Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study Tiotropium in patients with moderate COPD naive to maintenance therapy: a randomised placebo-controlled trial The effect of tiotropium on exacerbations and airflow in patients with COPD. Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: the 24-week, randomized, placebo-controlled AUGMENT COPD study Outcomes in COPD patients receiving tiotropium or salmeterol plus treatment with inhaled corticosteroids Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD 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 tiotropium on health-related quality of life as a primary efficacy endpoint in COPD Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2–4) Exacerbations in patients with chronic obstructive pulmonary disease receiving physical therapy: a cohort-nested randomised controlled trial A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease 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. Tolerance to bronchodilating effects of salmeterol in 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. A one-year trial of tiotropium Respimat plus usual therapy in COPD patients. A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol. 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.
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 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 This r and omised , double-blind , parallel-group , 1-yr study compared the effect of tiotropium 18 microg once daily ( n=500 ) and placebo  ( n=510 ) on exacerbations , associated health re source use ( HRU ) and  airflow limitation in chronic obstructive pulmonary disease ( COPD ) patients . The mean+/-sd number of exacerbations during the past year was 2.14+/-1.40 , the mean weekly morning peak expiratory flow ( PEF ) was 259.6+/-96.1 L.min-1 and the mean forced expiratory volume in one second ( FEV1 ) was 1.37+/-0.45 L. Tiotropium significantly delayed the time to first exacerbation by approximately 100 days , reduced the proportion of patients experiencing more than one exacerbation by 17 % , and decreased the number of exacerbations by 35 % and exacerbation days by 37 % versus placebo . Tiotropium also decreased HRU versus placebo , as indicated by the significant reductions in the use of concomitant respiratory medications , antibiotics and oral steroids , and the number of unscheduled physician contacts . Mean weekly morning PEF improved significantly with tiotropium versus placebo from week 1 until the end of the study . At the end of the study , tiotropium significantly improved trough ( pre-dose ) FEV1 , forced vital capacity , slow vital capacity and inspiratory capacity versus placebo . In conclusion , tiotropium reduced exacerbations and associated health re source use , and improved airflow over 1 yr in chronic obstructive pulmonary disease patients 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 Patients with COPD are frequently prescribed inhaled corticosteroids ( ICS ) ; however , it is unclear whether the treatment with ICS might modify responses to inhaled bronchodilators . Two 6-month , r and omized , placebo-controlled , double-blind , double-dummy , parallel-group studies of tiotropium 18 μg once daily , compared with salmeterol , 50 μg bid , had been conducted in patients with moderate-to-severe COPD . Efficacy was assessed by spirometry , transition dyspnea index ( TDI ) , St. George ’s Respiratory Question naire ( SGRQ ) , and exacerbations . Data from both studies were combined to form subgroups with regard to concurrent use of ICS .  796 patients receiving ICS were separately analyzed from 390 patients not receiving ICS . Mean age was 64 years , and pre-bronchodilator FEV1 was 1.06 L ( ICS group ) and 1.13 L ( non-ICS group ) . Both bronchodilators increased morning mean ± SE pre-dose FEV1 compared with placebo ( ICS groups : tiotropium 110 ± 20 mL , salmeterol 80 ± 20 mL ; non-ICS groups : tiotropium 150 ± 30 mL , salmeterol 110 ± 30 mL ; p > 0.05 for tiotropium vs salmeterol ) . Improvements in TDI and SGRQ and frequency of exacerbations also tended to be more profound for tiotropium . Treatment with tiotropium in patients with moderate-to-severe COPD was superior to salmeterol in lung function , irrespective of concurrent use of ICS Chronic obstructive pulmonary disease ( COPD ) patients experiencing frequent exacerbations demonstrate increased stable-state airway inflammation . Tiotropium has been shown to reduce exacerbation frequency , but its effect on airway inflammation is unknown . The aim of the present study was to investigate the effect of tiotropium on sputum inflammatory markers and exacerbation frequency .  Patients ( n = 142 ) were r and omised to receive tiotropium or placebo in addition to their usual medication for 1 yr . Sputum and serum cytokines were assayed by ELISA and exacerbation frequency calculated using a symptom-based diary . There was no difference in the area under the curve for sputum interleukin (IL)-6 or myeloperoxidase between the groups , but sputum IL-8 level was increased in the tiotropium arm . There was no difference between start and end of study in serum IL-6 or C-reactive protein level .  Tiotropium was associated with a 52 % reduction in exacerbation frequency ( 1.17 versus 2.46 exacerbations·yr−1 ) . Of patients on tiotropium , 43 % experienced at least one exacerbation , compared with 64 % on placebo  . The total number of exacerbation days was reduced compared with placebo ( 17.3 versus 34.5 days ) . Tiotropium  reduces exacerbation frequency in chronic obstructive pulmonary disease , but this effect does not appear to be due to a reduction in airway or systemic inflammation 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 Clinical manifestations of chronic obstructive pulmonary disease ( COPD ) , including airflow limitation , dyspnea , and activity limitation , ultimately lead to impaired health-related quality of life ( HRQoL ) . This 9-month , r and omized , double-blind , multicenter study compared the effect of once-daily tiotropium 18 μg and placebo on HRQoL , spirometric parameters , and exacerbations in 554 patients with moderate-to-severe COPD .  HRQoL was assessed using the St. George ’s Respiratory Question naire ( SGRQ ) and the new 8-item Visual Simplified Respiratory Question naire ( VSRQ ) , which is currently being vali date d. The primary efficacy endpoint was the proportion of patients achieving a reduction of at least 4 units in the SGRQ total score at study end ( Month 9 ) . Mean ± SD baseline SGRQ total score was 47.4 ± 18.1 . Significantly more tiotropium-treated patients achieved a reduction of at least 4 units in the SGRQ score  vs placebo at study end ( 59.1 % vs 48.2 % , respectively ;  p = 0.029 ) . Tiotropium  significantly improved spirometric parameters ( forced expiratory volume in 1 second [ FEV1 ] : 0.11 ± 0.02 L vs 0.01 ± 0.02 L ; between-group difference : 0.10 ± 0.03 L , p = 0.0001 ) and reduced exacerbations vs placebo . Maintenance treatment with tiotropium provided significant and clinical ly relevant improvements in HRQoL , as measured by the SGRQ 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 Background Physical exercise training aims at reducing disease-specific impairments and improving quality of life in patients with chronic obstructive pulmonary disease ( COPD ) . COPD exacerbations in particular negatively impact COPD progression . Physical therapy intervention seems indicated to influence exacerbations and their consequences . However , information on the effect of physical therapy on exacerbation occurrence is scarce . This study aims to investigate the potential of a protocol -directed physical therapy programme as a means to prevent or postpone exacerbations , to shorten the duration or to decrease the severity of exacerbations in patients with COPD who have recently experienced an exacerbation . Besides , this study focuses on the effect of protocol -directed physical therapy on health status and quality of life and on cost-effectiveness and cost-utility in patients with COPD who have recently experienced an exacerbation . Methods / Design A prospect i ve cohort of 300 COPD patients in all GOLD stages will be constructed . Patients will receive usual multidisciplinary COPD care including guideline -directed physical therapy .  Patients in this cohort who have GOLD stage 2 to 4 ( post-bronchodilator FEV1/FVC < 0.7 and FEV1 < 80 % of predicted ) , who receive reimbursement by health insurance companies for physical therapy ( post-bronchodilator Tiffeneau-index < 0.6 ) and who experience a COPD exacerbation will be asked within 56 days to participate in a cohort-nested prospect i ve r and omised controlled trial ( RCT ) . In this RCT , the intervention group will receive a strict physical therapy programme for patients with COPD . This protocol -directed physical therapy ( pdPT ) will be compared to a control group that will receive sham-treatment , meaning no or very low-intensity exercise training ( ST ) . An economic evaluation will be embedded in the RCT . Anthropometric measurements , comorbidities , smoking , functional exercise capacity , peripheral muscle strength , physical activity level , health related quality of life , patients ’ perceived benefit , physical therapy compliance , motivation level , level of effective mucus clearance , exacerbation symptoms and health care contacts due to COPD will be recorded . Follow-up measurements are scheduled at 3 and 6 weeks , 3 , 6 , 12 and 24 months after inclusion . Discussion Ways to minimise potential problems regarding the execution of this study will be discussed . Trial registration The Netherl and s National Trial Register NTR1972 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 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 Loss of bronchodilator effectiveness or tolerance has been observed with inhaled beta-agonists but not with inhaled anticholinergic medications . Initially , tolerance is reflected in loss of bronchial protection against stimuli followed by loss of bronchodilator properties . However , generally such observations have been reported in asthma . A 6-month r and omized , double-dummy placebo-controlled trial comparing tiotropium to salmeterol provided the opportunity to examine spirometric tolerance to long-acting beta-agonists in patients with COPD .  Spirometry was measured over 12h at baseline and at days 15 , 57 , 116 and 169 . Changes over time from baseline were compared relative to changes observed with placebo .  A total of 623 patients participated ( tiotropium = 209 , salmeterol = 213 , placebo = 201 ) . The groups were similar in age ( mean = 65 years ) , gender ( 75 % men ) , and baseline FEV1 ( mean = 1.08 + /- 0.37l [ 40 + /- 12 % predicted ] ) . Relative to placebo , both active drugs improved morning pre-drug , peak and average FEV1 and FVC throughout the trial . However , from day 1 to 169 , salmeterol was associated with a higher decline in average FEV1 and FVC ( 0 - 12h ) ( difference from placebo : -36 and -115 ml , P < 0.05 ) , which was most prominent over the 8 - 12 h period ( difference from placebo : -45 and -138 ml , P < 0.01 ) . Significant declines in peak FVC relative to placebo ( -83 ml , P < 0.05 ) but not FEV1 ( -12ml ) were observed with salmeterol . Tiotropium was associated with further improvements in spirometry from days 1 to 15 and no evidence of tolerance from day 15 to the end of the trial . In conclusion , tolerance to pharmacologic bronchodilation occurs with long-acting beta-agonists such as salmeterol and not with inhaled anticholinergics 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 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 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 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 : A number of long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist ( LABA ) fixed-dose combinations ( FDCs ) for treatment of moderate-to-very severe chronic obstructive pulmonary disease ( COPD ) have recently become available , but none have been directly compared in head-to-head r and omized controlled trials ( RCTs ) .
The purpose of this study was to assess the relative clinical benefit of all currently available LAMA/LABA FDCs using a Bayesian network meta- analysis ( NMA ) .