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 Chronic obstructive pulmonary disease ( COPD ) often coexists with other chronic diseases and comorbidities that can markedly influence patients ' health status and prognosis . This is particularly true for cardiovascular disease ( CVD ) . However , there have been no trials assessing the effect of COPD medications on CVD in patients with both diseases . The “ Study to Underst and Mortality and Morbidity in COPD ” ( SUMMIT ) aims at determining the impact of fluticasone furoate/vilanterol combination and the individual components on the survival of patients with moderate COPD and either a history of CVD or at increased risk for CVD . SUMMIT is a multicentre , r and omised , double-blind , parallel-group , placebo-controlled trial of 16 000 patients with moderate COPD r and omly assigned to once daily treatment with fluticasone furoate/vilanterol ( 100/25 & mgr;g ) , fluticasone furoate ( 100 & mgr;g ) , vilanterol ( 25 & mgr;g ) or matched placebo ; mortality is the primary end-point . The study is an event-driven trial powered by the comparison of furoate/vilanterol versus placebo . Secondary end-points are decline in forced expiratory volume in 1 s and effect on a composite cardiovascular end-point . This article describes the design of the SUMMIT study Background : TORCH ( Towards a Revolution in COPD Health ) is an international multicentre , r and omised , placebo-controlled clinical trial of inhaled fluticasone propionate/salmeterol combination treatment and its monotherapy components for maintenance treatment of moderately to severely impaired patients with chronic obstructive pulmonary disease ( COPD ) . The primary outcome is all-cause mortality . Cause-specific mortality and deaths related to COPD are additional outcome measures , but systematic methods for ascertainment of these outcomes have not previously been described . Methods : A Clinical Endpoint Committee ( CEC ) was tasked with categorising the cause of death and the relationship of deaths to COPD in a systematic , unbiased and independent manner . The key elements of the operation of the committee were the use of predefined principles of operation and definitions of cause of death and COPD -relatedness ; the independent review of cases by all members with development of a consensus opinion ; and a substantial infrastructure to collect medical information . Results : 911 deaths were review ed and consensus was reached in all . Cause-specific mortality was : cardiovascular 27 % , respiratory 35 % , cancer 21 % , other 10 % and unknown 8 % . 40 % of deaths were definitely or probably related to COPD . Adjudications were identical in 83 % of blindly re-adjudicated cases ( κ = 0.80 ) . COPD -relatedness was reproduced 84 % of the time ( κ = 0.73 ) . The CEC adjudication was equivalent to the primary cause of death recorded by the site investigator in 52 % of cases . Conclusion : A CEC can provide st and ardised , reliable and informative adjudication of COPD mortality that provides information which frequently differs from data collected from assessment by site investigators BACKGROUND Effects of β(2)-adrenergic receptor gene ( ADRB2 ) polymorphism on therapeutic responses to long-acting β(2)-adrenergic agonists have not been evaluated in long-term COPD trials . We aim ed to investigate the effects of the ADRB2 Gly16Arg polymorphism on response to formoterol alone or in combination with the inhaled corticosteroid budesonide in patients with COPD . METHODS Patients ≥ 40 years of age with moderate to very severe COPD from the 12-month trial I ( NCT00206167 ) or the 6-month trial II ( NCT00206154 ) were r and omly assigned to bid budesonide/formoterol pressurized metered-dose inhaler ( pMDI ) 320/9 μg or 160/9 μg , budesonide pMDI 320 μg + formoterol dry powder inhaler 9 μg ( trial II ) , budesonide pMDI 320 μg ( trial II ) , formoterol dry powder inhaler 9 μg , or placebo . The effect of Gly16Arg on predose FEV(1 ) and 1-h postdose FEV(1 ) , exacerbations , diary variables , and adverse events were analyzed . RESULTS No significant interaction between genotype and treatment response was observed for predose ( P ≥ .197 ) or postdose FEV(1 ) ( P ≥ .125 ) in either pharmacogenetic study ( n = 2,866 ) . The number of COPD exacerbations per patient-treatment year was low and similar across genotypes for the active treatment groups ( both studies ) . Percentages of patients with adverse events were similar across Gly16Arg genotype groups for each treatment . CONCLUSION Therapeutic response and tolerability to long-term treatment with formoterol alone or in combination with budesonide was not modified by ADRB2 Gly16Arg genotype in two large independent pharmacogenetic studies in patients with moderate to very severe COPD UNLABELLED Indacaterol is a novel , inhaled , long-acting β(2)-agonist providing 24-h bronchodilation with once-daily ( o.d . ) dosing in patients with COPD . In this double-blind , incomplete block crossover study , patients with moderate-to-severe COPD were r and omised to receive three treatment cycles from : indacaterol 300 μg o.d . dosed PM or AM , salmeterol 50 μg twice daily or placebo , each for 14 days . Trough FEV(1 ) was measured 24 h after indacaterol , and 12 h after salmeterol . Ninety-six patients ( mean age : 64 years ; post-bronchodilator FEV(1 ) 57 % predicted , FEV(1)/FVC 55 % ) were r and omised ; 83 completed . After 14 days , the difference vs. placebo  in trough FEV(1 ) for PM indacaterol was 200 mL ( p < 0.001 [ primary analysis ] ) and for AM indacaterol was 200 mL ( p < 0.001 ) . Compared with salmeterol , trough FEV(1 ) for PM indacaterol was 110 mL higher ( p < 0.001 ) , and for AM indacaterol was 50 mL higher ( p = NS ) . Over 14 days , vs. placebo , both PM and AM indacaterol improved the % of nights with no awakenings ( by 11.9 and 8.1 points ; p < 0.01 ) ; the % of days with no daytime symptoms ( by 6.7 and 5.5 points ; p < 0.05 ) ; and the % of days able to perform usual activities ( by 6.7 and 7.8 points ; p < 0.05 ) . Indacaterol provided 24-h bronchodilation and improvement in symptoms regardless of whether taken regularly in the morning or evening . CLINICAL TRIAL REGISTRATION Clinical Trials.gov NCT00615030 Background Debate continues as to whether acute bronchodilator responsiveness ( BDR ) predicts long-term outcomes in COPD . Furthermore , there is no consensus on a threshold for BDR . Methods At baseline and during the 4-year Underst and ing Potential Long-term Improvements in Function with Tiotropium ( UPLIFT ® ) trial , patients had spirometry performed before and after administration of ipratropium bromide 80 mcg and albuterol 400 mcg . Patients were split according to three BDR thresholds : ≥12 % + ≥200 mL above baseline ( criterion A ) , ≥15 % above baseline ( criterion B ) ; and ≥10 % absolute increase in percent predicted FEV1 values ( criterion C ) . Several outcomes ( pre-dose spirometry , exacerbations , St. George 's Respiratory Question naire [ SGRQ ] total score ) were assessed according to presence or absence of BDR in the treatment groups . Results 5783 of 5993 r and omized patients had evaluable pre- and post-bronchodilator spirometry at baseline . Mean age ( SD ) was 64 ( 8) years , with 75 % men , mean post-bronchodilator FEV1 1.33 ± 0.44 L ( 47.6 ± 12.7 % predicted ) and 30 % current smokers . At baseline , 52 % , 66 % , and 39 % of patients had acute BDR using criterion A , B , and C , respectively . The presence of BDR was variable at follow-up visits . Statistically significant improvements in spirometry and health outcomes  occurred with tiotropium regardless of the baseline BDR or criterion used . Conclusions A large proportion of COPD patients  demonstrate significant acute BDR . BDR in these patients is variable over time and differs according to the criterion used . BDR status at baseline does not predict long-term response to tiotropium . Assessment of acute BDR should not be used as a decision-making tool when prescribing tiotropium to patients with COPD UPLIFT ( Underst and ing Potential Long-Term Improvements in Function with Tiotropium ) , a 4-yr trial of tiotropium in chronic obstructive pulmonary disease , allowed for assessment of smoking status on long-term responses to maintenance bronchodilator therapy . 5,993 patients were r and omised ( tiotropium/placebo )  .  Lung function , St George 's Respiratory Question naire , exacerbations and adverse events were followed . Patients were characterised as  continuing smokers ( CS ) , continuing ex-smokers ( CE ) , or intermittent smokers ( IS ) based on self-reporting smoking behaviour . 60 % , 14 % and 26 % of patients were CE , CS and IS , respectively . The rate of forced expiratory volume in 1 s ( FEV1 ) decline for placebo patients was most rapid in CS ( -51±4 , -36±2 and -23±2 mL·yr−1 in CS , IS , and CE , respectively ) . Tiotropium did not alter FEV1 decline , but was associated with significant improvements in pre- and post-bronchodilator FEV1  over placebo that persisted throughout the 4-yr trial for each smoking status ( pre-bronchodilator : 125 , 55 and 97 mL at 48 months in CS , IS and CE , respectively ; p≤0.0003 ) . Tiotropium  reduced exacerbation risk in CS ( HR ( 95%CI ) 0.81 ( 0.68–0.97 ) ) , in CE ( 0.86 ( 0.79–0.93 ) ) and trended towards significance in IS ( 0.89 ( 0.80–1.01 ) ) . At 4 yrs , St George ’s Respiratory Question naire for tiotropium patients improved the most in CS ( -4.62 units , p = 0.0006 ) and the least in IS ( -0.54 units , p = 0.55 ) , compared 
    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 Chronic obstructive pulmonary disease ( COPD ) often coexists with other chronic diseases and comorbidities that can markedly influence patients ' health status and prognosis . This is particularly true for cardiovascular disease ( CVD ) . However , there have been no trials assessing the effect of COPD medications on CVD in patients with both diseases . The “ Study to Underst and Mortality and Morbidity in COPD ” ( SUMMIT ) aims at determining the impact of fluticasone furoate/vilanterol combination and the individual components on the survival of patients with moderate COPD and either a history of CVD or at increased risk for CVD . SUMMIT is a multicentre , r and omised , double-blind , parallel-group , placebo-controlled trial of 16 000 patients with moderate COPD r and omly assigned to once daily treatment with fluticasone furoate/vilanterol ( 100/25 & mgr;g ) , fluticasone furoate ( 100 & mgr;g ) , vilanterol ( 25 & mgr;g ) or matched placebo ; mortality is the primary end-point . The study is an event-driven trial powered by the comparison of furoate/vilanterol versus placebo . Secondary end-points are decline in forced expiratory volume in 1 s and effect on a composite cardiovascular end-point . This article describes the design of the SUMMIT study Background : TORCH ( Towards a Revolution in COPD Health ) is an international multicentre , r and omised , placebo-controlled clinical trial of inhaled fluticasone propionate/salmeterol combination treatment and its monotherapy components for maintenance treatment of moderately to severely impaired patients with chronic obstructive pulmonary disease ( COPD ) . The primary outcome is all-cause mortality . Cause-specific mortality and deaths related to COPD are additional outcome measures , but systematic methods for ascertainment of these outcomes have not previously been described . Methods : A Clinical Endpoint Committee ( CEC ) was tasked with categorising the cause of death and the relationship of deaths to COPD in a systematic , unbiased and independent manner . The key elements of the operation of the committee were the use of predefined principles of operation and definitions of cause of death and COPD -relatedness ; the independent review of cases by all members with development of a consensus opinion ; and a substantial infrastructure to collect medical information . Results : 911 deaths were review ed and consensus was reached in all . Cause-specific mortality was : cardiovascular 27 % , respiratory 35 % , cancer 21 % , other 10 % and unknown 8 % . 40 % of deaths were definitely or probably related to COPD . Adjudications were identical in 83 % of blindly re-adjudicated cases ( κ = 0.80 ) . COPD -relatedness was reproduced 84 % of the time ( κ = 0.73 ) . The CEC adjudication was equivalent to the primary cause of death recorded by the site investigator in 52 % of cases . Conclusion : A CEC can provide st and ardised , reliable and informative adjudication of COPD mortality that provides information which frequently differs from data collected from assessment by site investigators BACKGROUND Effects of β(2)-adrenergic receptor gene ( ADRB2 ) polymorphism on therapeutic responses to long-acting β(2)-adrenergic agonists have not been evaluated in long-term COPD trials . We aim ed to investigate the effects of the ADRB2 Gly16Arg polymorphism on response to formoterol alone or in combination with the inhaled corticosteroid budesonide in patients with COPD . METHODS Patients ≥ 40 years of age with moderate to very severe COPD from the 12-month trial I ( NCT00206167 ) or the 6-month trial II ( NCT00206154 ) were r and omly assigned to bid budesonide/formoterol pressurized metered-dose inhaler ( pMDI ) 320/9 μg or 160/9 μg , budesonide pMDI 320 μg + formoterol dry powder inhaler 9 μg ( trial II ) , budesonide pMDI 320 μg ( trial II ) , formoterol dry powder inhaler 9 μg , or placebo . The effect of Gly16Arg on predose FEV(1 ) and 1-h postdose FEV(1 ) , exacerbations , diary variables , and adverse events were analyzed . RESULTS No significant interaction between genotype and treatment response was observed for predose ( P ≥ .197 ) or postdose FEV(1 ) ( P ≥ .125 ) in either pharmacogenetic study ( n = 2,866 ) . The number of COPD exacerbations per patient-treatment year was low and similar across genotypes for the active treatment groups ( both studies ) . Percentages of patients with adverse events were similar across Gly16Arg genotype groups for each treatment . CONCLUSION Therapeutic response and tolerability to long-term treatment with formoterol alone or in combination with budesonide was not modified by ADRB2 Gly16Arg genotype in two large independent pharmacogenetic studies in patients with moderate to very severe COPD UNLABELLED Indacaterol is a novel , inhaled , long-acting β(2)-agonist providing 24-h bronchodilation with once-daily ( o.d . ) dosing in patients with COPD . In this double-blind , incomplete block crossover study , patients with moderate-to-severe COPD were r and omised to receive three treatment cycles from : indacaterol 300 μg o.d . dosed PM or AM , salmeterol 50 μg twice daily or placebo , each for 14 days . Trough FEV(1 ) was measured 24 h after indacaterol , and 12 h after salmeterol . Ninety-six patients ( mean age : 64 years ; post-bronchodilator FEV(1 ) 57 % predicted , FEV(1)/FVC 55 % ) were r and omised ; 83 completed . After 14 days , the difference vs. placebo  in trough FEV(1 ) for PM indacaterol was 200 mL ( p < 0.001 [ primary analysis ] ) and for AM indacaterol was 200 mL ( p < 0.001 ) . Compared with salmeterol , trough FEV(1 ) for PM indacaterol was 110 mL higher ( p < 0.001 ) , and for AM indacaterol was 50 mL higher ( p = NS ) . Over 14 days , vs. placebo , both PM and AM indacaterol improved the % of nights with no awakenings ( by 11.9 and 8.1 points ; p < 0.01 ) ; the % of days with no daytime symptoms ( by 6.7 and 5.5 points ; p < 0.05 ) ; and the % of days able to perform usual activities ( by 6.7 and 7.8 points ; p < 0.05 ) . Indacaterol provided 24-h bronchodilation and improvement in symptoms regardless of whether taken regularly in the morning or evening . CLINICAL TRIAL REGISTRATION Clinical Trials.gov NCT00615030 Background Debate continues as to whether acute bronchodilator responsiveness ( BDR ) predicts long-term outcomes in COPD . Furthermore , there is no consensus on a threshold for BDR . Methods At baseline and during the 4-year Underst and ing Potential Long-term Improvements in Function with Tiotropium ( UPLIFT ® ) trial , patients had spirometry performed before and after administration of ipratropium bromide 80 mcg and albuterol 400 mcg . Patients were split according to three BDR thresholds : ≥12 % + ≥200 mL above baseline ( criterion A ) , ≥15 % above baseline ( criterion B ) ; and ≥10 % absolute increase in percent predicted FEV1 values ( criterion C ) . Several outcomes ( pre-dose spirometry , exacerbations , St. George 's Respiratory Question naire [ SGRQ ] total score ) were assessed according to presence or absence of BDR in the treatment groups . Results 5783 of 5993 r and omized patients had evaluable pre- and post-bronchodilator spirometry at baseline . Mean age ( SD ) was 64 ( 8) years , with 75 % men , mean post-bronchodilator FEV1 1.33 ± 0.44 L ( 47.6 ± 12.7 % predicted ) and 30 % current smokers . At baseline , 52 % , 66 % , and 39 % of patients had acute BDR using criterion A , B , and C , respectively . The presence of BDR was variable at follow-up visits . Statistically significant improvements in spirometry and health outcomes  occurred with tiotropium regardless of the baseline BDR or criterion used . Conclusions A large proportion of COPD patients  demonstrate significant acute BDR . BDR in these patients is variable over time and differs according to the criterion used . BDR status at baseline does not predict long-term response to tiotropium . Assessment of acute BDR should not be used as a decision-making tool when prescribing tiotropium to patients with COPD UPLIFT ( Underst and ing Potential Long-Term Improvements in Function with Tiotropium ) , a 4-yr trial of tiotropium in chronic obstructive pulmonary disease , allowed for assessment of smoking status on long-term responses to maintenance bronchodilator therapy . 5,993 patients were r and omised ( tiotropium/placebo )  .  Lung function , St George 's Respiratory Question naire , exacerbations and adverse events were followed . Patients were characterised as  continuing smokers ( CS ) , continuing ex-smokers ( CE ) , or intermittent smokers ( IS ) based on self-reporting smoking behaviour . 60 % , 14 % and 26 % of patients were CE , CS and IS , respectively . The rate of forced expiratory volume in 1 s ( FEV1 ) decline for placebo patients was most rapid in CS ( -51±4 , -36±2 and -23±2 mL·yr−1 in CS , IS , and CE , respectively ) . Tiotropium did not alter FEV1 decline , but was associated with significant improvements in pre- and post-bronchodilator FEV1  over placebo that persisted throughout the 4-yr trial for each smoking status ( pre-bronchodilator : 125 , 55 and 97 mL at 48 months in CS , IS and CE , respectively ; p≤0.0003 ) . Tiotropium  reduced exacerbation risk in CS ( HR ( 95%CI ) 0.81 ( 0.68–0.97 ) ) , in CE ( 0.86 ( 0.79–0.93 ) ) and trended towards significance in IS ( 0.89 ( 0.80–1.01 ) ) . At 4 yrs , St George ’s Respiratory Question naire for tiotropium patients improved the most in CS ( -4.62 units , p = 0.0006 ) and the least in IS ( -0.54 units , p = 0.55 ) , compared 
    Output:
    