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: RATIONALE One-quarter to one-third of individuals with asthma smoke , which may affect response to therapy and contribute to poor asthma control . OBJECTIVES To determine if the response to an inhaled corticosteroid or a leukotriene receptor antagonist is attenuated in individuals with asthma who smoke . METHODS In a multicenter , placebo-controlled , double-blind , double-dummy , crossover trial , 44 nonsmokers and 39 light smokers with mild asthma were assigned r and omly to treatment twice daily with inhaled beclomethasone and once daily with oral montelukast . MEASUREMENTS AND MAIN RESULTS Primary outcome was change in prebronchodilator FEV(1 ) in smokers versus nonsmokers . Secondary outcomes included peak flow , PC(20 ) methacholine , symptoms , quality of life , and markers of airway inflammation . Despite similar FEV(1 ) , bronchodilator response , and sensitivity to methacholine at baseline , subjects with asthma who smoked had significantly more symptoms , worse quality of life , and lower daily peak flow than nonsmokers . Adherence to therapy did not differ significantly between smokers and nonsmokers , or between treatment arms . Beclomethasone significantly reduced sputum eosinophils and eosinophil cationic protein ( ECP ) in both smokers and nonsmokers , but increased FEV(1 ) ( 170 ml , p = 0.0003 ) only in nonsmokers . Montelukast significantly increased a.m. peak flow in smokers ( 12.6 L/min , p = 0.002 ) , but not in nonsmokers . CONCLUSIONS In subjects with mild asthma who smoke , the response to inhaled corticosteroids is attenuated , suggesting that adjustments to st and ard therapy may be required to attain asthma control . The greater improvement seen in some outcomes in smokers treated with montelukast suggests that leukotrienes may be important in this setting . Larger prospect i ve studies are required to determine whether leukotriene modifiers can be recommended for managing asthma in patients who smoke BACKGROUND Evidence is scarce on the relative risk-benefit of inhaled triple therapy , consisting of inhaled corticosteroid , long-acting muscarinic antagonist , and long-acting β2-agonist , versus dual bronchodilation for chronic obstructive pulmonary disease ( COPD ) . We aim ed to compare a single-inhaler triple combination of beclometasone dipropionate , formoterol fumarate , and glycopyrronium ( BDP/FF/G ) versus a single-inhaler dual bronchodilator combination of indacaterol plus glycopyrronium ( IND/GLY ) in terms of the rate of moderate-to-severe COPD exacerbations over 52 weeks of treatment . METHODS This r and omised , parallel-group , double-blind , double-dummy study was done at 187 sites across 17 countries . Eligible patients had symptomatic COPD , severe or very severe airflow limitation , at least one moderate or severe exacerbation in the previous year , and were receiving inhaled maintenance medication . After a 2 week run-in period with one inhalation per day of IND/GLY ( 85 μg/43 μg ) , patients were r and omly assigned ( 1:1 ) , via an interactive response technology system , to receive 52 weeks of treatment with two inhalations of extrafine BDP/FF/G ( 87 μg/5 μg/9 μg ) twice per day or one inhalation of IND/GLY ( 85 μg/43 μg ) per day . R and omisation was stratified by country and severity of airflow limitation . The primary endpoint was the rate of moderate-to-severe COPD exacerbations across 52 weeks of treatment in all r and omised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment . Safety was assessed in all patients who received at least one dose of study drug . This study is registered with Clinical Trials.gov , number NCT02579850 . FINDINGS Between May , 29 2015 , and July 10 , 2017 , 1532 patients received BDP/FF/G ( n=764 ) or IND/GLY ( n=768 ) . Moderate-to-severe exacerbation rates were 0·50 per patient per year ( 95 % CI 0·45 - 0·57 ) for BDP/FF/G and 0·59 per patient per year ( 0·53 - 0·67 ) for IND/GLY , giving a rate ratio of 0·848 ( 0·723 - 0·995 , p=0·043 ) in favour of BDP/FF/G. Adverse events were reported by 490 ( 64 % ) of 764 patients receiving BDP/FF/G and 516 ( 67 % ) of 768 patients receiving IND/GLY . Pneumonia occurred in 28 ( 4 % ) patients receiving BDP/FF/G versus 27 ( 4 % ) patients receiving IND/GLY . One treatment-related serious adverse event occurred in each group : dysuria in a patient receiving BDP/FF/G and atrial fibrillation in a patient receiving IND/GLY . INTERPRETATION In patients with symptomatic COPD , severe or very severe airflow limitation , and an exacerbation history despite maintenance therapy , extrafine BDP/FF/G significantly reduced the rate of moderate-to-severe exacerbations compared with IND/GLY , without increasing the risk of pneumonia . FUNDING Chiesi Farmaceutici BACKGROUND Few data are available for the efficacy of " triple therapy " with two long-acting bronchodilators and an inhaled corticosteroid in chronic obstructive pulmonary disease ( COPD ) . We design ed this study to assess efficacy of single-inhaler combination of an extra fine formulation of beclometasone dipropionate , formoterol fumarate , and glycopyrronium bromide ( BDP/FF/GB ) in COPD compared with beclometasone dipropionate and formoterol fumarate ( BDP/FF ) treatment . METHODS TRILOGY was a r and omised , parallel group , double-blind , active-controlled study done in 159 sites across 14 countries . The sites were a mixture of primary , secondary , and tertiary care providers , and specialist investigation units . Eligible patients with COPD had post-bronchodilator forced expiratory volume in 1 s ( FEV1 ) of lower than 50 % , one or more moderate-to-severe COPD exacerbation in the previous 12 months , COPD Assessment Test total score of 10 or more , and a Baseline Dyspnea Index focal score of 10 or less . Patients who met the inclusion and exclusion criteria at screening entered a 2-week open-label run-in period where they received beclometasone dipropionate ( 100 μg ) and formoterol fumarate ( 6 μg ) in two actuations twice daily . Patients were then r and omly assigned ( 1:1 ) with an interactive response technology system to either continue BDP ( 100 μg ) and FF ( 6 μg ) or step-up to BDP ( 100 μg ) , FF ( 6 μg ) , and GB ( 12·5 μg ) in two actuations twice daily for 52 weeks via pressurised metered-dose inhaler . The three co- primary endpoints were pre-dose FEV1 , 2-h post-dose FEV1 , and Transition Dyspnea Index ( TDI ) focal score , all measured at week 26 in the intention-to-treat population ( all patients who were r and omly assigned and received at least one dose of study drug and had at least one post-baseline efficacy assessment ) . Safety outcomes were measured in the safety population ( all patients who were r and omly assigned and received at least one dose of study drug ) . Secondary endpoints included moderate-to-severe COPD exacerbation rate over 52 weeks . This study is registered with Clinical Trials.gov number NCT01917331 . FINDINGS Between March 21 , 2014 , and Jan 14 , 2016 , 1368 patients received either BDP/FF/GB ( n=687 ) or BDP/FF ( n=681 ) . At week 26 , BDP/FF/GB improved pre-dose FEV1 by 0·081 L ( 95 % CI 0·052 - 0·109 ; p<0·001 ) and 2-h post-dose FEV1 by 0·117 L ( 0·086 - 0·147 ; p<0·001 ) compared with BDP/FF . Mean TDI focal scores at week 26 were 1·71 for BDP/FF/GB and 1·50 for BDP/FF , with a difference of 0·21 ( 95 % CI -0·08 to 0·51 ; p=0·160 ) . Adjusted annual moderate-to-severe exacerbation frequencies were 0·41 for BDP/FF/GB and 0·53 for BDP/FF ( rate ratio 0·77 [ 95 % CI 0·65 - 0·92 ] ; p=0·005 ) , corresponding to a 23 % reduction in exacerbations with BDP/FF/GB compared with BDP/FF . Adverse events were reported by 368 ( 54 % ) patients with BDP/FF/GB and 379 ( 56 % ) with BDP/FF . One serious treatment-related adverse event occurred ( atrial fibrillation ) in a patient in the BDP/FF/GB group . INTERPRETATION We provide evidence for the clinical benefits of stepping up patients with COPD from an inhaled corticosteroid/long-acting β2-agonist combination treatment to triple therapy using a single inhaler . FUNDING Chiesi Farmaceutici BACKGROUND The benefits of triple therapy for chronic obstructive pulmonary disease ( COPD ) with an inhaled glucocorticoid , a long‐acting muscarinic antagonist ( LAMA ) , and a long‐acting β2‐agonist ( LABA ) , as compared with dual therapy ( either inhaled glucocorticoid – LABA or LAMA – LABA ) , are uncertain . METHODS In this r and omized trial involving 10,355 patients with COPD , we compared 52 weeks of a once‐daily combination of fluticasone furoate ( an inhaled glucocorticoid ) at a dose of 100 μg , umeclidinium ( a LAMA ) at a dose of 62.5 μg , and vilanterol ( a LABA ) at a dose of 25 μg ( triple therapy ) with fluticasone furoate – vilanterol ( at doses of 100 μg and 25 μg , respectively ) and umeclidinium – vilanterol ( at doses of 62.5 μg and 25 μg , respectively ) . Each regimen was administered in a single Ellipta inhaler . The primary outcome was the annual rate of moderate or severe COPD exacerbations during treatment . RESULTS The rate of moderate or severe exacerbations in the triple‐therapy group was 0.91 per year , as compared with 1.07 per year in the fluticasone furoate – vilanterol group ( rate ratio with triple therapy , 0.85 ; 95 % confidence interval [ CI ] , 0.80 to 0.90 ; 15 % difference ; P<0.001 ) and 1.21 per year in the umeclidinium – vilanterol group ( rate ratio with triple therapy , 0.75 ; 95 % CI , 0.70 to 0.81 ; 25 % difference ; P<0.001 ) . The annual rate of severe exacerbations result ing in hospitalization in the triple‐therapy group was 0.13 , as compared with 0.19 in the umeclidinium – vilanterol group ( rate ratio , 0.66 ; 95 % CI , 0.56 to 0.78 ; 34 % difference ; P<0.001 ) . There was a higher incidence of pneumonia in the inhaled‐glucocorticoid groups than in the umeclidinium – vilanterol group , and the risk of clinician‐diagnosed pneumonia was significantly higher with triple therapy than with umeclidinium – vilanterol , as assessed in a time‐to‐first‐event analysis ( hazard ratio , 1.53 ; 95 % CI , 1.22 to 1.92 ; P<0.001 ) . CONCLUSIONS Triple therapy with fluticasone furoate , umeclidinium , and vilanterol result ed in a lower rate of moderate or severe COPD exacerbations than fluticasone furoate – vilanterol or umeclidinium – vilanterol in this population . Triple therapy also result ed in a lower rate of hospitalization due to COPD than umeclidinium – vilanterol . ( Funded by GlaxoSmithKline ; IMPACT Clinical Trials.gov number , NCT02164513 . RATIONALE Exacerbations are 
    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: RATIONALE One-quarter to one-third of individuals with asthma smoke , which may affect response to therapy and contribute to poor asthma control . OBJECTIVES To determine if the response to an inhaled corticosteroid or a leukotriene receptor antagonist is attenuated in individuals with asthma who smoke . METHODS In a multicenter , placebo-controlled , double-blind , double-dummy , crossover trial , 44 nonsmokers and 39 light smokers with mild asthma were assigned r and omly to treatment twice daily with inhaled beclomethasone and once daily with oral montelukast . MEASUREMENTS AND MAIN RESULTS Primary outcome was change in prebronchodilator FEV(1 ) in smokers versus nonsmokers . Secondary outcomes included peak flow , PC(20 ) methacholine , symptoms , quality of life , and markers of airway inflammation . Despite similar FEV(1 ) , bronchodilator response , and sensitivity to methacholine at baseline , subjects with asthma who smoked had significantly more symptoms , worse quality of life , and lower daily peak flow than nonsmokers . Adherence to therapy did not differ significantly between smokers and nonsmokers , or between treatment arms . Beclomethasone significantly reduced sputum eosinophils and eosinophil cationic protein ( ECP ) in both smokers and nonsmokers , but increased FEV(1 ) ( 170 ml , p = 0.0003 ) only in nonsmokers . Montelukast significantly increased a.m. peak flow in smokers ( 12.6 L/min , p = 0.002 ) , but not in nonsmokers . CONCLUSIONS In subjects with mild asthma who smoke , the response to inhaled corticosteroids is attenuated , suggesting that adjustments to st and ard therapy may be required to attain asthma control . The greater improvement seen in some outcomes in smokers treated with montelukast suggests that leukotrienes may be important in this setting . Larger prospect i ve studies are required to determine whether leukotriene modifiers can be recommended for managing asthma in patients who smoke BACKGROUND Evidence is scarce on the relative risk-benefit of inhaled triple therapy , consisting of inhaled corticosteroid , long-acting muscarinic antagonist , and long-acting β2-agonist , versus dual bronchodilation for chronic obstructive pulmonary disease ( COPD ) . We aim ed to compare a single-inhaler triple combination of beclometasone dipropionate , formoterol fumarate , and glycopyrronium ( BDP/FF/G ) versus a single-inhaler dual bronchodilator combination of indacaterol plus glycopyrronium ( IND/GLY ) in terms of the rate of moderate-to-severe COPD exacerbations over 52 weeks of treatment . METHODS This r and omised , parallel-group , double-blind , double-dummy study was done at 187 sites across 17 countries . Eligible patients had symptomatic COPD , severe or very severe airflow limitation , at least one moderate or severe exacerbation in the previous year , and were receiving inhaled maintenance medication . After a 2 week run-in period with one inhalation per day of IND/GLY ( 85 μg/43 μg ) , patients were r and omly assigned ( 1:1 ) , via an interactive response technology system , to receive 52 weeks of treatment with two inhalations of extrafine BDP/FF/G ( 87 μg/5 μg/9 μg ) twice per day or one inhalation of IND/GLY ( 85 μg/43 μg ) per day . R and omisation was stratified by country and severity of airflow limitation . The primary endpoint was the rate of moderate-to-severe COPD exacerbations across 52 weeks of treatment in all r and omised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment . Safety was assessed in all patients who received at least one dose of study drug . This study is registered with Clinical Trials.gov , number NCT02579850 . FINDINGS Between May , 29 2015 , and July 10 , 2017 , 1532 patients received BDP/FF/G ( n=764 ) or IND/GLY ( n=768 ) . Moderate-to-severe exacerbation rates were 0·50 per patient per year ( 95 % CI 0·45 - 0·57 ) for BDP/FF/G and 0·59 per patient per year ( 0·53 - 0·67 ) for IND/GLY , giving a rate ratio of 0·848 ( 0·723 - 0·995 , p=0·043 ) in favour of BDP/FF/G. Adverse events were reported by 490 ( 64 % ) of 764 patients receiving BDP/FF/G and 516 ( 67 % ) of 768 patients receiving IND/GLY . Pneumonia occurred in 28 ( 4 % ) patients receiving BDP/FF/G versus 27 ( 4 % ) patients receiving IND/GLY . One treatment-related serious adverse event occurred in each group : dysuria in a patient receiving BDP/FF/G and atrial fibrillation in a patient receiving IND/GLY . INTERPRETATION In patients with symptomatic COPD , severe or very severe airflow limitation , and an exacerbation history despite maintenance therapy , extrafine BDP/FF/G significantly reduced the rate of moderate-to-severe exacerbations compared with IND/GLY , without increasing the risk of pneumonia . FUNDING Chiesi Farmaceutici BACKGROUND Few data are available for the efficacy of " triple therapy " with two long-acting bronchodilators and an inhaled corticosteroid in chronic obstructive pulmonary disease ( COPD ) . We design ed this study to assess efficacy of single-inhaler combination of an extra fine formulation of beclometasone dipropionate , formoterol fumarate , and glycopyrronium bromide ( BDP/FF/GB ) in COPD compared with beclometasone dipropionate and formoterol fumarate ( BDP/FF ) treatment . METHODS TRILOGY was a r and omised , parallel group , double-blind , active-controlled study done in 159 sites across 14 countries . The sites were a mixture of primary , secondary , and tertiary care providers , and specialist investigation units . Eligible patients with COPD had post-bronchodilator forced expiratory volume in 1 s ( FEV1 ) of lower than 50 % , one or more moderate-to-severe COPD exacerbation in the previous 12 months , COPD Assessment Test total score of 10 or more , and a Baseline Dyspnea Index focal score of 10 or less . Patients who met the inclusion and exclusion criteria at screening entered a 2-week open-label run-in period where they received beclometasone dipropionate ( 100 μg ) and formoterol fumarate ( 6 μg ) in two actuations twice daily . Patients were then r and omly assigned ( 1:1 ) with an interactive response technology system to either continue BDP ( 100 μg ) and FF ( 6 μg ) or step-up to BDP ( 100 μg ) , FF ( 6 μg ) , and GB ( 12·5 μg ) in two actuations twice daily for 52 weeks via pressurised metered-dose inhaler . The three co- primary endpoints were pre-dose FEV1 , 2-h post-dose FEV1 , and Transition Dyspnea Index ( TDI ) focal score , all measured at week 26 in the intention-to-treat population ( all patients who were r and omly assigned and received at least one dose of study drug and had at least one post-baseline efficacy assessment ) . Safety outcomes were measured in the safety population ( all patients who were r and omly assigned and received at least one dose of study drug ) . Secondary endpoints included moderate-to-severe COPD exacerbation rate over 52 weeks . This study is registered with Clinical Trials.gov number NCT01917331 . FINDINGS Between March 21 , 2014 , and Jan 14 , 2016 , 1368 patients received either BDP/FF/GB ( n=687 ) or BDP/FF ( n=681 ) . At week 26 , BDP/FF/GB improved pre-dose FEV1 by 0·081 L ( 95 % CI 0·052 - 0·109 ; p<0·001 ) and 2-h post-dose FEV1 by 0·117 L ( 0·086 - 0·147 ; p<0·001 ) compared with BDP/FF . Mean TDI focal scores at week 26 were 1·71 for BDP/FF/GB and 1·50 for BDP/FF , with a difference of 0·21 ( 95 % CI -0·08 to 0·51 ; p=0·160 ) . Adjusted annual moderate-to-severe exacerbation frequencies were 0·41 for BDP/FF/GB and 0·53 for BDP/FF ( rate ratio 0·77 [ 95 % CI 0·65 - 0·92 ] ; p=0·005 ) , corresponding to a 23 % reduction in exacerbations with BDP/FF/GB compared with BDP/FF . Adverse events were reported by 368 ( 54 % ) patients with BDP/FF/GB and 379 ( 56 % ) with BDP/FF . One serious treatment-related adverse event occurred ( atrial fibrillation ) in a patient in the BDP/FF/GB group . INTERPRETATION We provide evidence for the clinical benefits of stepping up patients with COPD from an inhaled corticosteroid/long-acting β2-agonist combination treatment to triple therapy using a single inhaler . FUNDING Chiesi Farmaceutici BACKGROUND The benefits of triple therapy for chronic obstructive pulmonary disease ( COPD ) with an inhaled glucocorticoid , a long‐acting muscarinic antagonist ( LAMA ) , and a long‐acting β2‐agonist ( LABA ) , as compared with dual therapy ( either inhaled glucocorticoid – LABA or LAMA – LABA ) , are uncertain . METHODS In this r and omized trial involving 10,355 patients with COPD , we compared 52 weeks of a once‐daily combination of fluticasone furoate ( an inhaled glucocorticoid ) at a dose of 100 μg , umeclidinium ( a LAMA ) at a dose of 62.5 μg , and vilanterol ( a LABA ) at a dose of 25 μg ( triple therapy ) with fluticasone furoate – vilanterol ( at doses of 100 μg and 25 μg , respectively ) and umeclidinium – vilanterol ( at doses of 62.5 μg and 25 μg , respectively ) . Each regimen was administered in a single Ellipta inhaler . The primary outcome was the annual rate of moderate or severe COPD exacerbations during treatment . RESULTS The rate of moderate or severe exacerbations in the triple‐therapy group was 0.91 per year , as compared with 1.07 per year in the fluticasone furoate – vilanterol group ( rate ratio with triple therapy , 0.85 ; 95 % confidence interval [ CI ] , 0.80 to 0.90 ; 15 % difference ; P<0.001 ) and 1.21 per year in the umeclidinium – vilanterol group ( rate ratio with triple therapy , 0.75 ; 95 % CI , 0.70 to 0.81 ; 25 % difference ; P<0.001 ) . The annual rate of severe exacerbations result ing in hospitalization in the triple‐therapy group was 0.13 , as compared with 0.19 in the umeclidinium – vilanterol group ( rate ratio , 0.66 ; 95 % CI , 0.56 to 0.78 ; 34 % difference ; P<0.001 ) . There was a higher incidence of pneumonia in the inhaled‐glucocorticoid groups than in the umeclidinium – vilanterol group , and the risk of clinician‐diagnosed pneumonia was significantly higher with triple therapy than with umeclidinium – vilanterol , as assessed in a time‐to‐first‐event analysis ( hazard ratio , 1.53 ; 95 % CI , 1.22 to 1.92 ; P<0.001 ) . CONCLUSIONS Triple therapy with fluticasone furoate , umeclidinium , and vilanterol result ed in a lower rate of moderate or severe COPD exacerbations than fluticasone furoate – vilanterol or umeclidinium – vilanterol in this population . Triple therapy also result ed in a lower rate of hospitalization due to COPD than umeclidinium – vilanterol . ( Funded by GlaxoSmithKline ; IMPACT Clinical Trials.gov number , NCT02164513 . RATIONALE Exacerbations are 
    Output:
    