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 combination of the inhaled muscarinic antagonist umeclidinium ( UMEC ) with the long-acting β2-agonist vilanterol ( VI ) has been shown to provide significant improvements in lung function compared with UMEC , VI , or placebo ( PBO ) in patients with chronic obstructive pulmonary disease ( COPD ) . This study was specifically design ed to support these findings by assessing health-related quality of life and symptomatic outcomes in a similar population . Methods This was a 12-week multicenter , r and omized , double-blind , parallel-group , placebo-controlled study . Eligible patients were r and omized 1:1 to receive once-daily UMEC/VI 62.5/25 μg ( via ELLIPTA ® dry powder inhaler ) or PBO for 12 weeks . The primary endpoint was St George ’s Respiratory Question naire ( SGRQ ) total score at day 84 . Secondary efficacy endpoints included rescue albuterol use ( puffs/day ) over weeks 1–12 and trough forced expiratory volume in 1 second on day 84 . Adverse events were also assessed . Results A total of 496 patients were included in the intent-to-treat population in the UMEC/VI ( n=248 ) and PBO ( n=248 ) treatment groups . UMEC/VI 62.5/25 μg provided a significant and clinical ly meaningful improvement in SGRQ total score at day 84 versus PBO ( difference between treatments in SGRQ total score change from baseline : −4.03 [ 95 % confidence interval { CI } : −6.28 , −1.79 ] ; P<0.001 ) . UMEC/VI 62.5/25 μg result ed in a statistically significant reduction in rescue albuterol use versus PBO ( −0.7 puffs/day [ 95 % CI : −1.1 , −0.4 ] ; P<0.001 ) . UMEC/VI 62.5/25 μg provided a significant and clinical ly meaningful improvement in trough forced expiratory volume in 1 second on day 84 versus PBO ( 122 mL [ 95 % CI : 71 , 172 ] ; P<0.001 ) . The incidence of adverse events was similar between treatments ( 32 % and 30 % of patients in the UMEC/VI 62.5/25 μg and PBO groups , respectively ) . Conclusion The results of this study demonstrate that treatment with UMEC/VI 62.5/25 μg provides clinical ly important improvements in SGRQ and rescue medication use  versus PBO in patients with moderate-to-very-severe COPD BACKGROUND Previous studies showing that tiotropium improves multiple end points in patients with chronic obstructive pulmonary disease ( COPD ) led us to examine the long-term effects of tiotropium therapy . METHODS In this r and omized , double-blind trial , we compared 4 years of therapy with either tiotropium or placebo in patients with COPD who were permitted to use all respiratory medications except inhaled anticholinergic drugs . The patients were at least 40 years of age , with a forced expiratory volume in 1 second ( FEV(1 ) ) of 70 % or less after bronchodilation and a ratio of FEV(1 ) to forced vital capacity ( FVC ) of 70 % or less . Co primary end points were the rate of decline in the mean FEV(1 ) before and after bronchodilation beginning on day 30 . Secondary end points included measures of FVC , changes in response on St. George 's Respiratory Question naire ( SGRQ ) , exacerbations of COPD , and mortality . RESULTS Of a total of 5993 patients ( mean age , 65+/-8 years ) with a mean FEV(1 ) of 1.32+/-0.44 liters after bronchodilation ( 48 % of predicted value ) , we r and omly assigned 2987 to the tiotropium group and 3006 to the placebo group . Mean absolute improvements in FEV(1 ) in the tiotropium group were maintained throughout the trial ( ranging from 87 to 103 ml before bronchodilation and from 47 to 65 ml after bronchodilation ) , as compared with the placebo group ( P<0.001 ) . After day 30 , the differences between the two groups in the rate of decline in the mean FEV(1 ) before and after bronchodilation were not significant . The mean absolute total score on the SGRQ was improved ( lower ) in the tiotropium group , as compared with the placebo group , at each time point throughout the 4-year period ( ranging from 2.3 to 3.3 units , P<0.001 ) . At 4 years and 30 days , tiotropium was associated with a reduction in the risks of exacerbations , related hospitalizations , and respiratory failure . CONCLUSIONS In patients with COPD , therapy with tiotropium was associated with improvements in lung function , quality of life , and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV(1 ) . ( Clinical Trials.gov number , NCT00144339 . Introduction Chronic obstructive pulmonary disease ( COPD ) is associated with exercise limitation and physical inactivity , which are believed to have significant long-term negative health consequences for patients . While a number of COPD treatments and exercise training programmes increase exercise capacity , there is limited evidence for their effects on physical activity levels , with no clear association between exercise capacity and physical activity in clinical trials . Physical activity depends on a number of behaviour , environmental and physiological factors . We describe the design of the PHYSACTO trial , which is investigating the effects of bronchodilators , either alone or with exercise training , in combination with a st and ardised behaviour-change self-management programme , on exercise capacity and physical activity in patients with COPD . It is hypothesised that bronchodilators in conjunction with a behaviour-change self-management programme will improve physical activity and that this effect will be amplified by the addition of exercise training . Methods and analysis Patients are being recruited from 34 sites in Australia , New Zeal and , the USA , Canada and Europe . Patients receiving a multicomponent intervention design ed to support behaviour change related to physical activity are r and omised to four treatment arms : placebo , tiotropium , tiotropium+olo date rol , and tiotropium+olo date rol+exercise training . The primary outcome is improvement in exercise capacity after 8 weeks , measured by endurance time during a shuttle walk test . The secondary outcome is improvement in physical activity , including objective accelerometer assessment and patient-reported functioning using the Functional Performance Inventory — Short Form and the novel hybrid PROactive instrument . Additionally , the influence of moderating variables ( ie , factors influencing a patient 's choice to be physically active ) on increases in physical activity is also explored . Ethics and dissemination The study has been approved by the relevant Institutional Review Boards , Independent Ethics Committee and Competent Authority according to national and international regulations . The findings of the trial will be disseminated through relevant peer- review ed journals and international conference presentations . Trial registration number NCT02085161 Introduction The once-daily long-acting muscarinic antagonist ( LAMA ) tiotropium and once-daily long-acting β2-agonist ( LABA ) olo date rol have been studied as a once-daily fixed-dose combination ( FDC ) in patients with chronic obstructive pulmonary disease ( COPD ) . Two large , 52-week , double-blind , parallel-group studies in patients with moderate – very severe COPD demonstrated that tiotropium + olo date rol significantly improved lung function and symptoms versus the monocomponents . This post hoc analysis determined effects on lung function by prior LAMA or LABA maintenance treatment and initial disease severity . Methods 5162 patients were r and omized and treated with olo date rol 5 µg , tiotropium 2.5 µg , tiotropium 5 µg , tiotropium + olo date rol 2.5/5 µg , or tiotropium + olo date rol 5/5 µg ( all once daily via Respimat ® inhaler ) . Primary efficacy ( lung-function ) end points were forced expiratory volume in 1 s ( FEV1 ) area under the curve from 0 to 3 h ( AUC0–3 ) and trough FEV1 responses ( i.e. , change from baseline ) . Pooled data are presented for the following subgroups : prior maintenance treatment with LAMA or LABA , Global initiative for chronic Obstructive Lung Disease ( GOLD ) 2 ( predicted FEV1 50 % to < 80 % ) and 3 ( 30 % to < 50%)/4 ( < 30 % ) , sex , age , and prior use of inhaled corticosteroids . Results Tiotropium + olo date rol FDC improved lung function over the monocomponents in patients with GOLD 2 and 3–4 disease , irrespective of prior LAMA or LABA maintenance therapy ; most comparisons between FDCs and their respective monocomponents were statistically significant ( P < 0.05 ) . FEV1 AUC0–3 and trough FEV1 responses for the individual treatments were generally greater in patients with less severe COPD at baseline . Conclusions Tiotropium + olo date rol 5/5 µg  significantly improved FEV1 AUC0–3 and trough FEV1 in all GOLD severity groups compared to olo date rol 5 µg and tiotropium 5 µg alone , irrespective of whether patients had received prior LAMA or LABA maintenance treatment . Improvements from baseline in lung function were generally greater in patients with less severe disease . Funding Boehringer Ingelheim . Trial registration : Clinical Trials.gov numbers , NCT01431274 and NCT01431287 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 Clin 
    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 combination of the inhaled muscarinic antagonist umeclidinium ( UMEC ) with the long-acting β2-agonist vilanterol ( VI ) has been shown to provide significant improvements in lung function compared with UMEC , VI , or placebo ( PBO ) in patients with chronic obstructive pulmonary disease ( COPD ) . This study was specifically design ed to support these findings by assessing health-related quality of life and symptomatic outcomes in a similar population . Methods This was a 12-week multicenter , r and omized , double-blind , parallel-group , placebo-controlled study . Eligible patients were r and omized 1:1 to receive once-daily UMEC/VI 62.5/25 μg ( via ELLIPTA ® dry powder inhaler ) or PBO for 12 weeks . The primary endpoint was St George ’s Respiratory Question naire ( SGRQ ) total score at day 84 . Secondary efficacy endpoints included rescue albuterol use ( puffs/day ) over weeks 1–12 and trough forced expiratory volume in 1 second on day 84 . Adverse events were also assessed . Results A total of 496 patients were included in the intent-to-treat population in the UMEC/VI ( n=248 ) and PBO ( n=248 ) treatment groups . UMEC/VI 62.5/25 μg provided a significant and clinical ly meaningful improvement in SGRQ total score at day 84 versus PBO ( difference between treatments in SGRQ total score change from baseline : −4.03 [ 95 % confidence interval { CI } : −6.28 , −1.79 ] ; P<0.001 ) . UMEC/VI 62.5/25 μg result ed in a statistically significant reduction in rescue albuterol use versus PBO ( −0.7 puffs/day [ 95 % CI : −1.1 , −0.4 ] ; P<0.001 ) . UMEC/VI 62.5/25 μg provided a significant and clinical ly meaningful improvement in trough forced expiratory volume in 1 second on day 84 versus PBO ( 122 mL [ 95 % CI : 71 , 172 ] ; P<0.001 ) . The incidence of adverse events was similar between treatments ( 32 % and 30 % of patients in the UMEC/VI 62.5/25 μg and PBO groups , respectively ) . Conclusion The results of this study demonstrate that treatment with UMEC/VI 62.5/25 μg provides clinical ly important improvements in SGRQ and rescue medication use  versus PBO in patients with moderate-to-very-severe COPD BACKGROUND Previous studies showing that tiotropium improves multiple end points in patients with chronic obstructive pulmonary disease ( COPD ) led us to examine the long-term effects of tiotropium therapy . METHODS In this r and omized , double-blind trial , we compared 4 years of therapy with either tiotropium or placebo in patients with COPD who were permitted to use all respiratory medications except inhaled anticholinergic drugs . The patients were at least 40 years of age , with a forced expiratory volume in 1 second ( FEV(1 ) ) of 70 % or less after bronchodilation and a ratio of FEV(1 ) to forced vital capacity ( FVC ) of 70 % or less . Co primary end points were the rate of decline in the mean FEV(1 ) before and after bronchodilation beginning on day 30 . Secondary end points included measures of FVC , changes in response on St. George 's Respiratory Question naire ( SGRQ ) , exacerbations of COPD , and mortality . RESULTS Of a total of 5993 patients ( mean age , 65+/-8 years ) with a mean FEV(1 ) of 1.32+/-0.44 liters after bronchodilation ( 48 % of predicted value ) , we r and omly assigned 2987 to the tiotropium group and 3006 to the placebo group . Mean absolute improvements in FEV(1 ) in the tiotropium group were maintained throughout the trial ( ranging from 87 to 103 ml before bronchodilation and from 47 to 65 ml after bronchodilation ) , as compared with the placebo group ( P<0.001 ) . After day 30 , the differences between the two groups in the rate of decline in the mean FEV(1 ) before and after bronchodilation were not significant . The mean absolute total score on the SGRQ was improved ( lower ) in the tiotropium group , as compared with the placebo group , at each time point throughout the 4-year period ( ranging from 2.3 to 3.3 units , P<0.001 ) . At 4 years and 30 days , tiotropium was associated with a reduction in the risks of exacerbations , related hospitalizations , and respiratory failure . CONCLUSIONS In patients with COPD , therapy with tiotropium was associated with improvements in lung function , quality of life , and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV(1 ) . ( Clinical Trials.gov number , NCT00144339 . Introduction Chronic obstructive pulmonary disease ( COPD ) is associated with exercise limitation and physical inactivity , which are believed to have significant long-term negative health consequences for patients . While a number of COPD treatments and exercise training programmes increase exercise capacity , there is limited evidence for their effects on physical activity levels , with no clear association between exercise capacity and physical activity in clinical trials . Physical activity depends on a number of behaviour , environmental and physiological factors . We describe the design of the PHYSACTO trial , which is investigating the effects of bronchodilators , either alone or with exercise training , in combination with a st and ardised behaviour-change self-management programme , on exercise capacity and physical activity in patients with COPD . It is hypothesised that bronchodilators in conjunction with a behaviour-change self-management programme will improve physical activity and that this effect will be amplified by the addition of exercise training . Methods and analysis Patients are being recruited from 34 sites in Australia , New Zeal and , the USA , Canada and Europe . Patients receiving a multicomponent intervention design ed to support behaviour change related to physical activity are r and omised to four treatment arms : placebo , tiotropium , tiotropium+olo date rol , and tiotropium+olo date rol+exercise training . The primary outcome is improvement in exercise capacity after 8 weeks , measured by endurance time during a shuttle walk test . The secondary outcome is improvement in physical activity , including objective accelerometer assessment and patient-reported functioning using the Functional Performance Inventory — Short Form and the novel hybrid PROactive instrument . Additionally , the influence of moderating variables ( ie , factors influencing a patient 's choice to be physically active ) on increases in physical activity is also explored . Ethics and dissemination The study has been approved by the relevant Institutional Review Boards , Independent Ethics Committee and Competent Authority according to national and international regulations . The findings of the trial will be disseminated through relevant peer- review ed journals and international conference presentations . Trial registration number NCT02085161 Introduction The once-daily long-acting muscarinic antagonist ( LAMA ) tiotropium and once-daily long-acting β2-agonist ( LABA ) olo date rol have been studied as a once-daily fixed-dose combination ( FDC ) in patients with chronic obstructive pulmonary disease ( COPD ) . Two large , 52-week , double-blind , parallel-group studies in patients with moderate – very severe COPD demonstrated that tiotropium + olo date rol significantly improved lung function and symptoms versus the monocomponents . This post hoc analysis determined effects on lung function by prior LAMA or LABA maintenance treatment and initial disease severity . Methods 5162 patients were r and omized and treated with olo date rol 5 µg , tiotropium 2.5 µg , tiotropium 5 µg , tiotropium + olo date rol 2.5/5 µg , or tiotropium + olo date rol 5/5 µg ( all once daily via Respimat ® inhaler ) . Primary efficacy ( lung-function ) end points were forced expiratory volume in 1 s ( FEV1 ) area under the curve from 0 to 3 h ( AUC0–3 ) and trough FEV1 responses ( i.e. , change from baseline ) . Pooled data are presented for the following subgroups : prior maintenance treatment with LAMA or LABA , Global initiative for chronic Obstructive Lung Disease ( GOLD ) 2 ( predicted FEV1 50 % to < 80 % ) and 3 ( 30 % to < 50%)/4 ( < 30 % ) , sex , age , and prior use of inhaled corticosteroids . Results Tiotropium + olo date rol FDC improved lung function over the monocomponents in patients with GOLD 2 and 3–4 disease , irrespective of prior LAMA or LABA maintenance therapy ; most comparisons between FDCs and their respective monocomponents were statistically significant ( P < 0.05 ) . FEV1 AUC0–3 and trough FEV1 responses for the individual treatments were generally greater in patients with less severe COPD at baseline . Conclusions Tiotropium + olo date rol 5/5 µg  significantly improved FEV1 AUC0–3 and trough FEV1 in all GOLD severity groups compared to olo date rol 5 µg and tiotropium 5 µg alone , irrespective of whether patients had received prior LAMA or LABA maintenance treatment . Improvements from baseline in lung function were generally greater in patients with less severe disease . Funding Boehringer Ingelheim . Trial registration : Clinical Trials.gov numbers , NCT01431274 and NCT01431287 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 Clin 
    Output:
    