aclidinium/formoterol may be an effective treatment for patients with COPD .Trial registration Clinical Trials.gov : NCT01462942 BACKGROUND Tiotropium + olo date rol improves lung function and symptoms compared to monotherapies in chronic obstructive pulmonary disease ( COPD ) . The OTEMTO 1 and 2 studies investigated the effects of tiotropium + olo date rol on lung function and health-related quality of life compared to placebo in patients with moderate to severe COPD . METHODS In these two replicate , double-blind , parallel-group , placebo-controlled trials , patients were r and omised to receive tiotropium + olo date rol 5/5 μg , 2.5/5 μg , tiotropium 5 μg or placebo for 12 weeks , via the Respimat ( ® ) inhaler . Primary end points were St George 's Respiratory Question naire ( SGRQ ) total score , forced expiratory volume in 1 s ( FEV1 ) area under the curve from 0 to 3 h ( AUC0 - 3 ) response and trough FEV1 response . RESULTS In OTEMTO 1 and 2 , tiotropium + olo date rol 5/5 μg improved SGRQ total score by 4.89 ( 95 % confidence interval [ CI ] -6.90 , -2.88 ) and 4.56 ( 95 % CI -6.50 , -2.63 ) units versus placebo ( both p < 0.0001 ) , and 2.49 ( 95 % CI -4.47 , -0.51 ; p < 0.05 ) and 1.72 ( 95 % CI -3.63 , 0.19 ) units versus tiotropium 5 μg . Tiotropium + olo date rol 2.5/5 μg significantly improved SGRQ score compared to placebo . Both doses significantly improved FEV1 AUC0 - 3 response compared to placebo and tiotropium 5 μg . Tiotropium + olo date rol 5/5 and 2.5/5 μg also significantly improved trough FEV1 response compared to placebo ( both studies ) and separated from tiotropium 5 μg in OTEMTO 2 . Adverse-event incidence was similar between treatment groups . CONCLUSION Tiotropium + olo date rol improved lung function and quality of life compared to placebo and tiotropium 5 μg . TRIAL REGISTRATION Clinical Trials.gov : NCT01964352 and NCT02006732 BACKGROUND We evaluated the effect of dual , longacting inhaled bronchodilator treatment on exacerbations in patients with severe and very severe chronic obstructive pulmonary disease ( COPD ) . METHODS In this parallel-group study , 2224 patients ( aged ≥40 years , Global Initiative for Chronic Obstructive Lung Disease stages III-IV , and one or more moderate COPD exacerbation in the past year ) were r and omly assigned ( 1:1:1 ; via interactive voice response or web system ; stratified for smoking status ) to once-daily QVA149 ( fixed-dose combination of indacaterol 110 μg and glycopyrronium 50 μg ) , glycopyrronium 50 μg , or tiotropium 18 μg for 64 weeks . Assignment to QVA149 and glycopyrronium was double-blind ; tiotropium was open-label . Efficacy was assessed in all patients r and omly assigned to treatment groups who received at least one dose of study drug ; safety was assessed in all patients who received at least one dose whether or not they were assigned to a group . The primary objective was to show superiority  of QVA149 versus glycopyrronium for rate of moderate to severe COPD exacerbations ( defined by worsening symptoms and categorised by treatment requirements ) during treatment . This completed trial is registered at Clinical Trials.gov , NCT01120691 . FINDINGS Between April 27 , 2010 , and July 11 , 2012 , 741 patients were r and omly assigned to receive QVA149 , 741 to receive glycopyrronium , and 742 to receive tiotropium ( 729 , 739 , and 737 patients , respectively , analysed for efficacy ) . QVA149 significantly reduced the rate of moderate to severe exacerbations  versus glycopyrronium by 12 % ( annualised rate of exacerbations 0·84 [ 95 % CI 0·75 - 0·94 ] vs 0·95 [ 0·85 - 1·06 ] ; rate ratio 0·88 , 95 % CI 0·77 - 0·99 , p=0·038 ) . Adverse events ( including exacerbations ) were reported for 678 ( 93 % ) of 729 patients on QVA149 , 694 ( 94 % ) of 740 on glycopyrronium , and 686 ( 93 % ) of 737 on tiotropium . Incidence of serious adverse events was similar between groups ( 167 [ 23 % ] patients on QVA149 , 179 [ 24 % ] on glycopyrronium , and 165 [ 22 % ] on tiotropium ) ; COPD worsening was the most frequent serious adverse event ( 107 [ 15 % ] patients on QVA149 , 116 [ 16 % ] on glycopyrronium , 87 [ 12 % ] on tiotropium ) . INTERPRETATIONS The dual bronchodilator QVA149 was superior in preventing moderate to severe COPD exacerbations compared with the single longacting antimuscarinic bronchodilator glycopyrronium , with concomitant improvements in lung function and health status . These results indicate the potential of dual bronchodilation as a treatment option for patients with severe and very severe COPD . FUNDING Novartis Pharma AG BACKGROUND Few studies of the efficacy and safety of therapy with combinations of salmeterol/fluticasone propionate ( SFCs ) have been conducted in Chinese patients with COPD , and the benefits of combination therapy in nonsmoking patients with COPD are , to our knowledge , not known . STUDY OBJECTIVES The aims were to establish the efficacy and tolerability of the therapy with SFC ( salmeterol , 50 microg/fluticasone , 500 microg , twice daily ) in the management of Chinese COPD patients and to investigate the effectiveness of SFC in nonsmokers with COPD . METHODS AND PATIENTS This was a r and omized , double-blind , placebo-controlled , parallel-group , multicenter study . Changes in prebronchodilator and postbronchodilator FEV(1 ) , quality of life determined by the St. George Respiratory Question naire ( SGRQ ) scores , relief bronchodilator use , nighttime awakenings , and frequency of exacerbations of COPD were measured in patients r and omized to receive SFC ( n = 297 ) or placebo ( n = 148 ) . Never-smokers , former smokers , and current smokers accounted for 11.7 % , 66.7 % , and 21.6 % , respectively , of the study population . RESULTS After 24 weeks , the mean changes in prebronchodilator and postbronchodilator FEV(1 ) were 180 mL ( 95 % confidence interval [ CI ] , approximately 91 to 268 ; p < 0.001 ) and 65 mL ( 95 % CI , approximately 14 to 115 ; p = 0.012 ) , respectively , greater for the SFC group than that for the placebo group . The differences in response to treatment were significant ( all p < 0.0001 ) in former or current smokers but not in never-smokers ( p > 0.05 ) . The mean improvement in the total SGRQ score for the SFC group was 5.74 ( p < 0.01 ) greater than that for the placebo group . SFC significantly reduced the frequency of nighttime awakenings and the use of relief bronchodilator . The adjusted ratio of exacerbations of COPD for the SFC group relative to the placebo group was 0.61 ( 95 % CI , approximately 0.45 to 0.84 ; p < 0.01 ) . There were no significant differences between the SFC and placebo groups in safety measures . CONCLUSIONS SFC therapy achieved sustained improvement in lung function , quality of life , and control of symptoms , and was well tolerated in Chinese patients . Greater improvements in lung function were found only for COPD patients with a history of smoking . TRIAL REGISTRATION http://ctr.gsk.co.uk/ Summary /fluticasone_salmeterol/ study list.asp Identifier : No. SCO100540 The aim of these studies was to compare the efficacy and the safety of tiotropium , delivered via Respimat Soft Mist Inhaler ( SMI ) , a novel multi-dose , propellant-free inhaler , with ipratropium pressurized metered-dose inhaler ( pMDI ) in chronic obstructive pulmonary disease ( COPD ) patients . Two identical , 12-week , multi-national , r and omized , double-blind , double-dummy , parallel-group , active- and placebo-controlled studies were performed . COPD patients were r and omized to treatment with either inhaled tiotropium ( 5 or 10 microg ) via Respimat SMI administered once daily , ipratropium ( 36 microg ) pMDI QID or placebo . The primary endpoint was the mean trough forced expiratory volume in 1s ( FEV(1 ) ) response after 12 weeks of treatment . Secondary endpoints included other spirometry measures and rescue medication use .  A total of 719 patients were r and omized ; the majority were male ( 69 % ) with a mean pre-bronchodilator FEV(1 ) ( % predicted ) of 40.7 % . The mean treatment differences between tiotropium 5 and 10 microg and placebo for the primary endpoint ( mean trough FEV(1 ) response at week 12 ) were 0.118 and 0.149L , respectively ( both P<0.0001 ) . Treatment differences between tiotropium 5 and 10 microg and ipratropium were 0.064L ( P=0.006 ) and 0.095L ( P<0.0001 ) . The increases in peak FEV(1 ) , FEV(1 ) AUC((0 - 6h ) ) and FVC for both tiotropium doses were statistically superior to placebo ( P<0.01 ) and higher than ipratropium . All active treatments significantly reduced the rescue medication use compared with placebo , but only tiotropium 10 microg was statistically superior to ipratropium ( P=0.04 ) . The incidence of adverse events was comparable across groups . In conclusion , tiotropium 5 and 10 microg daily , delivered via Respimat SMI , significantly improved lung function compared with ipratropium pMDI and placebo STUDY OBJECTIVE To compare the bronchodilator efficacy and safety of tiotropium and placebo . DESIGN A 3-month , r and omized , double-blind , placebo-controlled , multicenter trial . SETTING Outpatient . PATIENTS Four hundred seventy patients with stable COPD ( mean FEV(1 ) = 38.6 % predicted ) . INTERVENTIONS Tiotropium 18 microg ( N = 279 ) or placebo ( N = 191 ) given once daily via a lactose-based dry-powder inhaler device . MEASUREMENTS AND RESULTS Spirometry was evaluated on days 1 , 8 , 50 , and 92 . Data were expressed as the mean trough ( ie , before morning dose ; 23 to 24 h after previous dose ) and average response observed in the 3 h after the dose was received . Tiotropium produced significant improvement in trough FEV(1 ) and FVC , averaging 12 % greater than baseline on day 8 ; these improvements were maintained on days 50 and 92 . The average postdose FEV(1 ) was 16 % greater than baseline on day 1 and 20 % greater than baseline on day 92 ; FVC was 17 % greater than baseline on day 1 and 19 % greater than baseline on day 92 . Tiotropium was significantly more effective than placebo in both trough and average FEV(1 ) and FVC response ( p < 0.001 ) . These spirometric effects were corroborated by significant improvements in daily morning and evening peak expiratory flow rate , as well as a reduction in " as-needed " albuterol use . Symptoms of wheezing and shortness of breath were significantly less in patients receiving tiotropium , and the physician global assessment noted overall improvements with those treated with tiotropium relative to placebo . The most common reported adverse event after tiotropium was dry mouth ( 9.3 % vs 1.6 % relative to placebo ; p < 0.05 ) . CONCLUSIONS These data demonstrate that tiotropium is a safe and effective once-daily anticholinergic bronchodilator and should prove useful as first-line maintenance therapy in COPD STUDY OBJECTIVES To compare the efficacy and safety of the inhaled corticosteroid fluticasone propionate ( FP ) and the inhaled long-acting beta(2)-agonist salmeterol ( SM ) , when administered together in a single device ( Diskus ; GlaxoSmithKline , Inc ; Research Triangle Park , NC ) , with that of placebo and the individual agents alone in patients with COPD . DESIGN R and omized , double-blind , multicenter , placebo-controlled study . SETTING Seventy-six investigative sites in the United States . PATIENTS Seven hundred twenty-three patients > or = 40 years of age with COPD and a mean baseline FEV(1 ) of 42 % predicted . INTERVENTIONS FP ( 250 microg ) , SM ( 50 microg ) , FP plus SM combined in a single inhaler ( FSC ) , or placebo administered twice daily through the Diskus device for 24 weeks . MEASUREMENTS Primary efficacy measures were morning predose ( ie , trough FEV(1 ) ) for FSC compared with SM and 2-h postdose FEV(1 ) for FSC compared with FP . Other efficacy measures were as follows : morning peak expiratory flow rate ( PEF ) ; transition dyspnea index ; chronic respiratory disease question naire ; chronic bronchitis symptom question naire ; exacerbations ; and other symptomatic measures . RESULTS At Endpoint ( ie , the last on-treatment , post-baseline assessment ) , treatment with FSC significantly ( p < or = 0.012 ) increased the morning predose FEV(1 ) ( 165 mL ) compared with SM ( 91 mL ) and placebo ( 1 mL ) , and significantly ( p < or = 0.001 ) increased the 2-h postdose FEV(1 ) ( 281 mL ) compared with FP ( 147 mL ) and placebo ( 58 mL ) . Improvements in lung function with FSC compared with FP and SM , and with FP and SM compared with placebo , as measured by the average daily morning PEF , was observed within approximately 24 h after the initiation of treatment , indicating an early onset of effect ( p < or = 0.034 ) . Compared with placebo , FSC significantly improved dyspnea , quality of life , and symptoms of chronic bronchitis . The incidence of adverse effects ( except for an increase in oral c and idiasis with FSC and FP ) were similar among the treatment groups . CONCLUSIONS Treatment with FSC ( FP , 250 microg , and SM , 50 microg ) twice daily substantially improved morning lung function and sustained these improvements for over a period of 24 weeks compared with FP or SM treatment alone in patients with COPD , with no additional safety concerns for the combination treatment vs that with the individual components RATIONALE Indacaterol is the first once-daily , long-acting inhaled beta(2)-agonist bronchodilator studied in patients with chronic obstructive pulmonary disease ( COPD ) . OBJECTIVES To demonstrate greater efficacy of indacaterol versus placebo on FEV(1 ) at 24 hours post dose ( trough ) after 12 weeks , to compare efficacy with placebo and tiotropium , and to evaluate safety and tolerability over 26 weeks . MEASUREMENTS Patients with moderate-to-severe COPD were r and omized to double-blind indacaterol 150 or 300 microg or placebo , or open-label tiotropium 18 microg , all once daily , for 26 weeks . The primary efficacy outcome was trough FEV(1 ) at 12 weeks . Additional analyses ( not adjusted for multiplicity ) included transition dyspnea index ( TDI ) , health status ( St George 's Respiratory Question naire [ SGRQ ] ) , and exacerbations . Serum potassium , blood glucose , and QTc interval were measured . RESULTS A total of 1,683 patients ( age , 63.3 yr ; post-bronchodilator FEV(1 ) , 56 % predicted ; FEV(1)/FVC , 0.53 ) were r and omized to the four treatment arms . Trough FEV(1 ) at Week 12 increased versus placebo by 180 ml with both indacaterol doses and by 140 ml with tiotropium ( all P < 0.001 vs. placebo ) . At Week 26 , for indacaterol 150/300 microg , respectively , versus placebo , TDI increased ( 1.00/1.18 , P < 0.001 ) and SGRQ total score decreased ( -3.3/-2.4 , P < 0.01 ) ; corresponding results with tiotropium were 0.87 ( P < 0.001 ) for TDI and ( -1.0 , P = not significant ) for SGRQ total score . The incidence of adverse events , low serum potassium , high blood glucose , and prolonged QTc interval was similar across treatments . CONCLUSIONS Indacaterol was an effective once-daily bronchodilator and was at least as effective as tiotropium in improving clinical outcomes for patients with COPD . Clinical trial registered with clinical trials.gov ( NCT 00463567 ) BACKGROUND A study was undertaken to record exacerbations and health re source use in patients with COPD during 6 months of treatment with  tiotropium , salmeterol , or matching placebos . METHODS Patients with COPD were enrolled in two 6-month r and omised , placebo controlled , double blind , double dummy studies of tiotropium 18 micro g once daily via H and iHaler or salmeterol 50 micro g twice daily via a metered dose inhaler . The two trials were combined for analysis of heath outcomes consisting of exacerbations , health re source use , dyspnoea ( assessed by the transitional dyspnoea index , TDI ) , health related quality of life ( assessed by St George 's Respiratory Question naire , SGRQ ) , and spirometry . RESULTS 1207 patients participated in the study  ( tiotropium 402 , salmeterol 405 , placebo 400 ) . Compared with placebo , tiotropium but not salmeterol was associated with a significant delay in the time to onset of the first exacerbation . Fewer COPD exacerbations/patient year occurred in the tiotropium group ( 1.07 ) than in the placebo group ( 1.49 , p<0.05 ) ; the salmeterol group ( 1.23 events/year ) did not differ from placebo . The tiotropium group had 0.10 hospital admissions per patient year for COPD exacerbations compared with 0.17 for salmeterol and 0.15 for placebo ( not statistically different ) . For all causes ( respiratory and non-respiratory ) tiotropium , but not salmeterol , was associated with fewer hospital admissions while both groups had fewer days in hospital than the placebo group . The number of days during which patients were unable to perform their usual daily activities was lowest in the tiotropium group ( tiotropium 8.3 ( 0.8 ) , salmeterol 11.1 ( 0.8 ) , placebo 10.9 ( 0.8 ) , p<0.05 ) . SGRQ total score improved by 4.2 ( 0.7 ) , 2.8 ( 0.7 ) and 1.5 ( 0.7 ) units during the 6 month trial for the tiotropium , salmeterol and placebo groups , respectively ( p<0.01 tiotropium v placebo ) . Compared with placebo , TDI focal score improved in both the tiotropium group ( 1.1 ( 0.3 ) units , p<0.001 ) and the salmeterol group ( 0.7 ( 0.3 ) units , p<0.05 ) . Evaluation of morning pre-dose FEV(1 ) , peak FEV(1 ) and mean FEV(1 ) ( 0 - 3 hours ) showed that tiotropium was superior to salmeterol while both active drugs were more effective than placebo . CONCLUSIONS Exacerbations of COPD and health re source usage were positively affected by daily treatment with tiotropium . With the exception of the number of hospital days associated with all causes , salmeterol twice daily result ed in no significant changes compared with placebo . Tiotropium also improved health related quality of life , dyspnoea , and lung function in patients with COPD This r and omized controlled trial examined the benefits of combining an inhaled corticosteroid , fluticasone propionate ( F ) , with an inhaled long-acting beta(2)-agonist , salmeterol ( S ) , to treat the inflammatory and bronchoconstrictive components of chronic obstructive pulmonary disease ( COPD ) . A total of 691 patients with COPD received the combination of F and S ( FSC ) , S ( 50 mcg ) , F ( 500 mcg ) , or placebo twice daily via the Diskus device for 24 weeks . A significantly greater increase in predose FEV(1 ) at the endpoint was observed after FSC ( 156 ml ) compared with S ( 107 ml , p = 0.012 ) and placebo ( -4 ml , p < 0.0001 ) . A significantly greater increase in 2-hour postdose FEV(1 ) at the endpoint was observed after treatment with FSC ( 261 ml ) compared with F ( 138 ml , p < 0.001 ) and placebo ( 28 ml , p < 0.001 ) . There were greater improvements in the Transition Dyspnea Index with FSC ( 2.1 ) compared with F ( 1.3 , p = 0.033 ) , S ( 0.9 , p < 0.001 ) , and placebo ( 0.4 , p < 0.0001 ) . The incidence of adverse effects ( except for an increase in oral c and idiasis with FSC and F ) was similar among the treatment groups . We conclude that FSC improved lung function and reduced the severity of dyspnea compared with individual components and placebo BACKGROUND Patients with mild or moderate chronic obstructive pulmonary disease ( COPD ) rarely receive medications , because they have few symptoms . We hypothesized that long‐term use of tiotropium would improve lung function and ameliorate the decline in lung function in patients with mild or moderate COPD . METHODS In a multicenter , r and omized , double‐blind , placebo‐controlled trial that was conducted in China , we r and omly assigned 841 patients with COPD of Global Initiative for Chronic Obstructive Lung Disease ( GOLD ) stage 1 ( mild ) or 2 ( moderate ) severity to receive a once‐daily inhaled dose ( 18 μg ) of tiotropium ( 419 patients ) or matching placebo ( 422 ) for 2 years . The primary end point was the between‐group difference in the change from baseline to 24 months in the forced expiratory volume in 1 second ( FEV1 ) before bronchodilator use . Secondary end points included the between‐group difference in the change from baseline to 24 months in the FEV1 after bronchodilator use and the between‐group difference in the annual decline in the FEV1 before and after bronchodilator use from day 30 to month 24 . RESULTS Of 841 patients who underwent r and omization , 388 patients in the  tiotropium  group and 383 in the  placebo  group were included in the full analysis set . The FEV1 in patients who received tiotropium was higher than in those who received placebo throughout the trial ( ranges of mean differences , 127 to 169 ml before bronchodilator use and 71 to 133 ml after bronchodilator use ; P<0.001 for all comparisons ) . There was no significant amelioration of the mean ( ±SE ) annual decline in the FEV1 before bronchodilator use : the decline was 38±6 ml per year in the tiotropium group and 53±6 ml per year in the placebo group ( difference , 15 ml per year ; 95 % confidence interval [ CI ] , ‐1 to 31 ; P=0.06 ) . In contrast , the annual decline in the FEV1 after bronchodilator use was significantly less in the tiotropium group than in the placebo group ( 29±5 ml per year vs. 51±6 ml per year ; difference , 22 ml per year [ 95 % CI , 6 to 37 ] ; P=0.006 ) . The incidence of adverse events was generally similar in the two groups . CONCLUSIONS Tiotropium  result ed in a higher FEV1  than placebo at 24 months and ameliorated the annual decline in the FEV1 after bronchodilator use in patients with COPD of GOLD stage 1 or 2 . ( Funded by Boehringer Ingelheim and others ; Tie‐ COPD Clinical Trials.gov number , NCT01455129 . BACKGROUND Patients with chronic obstructive pulmonary disease ( COPD ) who smoke have a greater annual rate of decline in forced expiratory volume in 1 s ( FEV(1 ) ) than those patients who have stopped smoking . OBJECTIVES To assess the effect of tiotropium on pre-dose ( trough ) FEV(1 ) in patients with COPD followed in Canada . METHODS A total of 913 patients were r and omly assigned to receive either tiotropium 18 mug once daily ( n=608 ) or placebo ( usual care minus inhaled anticholinergics ) ( n=305 ) for 48 weeks in the present r and omized , double-blind , parallel-group study . The effect of tiotropium on measurements of lung function ( FEV(1 ) , FEV(6 ) and forced vital capacity ) , symptoms , health-related quality of life ( St George 's Respiratory Question naire ) and exacerbations were examined . RESULTS Tiotropium improved trough FEV(1 ) in both current and ex-smokers compared with placebo .  Baseline FEV(1 ) in smokers and ex-smokers was 1.03 L and 0.93 L , respectively ( P<0.001 ) . At week 48 , the mean difference between the tiotropium and placebo groups was 0.14+/-0.04 L ( P<0.001 ) in the smoker group and 0.08+/-0.02 L ( P<0.0001 ) in the ex-smoker group . Tiotropium also significantly improved trough forced vital capacity and FEV(6 ) compared with placebo throughout the treatment period ( P<0.05 , for all ) . Furthermore , tiotropium significantly improved the St George 's Respiratory Question naire total score compared with placebo at week 48 ( 40.9 versus 43.7 units , P<0.005 ) . CONCLUSIONS Compared with the placebo group , tiotropium provides sustained improvements in lung function in patients with COPD , with improvements for smokers and ex-smokers STUDY OBJECTIVE To compare the efficacy and safety of ipratropium bromide reformulated with the chlorofluorocarbon (CFC)-free propellant hydrofluoroalkane (HFA)-134a ( ipratropium bromide HFA ) to that of the marketed ipratropium bromide inhalation aerosol ( containing CFC ) in patients with COPD . DESIGN This was a r and omized , double-blind , parallel-group , placebo-controlled , multicenter trial . The primary efficacy parameter was acute bronchodilator response . The primary end points were peak change in FEV(1 ) from baseline and area under the response-time curve . SETTING Thirty-one clinical centers in the United States participated in this project . PATIENTS A total of 507 patients with moderate-to-severe COPD were r and omized , and 444 patients completed the trial . INTERVENTIONS Twelve weeks of treatment four times daily with one of the following : ipratropium bromide HFA , 42 microg ; ipratropium bromide HFA , 84 microg ; HFA placebo ; ipratropium bromide inhalation aerosol , 42 microg ; or CFC placebo . MEASUREMENTS AND RESULTS Patients in all active treatment groups had significant bronchodilator responses as shown by increases in mean FEV(1 ) from baseline of at least 15 % . Bronchodilator response in all active treatment groups was also significantly more than their respective placebo treatments based on FEV(1 ) , area under the time-response curve from 0 to 6 h , and peak response . FVC results were similar to those seen with FEV(1 ) . There were no significant differences in adverse events , laboratory findings , or ECG findings among the treatment groups . CONCLUSIONS Ipratropium bromide HFA , 42 and mgr;g , provided bronchodilation comparable to the marketed ipratropium bromide CFC , 42 and mgr;g , over 12 weeks of regular use 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 , r and omized , 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 clinical ly 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 Background : Chronic obstructive pulmonary disease ( COPD ) is characterized by airflow limitation , which results in the progressive development of dyspnea and exercise limitation . Objective and Methods : To compare the effect of tiotropium with placebo on forced vital capacity ( FVC ) in patients with moderate-to-severe COPD and lung hyperinflation , using exercise endurance , dyspnea and health-related quality of life ( HRQoL ) as secondary endpoints . One hundred patients were r and omized to receive either tiotropium 18 µg once daily or placebo for 12 weeks . Results : Trough ( predose ) FVC was significantly improved with tiotropium compared to placebo on day 42 ( 0.27 ± 0.08 liters ) and 84 ( 0.20 ± 0.08 liters ; p < 0.05 for both ) . Trough inspiratory capacity ( IC ) was also significantly improved with tiotropium compared to placebo on day 42 ( 0.16 ± 0.07 liters ) and 84 ( 0.15 ± 0.07 liters ; p < 0.05 for both ) . Tiotropium increased the mean distance walked during the shuttle walking test by 33 ± 12 ( day 42 ) and 36 ± 14 m ( day 84 ) compared to placebo ( p < 0.05 for both ) . On day 84 , 59 % of the patients in the tiotropium group and 35 % of the patients in the placebo group had significant and clinical ly meaningful improvements in the St. George ’s Respiratory Question naire total score ( p < 0.05 ) . Numerical decreases in the focal score in the Transition Dyspnea Index in patients receiving tiotropium versus placebo suggest that tiotropium also improved dyspnea during activities of daily living . Conclusion : Tiotropium 18 µg once daily reduced hyperinflation with consequent improvements in walking distance and HRQoL in patients with COPD and lung hyperinflation BACKGROUND Long-term safety , particularly cardiovascular safety , is of special interest in maintenance treatment of chronic obstructive pulmonary disease ( COPD ) with long-acting β2-agonists and long-acting muscarinic antagonists , given potential cardiovascular effects . METHODS Two 52-week Phase III trials ( TONADO ® ) investigated tiotropium/olo date rol ( 5/5 and 2.5/5 μg ) versus tiotropium 2.5 , 5 μg and olo date rol 5 μg . In a pre-specified safety analysis , investigator-reported treatment-emergent adverse events ( AEs ) , electrocardiogram and laboratory data were pooled . All serious AE ( SAE ) reports were review ed by an independent Adjudication Committee , which assessed whether deaths , hospitalisations or intubations were respiratory , cardiovascular , cerebrovascular or other disease related . Subgroup analyses investigated cardiovascular safety including major cardiac events in patients with cardiovascular co-morbidities . RESULTS This analysis comprised 3100 patients with moderate to very severe COPD , treated for ≤1 year , including 784 patients with cardiovascular co-morbidities .  AEs were balanced across treatments in the total population as well as in patient subgroups with pre-existing cardiovascular co-morbidities . The incidence and nature of events were consistent with the disease under study and a 1-year trial duration . 494/3100 patients contributed to an adjudicated analysis of SAEs : 260 had respiratory-related , 53 had cardiovascular-related and 16 had cerebrovascular-related SAEs . Incidences of these SAEs were comparable between treatments . There was no evidence of any increased risk for the combination compared to the monotherapy groups . CONCLUSIONS These data provide confidence for clinicians that tiotropium/olo date rol 5/5 μg can be safely administered once-daily to patients with moderate to very severe COPD long-term , including those with significant cardiovascular co-morbidity . TRIAL REGISTRY Clinical Trials.gov , Nos. : NCT01431274 , NCT01431287 BACKGROUND The combination of an inhaled corticosteroid ( ICS ) and a long-acting bronchodilator is recommended in the treatment of patients with chronic obstructive pulmonary disease ( COPD ) who have frequent exacerbations .  Budesonide/formoterol dry powder inhaler ( DPI ) has demonstrated efficacy and tolerability in patients with COPD . OBJECTIVE To evaluate the efficacy and tolerability of budesonide/formoterol administered via one hydrofluoroalkane pressurized metered-dose inhaler ( pMDI ) in patients with COPD . METHODS This was a 6-month , r and omized , double-blind , double-dummy , placebo-controlled , parallel-group , multicentre study ( NCT00206154 ) of 1704 patients aged > or = 40 years with moderate to very severe COPD conducted in 194 centres in the US , Czech Republic , the Netherl and s , Pol and and South Africa . After 2 weeks of treatment based on previous therapy ( ICSs and short-acting bronchodilators allowed during the run-in period ) , patients received one of the following treatments administered twice daily : budesonide/formoterol pMDI 160/4.5 microg x two inhalations ( 320/9 microg ) ; budesonide/formoterol pMDI 80/4.5 microg x two inhalations ( 160/9 microg ) ; budesonide pMDI 160 microg x two inhalations ( 320 microg ) plus formoterol DPI 4.5 microg x two inhalations ( 9 microg ) ; budesonide pMDI 160 microg x two inhalations ( 320 microg ) ; formoterol DPI 4.5 microg x two inhalations ( 9 microg ) ; or placebo . MAIN OUTCOME MEASURES The co- primary efficacy variables were pre-dose forced expiratory volume in 1 second ( FEV(1 ) ) and 1-hour post-dose FEV(1 ) . RESULTS Budesonide/formoterol 320/9 microg demonstrated significantly greater improvements in pre-dose FEV(1 ) versus formoterol ( p = 0.026 ; pre-specified primary comparator ) and 1-hour post-dose FEV(1 ) versus budesonide ( p < 0.001 ; pre-specified primary comparator ) ; budesonide/formoterol 160/9 microg demonstrated significantly greater improvements versus budesonide ( p < 0.001 ) for 1-hour post-dose FEV(1 ) but not versus formoterol for pre-dose FEV(1 ) . Dyspnoea ( measured using the Breathlessness Diary ) and health-related quality -of-life ( HR-QOL ) scores ( based on the St George 's Respiratory Question naire total score ) were significantly improved with both dosage strengths of budesonide/formoterol compared with budesonide , formoterol and placebo ( p < or = 0.044 for all ) . Although not powered a priori for comparisons , the number of exacerbations per patient-treatment year requiring treatment with oral corticosteroids and /or hospitalization was numerically ( 20 - 25 % ) lower with the budesonide-containing treatments ( 0.710 - 0.884 ) versus formoterol ( 1.098 ) and placebo ( 1.110 ) . This result was driven by the exacerbations requiring treatment with oral corticosteroids ( 79 - 120 events ) . The number of exacerbations result ing in hospitalization was very low across treatment groups ( 11 - 22 ) ; the number per patient-treatment year was significantly different for budesonide/formoterol 320/9 microg ( 0.158 ) versus other treatment groups ( 0.081 - 0.108 ) except budesonide/formoterol 160/9 microg ( 0.139 ) , and for budesonide/formoterol 160/9 microg versus formoterol ( 0.081 ) [ p < or = 0.05 ] . All treatments were generally well tolerated . The incidence of individual non-fatal serious adverse events was similar across all treatment groups , except COPD , which was highest in the budesonide/formoterol 320/9 microg group ( 6.1 % ) and lowest in the budesonide ( 3.6 % ) and formoterol ( 3.9 % ) groups , with a range of 4.3 - 4.6 % in the budesonide/formoterol 160/9 microg , budesonide plus formoterol and placebo groups . Budesonide/formoterol had a safety profile comparable with that of the monocomponents and placebo . There was no increase in the incidence of pneumonia in the active treatment groups relative to placebo . CONCLUSIONS Budesonide/formoterol pMDI 320/9 microg demonstrated significantly greater efficacy for pulmonary function on both co- primary endpoints versus the pre-specified comparators ( formoterol DPI 9 microg for pre-dose FEV(1 ) and budesonide pMDI 320 microg for 1-hour post-dose FEV(1 ) ) . Budesonide/formoterol pMDI 160/9 microg demonstrated significantly greater efficacy for 1-hour post-dose FEV(1 ) versus budesonide pMDI 320 microg . Dyspnoea scores and HR-QOL were significantly improved with both budesonide/formoterol pMDI dosage strengths versus both monocomponents and placebo . Both budesonide/formoterol pMDI dosage strengths were well tolerated relative to the monocomponents and placebo RATIONALE In the 4-year UPLIFT trial , tiotropium improved lung function and health-related quality of life and decreased exacerbations compared with usual respiratory medications except inhaled anticholinergics in patients with chronic obstructive pulmonary disease ( COPD ) . Mortality and its causes was a secondary endpoint in UPLIFT . OBJECTIVES We describe the effect of tiotropium on survival and analyze differences between mortality during treatment and during follow-up of discontinued patients . METHODS This study involved a r and omized , double-blind trial comparing tiotropium with placebo in patients with COPD ( > or=40 yr of age ; postbronchodilator FEV(1 ) < or=70 % ; FEV(1)/FVC < or=70 % ) .  Mortality was evaluated during treatment and with follow-up of discontinued patients . Cause of death was adjudicated by an endpoint committee . MEASUREMENTS AND MAIN RESULTS A total of 5,993 patients were r and omized , 3,006 to placebo and 2,987 to tiotropium .  While patients were receiving treatment , there were 792 deaths , with a lower risk in the tiotropium group ( hazard ratio , 0.84 ; 95 % confidence interval [ CI ] , 0.73 - 0.97 ) . Statistical significance was observed at the end of the protocol -defined treatment period ( P = 0.034 ) but not 30 days thereafter ( P = 0.086 ) . Adjustment by GOLD stage , sex , age , baseline smoking behavior , and baseline respiratory medications subgroups did not alter the results of the analysis . The most common causes of death adjudicated by an independent end-point committee were lower respiratory , cancer , general disorders , and cardiac disorders . The hazard ratios for lower respiratory and cardiac mortality during treatment were 0.86 ( 95 % CI , 0.68 - 1.09 ) and 0.86 ( 95 % CI , 0.75 - 0.99 ) , respectively . CONCLUSIONS Treatment with tiotropium over 4 years is associated with decreased mortality , with the effect being most prominent in the cardiac and respiratory systems AIMS Evaluation of tiotropium  efficacy in patients with mild chronic obstructive pulmonary disease ( COPD ) defined by the 2003 Swedish Society of Respiratory Medicine guidelines ( post-bronchodilator FEV1/FVC < 70 % ; FEV1 > 60 % predicted ) . METHODS In this 12-week , r and omised , double-blind , placebo-controlled study of tiotropium 18 mcg once daily versus placebo , respiratory function was assessed on Days 1 , 15 and 85 ( baseline : pre-dose Day 1 ) . RESULTS Mean+/-SD baseline FEV1 ( % predicted ) was 73.4+/-12.5 ( tiotropium , n=107 ; placebo , n=117 ) . Tiotropium significantly improved change from baseline in area under the curve from pre-dose to 2 hours post-dose ( AUC0 - 2 h ) FEV1 versus placebo , by 166+/-26 mL ( mean+/-SE ) at study end ( p<0.0001 ) . With tiotropium , there were significant increases in the change in AUC0 - 2 h FVC versus baseline , and trough FEV1 and FVC , versus placebo , on all test days ( p<0.01 ) . Adverse event rates were similar . CONCLUSION Compared with placebo , tiotropium improved lung function in patients with mild COPD 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  r and omised ( 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 Question naire ( 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 . Aclidinium/formoterol achieves significantly greater bronchodilation than salmeterol/fluticasone in stable COPD BACKGROUND Tiotropium delivered at a dose of 5 μg with the Respimat inhaler showed efficacy similar to that of 18 μg of tiotropium delivered with the H and iHaler inhalation device in placebo-controlled trials involving patients with chronic obstructive pulmonary disease ( COPD ) . Although tiotropium H and iHaler was associated with reduced mortality , as compared with placebo , more deaths were reported with tiotropium Respimat than with placebo . METHODS In this r and omized , double-blind , parallel-group trial involving 17,135 patients with COPD , we evaluated the safety and efficacy of tiotropium Respimat at a once-daily dose of 2.5 μg or 5 μg , as compared with tiotropium H and iHaler at a once-daily dose of 18 μg . Primary end points were the risk of death ( noninferiority study , Respimat at a dose of 5 μg or 2.5 μg vs. H and iHaler ) and the risk of the first COPD exacerbation ( superiority study , Respimat at a dose of 5 μg vs. H and iHaler ) . We also assessed cardiovascular safety , including safety in patients with stable cardiac disease . RESULTS During a mean follow-up of 2.3 years , Respimat was noninferior to H and iHaler with respect to the risk of death ( Respimat at a dose of 5 μg vs. H and iHaler : hazard ratio , 0.96 ; 95 % confidence interval [ CI ] , 0.84 to 1.09 ; Respimat at a dose of 2.5 μg vs. H and iHaler : hazard ratio , 1.00 ; 95 % CI , 0.87 to 1.14 ) and not superior to H and iHaler with respect to the risk of the first exacerbation ( Respimat at a dose of 5 μg vs. H and iHaler : hazard ratio , 0.98 ; 95 % CI , 0.93 to 1.03 ) . Causes of death and incidences of major cardiovascular adverse events were similar in the three groups . CONCLUSIONS Tiotropium Respimat at a dose of 5 μg or 2.5 μg had a safety profile and exacerbation efficacy similar to those of tiotropium H and iHaler at a dose of 18 μg in patients with COPD . ( Funded by Boehringer Ingelheim ; TIOSPIR Clinical Trials.gov number , NCT01126437 . ) In this r and omised double-blind study , patients > or=40 years old with COPD , a smoking history of > or=10 pack-years , a pre-bronchodilator FEV(1 ) of < or=60 % predicted and an FEV(1)/FVC of < or=70 % received tiotropium 5 microg or placebo via Respimat inhaler once daily for 48 weeks . Other medications were permitted except inhaled anticholinergics . Co- primary endpoints were trough FEV(1 ) and the time to first exacerbation . Adverse events were followed and vital status regularly assessed . In all , 3991 patients ( mean age , 65 years [ SD , 9 years ] ) were evaluable . Mean baseline FEV(1 ) was 1.11 L ( 0.40 L ) or 40 % ( 12 % ) of predicted normal . Adjusted mean differences in trough FEV(1 ) and trough FVC at Week 48 ( tiotropium minus placebo ) were 102 and 168 ml respectively ( p < 0.0001 , both ) . Tiotropium delayed time to first exacerbation relative to placebo ( hazard ratio [ HR ] , 0.69 [ 95 % CI , 0.63 - 0.77 ] ) and time to first hospital-treated exacerbation ( HR , 0.73 [ 0.59 - 0.90 ] ) . SGRQ score at Week 48 was 2.9 units lower with tiotropium ( p < 0.0001 ) . Adverse and serious adverse events were balanced across treatment groups and similar in profile to previous tiotropium trials . The rate ratio for a major adverse cardiovascular event during the treatment period + 30 days was 1.12 ( 0.67 - 1.86 ) . By the end of planned treatment ( Day 337 ) 52 patients on tiotropium ( incidence rate per 100 years , 2.94 ) and 38 on placebo ( 2.13 ) had died ( HR = 1.38 [ 0.91 - 2.10 ] ; p = 0.13 ) . Lung function , exacerbations and quality of life were improved by tiotropium 5 microg Respimat but a numerical imbalance was seen in all-cause mortality . The protocol is registered on the European Clinical Trials Data base as trial number 2006 - 001009 - 27 and in the Clinical Trials.gov data base as NCT00387088 BACKGROUND Once-daily combination treatment is an attractive maintenance therapy for COPD . However , the dose of inhaled corticosteroid to use in a once-daily combination is unknown . We compared two strengths of fluticasone furoate ( FF ) plus vilanterol ( VI ) , the same strengths of the individual components , and placebo . METHODS Multicentre , r and omised , 24-week , double-blind , placebo-controlled , parallel-group study in stable , moderate-to-severe COPD subjects ( N = 1224 ) . Subjects were r and omised to FF/VI ( 200/25 μg ; 100/25 μg ) , FF ( 200 μg ; 100 μg ) , VI 25 μg , or placebo , once daily in the morning . Co- primary efficacy endpoints ; 0 - 4 h weighted mean ( wm ) FEV(1 ) on day 168 , and change from baseline in trough ( 23 - 24 h post-dose ) FEV(1 ) on day 169 . The primary safety objective was adverse events ( AEs ) . RESULTS There was a statistically significant ( p < 0.001 ) increase in wm FEV(1 ) ( 209 ml ) and trough FEV(1 ) ( 131 ml ) for FF/VI 200/25 μg vs. placebo ; similar changes were seen for FF/VI 100/25 μg vs. placebo . Whereas the difference between FF/VI 200/25 μg and VI 25 μg in change from baseline trough FEV(1 ) ( 32 ml ) was not statistically significant ( p = 0.224 ) , the difference between FF/VI 200/25 μg and FF 200 μg for wm FEV(1 ) ( 168 ml ) was significantly different ( p < 0.001 ) . VI 25 μg significantly improved wm and trough FEV(1 ) vs. placebo ( 185 ml and 100 ml , [ corrected ] respectively ) . No increase was seen in on-treatment AEs or serious AEs ( SAEs ) , with active therapy vs. placebo . CONCLUSIONS FF/VI provides rapid and significant sustained improvement in FEV(1 ) in subjects with moderate-to-severe COPD , which was not influenced by the dose of FF . These data suggest that FF/VI may offer clinical efficacy in COPD and warrants additional study . GSK study number : HZC112207 . Clinical Trials.gov : NCT01054885 Background and Objectives Aclidinium bromide is a long-acting muscarinic antagonist approved for the long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease ( COPD ) . This 12-week phase III study evaluated efficacy and tolerability of aclidinium 200 or 400 μg in patients with moderate-to-severe COPD . Methods In this double-blind study , 544 patients with COPD were r and omized to placebo or twice-daily aclidinium 200 or 400 μg administered by Genuair ® /Pressair ® . Lung function , health status [ measured by the St. George ’s Respiratory Question naire ( SGRQ ) ] , dyspnea [ measured using the Transition Dyspnea Index ( TDI ) ] , and safety were assessed throughout the study . Results Mean changes from baseline in morning trough forced expiratory volume in 1 s ( FEV1 ) at week 12 ( primary endpoint ) were significantly higher for aclidinium than for placebo ( 200 μg , 51 mL ; 400 μg , 72 mL ; both p < 0.05 ) . Aclidinium also significantly improved other lung function outcomes . At week 12 , improvements from baseline were observed with aclidinium  in SGRQ total score ( 200 μg , −6.0 ; 400 μg , −5.4 ) and TDI focal score ( 200 μg , 1.0 ; 400 μg , 1.3 ) . Furthermore , clinical ly important improvements in SGRQ total and TDI focal scores were achieved by 45 and 51 % of patients , respectively , who received aclidinium 400 μg , with a significant difference versus placebo for TDI ( p < 0.05 ) . Anticholinergic-related adverse events ( e.g. , dry mouth ) were infrequent , occurring < 2 % for any event in any treatment group . Both aclidinium doses were well tolerated . Conclusion This study demonstrates efficacy and safety  of aclidinium in COPD patients . Unexpected baseline imbalances between treatment groups may have impacted the aclidinium treatment benefit in this study The aim of this pilot study was to explore the relative efficacy in terms of improvement in symptoms and lung function of combining fluticasone propionate/salmeterol combination ( FSC ) and tiotropium in patients with severe-to-very severe stable COPD . Ninety patients were r and omized to receive 3 months of treatment in one of three treatment groups : ( 1 ) FSC 500/50 microg Diskus , 1 inhalation twice daily+placebo H and ihaler 1 inhalation once-daily daily ; ( 2 ) tiotropium 18 microg H and ihaler , 1 inhalation once daily+placebo Diskus , 1 inhalation twice daily ; ( 3 ) FSC 500/50 microg Diskus , 1 inhalation twice daily+tiotropium 18 microg H and ihaler , 1 inhalation once-daily daily . Patients attended the clinic before and after 1 month , 2 months , and 3 months of treatment for evaluations of pulmonary function , and dyspnea , which was assessed using a visual analog scale ( VAS ) . Also the supplemental salbutamol use was measured . Eighty-one patients completed the 3-month treatment period : 26 patients receiving FSC , 26 patients receiving tiotropium , and 29 patients receiving FSC+tiotropium .  Patients were withdrawn for COPD exacerbation . Improvements in trough FEV(1 ) with all treatments medications were observed by the first month when trough FEV(1 ) had improved significantly above baseline by 74 mL ( p<0.05 ) in the tiotropium group , by 117 mL ( p<0.05 ) in the FSC group and by 115 mL ( p<0.05 ) in FSC+tiotropium group . At the end of the study , trough FEV(1 ) had improved significantly above baseline by 141 mL ( p<0.05 ) in the tiotropium group , by 140 mL ( p<0.05 ) in the FSC group and by 186 mL ( p<0.05 ) in FSC+tiotropium group . The difference between FSC and tiotropium appeared to decrease , that between FSC and FSC+tiotropium appeared to increase and that between tiotropium and FSC+tiotropium remained almost similar with study duration . Our results suggest that adding FSC and tiotropium may provide benefits in symptomatic patients with severe-to-very severe stable COPD BACKGROUND QVA149 is an inhaled fixed-dose combination therapy under development for the treatment of chronic obstructive pulmonary disease ( COPD ) . It combines indacaterol ( a longacting β2-agonist ) with glycopyrronium ( a longacting muscarinic antagonist ) as a dual bronchodilator . We aim ed to compare the efficacy , safety , and tolerability of QVA149 versus salmeterol-fluticasone ( SFC ) over 26 weeks in patients with moderate-to-severe COPD . METHODS In this multicentre double-blind , double-dummy , parallel-group study , 523 patients ( age 40 years or older , Global Initiative for Chronic Obstructive Lung Disease [ GOLD ] stages II-III , without exacerbations in the previous year ) were r and omly assigned ( 1:1 ; via automated , interactive response technology and stratified for smoking status ) to once-daily QVA149 110/50 μg or twice-daily SFC 50/500 μg for 26 weeks . Efficacy was assessed in the full analysis set ( r and omised patients who received at least one dose of study drug ) ; safety was assessed in all patients who received at least one dose of study drug . The primary endpoint was to demonstrate the superiority of QVA149 compared with SFC for the st and ardised area under the curve from 0 to 12 h post dose for forced expiratory volume in 1 second ( FEV1 AUC0 - 12h ) after 26 weeks of treatment . This trial was registered at Clinical Trial.gov , NCT01315249 . FINDINGS Between March 25 , 2011 , and March 12 , 2012 , 259 patients were r and omly assigned to receive QVA149 and 264 to receive SFC . At week 26 , FEV1 AUC0 - 12h was significantly higher with QVA149 than with SFC ( treatment difference 0·138 L ; 95 % CI 0·100 - 0·176 ; p<0·0001 ) . Overall incidence of adverse events ( including COPD exacerbations ) was 55·4 % ( 143 of 258 ) for the QVA149 group and 60·2 % ( 159 of 264 ) for the SFC group . Incidence of serious adverse events was similar between treatment groups ( QVA149 , 13 of 258 [ 5·0 % ] ; SFC 14 of 264 [ 5·3 % ] ) ; COPD worsening was the most frequent serious adverse event ( one of 13 [ 0·4 % ] and three of 14 [ 1·1 % ] , respectively ) . INTERPRETATION Once-daily QVA149 provides significant , sustained , and clinical ly meaningful improvements in lung function versus twice-daily SFC , with significant symptomatic benefit . These results indicate the potential of dual bronchodilation as a treatment option for non-exacerbating symptomatic COPD patients . FUNDING Novartis Pharma AG BACKGROUND A study was undertaken to evaluate and compare the efficacy and safety of tiotropium and ipratropium during long term treatment in patients with stable chronic obstructive pulmonary disease ( COPD ) . METHODS 288 patients of mean ( SD ) age 65 ( 8) years and forced expiratory volume in one second ( FEV(1 ) ) 41 (12)% predicted participated in a 14 centre , double blind , double dummy , parallel group study and were r and omised after a run in period of two weeks to receive either tiotropium 18 microg once daily from a dry powder inhaler ( H and iHaler ; two thirds of patients ) or ipratropium 40 microg four times daily from a metered dose inhaler ( one third of patients ) for a period of 13 weeks . Outcome measures were lung function , daily records of peak expiratory flow ( PEF ) , and the use of concomitant salbutamol . FEV(1 ) and forced vital capacity ( FVC ) were measured one hour before and immediately before inhalation ( mean value of the two measurements on test day 1 was the baseline value while on all other test days it was known as the trough FEV(1 ) and FVC ) , and 0.5 , 1 , 2 , 3 , 4 , 5 , and 6 hours after inhalation of the study drug on days 1 , 8 , 50 , and 92 . RESULTS During treatment tiotropium achieved a significantly greater improvement than  ipratropium  ( p<0.05 ) in trough , average , and peak FEV(1 ) levels and in trough and average FVC levels . The trough FEV(1 ) response on days 8 , 50 , and 92 ranged between 0.15 l ( 95 % CI 0.11 to 0.19 ) and 0.16 l ( 95 % CI 0.12 to 0.20 ) for tiotropium and between 0.01 l ( 95 % CI -0.03 to 0.05 ) and 0.03 l ( 95 % CI 0.01 to 0 . 07 ) for ipratropium . The trough FVC response on days 8 , 50 , and 92 ranged between 0.34 l ( 95 % CI 0.28 to 0.40 ) and 0.39 l ( 95 % CI 0.31 to 0.47 ) for tiotropium and between 0.08 l ( 95 % CI 0.00 to 0.16 ) and 0.18 l ( 95 % CI 0.08 to 0.28 ) for ipratropium . On all test days tiotropium produced a greater improvement in FEV(1 ) than ipratropium starting three hours after inhalation ( p<0.05 ) . During treatment weekly mean morning and evening peak expiratory flow ( PEF ) was consistently better in the tiotropium group than in the ipratropium group , the difference in morning PEF being significant up through week 10 and in evening PEF up through week 7 of treatment ( p<0.05 ) . The use of concomitant salbutamol was also lower in the tiotropium group ( p<0.05 ) . The only drug related adverse event was dry mouth  ( tiotropium 14.7 % , ipratropium 10.3 % of patients ) . CONCLUSIONS Tiotropium in a dose of 18 microg inhaled once daily using the H and iHaler was significantly more effective than 40 microg ipratropium four times daily in improving trough , average , and peak lung function over the 13 week period . The safety profile of tiotropium was similar to ipratropium . These data support the use of tiotropium as first line treatment for the long term maintenance treatment of patients with airflow obstruction due to COPD BACKGROUND Long-acting beta-agonists and inhaled corticosteroids are used to treat chronic obstructive pulmonary disease ( COPD ) , but their effect on survival is unknown . METHODS We conducted a r and omized , double-blind trial comparing salmeterol at a dose of 50 microg plus fluticasone propionate at a dose of 500 microg twice daily ( combination regimen ) , administered with a single inhaler , with placebo , salmeterol alone , or fluticasone propionate alone for a period of 3 years . The primary outcome was death from any cause for the comparison between the combination regimen and placebo ; the frequency of exacerbations , health status , and spirometric values were also assessed . RESULTS Of 6112 patients in the efficacy population , 875 died within 3 years after the start of the study treatment .  All-cause mortality rates were 12.6 % in the combination-therapy group , 15.2 % in the placebo group , 13.5 % in the salmeterol group , and 16.0 % in the fluticasone group . The hazard ratio for death in the combination-therapy group , as compared with the placebo group , was 0.825 ( 95 % confidence interval [ CI ] , 0.681 to 1.002 ; P=0.052 , adjusted for the interim analyses ) , corresponding to a difference of 2.6 percentage points or a reduction in the risk of death of 17.5 % . The mortality rate for salmeterol alone or fluticasone propionate alone did not differ significantly from that for placebo . As compared with placebo , the combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85 and improved health status and spirometric values ( P<0.001 for all comparisons with placebo ) . There was no difference in the incidence of ocular or bone side effects . The probability of having pneumonia reported as an adverse event was higher among patients receiving medications containing fluticasone propionate ( 19.6 % in the combination-therapy group and 18.3 % in the fluticasone group ) than in the placebo group ( 12.3 % , P<0.001 for comparisons between these treatments and placebo ) . CONCLUSIONS The reduction in death from all causes among patients with COPD in the combination-therapy group did not reach the predetermined level of statistical significance . There were significant benefits in all other outcomes among these patients . ( Clinical Trials.gov number , NCT00268216 [ Clinical Trials.gov ] . ) Context Tiotropium , a new once-daily inhaled anticholinergic bronchodilator , has been shown to improve lung function in patients with chronic obstructive pulmonary disease ( COPD ) . Previous studies have suggested that it may also decrease the frequency of exacerbations and hospitalizations in these patients . Contribution This r and omized , parallel-group , double-blind , placebo-controlled study in patients with moderate to severe COPD showed a small but statistically significant decrease in the exacerbation rate during the 6-month study period . Caution s The study period was relatively short , and the beneficial effects were modest . The Editors Exacerbations of chronic obstructive pulmonary disease ( COPD ) can lead to costly and clinical ly significant consequences . Proven treatments for exacerbations are only modestly effective ( 1 , 2 ) . Recovery from even mild exacerbations may be protracted ( 3 ) . Frequent exacerbations are associated with impaired quality of life and a more rapid decline in lung function over time ( 4 , 5 ) . Patients with severe exacerbations commonly seek care in emergency departments , and many of these patients are hospitalized . In 2000 , COPD was responsible for 1.5 million emergency department visits and 726000 hospitalizations in the United States ( 6 ) . Economic analyses suggest that hospitalization alone consumes up to 70 % of all medical expenses for patients with COPD ( 7 , 8) . Interventions that reduce the frequency or severity of exacerbations are a highly desirable but poorly met medical need . An expert panel convened by the National Heart , Lung , and Blood Institute assigned a high priority to clinical research that might improve the management of COPD exacerbations ( 9 ) . Tiotropium is a newly developed , once-daily inhaled anticholinergic bronchodilator . Because of its very slow dissociation from muscarinic M3 receptors , 1 inhaled dose produces sustained bronchodilation for at least 24 hours ( 10 ) . In controlled clinical trials , compared with placebo or the short-acting anticholinergic bronchodilator ipratropium , tiotropium improved lung function , dyspnea , and health-related quality of life in patients with COPD ( 11 , 12 ) . An analysis of adverse event reports su bmi tted during those studies suggested that tiotropium might also reduce exacerbation and COPD -related hospitalization rates . Therefore , we design ed a clinical trial to prospect ively test the hypothesis that tiotropium reduces exacerbations and hospitalizations due to COPD . Methods Study Design Our study was a parallel-group , r and omized , double-blind , placebo-controlled trial in patients with moderate to severe COPD conducted at 26 Veterans Affairs medical centers in the United States . The sole intervention was tiotropium given by inhalation once daily . The principal outcomes were the percentage of patients experiencing at least 1 exacerbation and the percentage of patients with at least 1 hospitalization due to a COPD exacerbation during a 6-month treatment period . The protocol is consistent with the principles of Helsinki . The institutional review boards of participating medical centers approved the study . All trial participants provided written informed consent . Patients All men and women receiving medical care at participating Veterans Affairs medical centers were potential study participants . We enrolled enough participants to ensure a minimum of 1800 r and omly assigned patients . Eligibility criteria included an age of 40 years or older , a cigarette smoking history of 10 pack-years or more , a clinical diagnosis of COPD , and an FEV1 of 60 % predicted or less and 70 % or less of the FVC . Exclusion criteria were a clinical diagnosis of asthma , a myocardial infa rct ion within the previous 6 months , a serious cardiac arrhythmia or hospitalization for heart failure within the previous year , known moderate to severe renal impairment , moderate to severe symptomatic prostatic hypertrophy or bladder-neck obstruction , narrow-angle glaucoma , current radiation or chemotherapy for a malignant condition , or inability to give informed consent . We also excluded patients who took systemic corticosteroids at unstable doses , or in regular daily doses of 20 mg or more of prednisone ( or equivalent ) , or who had not fully recovered from an exacerbation for at least 30 days before the first study visit . We gathered baseline data on respiratory disease and other relevant medical history by question naire . Procedures We allocated eligible patients in equal numbers to receive tiotropium or placebo according to a central ly generated blocked r and omization list . We generated a single r and omization and assigned blocks to centers . We provided r and omly assigned patients with training and detailed instructions on the use of the dry powder inhalation device ( H and iHaler , Boehringer Ingelheim Pharma GmbH & Co. KG , Biberach , Germany ) ( 13 ) . Blinding of supplies was performed at Boehringer Ingelheim before distribution to investigational sites . The double-blind remained in place until all patients were clinical ly complete or until a serious adverse event required unblinding . Each morning during the trial , patients inhaled 1 capsule of tiotropium ( 18 g ) or 1 identical placebo capsule . Participants otherwise received usual medical care , except that they could not take any open-label anticholinergic bronchodilator . They continued taking all other respiratory medications ( including inhaled corticosteroids and long-acting -agonists ) , and primary providers were allowed to prescribe additional medications according to medical need . Primary providers also prescribed antibiotics and systemic steroid prescriptions for exacerbations without restrictions . For purpose s of recall , patients kept a daily diary throughout the treatment period , recording information about specific respiratory symptoms , medications taken for exacerbations , clinic visits , and hospitalizations . We collected information about exacerbations and health care utilization by interviews when patients made site visits at 3 and 6 months and by telephone calls at 1-month intervals between visits . We assessed study drug adherence by query and by counting returned capsules .  Participants performed spirometry before and 90 minutes after inhalation of study drug at baseline and again at the 3-month and 6-month visits . We encouraged patients to complete study visits and to provide all requested medical information even if they prematurely discontinued the study drug therapy . However , patients who discontinued the study drug therapy did not have 90-minute postinhalation spirometry testing at subsequent study visits . All open-label bronchodilators and the study drug were withheld overnight before spirometry . Study sites performed spirometry by using a common predictive nomogram with equipment and methods that conformed to American Thoracic Society recommendations ( 14 , 15 ) . Objectives We aim ed to determine whether tiotropium decreased COPD exacerbations and hospitalizations due to exacerbations . Outcome Measures The co primary outcomes were the percentage of patients with a COPD exacerbation and the percentage of patients with a hospitalization due to COPD exacerbation . We defined an exacerbation as a complex of respiratory symptoms ( increase or new-onset ) of more than 1 of the following : cough , sputum , wheezing , dyspnea , or chest tightness with a duration of at least 3 days requiring treatment with antibiotics or systemic steroids , hospitalization , or both . The study team at each site requested discharge summaries for all hospitalizations , wherever they occurred . We identified hospitalizations due to COPD exacerbations from events on case report forms that met the protocol definition of an exacerbation and where review of discharge summaries and other available medical records indicated that the event result ed in a hospitalization . We also considered an event to be a hospitalization if a patient was held and treated for an acute respiratory condition in an urgent care department or in an observation unit for longer than 24 hours . Admissions to nursing homes or other extended care facilities were not considered hospitalizations . Secondary outcomes included time to first COPD exacerbation and time to first hospitalization due to COPD exacerbation , the frequencies of exacerbations and of exacerbation-related health care utilization ( hospitalizations , hospitalization days , unscheduled clinic visits , antibiotic treatment days , and systemic corticosteroid treatment days ) , the frequencies of all-cause hospitalizations and hospitalization days , and results of spirometry . Statistical Analysis We analyzed the data by using a modified intention-to-treat principle . Therefore , we included all available data for the patients with any follow-up contact who took at least 1 capsule of study drug in the analysis up to their first event ( for the time-to-event end points ) or their withdrawal from the trial . For the time-to-event end points , we censored patients without an event at the end of their participation in the trial . Although we intended to follow all patients for the full 6 months , some patients were lost to follow-up . We h and led missing data by using longitudinal data analysis methods ( spirometry ) , analysis of observed data only ( number of events ) , or analysis methods for censored data ( time-to-event data ) . For the percentage of patients with an event , we considered that patients who discontinued the study drug therapy before having an event did not have an event . We analyzed the co primary end points by using a CochranMantelHaenszel test with center as a stratum . We used a stepwise procedure to test the percentage of patients with an exacerbation and , if rejected , to test percentage of patients with a hospitalization due to COPD exacerbation , each at a 2-sided level of 0.05 . Because of the prespecified closed testing procedure , no adjustment for multiplicity was required . We calculated that a sample size of 1800 patients would have 80 % power to BACKGROUND QVA149 is an inhaled , once-daily fixed-dose dual bronchodilator combination of the long-acting β2-agonist indacaterol and long-acting muscarinic antagonist glycopyrronium ( NVA237 ) for the treatment of chronic obstructive pulmonary disease ( COPD ) . We investigated the safety and efficacy of QVA149 over 52 weeks . METHODS This 52-week , multicenter , double-blind , parallel-group ,  placebo-controlled  study r and omized ( 2:1 ) patients with moderate-to-severe COPD to once-daily  QVA149 ( 110 μg indacaterol/50 μg glycopyrronium ) or placebo delivered via the Breezhaler device . Primary endpoint was safety and tolerability for treatment-emergent adverse events ( AEs ) . Secondary endpoints included safety based on vital signs , electrocardiograms ( ECGs ) , laboratory evaluations , and pre-dose forced expiratory volume in 1 s ( FEV1 ) . RESULTS Of 339 patients r and omized , QVA149 [ n = 226 ] , placebo [ n = 113 ] ; 76.9 % male , mean age : 62.6 years , post-bronchodilator FEV1 : 57.4 % predicted , 83.5 % completed study . A smaller percentage of patients discontinued in the QVA149 group ( 14.2 % ) compared with placebo ( 21.2 % ) . Overall incidence of AEs was similar in the QVA149 ( 57.8 % ) and placebo ( 56.6 % ) groups , with most AEs being mild to moderate in severity . The numerical differences in some AEs observed could be at least in part explained by differences in baseline patient characteristics . No clinical ly relevant differences were observed between treatment groups for vital signs or ECG parameters . The five deaths reported were unrelated to study medication ( QVA149 , n = 4 [ 1.8 % ] ; placebo , n = 1 [ 0.9 % ] ) . QVA149 demonstrated rapid and clinical ly meaningful bronchodilation sustained over 52 weeks versus placebo . CONCLUSION QVA149 demonstrated a good safety and tolerability profile , providing rapid and sustained bronchodilation over 52 weeks in patients with moderate-to-severe COPD . Clinical Trials.gov identifier : NCT01120717 STUDY OBJECTIVE To examine the efficacy and safety of the once-daily , inhaled , long-acting muscarinic antagonist/β2-agonist combination umeclidinium/vilanterol ( UMEC/VI ) compared with UMEC and VI monotherapies in patients with chronic obstructive pulmonary disease ( COPD ) . METHODS In this 24-week , double-blind , placebo-controlled , parallel-group study ( Clinical Trials.gov : NCT01313650 ) eligible patients were r and omised 3:3:3:2 to treatment with  UMEC/VI 62.5/25 mcg , UMEC 62.5 mcg , VI 25 mcg or placebo administered once daily via dry powder inhaler ( N = 1532 ; intent-to-treat population ) . Primary endpoint was trough forced expiratory volume in one second ( FEV1 ) on Day 169 ( 23 - 24 h post-dose ) . Additional lung-function , symptomatic , and health-related quality -of-life endpoints were assessed , including 0 - 6 h weighted-mean FEV1 , rescue salbutamol use , Transition Dyspnoea Index ( TDI ) , Shortness Of Breath With Daily Activity ( SOBDA ) and St. George 's Respiratory Question naire ( SGRQ ) scores . Safety evaluations included adverse events ( AEs ) , vital signs , 12-lead/24-h Holter electrocardiography parameters and clinical laboratory/haematology measurements . RESULTS All active treatments produced statistically significant improvements in trough FEV1 compared with placebo on Day 169 ( 0.072 - 0.167 L , all p < 0.001 ) ; increases with UMEC/VI 62.5/25 mcg were significantly greater than monotherapies ( 0.052 - 0.095 L , p ≤ 0.004 ) . Improvements were observed for UMEC/VI 62.5/25 mcg vs placebo for weighted-mean FEV1 on Day 168 ( 0.242 L , p < 0.001 ) , rescue salbutamol use during Weeks 1 - 24 ( -0.8 puffs/day , p = 0.001 ) , TDI ( 1.2 units , p < 0.001 ) , SOBDA ( -0.17 units , p < 0.001 ) and SGRQ ( -5.51 units , p < 0.001 ) scores . No clinical ly-significant changes in vital signs , electrocardiography , or laboratory parameters were observed . CONCLUSION Once-daily UMEC/VI 62.5/25 mcg was well tolerated and provided clinical ly-significant improvements in lung function and symptoms in patients with COPD BACKGROUND Most guidelines recommend either a long-acting beta-agonist ( LABA ) plus an inhaled glucocorticoid or a long-acting muscarinic antagonist ( LAMA ) as the first-choice treatment for patients with chronic obstructive pulmonary disease ( COPD ) who have a high risk of exacerbations . The role of treatment with a LABA-LAMA regimen in these patients is unclear . METHODS We conducted a 52-week , r and omized , double-blind , double-dummy , noninferiority trial . Patients who had COPD with a history of at least one exacerbation during the previous year were r and omly assigned to receive , by inhalation , either the LABA indacaterol ( 110 μg ) plus the LAMA glycopyrronium ( 50 μg ) once daily or the LABA salmeterol ( 50 μg ) plus the inhaled glucocorticoid fluticasone ( 500 μg ) twice daily . The primary outcome was the annual rate of all COPD exacerbations . RESULTS A total of 1680 patients were assigned to the indacaterol-glycopyrronium group , and 1682 to the salmeterol-fluticasone group .  Indacaterol-glycopyrronium showed not only noninferiority but also superiority to salmeterol-fluticasone in reducing the annual rate of all COPD exacerbations ; the rate was 11 % lower in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group ( 3.59 vs. 4.03 ; rate ratio , 0.89 ; 95 % confidence interval [ CI ] , 0.83 to 0.96 ; P=0.003 ) . The indacaterol-glycopyrronium group had a longer time to the first exacerbation than did the salmeterol-fluticasone group ( 71 days [ 95 % CI , 60 to 82 ] vs. 51 days [ 95 % CI , 46 to 57 ] ; hazard ratio , 0.84 [ 95 % CI , 0.78 to 0.91 ] , representing a 16 % lower risk ; P<0.001 ) . The annual rate of moderate or severe exacerbations was lower in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group ( 0.98 vs. 1.19 ; rate ratio , 0.83 ; 95 % CI , 0.75 to 0.91 ; P<0.001 ) , and the time to the first moderate or severe exacerbation was longer in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group ( hazard ratio , 0.78 ; 95 % CI , 0.70 to 0.86 ; P<0.001 ) , as was the time to the first severe exacerbation ( hazard ratio , 0.81 ; 95 % CI , 0.66 to 1.00 ; P=0.046 ) . The effect of indacaterol-glycopyrronium versus salmeterol-fluticasone on the rate of COPD exacerbations was independent of the baseline blood eosinophil count . The incidence of adverse events and deaths was similar in the two groups . The incidence of pneumonia was 3.2 % in the indacaterol-glycopyrronium group and 4.8 % in the salmeterol-fluticasone group ( P=0.02 ) . CONCLUSIONS Indacaterol-glycopyrronium was more effective than salmeterol-fluticasone in preventing COPD exacerbations in patients with a history of exacerbation during the previous year . ( Funded by Novartis ; FLAME Clinical Trials.gov number , NCT01782326 . ) BACKGROUND AND OBJECTIVE Aclidinium bromide ( ' aclidinium ' ) is a novel , inhaled long-acting muscarinic antagonist . Therapeutic effects of aclidinium on chronic obstructive pulmonary disease ( COPD ) have been demonstrated in Caucasian population s in several clinical trials . This was a r and omized , double-blind , multi-centre phase-3 clinical trial to evaluate the efficacy and safety of aclidinium in a Korean population . METHODS A total of 263 Korean patients with moderate-to-severe COPD were r and omized to receive aclidinium ( 400 μg , bd ) ( Genuai ) or placebo via a dry-powder inhaler . The primary end point was change in trough forced expiratory volume in one second ( FEV1 ) at 12 weeks . Other lung function measurements , COPD exacerbation , health status ( St George 's Respiratory Question naire ( SGRQ ) , dyspnoea ( Transition Dyspnea Index ( TDI ) and safety were assessed throughout the study period . RESULTS A significant improvement in trough FEV1 from baseline was shown with aclidinium compared with the placebo ( 0.126 L , P < 0.0001 ) . Significant improvements were also demonstrated in peak FEV1 ( 0.190 L , P < 0.0001 ) , SGRQ and TDI . Furthermore , aclidinium significantly reduced the prevalence of exacerbations ( aclidinium , 5.4 % ; placebo , 15.6 % , P < 0.05 ) , and the duration of exacerbations was shorter compared with placebo ( rate ratio : 0.27 ; P < 0.05 ) . Aclidinium ( 400 μg ) was well tolerated and the prevalence of adverse events was comparable with the placebo . CONCLUSIONS Inhaled aclidinium ( 400 μg ) was shown to be safe and efficacious in Korean patients with moderate-to-severe COPD . CLINICAL TRIAL REGISTRATION NCT01636401 at Clinical trials.gov
Purpose To assess the comparative efficacy of short-acting muscarinic antagonists ( SAMAs ) , long-acting muscarinic antagonists ( LAMAs ) , LAMA in combination with long-acting beta-agonists ( LABAs ; LAMA/LABAs ) and inhaled corticosteroids ( ICS ) in combination with LABA ( ICS/LABAs ) for the maintenance treatment of COPD .