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: Identification of a biomarker that predicts response to inhaled corticosteroids ( ICS ) would help evaluate the risk/benefit profile of ICS in chronic obstructive pulmonary disease ( COPD ) and guide treatment . The ISOLDE study r and omised 751 patients ( mean post-bronchodilator forced expiratory volume in 1 s ( FEV1 ) 1.4 L : 50 % predicted normal ) to fluticasone propionate 500 μg twice daily or placebo for 3 years , finding no difference in FEV1 rate of decline between treatments ( p=0.16 ) and a significant reduction in median exacerbation rate with fluticasone propionate versus placebo ( p=0.026 ) . We re-analysed ISOLDE results by baseline blood eosinophil count to investigate whether eosinophil level predicts ICS benefit . Patients with eosinophils < 2 % ( n=456 ) had a similar rate of post-bronchodilator FEV1 decline  with fluticasone propionate as placebo ( –2.9 mL·year−1 ; p=0.688 ) . With eosinophils ≥2 % ( n=214 ) , the rate of decline decreased by 33.9 mL·year−1 with fluticasone propionate versus placebo ( p=0.003 ) . Exacerbation rate reduction on ICS  for fluticasone propionate versus placebo was higher in the eosinophil < 2 % group compared with the ≥2 % group ; time-to-first moderate/severe exacerbation was not different between treatments in either group . A baseline blood eosinophil count of ≥2 % identifies a group of COPD patients with slower rates of decline in FEV1 when treated with ICS : prospect i ve testing of this hypothesis is now warranted . Blood eosinophil level identifies COPD patients showing a slower rate of lung function decline when treated with ICS 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 Findings from previous studies showed that mepolizumab significantly reduces the rate of exacerbations in patients with severe eosinophilic asthma . To assess the relationship between baseline blood eosinophil counts and efficacy of mepolizumab we did a secondary analysis of data from two studies , stratifying patients by different baseline blood eosinophil thresholds . METHODS We did a post-hoc analysis of data , which was completed on Sept 25 , 2015 , from two r and omised , double-blind , placebo-controlled studies of at least 32 weeks duration ( NCT01000506 [ DREAM ] and NCT01691521 [ MENSA ] ) done between 2009 and 2014 . In these studies , mepolizumab ( DREAM 75 mg , 250 mg , or 750 mg intravenously ; MENSA : 75 mg intravenously or 100 mg subcutaneously ) versus placebo was given at 4-week intervals in addition to st and ard care ( high-dose inhaled corticosteroids plus ≥1 additional controller with or without daily oral corticosteroids ) to patients aged 12 years or older with a clinical diagnosis of asthma , a history of at least two exacerbations in the previous year that required systemic corticosteroid treatment , and evidence of eosinophilic airway inflammation . The primary endpoint in both studies was the annual rate of clinical ly significant exacerbations ( defined as worsening of asthma that required the use of systemic corticosteroids , or admission to hospital , or an emergency-room visit , or a combination of these occurrences ) . In our analysis , the primary outcome was the annualised rate of exacerbations in patients stratified by baseline eosinophil counts ( ≥150 cells per μL , ≥300 cells per μL , ≥400 cells per μL , and ≥500 cells per μL ) and baseline blood eosinophil ranges ( < 150 cells per μL , ≥150 cells per μL to < 300 cells per μL , ≥300 cells per μL to < 500 cells per μL , and ≥500 cells per μL ) . We based our analysis on the intention-to-treat population s of the two original studies , and all mepolizumab doses were combined for analysis . FINDINGS Of 1192 patients , 846 received mepolizumab and 346 received placebo  . The overall rate of mean exacerbations per person per year was reduced from 1·91 with placebo to 1·01 with mepolizumab ( 47 % reduction ; rate ratio [ RR ] 0·53 , 95 % CI 0·44 - 0·62 ; p<0·0001 ) . The exacerbation rate reduction  with mepolizumab versus placebo increased progressively from 52 % ; 0·48 , 0·39 - 0·58 ) in patients with a baseline blood eosinophil count of at least 150 cells per μL to 70 % ; 0·30 , 0·23 - 0·40 ] ) in patients with a baseline count of at least 500 cells per μL. At a baseline count less than 150 cells per μL , predicted efficacy of mepolizumab was reduced . INTERPRETATION Our analysis has shown a close relationship between baseline blood eosinophil count and clinical efficacy of mepolizumab in patients with severe eosinophilic asthma and a history of exacerbations . We noted clinical ly relevant reductions in exacerbation frequency in patients with a count of 150 cells per μL or more at baseline . The use of this baseline biomarker will help to select patients who are likely to achieve important asthma outcomes with mepolizumab . FUNDING GlaxoSmithKline BACKGROUND Blood eosinophil counts might predict response to inhaled corticosteroids ( ICS ) in patients with chronic obstructive pulmonary disease ( COPD ) and a history of exacerbations . We used data from the WISDOM trial to assess whether patients with COPD with higher blood eosinophil counts would be more likely to have exacerbations if ICS treatment was withdrawn . METHODS WISDOM was a 12-month , r and omised , parallel-group trial in which patients received 18 μg tiotropium , 100 μg salmeterol , and 1000 μg fluticasone propionate daily for 6 weeks and were then r and omly assigned ( 1:1 ) electronically to receive either continued or reduced ICS over 12 weeks . We did a post-hoc analysis after complete ICS withdrawal ( months 3 - 12 ) to compare rate of exacerbations and time to exacerbation outcomes on the basis of blood eosinophil subgroups of increasing cutoff levels . The WISDOM trial is registered at Clinical Trials.gov , number NCT00975195 . FINDINGS In the 2296 patients receiving treatment after ICS withdrawal  , moderate or severe exacerbation rate  was higher in the ICS-withdrawal group versus the ICS-continuation group in patients with eosinophil counts ( out of total white blood cell count ) of 2 % or greater ( rate ratio 1·22 [ 95 % CI 1·02 - 1·48 ] ) , 4 % or greater ( 1·63 [ 1·19 - 2·24 ] ) , and 5 % or greater ( 1·82 [ 1·20 - 2·76 ] ) . The increase in exacerbation rate became more pronounced as the eosinophil cutoff level rose , with significant treatment-by-subgroup interaction reached for 4 % and 5 % only . Similar results were seen with eosinophil cutoffs of 300 cells per μL and 400 cells per μL , and mutually exclusive subgroups . INTERPRETATION Blood eosinophil counts at screening were related to the exacerbation rate after complete ICS withdrawal in patients with severe to very severe COPD and a history of exacerbations . Our data suggest that counts of 4 % or greater or 300 cells per μL or more might identify a deleterious effect of ICS withdrawal , an effect not seen in most patients with eosinophil counts below these thresholds . FUNDING Boehringer Ingelheim 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 
    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: Identification of a biomarker that predicts response to inhaled corticosteroids ( ICS ) would help evaluate the risk/benefit profile of ICS in chronic obstructive pulmonary disease ( COPD ) and guide treatment . The ISOLDE study r and omised 751 patients ( mean post-bronchodilator forced expiratory volume in 1 s ( FEV1 ) 1.4 L : 50 % predicted normal ) to fluticasone propionate 500 μg twice daily or placebo for 3 years , finding no difference in FEV1 rate of decline between treatments ( p=0.16 ) and a significant reduction in median exacerbation rate with fluticasone propionate versus placebo ( p=0.026 ) . We re-analysed ISOLDE results by baseline blood eosinophil count to investigate whether eosinophil level predicts ICS benefit . Patients with eosinophils < 2 % ( n=456 ) had a similar rate of post-bronchodilator FEV1 decline  with fluticasone propionate as placebo ( –2.9 mL·year−1 ; p=0.688 ) . With eosinophils ≥2 % ( n=214 ) , the rate of decline decreased by 33.9 mL·year−1 with fluticasone propionate versus placebo ( p=0.003 ) . Exacerbation rate reduction on ICS  for fluticasone propionate versus placebo was higher in the eosinophil < 2 % group compared with the ≥2 % group ; time-to-first moderate/severe exacerbation was not different between treatments in either group . A baseline blood eosinophil count of ≥2 % identifies a group of COPD patients with slower rates of decline in FEV1 when treated with ICS : prospect i ve testing of this hypothesis is now warranted . Blood eosinophil level identifies COPD patients showing a slower rate of lung function decline when treated with ICS 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 Findings from previous studies showed that mepolizumab significantly reduces the rate of exacerbations in patients with severe eosinophilic asthma . To assess the relationship between baseline blood eosinophil counts and efficacy of mepolizumab we did a secondary analysis of data from two studies , stratifying patients by different baseline blood eosinophil thresholds . METHODS We did a post-hoc analysis of data , which was completed on Sept 25 , 2015 , from two r and omised , double-blind , placebo-controlled studies of at least 32 weeks duration ( NCT01000506 [ DREAM ] and NCT01691521 [ MENSA ] ) done between 2009 and 2014 . In these studies , mepolizumab ( DREAM 75 mg , 250 mg , or 750 mg intravenously ; MENSA : 75 mg intravenously or 100 mg subcutaneously ) versus placebo was given at 4-week intervals in addition to st and ard care ( high-dose inhaled corticosteroids plus ≥1 additional controller with or without daily oral corticosteroids ) to patients aged 12 years or older with a clinical diagnosis of asthma , a history of at least two exacerbations in the previous year that required systemic corticosteroid treatment , and evidence of eosinophilic airway inflammation . The primary endpoint in both studies was the annual rate of clinical ly significant exacerbations ( defined as worsening of asthma that required the use of systemic corticosteroids , or admission to hospital , or an emergency-room visit , or a combination of these occurrences ) . In our analysis , the primary outcome was the annualised rate of exacerbations in patients stratified by baseline eosinophil counts ( ≥150 cells per μL , ≥300 cells per μL , ≥400 cells per μL , and ≥500 cells per μL ) and baseline blood eosinophil ranges ( < 150 cells per μL , ≥150 cells per μL to < 300 cells per μL , ≥300 cells per μL to < 500 cells per μL , and ≥500 cells per μL ) . We based our analysis on the intention-to-treat population s of the two original studies , and all mepolizumab doses were combined for analysis . FINDINGS Of 1192 patients , 846 received mepolizumab and 346 received placebo  . The overall rate of mean exacerbations per person per year was reduced from 1·91 with placebo to 1·01 with mepolizumab ( 47 % reduction ; rate ratio [ RR ] 0·53 , 95 % CI 0·44 - 0·62 ; p<0·0001 ) . The exacerbation rate reduction  with mepolizumab versus placebo increased progressively from 52 % ; 0·48 , 0·39 - 0·58 ) in patients with a baseline blood eosinophil count of at least 150 cells per μL to 70 % ; 0·30 , 0·23 - 0·40 ] ) in patients with a baseline count of at least 500 cells per μL. At a baseline count less than 150 cells per μL , predicted efficacy of mepolizumab was reduced . INTERPRETATION Our analysis has shown a close relationship between baseline blood eosinophil count and clinical efficacy of mepolizumab in patients with severe eosinophilic asthma and a history of exacerbations . We noted clinical ly relevant reductions in exacerbation frequency in patients with a count of 150 cells per μL or more at baseline . The use of this baseline biomarker will help to select patients who are likely to achieve important asthma outcomes with mepolizumab . FUNDING GlaxoSmithKline BACKGROUND Blood eosinophil counts might predict response to inhaled corticosteroids ( ICS ) in patients with chronic obstructive pulmonary disease ( COPD ) and a history of exacerbations . We used data from the WISDOM trial to assess whether patients with COPD with higher blood eosinophil counts would be more likely to have exacerbations if ICS treatment was withdrawn . METHODS WISDOM was a 12-month , r and omised , parallel-group trial in which patients received 18 μg tiotropium , 100 μg salmeterol , and 1000 μg fluticasone propionate daily for 6 weeks and were then r and omly assigned ( 1:1 ) electronically to receive either continued or reduced ICS over 12 weeks . We did a post-hoc analysis after complete ICS withdrawal ( months 3 - 12 ) to compare rate of exacerbations and time to exacerbation outcomes on the basis of blood eosinophil subgroups of increasing cutoff levels . The WISDOM trial is registered at Clinical Trials.gov , number NCT00975195 . FINDINGS In the 2296 patients receiving treatment after ICS withdrawal  , moderate or severe exacerbation rate  was higher in the ICS-withdrawal group versus the ICS-continuation group in patients with eosinophil counts ( out of total white blood cell count ) of 2 % or greater ( rate ratio 1·22 [ 95 % CI 1·02 - 1·48 ] ) , 4 % or greater ( 1·63 [ 1·19 - 2·24 ] ) , and 5 % or greater ( 1·82 [ 1·20 - 2·76 ] ) . The increase in exacerbation rate became more pronounced as the eosinophil cutoff level rose , with significant treatment-by-subgroup interaction reached for 4 % and 5 % only . Similar results were seen with eosinophil cutoffs of 300 cells per μL and 400 cells per μL , and mutually exclusive subgroups . INTERPRETATION Blood eosinophil counts at screening were related to the exacerbation rate after complete ICS withdrawal in patients with severe to very severe COPD and a history of exacerbations . Our data suggest that counts of 4 % or greater or 300 cells per μL or more might identify a deleterious effect of ICS withdrawal , an effect not seen in most patients with eosinophil counts below these thresholds . FUNDING Boehringer Ingelheim 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 
    Output:
    