Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD A randomised double-blind, placebo-controlled, long-term extension study of the efficacy, safety and tolerability of fixed-dose combinations of aclidinium/formoterol or monotherapy in the treatment of 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 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. Effect of fluticasone propionate/salmeterol on lung hyperinflation and exercise endurance in COPD. Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study. Indacaterol improves lung hyperinflation and physical activity in patients with moderate chronic obstructive pulmonary disease - a randomized, multicenter, double-blind, placebo-controlled study Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2–4) Blinded 12-week comparison of once-daily indacaterol and tiotropium in COPD 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 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. Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium. Formoterol mono- and combination therapy with tiotropium in patients with COPD: a 6-month study. Integrating indacaterol dose selection in a clinical study in COPD using an adaptive seamless design. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Improved daytime spirometric efficacy of tiotropium compared with salmeterol in patients with COPD. Efficacy and Safety of Glycopyrrolate/Formoterol Metered Dose Inhaler Formulated Using Co‐Suspension Delivery Technology in Patients With COPD FLIGHT1 and FLIGHT2: Efficacy and Safety of QVA149 (Indacaterol/Glycopyrrolate) versus Its Monocomponents and Placebo in Patients with Chronic Obstructive Pulmonary Disease. A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol. Effects of a combination of umeclidinium/vilanterol on exercise endurance in patients with chronic obstructive pulmonary disease: two randomized, double-blind clinical trials Computed tomography assessment of airway dimensions with combined tiotropium and indacaterol therapy in COPD patients. Effect of long-acting β2-agonists olodaterol and formoterol on heart rate and blood pressure in chronic obstructive pulmonary disease patients. Improved lung function and patient-reported outcomes with co-suspension delivery technology glycopyrrolate/formoterol fumarate metered dose inhaler in COPD: a randomized Phase III study conducted in Asia, Europe, and the USA Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Long-term safety of glycopyrrolate: A randomized study in patients with moderate-to-severe COPD (GEM3). Tiotropium versus salmeterol for the prevention of exacerbations of COPD.
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 The aim of this study was to test the hypothesis that use of tiotropium , a new long-acting anticholinergic bronchodilator , would be associated with sustained reduction in lung hyperinflation and , thereby , would improve exertional dyspnoea and exercise performance in patients with chronic obstructive pulmonary disease . A r and omised , double-blind , placebo-controlled , parallel-group study was conducted in 187 patients ( forced expiratory volume in one second 44±13 % pred ) : 96 patients received 18 µg tiotropium and 91 patients received placebo once daily for 42 days . Spirometry , plethysmographic lung volumes , cycle exercise endurance and exertional dyspnoea intensity at 75 % of each patient 's maximal work capacity were compared . On day 42 , the use of tiotropium was associated with the following effects at pre-dose and post-dose measurements as compared to  placebo : vital capacity and inspiratory capacity ( IC ) increased , with inverse decreases in residual volume and functional residual capacity  . Tiotropium  increased post-dose exercise endurance time by 105±40 s ( 21 % ) as compared to placebo on day 42 . At a st and ardised time near end-exercise ( isotime ) , IC , tidal volume and minute ventilation all increased , whilst dyspnoea decreased by 0.9±0.3 Borg scale units . In conclusion , the use of tiotropium was associated with sustained reductions of lung hyperinflation at rest and during exercise . Result ant increases in inspiratory capacity permitted greater expansion of tidal volume and contributed to improvements in both exertional dyspnoea and exercise endurance INTRODUCTION Aclidinium bromide/formoterol fumarate ( AB/FF ) 400/12 μg efficacy and safety was demonstrated in two 6-month Phase III studies ( AUGMENT and ACLIFORM ) and a 12-month study in patients with moderate to severe chronic obstructive pulmonary disease ( COPD ) . This Phase III , double-blind , placebo-controlled , 6-month AUGMENT extension investigated the long-term safety and tolerability of AB/FF 400/12 μg ( NCT01572792 ) . METHODS Patients were r and omised in AUGMENT  ( 1:1:1:1:1 ) to twice-daily AB/FF 400/12 μg , AB/FF 400/6 μg , AB 400 μg , FF 12 μg or placebo . Patients completing AUGMENT were invited to continue the same treatment in the extension . Adverse events ( AEs ) , major adverse cardiovascular events ( MACE ) , laboratory tests , electrocardiograms and vital signs were recorded . Efficacy was assessed . RESULTS Of 1322 patients completing AUGMENT , 921 enrolled and 780 completed the extension .  AE incidence was low and comparable across treatment groups ; most common were nasopharyngitis ( range 4.8%-9.3 % ) , urinary tract infection ( range 4.1%-8.8 % ) and upper respiratory tract infection ( range 2.7%-5.5 % ) . Serious AEs ( SAEs ) and MACE were low ( ranges 6.8%-7.7 % and 0.5%-1.5 % , respectively ) . Significant improvements in bronchodilation and dyspnoea were maintained over 52 weeks versus placebo . Trends towards improvements in other symptoms and health status were observed versus placebo and monotherapies . AB/FF combinations increased the time to first exacerbation by approximately 30 % versus placebo ( p < 0.05 ) . CONCLUSION AB/FF 400/12 μg was well tolerated over 52 weeks with low incidences of AEs , SAEs and MACE that were comparable across treatment groups . Improvements in bronchodilation , symptoms and health status were maintained across 52 weeks 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 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 STUDY OBJECTIVE To examine the effect of fluticasone propionate , 250 microg/salmeterol , 50 microg combination ( FSC 250/50 ) twice daily on lung hyperinflation and associated measures of exercise performance in patients with COPD . DESIGN This was a r and omized , double-blind , parallel-group study . PATIENTS Eligible patients were > or = 40 years old with a diagnosis of COPD , prealbuterol FEV(1 ) < 70 % of predicted , FEV1/FVC ratio > or = 0.70 , and functional residual capacity ( FRC ) > or = 120 % of predicted normal . INTERVENTIONS Patients were r and omized to FSC 250/50 ; salmeterol , 50 microg ; or placebo twice daily for 8 weeks . Predose and postdose spirometry , plethysmography , and constant-load cycle cardiopulmonary exercise test evaluations were compared . The primary comparison was FSC 250/50 with placebo . The salmeterol group was included for exploratory comparisons with FSC 250/50 . RESULTS A total of 185 patients ( mean baseline FEV1 of 41 % predicted ) were enrolled . At rest , FSC 250/50 significantly reduced postdose FRC and increased inspiratory capacity ( IC ) compared with placebo ( differences of - 0.35 + /- 0.12 L and 0.33 + /- 0.06 L [ mean + /- SE ] , respectively , at week 8 ; p > or = 0.003 ) and increased exercise endurance time ( difference , 132 + /- 45 s ; p = 0.004 ) . At a st and ardized time during exercise ( isotime ) , FSC 250/50 increased postdose IC by 0.20 + /- 0.05 L over placebo with associated improvements in tidal volume and minute ventilation ( p < 0.05 vs placebo at week 8) . Improvement in exercise time was significantly correlated with the increase in IC ( r = 0.45 , p < 0.001 ) but not FEV1 ( r = 0.23 , p = 0.08 ) . Predose comparisons of FSC 250/50 with salmeterol and placebo favored FSC 250/50 . CONCLUSION We conclude that FSC 250/50 decreases lung hyperinflation at rest and during exercise with an associated increase in exercise endurance time when compared with placebo BACKGROUND We compared the efficacy and safety of indacaterol and tiotropium in patients with severe chronic obstructive pulmonary disease ( COPD ) and a history of at least one moderate to severe exacerbation in the previous 12 months . METHODS In this multicentre , r and omised , blinded , double-dummy , parallel group study , we enrolled patients aged 40 years or older with severe COPD and at least one exacerbation within the previous year . We used a computer-generated sequence to r and omly allocate patients ( 1:1 ; stratified by baseline inhaled corticosteroid use , with the balance of treatments maintained at country level ) to receive either indacaterol ( 150 μg ) or tiotropium ( 18 μg ) once-daily for 52 weeks . Our primary and key secondary objectives were to investigate whether indacaterol was non-inferior to tiotropium  for trough forced expiratory volume in 1 s ( FEV1 ) at week 12 ( primary endpoint ) , and for rate of exacerbations at week 52 ( secondary endpoint ) . Analysis population s for the primary and key secondary endpoints were per- protocol sets . The safety set included all patients who received at least one dose of study drug . This study is registered with Clinical Trials.gov , number NCT00845728 . FINDINGS Between March 16 , 2009 , and July 5 , 2012 , we enrolled and r and omly allocated 3444 patients : 1723 to indacaterol and 1721 to tiotropium . At week 12 , the estimated least squares mean trough FEV1 difference between the groups was -0.011 L ( least squares mean with indacaterol [ n=1450 ] 1.134 L [ SE 0.008 ] vs tiotropium [ n=1467 ] 1.145 L [ 0.008 ] ; one-sided 97.5 % CI lower limit -0.026 L ; p<0.0001 ) . The lower limit of the 97.5 % CI was above the prespecified non-inferiority margin of -0.055 L , suggesting that indacaterol was non-inferior to tiotropium . Indacaterol did not show non-inferiority in terms of annualised exacerbation rates : 0.79 ( indacaterol , n=1529 ) versus 0.61 ( tiotropium , n=1543 ) ; ratio 1.29 ( one-sided 97.5 % CI upper limit 1.44 ) . In the safety set , we recorded no between-group difference in the number of patients who had adverse events  ( indacaterol 1119 [ 65 % ] of 1721 patients vs tiotropium 1065 [ 62 % ] of 1718 patients ) or serious adverse events  ( indacaterol , 263 [ 15 % ] of 1721 patients vs tiotropium , 255 [ 15 % ] of 1718 patients ) . Respiratory disorders , particularly worsening of COPD , were the most common adverse events ( COPD : indacaterol , 747 [ 43 % ] of 1721 patients and tiotropium , 665 [ 39 % ] of 1718 patients ) and serious adverse events ( COPD : indacaterol , 147 [ 9 % ] of 1721 patients and tiotropium , 121 [ 7 % ] of 1718 patients ) . INTERPRETATION Indacaterol and tiotropium provided clinical ly relevant improvements in lung function with comparable safety profiles . Tiotropium afforded greater protection from exacerbations , although the absolute number of events was small and the difference between treatments is of uncertain clinical importance . The present data offer evidence consistent with current guidelines . FUNDING Novartis Pharma AG Background Indacaterol is a long-acting beta-2 agonist for once-daily treatment of COPD . We evaluated the effects of indacaterol 150 μg on lung hyperinflation compared with placebo and open-label tiotropium 18 μg . We measured physical activity during treatment with indacaterol 150 μg and matched placebo . Methods We performed a r and omized , three-period , cross-over study ( 21 days of treatment separated by two wash-out periods of 13 days ) with indacaterol 150 μg or matching placebo and tiotropium 18 μg . Lung function was assessed by body plethysmography and spirometry  . Physical activity was measured for one week by a multisensory armb and at the end of both treatment periods with indacaterol/matched placebo . The primary endpoint was peak inspiratory capacity at the end of each treatment period . Results 129 patients ( mean age , 61 years ; mean post-bronchodilator FEV1 , 64 % ) , were r and omized and 110 patients completed the study . Peak inspiratory capacity was 0.22 L greater with Indacaterol at day 21 compared to placebo ( p < 0.001 ) . Similar results were observed for tiotropium . Both bronchodilators also significantly improved other parameters of lung hyperinflation compared with placebo . All parameters of physical activity were significantly increased during treatment with indacaterol versus placebo . Conclusions Indacaterol 150 μg improved lung hyperinflation in patients with moderate COPD , which was associated with an increase of physical activity . Trial registration Clinical Trials.gov registration number : NCT01012765 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 Two , once daily ( q.d . ) inhaled bronchodilators are available for the treatment of chronic obstructive pulmonary disease ( COPD ): the & bgr;2-agonist indacaterol and the anticholinergic tiotropium . This blinded study compared the efficacy of these two agents and assessed their safety and tolerability . Patients with moderate-to-severe COPD were r and omised to treatment with indacaterol 150 μg q.d . ( n=797 ) or tiotropium 18 μg q.d . ( n=801 ) for 12 weeks . After 12 weeks , the two treatments had similar overall effects on “ trough ” ( 24 h post-dose ) forced expiratory volume in 1 s.  Indacaterol-treated patients had greater improvements in transition dyspnoea index ( TDI ) total score ( least squares means 2.01 versus 1.43 ; p<0.001 ) and St George ’s Respiratory Question naire ( SGRQ ) total score ( least squares means 37.1 versus 39.2 ; p<0.001 ; raw mean change from baseline -5.1 versus -3.0 ) , and were significantly more likely to achieve clinical ly relevant improvements in these end-points ( indacaterol versus tiotropium odds ratios of 1.49 for TDI and 1.43 for SGRQ , both p<0.001 ) . Adverse events were recorded for 39.7 % and 37.2 % of patients in the indacaterol and tiotropium treatment groups , respectively . The most frequent adverse events were COPD worsening , cough and nasopharyngitis . Both bronchodilators demonstrated spirometric efficacy . The two treatments were well tolerated with similar adverse event profiles . Compared with tiotropium , indacaterol provided significantly greater improvements in clinical outcomes 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 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 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 ) Although guidelines recommend combining long-acting bronchodilators in COPD , data are limited . We examined the clinical efficacy and safety of formoterol , tiotropium and the combination in patients with COPD . Eight hundred and forty-seven patients with COPD ( mean FEV(1 ) 52 % predicted ; FEV(1)/FVC 53 % ) were r and omized to receive one of the following four treatments for 24 weeks : formoterol 10 microg b.i.d . plus tiotropium 18 microg o.d . ; formoterol 10 microg b.i.d . ; tiotropium 18 microg o.d . , or placebo . The study was partially blinded ( formoterol and placebo ) . For the primary endpoint , FEV(1 ) 2h post-dose after 24 weeks , there were small differences in favour of the combination therapy versus formoterol ( 0.07 L , p=0.044 ) or tiotropium ( 0.06 L , p=0.066 ) . All three treatments were superior to placebo ( p<0.001 ) . The combination was statistically superior to monotherapy for : the primary endpoint ( p=0.044 vs. formoterol ) ; FEV(1 ) 5 min after the first dose ( p<0.001 ) and at 12 weeks ( p<0.05 vs. tiotropium ) ; and peak expiratory flow averaged over the first 6 weeks ( p<0.001 vs. both ) . The three active treatments were significantly more effective than placebo for secondary endpoints : COPD -related ' bad days ' , symptoms , use of rescue medication and peak expiratory flow , and aspects of health-related quality of life . The overall incidence of adverse events was similar with all active treatments , although COPD -related adverse events were more common with tiotropium . Combined bronchodilator therapy may be a valuable treatment option for patients with COPD BACKGROUND The drug development process can be streamlined by combining the traditionally separate stages of dose-finding ( Phase IIb ) and confirmation of efficacy and safety ( Phase III ) using an adaptive seamless design . This approach was used in a clinical study of indacaterol , a novel once-daily ( od ) inhaled long-acting beta(2)-adrenoreceptor agonist bronchodilator for the treatment of COPD ( chronic obstructive pulmonary disease ) . METHODS The study comprised a dose-finding stage with dose selection after 14 days of treatment , and a second stage evaluating efficacy and safety during 26 weeks of treatment . The dose-finding stage included seven r and omized treatment arms : double-blind indacaterol 75 microg , 150 microg , 300 microg or 600 microg od , the beta(2)-adrenoceptor agonist formoterol 12 microg twice-daily or placebo , or the anticholinergic tiotropium 18 microg od open-label . An independent data monitoring committee selected two indacaterol doses based on unblinded results of an interim analysis performed by an independent statistician . The sponsor , investigators and patients remained blinded to the results . The indacaterol doses were selected using pre-set efficacy criteria for trough ( 24-h post-dose ) and early ( 1 - 4 h post-dose ) bronchodilator effect after 14 days , and all safety data . To qualify for selection , the doses had to exceed a threshold for clinical relevance or be superior to either tiotropium or formoterol , whichever was the highest value . Selected doses were continued into the second , 26-week stage . The two other indacaterol doses not selected , and formoterol , were discontinued following dose selection . RESULTS 801 patients with moderate-to-severe COPD were evaluated . Indacaterol 150 microg was the lowest effective dose , exceeding criteria for trough FEV(1 ) ( reference value 140 mL vs placebo ) and FEV(1 ) AUC(1 - 4 h ) ( reference value 220 mL vs placebo ) . No safety signal was observed with any dose of indacaterol . Thus , indacaterol 150 and 300 microg were selected to continue into the second , 26-week stage . CONCLUSION The adaptive seamless design is a novel and efficient way to combine dose selection with efficacy evaluation and safety confirmation in a single trial 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 BACKGROUND The Global Initiative for Chronic Obstructive Lung Disease ( GOLD ) recommends long-acting bronchodilators as first-line maintenance treatment for patients with chronic obstructive pulmonary disease ( COPD ) . A study was conducted comparing the long-acting anticholinergic tiotropium with the long-acting beta-agonist salmeterol to confirm the significant improvements in daytime bronchodilator efficacy seen with tiotropium in previous studies . METHODS R and omized , double-blind , double-dummy , parallel-group study , comparing daytime bronchodilator efficacy of tiotropium 18 mcg once daily with salmeterol 50 mcg twice daily in patients with COPD . Serial spirometry was performed over 12 h after 12 weeks of treatment . Co- primary endpoints were average ( over 12 h ) and peak FEV1 at 12 weeks . RESULTS 653 patients were r and omized ( 328 tiotropium , 325 salmeterol ) : mean age 64 years ; 66 % male ; mean baseline FEV1 1.05 l ( 37.7 % predicted ) . After 12 weeks , the average post-dose FEV1 over 12 h was significantly higher with tiotropium compared with salmeterol ( 167 vs. 130 mL , respectively , p=0.03 ) , as was peak FEV1 ( 262 vs. 216 ml , respectively , p=0.01 ) . The average FEV1 responses from 0 - 6 h and 6 - 12 h were higher in the tiotropium group compared with salmeterol ( p<0.05 ) . Peak and average FVC were significantly higher with tiotropium compared with salmeterol ( p<0.01 ) . Morning pre-dose FEV1 responses were not significantly different ; however , tiotropium demonstrated a significantly higher pre-dose FVC than salmeterol ( p<0.05 ) . CONCLUSION Tiotropium demonstrated significantly greater post-dose improvements in spirometric parameters compared with salmeterol . These improvements were sustained over 12 Background : Long‐acting muscarinic antagonist (LAMA)/long‐acting & bgr;2‐agonist ( LABA ) combinations are a treatment option for patients with COPD who continue to have symptoms despite treatment with a LAMA or a LABA alone . The Efficacy and Safety of PT003 , PT005 , and PT001 in Subjects with Moderate‐to‐Very Severe COPD ( PINNACLE‐1 ) ( NCT01854645 ) and the Multi‐Center Study to Assess the Efficacy and Safety of PT003 , PT005 , and PT001 in Subjects with Moderate‐to‐Very Severe COPD ( PINNACLE‐2 ) ( NCT01854658 ) trials investigated the efficacy and safety of a novel glycopyrrolate [GP]/formoterol [ FF ] 18/9.6‐&mgr;g ( GFF ) metered dose inhaler ( MDI ) formulated using the Co‐Suspension Delivery Technology in patients with moderate‐to‐very severe COPD . Methods : These two phase III trials took place over 24 weeks and were r and omized , double blind , and placebo controlled ; 2,103 and 1,615 patients ( 40–80 years of age ) , respectively , were r and omized . Patients received GFF MDI , GP MDI 18 & mgr;g , FF MDI 9.6 & mgr;g , or placebo MDI ( all twice daily ) , or tiotropium 18 & mgr;g dry powder inhaler ( once daily in PINNACLE‐1 only [ open‐label active comparator ] ) . Efficacy and safety were assessed . Results : At week 24 , differences in change from baseline in the morning predose trough FEV1 for GFF MDI vs placebo MDI , GP MDI , and FF MDI were 150 mL , 59 mL , and 64 mL in PINNACLE‐1 ( all P < .0001 ) and 103 mL , 54 mL , and 56 mL in PINNACLE‐2 ( all P < .001 ) , respectively . There were no significant safety findings ( incidence of adverse events was similar between treatment arms ) . Conclusions : We conclude that GFF MDI 18/9.6 & mgr;g demonstrated superiority over placebo and monocomponent MDIs and was well tolerated , thus providing an additional treatment option for patients with moderate‐to‐very severe COPD . Trial Registry : Clinical Trials.gov ; No. : NCT01854645 and No. NCT01854658 ; URL : www . clinical trials.gov RATIONALE Current Global Initiative for Chronic Obstructive Lung Disease ( GOLD ) strategy recommends the combination of two long-acting bronchodilators of different pharmacologic classes for the management of chronic obstructive pulmonary disease ( COPD ) if symptoms are not adequately controlled by a single bronchodilator . OBJECTIVES The FLIGHT1 and FLIGHT2 studies evaluated the efficacy and safety of QVA149 ( indacaterol/glycopyrrolate ) , a fixed-dose combination of a long-acting β2-agonist ( indacaterol ) and a long-acting muscarinic antagonist ( glycopyrrolate ) , compared with its monocomponents and placebo in patients with moderate-to-severe COPD . METHODS FLIGHT1 and FLIGHT2 were 12-week , identical , multicenter , r and omized , double-blind , parallel-group , placebo- and active-controlled studies . Patients were r and omized ( 1:1:1:1 ) to indacaterol/glycopyrrolate ( 27.5/15.6 μg twice daily ) , indacaterol ( 27.5 μg twice daily ) , glycopyrrolate ( 15.6 μg twice daily ) , or placebo , all delivered via the Neohaler device . The primary objective was to demonstrate the superiority of indacaterol/glycopyrrolate versus its monocomponents for st and ardized area under the curve from 0 - 12 hours for FEV1 at Week 12 . Secondary objectives included St. George 's Respiratory Question naire total score and transition dyspnea index total score and reduction in daily rescue medication use with indacaterol/glycopyrrolate versus placebo . MEASUREMENTS AND MAIN RESULTS In total , 2,038 patients were included in the pooled analysis . Indacaterol/glycopyrrolate was statistically superior in terms of FEV1 area under the curve from 0 - 12 hours compared with its monocomponents ( P < 0.001 ) . Statistically and clinical ly meaningful improvements in St. George 's Respiratory Question naire total score , transition dyspnea index total score , and reduction in rescue medication use were observed with indacaterol/glycopyrrolate compared with placebo ( P < 0.001 ) . The safety profile was comparable across the treatment groups . CONCLUSIONS Indacaterol/glycopyrrolate twice daily can be an alternative treatment option for the management of symptomatic patients with moderate-to-severe COPD . Clinical trial registered with www . clinical trials.gov ( NCT 01727141 and NCT 0171251 ) BACKGROUND Tiotropium , a once-daily anticholinergic , and salmeterol represent two inhaled , long-acting bronchodilators from different pharmacologic classes . A trial was design ed to examine the efficacy and safety of both compounds with multiple outcome measures , including lung function , dyspnea , and health-related quality of life ( HRQoL ) in patients with COPD . METHODS A 6-month , r and omized , placebo-controlled , double-blind , double-dummy , parallel-group study of tiotropium , 18 microg once daily via dry-powder inhaler , compared with salmeterol , 50 microg bid via metered-dose inhaler , was conducted in patients with COPD .  Efficacy was assessed by 12-h monitoring of spirometry , transition dyspnea index ( TDI ) , and the St. George 's Respiratory Question naire ( SGRQ ) . RESULTS A total of 623 patients participated ( tiotropium , n= 209 ; salmeterol , n = 213 ; and  placebo , n = 201 ) . The groups were similar in age ( mean , 65 years ) , gender ( 75 % men ) , and baseline FEV(1 ) ( mean , 1.08 + /- 0.37 L ; percent predicted , 40 + /- 12 % [ + /- SD ] ) . Compared with placebo treatment , the mean predose morning FEV(1 ) following 6 months of therapy increased significantly more for the tiotropium group ( 0.14 L ) than the salmeterol group ( 0.09 L ; p < 0.01 ) . The average FEV(1 ) ( 0 to 12 h ) for tiotropium was statistically superior to salmeterol ( difference , 0.08 L ; p < 0.001 ) . Tiotropium improved TDI focal score by 1.02 U compared with placebo ( p = 0.01 ) , whereas there was no significant change in TDI focal score with salmeterol ( 0.24 U ) . Tiotropium was superior to salmeterol in improving TDI focal score ( p < 0.05 ) . At 6 months , the mean improvement in SGRQ total score vs baseline was tiotropium , - 5.14 U ( p < 0.05 vs placebo ) ; salmeterol , - 3.54 U ( p = 0.4 vs placebo ) ; and placebo , - 2.43 U. A statistically higher proportion of patients receiving tiotropium achieved at least a 4-U change in SGRQ score compared to patients receiving placebo . Both active drugs reduced the need for rescue albuterol ( p < 0.0001 ) . CONCLUSIONS Tiotropium once daily produces superior bronchodilation , improvements in dyspnea , and proportion of patients achieving meaningful changes in HRQoL compared to twice-daily salmeterol in patients with COPD Objective : Exercise intolerance is a hallmark of chronic obstructive pulmonary disease ( COPD ) . Methods : Patients with COPD were r and omized in two multicentre , double-blind , incomplete block crossover studies . Patients received two of six treatments in sequence ( 12 weeks each ) : placebo , umeclidinium (UMEC)/vilanterol ( VI ) ( 125/25 mcg or 62.5/25 mcg ) , VI ( 25 mcg ) or UMEC ( 62.5 mcg or 125 mcg ) . Exercise endurance time ( EET ) and trough forced expiratory volume in 1 second ( FEV1 ) ( Week 12 ) were co- primary endpoints . Safety was monitored throughout . Results : Both studies showed similar 3-hour post-dose EET improvements from baseline for UMEC/VI ( Week 12 ) . Significant EET improvements were observed with both UMEC/VI doses versus placebo at Week 12 in Study 418 ( UMEC/VI 125/25 mcg : 65.8 s ; p = 0.005 ; UMEC/VI 62.5/25 mcg : 69.4 s ; p = 0.003 ) , but not in Study 417 , where a placebo effect was evident . Post hoc integrated data analysis showed significant but smaller EET improvements for both UMEC/VI doses versus placebo at Week 12 ( UMEC/VI 125/25 mcg : 47.5 s ; p = 0.002 ; UMEC/VI 62.5/25 mcg : 43.7 s ; p = 0.001 ) . Both studies showed trough FEV1 improvements at Week 12 for both UMEC/VI doses . The incidence of adverse events was similar between treatment groups within each study . Conclusions : UMEC/VI improved lung function and EET BACKGROUND AND OBJECTIVE Combining a long-acting muscarinic antagonist with a long-acting β₂-agonist has been shown to be pharmacologically useful in patients with chronic obstructive pulmonary disease ( COPD ) . The aim of the present study was to evaluate the effectiveness of the dual bronchodilator therapy on airway dimensions in COPD . METHODS Patients ( n = 54 ) were r and omly assigned to receive tiotropium ( 18 μg once daily ) , indacaterol ( 150 μg once daily ) or tiotropium plus indacaterol for 16 weeks . Quantitative computed tomography ( CT ) , pulmonary function and health status ( St. George 's Respiratory Question naire ) were measured . RESULTS Compared with tiotropium or indacaterol alone , combination therapy result ed in a significant decrease in percentage wall area ( WA% ) and wall thickness , corrected for body surface area , and an increase in luminal area ( Ai/BSA ) . Concurrent treatment was superior to monotherapy in physiological indices , including forced vital capacity , forced expiratory volume in 1 s ( FEV₁ ) and inspiratory capacity . The changes in WA% and Ai/BSA were significantly correlated with changes in FEV₁ ( r = -0.44 , P < 0.01 and r = 0.37 , P < 0.01 ) . There were more significant improvements in SGRQ scores after treatment with combined therapy than with either treatment alone . CONCLUSIONS Concurrent therapy with tiotropium and indacaterol is effective for COPD patients to promote reduction in airway wall thickness , bronchodilation , and improvements in lung function compared with a single inhaler BACKGROUND Cardiovascular comorbidities are common in chronic obstructive pulmonary disease ( COPD ) , and elevated heart rate reflects increased cardiovascular risk over time , which is associated with unfavourable neurohumoral activation . Long-acting β2-agonists ( LABAs ) are established treatments in COPD , but potentially increase heart rate . We report a post hoc pooled analysis of the effect of olo date rol ( 5 or 10 μg ) or formoterol ( 12 μg ) on heart rate and blood pressure ( BP ) in Global Initiative for Chronic Obstructive Lung Disease Stage 2 - 4 COPD patients . METHODS Four r and omised , double-blind , placebo-controlled , Phase III studies were analysed . Changes in heart rate and systolic/diastolic BP were measured before and after dosing with the study medication at each visit . RESULTS At each study visit , the increase in pre-dose heart rate was numerically lower with both LABAs compared with placebo . Systolic and diastolic BP were decreased with all treatments . Short-term ( pre-dose to 40 min post-dose ) effects of drug administration on heart rate were small and similar for all treatment arms ( between -3 and + 1 beats per minute ) . CONCLUSION Heart rate and BP were not adversely influenced in this study involving long-term administration of olo date rol or formoterol in patients with moderate-to-severe COPD . This supports the cardiovascular safety of LABAs in COPD maintenance treatment Background COPD is a major global cause of mortality and morbidity . PINNACLE-4 evaluated the efficacy and safety of GFF MDI ( glycopyrrolate/formoterol fumarate metered dose inhaler ) in patients from Asia , Europe , and the USA with moderate-to-very severe COPD . Methods In this double-blind , placebo-controlled , Phase III study , patients were r and omized to treatment with GFF MDI 18/9.6 μg , glycopyrrolate ( GP ) MDI 18 μg , formoterol fumarate ( FF ) MDI 9.6 μg , or placebo MDI ( all twice daily ) for 24 weeks . Lung function , patient-reported outcomes ( symptoms and health-related quality of life ) , and safety were assessed . Results Of the 1,756 patients r and omized , 1,740 patients were included in the intent-to-treat population ( mean age 64.2 years , 74.1 % male , and 40.2 % Asian ) .  GFF MDI significantly improved morning predose trough FEV1 at Week 24 ( primary endpoint ) vs placebo MDI , GP MDI , and FF MDI ( least squares mean differences : 165 , 59 , and 72 mL , respectively ; all P<0.0001 ) . GFF MDI also significantly improved other lung function endpoints vs placebo MDI , GP MDI , and FF MDI and patient-reported outcomes vs placebo MDI and GP MDI . A larger proportion of patients treated with GFF MDI achieved the minimum clinical ly important difference in Transition Dyspnea Index score vs GP MDI and placebo MDI and in St George ’s Respiratory Question naire score vs placebo MDI . Adverse event rates were similar across treatment groups . Conclusion These results demonstrated the efficacy of GFF MDI  in patients with moderate-to-very severe COPD . GFF MDI was well tolerated , with a safety profile commensurate with long-acting bronchodilators 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 Chronic obstructive pulmonary disease ( COPD ) is one of the leading causes of death in the United States . Long-acting muscarinic antagonists ( LAMAs ) are a class of medications used as maintenance therapy for COPD . The GEM3 ( Glycopyrrolate Effect on syMptoms and lung function ) study assessed the long-term safety and efficacy of a LAMA , glycopyrrolate ( GLY ) 15.6 μg twice daily ( b.i.d . ) , compared with an approved long-acting β2-agonist ( LABA ) , indacaterol ( IND ) 75 μg once daily ( q.d . ) in patients with stable , symptomatic COPD with moderate-to-severe airflow limitation . METHODS This 52-week , multicenter , double-blind , parallel-group study r and omized patients ( 1:1 ) of the United States to receive GLY 15.6 μg b.i.d . or IND 75 μg q.d . both delivered via the Neohaler ( ® ) device . The primary objective was to assess the safety and tolerability in terms of adverse event ( AE ) reporting rates over 52 weeks . Safety was also determined by evaluating multiple secondary endpoints , including vital signs , electrocardiograms ( ECGs ) , and time to first moderate or severe exacerbation . Efficacy-related secondary endpoints included pre-dose forced expiratory volume in one second ( FEV1 ) and forced vital capacity ( FVC ) . RESULTS Of the 511 r and omized patients ( GLY , n = 254 ; IND , n = 257 ) , 81.6 % completed the study . The overall incidences of AEs ( GLY , 77.3 % ; IND , 77.0 % ) and serious AEs ( GLY , 13.1 % ; IND , 13.3 % ) were comparable between the groups . The incidence of major adverse cardiovascular events was low and comparable between the groups . No clinical ly relevant differences for vital signs or ECG parameters were observed between the treatment groups . The three sudden deaths reported within 30 days of the treatment ( GLY , n = 2 ; IND , n = 1 ) were adjudicated as unrelated to the study medication . In terms of efficacy , GLY 15.6 μg b.i.d . showed improvements in pre-dose FEV1 and FVC from baseline , which was comparable to those with IND 75 μg q.d . , with no statistically significant differences . No significant differences were observed between the treatment groups in the time to first moderate or severe COPD exacerbation . CONCLUSION GLY 15.6 μg b.i.d . showed a long-term safety profile comparable to that of IND 75 μg q.d . and provided rapid and sustained bronchodilation over 52 weeks in patients with COPD with moderate-to-severe airflow limitation . CLINICAL TRIAL REGISTRATION NUMBER NCT01697696 BACKGROUND Treatment guidelines recommend the use of inhaled long-acting bronchodilators to alleviate symptoms and reduce the risk of exacerbations in patients with moderate-to-very-severe chronic obstructive pulmonary disease ( COPD ) but do not specify whether a long-acting anticholinergic drug or a β(2)-agonist is the preferred agent . We investigated whether the anticholinergic drug tiotropium is superior to the β(2)-agonist salmeterol in preventing exacerbations of COPD . METHODS In a 1-year , r and omized , double-blind , double-dummy , parallel-group trial , we compared the effect of treatment with 18 μg of tiotropium once daily with that of 50 μg of salmeterol twice daily on the incidence of moderate or severe exacerbations in patients with moderate-to-very-severe COPD and a history of exacerbations in the preceding year . RESULTS A total of 7376 patients were r and omly assigned to and treated with tiotropium ( 3707 patients ) or salmeterol ( 3669 patients ) . Tiotropium , as compared with salmeterol , increased the time to the first exacerbation ( 187 days vs. 145 days ) , with a 17 % reduction in risk ( hazard ratio , 0.83 ; 95 % confidence interval [ CI ] , 0.77 to 0.90 ; P<0.001 ) . Tiotropium also increased the time to the first severe exacerbation ( hazard ratio , 0.72 ; 95 % CI , 0.61 to 0.85 ; P<0.001 ) , reduced the annual number of moderate or severe exacerbations ( 0.64 vs. 0.72 ; rate ratio , 0.89 ; 95 % CI , 0.83 to 0.96 ; P=0.002 ) , and reduced the annual number of severe exacerbations ( 0.09 vs. 0.13 ; rate ratio , 0.73 ; 95 % CI , 0.66 to 0.82 ; P<0.001 ) . Overall , the incidence of serious adverse events and of adverse events leading to the discontinuation of treatment was similar in the two study groups . There were 64 deaths ( 1.7 % ) in the tiotropium group and 78 ( 2.1 % ) in the salmeterol group . CONCLUSIONS These results show that , in patients with moderate-to-very-severe COPD  , tiotropium is more effective than salmeterol in preventing exacerbations . ( Funded by Boehringer Ingelheim and Pfizer ; Clinical Trials.gov number , NCT00563381 . )
Inhaled bronchodilators including long-acting beta-agonist ( LABA ) and long-acting muscarinic antagonist ( LAMA ) play a central role in the treatment of stable chronic obstructive pulmonary disease ( COPD ) .
However , it is still unclear whether LABA or LAMA should be used for the initial treatment .
Therefore , we conducted a systematic review and meta- analysis to evaluate the efficacy and safety of LABA versus LAMA in patients with stable COPD .