human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 
    Output:
    
agent
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 
    Output:
    