Smoking affects response to inhaled corticosteroids or leukotriene receptor antagonists in asthma. Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial Single inhaler triple therapy versus inhaled corticosteroid plus long-acting β2-agonist therapy for chronic obstructive pulmonary disease (TRILOGY): a double-blind, parallel group, randomised controlled trial Once‐Daily Single‐Inhaler Triple versus Dual Therapy in Patients with COPD The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Effects of Adding Tiotropium or Aclidinium as Triple Therapy Using Impulse Oscillometry in COPD Effects of Tiotropium and Salmeterol/Fluticasone Propionate on Airway Wall Thickness in Chronic Obstructive Pulmonary Disease Magnitude of umeclidinium/vilanterol lung function effect depends on monotherapy responses: Results from two randomised controlled trials. Glycopyrronium once-daily significantly improves lung function and health status when combined with salmeterol/fluticasone in patients with COPD: the GLISTEN study—a randomised controlled trial The impact of tiotropium on mortality and exacerbations when added to inhaled corticosteroids and long-acting β-agonist therapy in COPD. Influence of cigarette smoking on inhaled corticosteroid treatment in mild asthma Comparative Efficacy of Once-Daily Umeclidinium/Vilanterol and Tiotropium/Olodaterol Therapy in Symptomatic Chronic Obstructive Pulmonary Disease: A Randomized Study Predictors of exacerbation risk and response to budesonide in patients with chronic obstructive pulmonary disease: a post-hoc analysis of three randomised trials. Community Assessment of COPD Health Care (COACH) study: a clinical audit on primary care performance variability in COPD care Determinants of medical prescriptions for COPD care: an analysis of the EPOCONSUL clinical audit Triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicentre, phase 3 randomised controlled trial. Randomized clinical trials with run-in periods: frequency, characteristics and reporting Randomized controlled trials of pharmacological treatments to prevent COPD exacerbations: applicability to real-life patients Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomised controlled trial FULFIL Trial: Once‐Daily Triple Therapy for Patients with Chronic Obstructive Pulmonary Disease
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 key drivers of morbidity and mortality in chronic obstructive pulmonary disease ( COPD ) . OBJECTIVES We compared the relative efficacy of the long-acting inhaled bronchodilator/antiinflammatory combination ( salmeterol/fluticasone propionate ) 50/500 microg twice daily and the long-acting bronchodilator ( tiotropium ) 18 microg once daily in preventing exacerbations and related outcomes in severe and very severe COPD . METHODS A total of 1,323 patients ( mean age , 64 yr , post-bronchodilator FEV1 , 39 % predicted ) were r and omized in this 2-year , double-blind , double-dummy parallel study . MEASUREMENTS AND MAIN RESULTS Primary endpoint was health care utilization exacerbation rate . Other endpoints included health status measured by St. George 's Respiratory Question naire ( SGRQ ) , mortality , adverse events , and study withdrawal . Probability of withdrawing from the study was 29 % greater with tiotropium than salmeterol/fluticasone propionate ( P = 0.005 ) . The modeled annual exacerbation rate was 1.28 in the salmeterol/fluticasone propionate group and 1.32 in the tiotropium group ( rate ratio , 0.967 ; 95 % confidence interval [ CI ] , 0.836 - 1.119 ] ; P = 0.656 ) . The SGRQ total score was statistically significantly lower at 2 years on salmeterol/fluticasone propionate versus tiotropium ( difference 2.1 units ; 95 % CI , 0.1 - 4.0 ; P = 0.038 ) . Mortality was significantly lower in the salmeterol/fluticasone propionate group ; 21 ( 3 % ) of patients in this group died compared with 38 ( 6 % ) in the tiotropium group ( P = 0.032 ) . More pneumonias were reported in the salmeterol/fluticasone propionate group relative to tiotropium ( P = 0.008 ) . CONCLUSIONS We found no difference in exacerbation rate between salmeterol/fluticasone propionate and tiotropium . More patients failed to complete the study while receiving tiotropium . A small statistically significant beneficial effect was found on health status , with an unexpected finding of lower deaths in salmeterol/fluticasone propionate-treated patients . Clinical trial registered with www . clinical trials.gov ( NCT 00361959 ) Introduction Long-acting muscarinic antagonists confer improvements in spirometry when used in addition to inhaled corticosteroids and long-acting beta-agonists ( ICS/LABA ) in COPD . The dual objectives of this proof of concept study were to evaluate trough effects of tiotropium ( TIO ) or aclidinium ( ACL ) when used as triple therapy and to assess if impulse oscillometry ( IOS ) might be more sensitive than spirometry in detecting subtle differences in bronchodilator response . Methods Patients with moderate to severe COPD already taking ICS/LABA were r and omized to receive add-on therapy in cross-over fashion with either TIO 18 µg od or ACL 322 µg bid for 2–3 weeks each . Measurements of IOS , spirometry , 6-min walk test , St George ’s Respiratory Question naire ( SGRQ ) and Baseline/Transition Dyspnoea Index ( TDI ) were made at baseline and after chronic dosing at trough ( 12 h for ACL and 24 h for TIO ) , in addition to domiciliary diurnal spirometry . Results 13 patients were completed : mean age 69 years , FEV1 52 % predicted , FEV1/FVC 0.48 , and R5 202 % predicted . There were no differences in any visit-based trough IOS or spirometry outcomes comparing TIO versus ACL . Resonant frequency but not total airway resistance at 5 Hz ( R5 ) significantly improved from baseline with both treatments while peripheral airway resistance ( R5–R20 ) significantly improved with ACL . Visit-based FEV1 , and forced and relaxed vital capacity were also significantly improved from baseline with both treatments . There were no significant differences in diurnal FEV1 and FEV6 profiles between treatments . 6-min walk distance and post-walk fatigue significantly improved from baseline with ACL , while post-walk dyspnea improved with TIO . SGRQ symptom score significantly improved to a similar degree with both treatments . TDI significantly improved with ACL versus TIO by 1.54 units . Conclusion We observed comparable bronchodilator efficacy at trough with TIO and ACL when used as triple therapy in COPD , while IOS was no more sensitive than spirometry Background : Triple inhalation therapy with tiotropium ( Tio ) and salmeterol/fluticasone propionate combination ( SFC ) is widely used in the treatment of chronic obstructive pulmonary disease ( COPD ) . However , the effects of triple therapy on airway structural changes remain unknown . Objective : The aim of the study was to assess the effects of Tio , salmeterol ( SM ) , SFC and Tio plus SFC on airway dimensions in COPD . Methods : A r and omized , open-label , 4-way study ( n = 60 ) was conducted comparing 16-week treatment periods of Tio ( 18 μg once daily ) , SM ( 50 μg twice daily ) , SFC ( 50/250 μg twice daily ) and Tio ( 18 μg once daily ) plus SFC ( 50/250 μg twice daily ) . Airway dimensions were assessed by a vali date d CT technique , and airway wall area ( WA ) corrected for body surface area ( BSA ) , percentage WA ( WA% ) , wall thickness/√BSA and luminal area (Ai)/BSA at the right apical segmental bronchus were measured . Pulmonary function and the St. George 's Respiratory Question naire ( SGRQ ) were evaluated . Results : Tio plus SFC result ed in a significant decrease in WA corrected for BSA and WA% compared with Tio , SM and SFC ( p < 0.05 for all ) . The changes in WA% and Ai/BSA were significantly correlated with changes in forced expiratory volume in 1 s ( r = -0.86 , p < 0.001 , and r = 0.48 , p < 0.05 , respectively ) . There were more significant improvements in SGRQ scores after treatment with triple therapy than after the 3 other treatments . Conclusions : Tio plus SFC therapy is more effective than Tio , SM and SFC for reducing airway wall thickness in COPD PURPOSE Dual therapy with bronchodilators of different pharmacological classes may produce greater lung function improvements than either drug alone . However , the relationship between a patient 's response to monotherapy and response to dual bronchodilator therapy is currently unknown . We aim ed to investigate whether dual therapy with umeclidinium/vilanterol provides additional benefit over umeclidinium or vilanterol monotherapy in patients with chronic obstructive pulmonary disease ( COPD ) identified as responsive ( increase from baseline in forced expiratory volume in 1s [ FEV1 ] of ≥ 12 % and ≥ 200 mL , Day 1 ) or non-responsive to monotherapy . METHODS In two r and omised , double-blind , three-way complete-block , cross-over studies ( DB2116132 n = 207 ; DB2116133 n = 182 ; intent-to-treat ) , all patients ( moderate-to-very severe COPD ) were r and omised to 1 of 6 sequences and received once-daily umeclidinium 62.5 mcg , vilanterol 25 mcg , and umeclidinium/vilanterol 62.5/25 mcg ( one treatment/14-day period ; 10 - 14-day washout ) . Key endpoints were 0 - 6 h weighted mean FEV1 ( Day 14 ) and trough FEV1 ( Day 15 ) . Adverse events , vital signs and COPD exacerbations were assessed . Pooled data are presented . RESULTS Umeclidinium/vilanterol significantly ( p ≤ 0.001 , unless stated otherwise ) increased 0 - 6 h weighted mean FEV1 versus umeclidinium in umeclidinium-responders ( + 114 mL ) , versus vilanterol in vilanterol-responders ( + 92 mL ) and versus umeclidinium ( + 70 mL ) and vilanterol ( + 62 mL ) in non-responders . Improvements in trough FEV1 occurred with umeclidinium/vilanterol versus umeclidinium in umeclidinium-responders ( + 77 mL ) , versus vilanterol in vilanterol-responders ( + 86 mL ) , and versus umeclidinium ( + 42 mL [ p = 0.020 ] ) and vilanterol ( + 58 mL ) in non-responders . All treatments were well tolerated . CONCLUSIONS Once-daily umeclidinium/vilanterol  significantly improved lung function in patients with COPD , with quantitatively greater improvements in patients identified as responders to umeclidinium and vilanterol monotherapy than non-responders Background The optimal use of various therapeutic combinations for moderate/severe chronic obstructive pulmonary disease ( COPD ) is unclear . The GLISTEN trial compared the efficacy of two long-acting anti-muscarinic antagonists ( LAMA ) , when combined with an inhaled corticosteroid ( ICS ) and a long-acting β2 agonist ( LABA ) . Methods This r and omised , blinded , placebo-controlled trial in moderate/severe COPD patients compared once-daily glycopyrronium ( GLY ) 50 µg , once-daily tiotropium ( TIO ) 18 µg or placebo ( PLA ) , when combined with salmeterol/fluticasone propionate ( SAL/FP ) 50/500 µg twice daily . The primary objective was to determine the non-inferiority of GLY+SAL/FP versus TIO+SAL/FP  on trough FEV1 after 12 weeks . An important secondary objective was whether addition of GLY to SAL/FP was better than SAL/FP alone . Results 773 patients ( mean FEV1 57.2 % predicted ) were r and omised ; 84.9 % completed the trial . At week 12 , GLY+SAL/FP demonstrated non-inferiority to TIO+SAL/FP  for trough FEV1 : least square mean treatment difference ( LSMdiff ) −7 mL ( SE 17.4 ) with a lower limit for non-inferiority of −60 mL. There was significant increase in week 12 trough FEV1  with GLY+SAL/FP versus PLA+SAL/FP ( LSMdiff 101 mL , p<0.001 ) . At 12 weeks , GLY+SAL/FP produced significant improvement in St George 's Respiratory Question naire total score versus PLA+SAL/FP ( LSMdiff −2.154 , p=0.02 ) . GLY+SAL/FP  demonstrated significant rescue medication reduction versus PLA+SAL/FP ( LSMdiff −0.72 puffs/day , p<0.001 ) . Serious adverse events were similar for GLY+SAL/FP , TIO+SAL/FP and PLA+SAL/FP with an incidence of 5.8 % , 8.5 % and 5.8 % , respectively . Conclusions GLY+SAL/FP showed comparable improvements in lung function , health status and rescue medication to TIO+SAL/FP . Importantly , addition of GLY to SAL/FP demonstrated significant improvements in lung function , health status and rescue medication compared to SAL/FP . Trial registration number NCT01513460 BACKGROUND Tiotropium has been shown to improve lung function , quality of life , and exacerbations and reduce mortality when compared with placebo in COPD . It remains unclear whether benefits are seen when tiotropium is used in conjunction with inhaled corticosteroids ( ICSs ) plus long-acting β-agonists ( LABAs ) . METHODS We performed a retrospective cohort study using a National Health Service data base of patients with COPD in Tayside , Scotl and , between 2001 and 2010 that is linked with data bases regarding hospital admissions , pharmacy prescriptions , and death registries . The impact of the addition of tiotropium ( Tio ) to ICS + LABA therapy on all-cause mortality , hospital admissions for respiratory disease , and emergency oral corticosteroid bursts was evaluated . Adjusted hazard ratios ( HRs ) were calculated by Cox regression after inclusion of the following covariates : cardiovascular and respiratory disease , diabetes , smoking , age , sex , and deprivation index . RESULTS A total of 1,857 patients were given ICS + LABA + Tio , and 996 were given ICS + LABA  . Mean follow-up was 4.65 years . The adjusted HR for all-cause mortality  for ICS + LABA + Tio vs ICS + LABA was 0.65 ( 95 % CI , 0.57 - 0.75 ; P < .001 ) . Adjusted HRs for hospital admissions and oral corticosteroid bursts were 0.85 ( 95 % CI , 0.73 - 0.99 ; P = .04 ) and 0.71 ( 95 % CI , 0.63 - 0.80 ; P < .001 ) , respectively . CONCLUSIONS The study suggests that the addition of tiotropium to ICSs and LABA therapy may confer benefits in reducing all-cause mortality , hospital admissions , and oral corticosteroid bursts in patients with COPD .  Triple therapy is widely used in the real-life management of COPD , with only limited scientific support . The study supports the use of triple therapy in COPD and provides a platform for r and omized controlled trials specifically addressing this topic Background : Although inhaled corticosteroids have an established role in the treatment of asthma , studies have tended to concentrate on non-smokers and little is known about the possible effect of cigarette smoking on the efficacy of treatment with inhaled steroids in asthma . A study was undertaken to investigate the effect of active cigarette smoking on responses to treatment with inhaled corticosteroids in patients with mild asthma . Methods : The effect of treatment with inhaled fluticasone propionate ( 1000 μg daily ) or placebo for 3 weeks was studied in a double blind , prospect i ve , r and omised , placebo controlled study of 38 steroid naïve adult asthmatic patients ( 21 non-smokers ) . Efficacy was assessed using morning and evening peak expiratory flow ( PEF ) readings , spirometric parameters , bronchial hyperreactivity , and sputum eosinophil counts . Comparison was made between responses to treatment in non-smoking and smoking asthmatic patients . Results : There was a significantly greater increase in mean morning PEF in non-smokers than in smokers following inhaled fluticasone ( 27 l/min v –5 l/min ) . Non-smokers had a statistically significant increase in mean morning PEF ( 27 l/min ) , mean forced expiratory volume in 1 second ( 0.17 l ) , and geometric mean PC20 ( 2.6 doubling doses ) , and a significant decrease in the proportion of sputum eosinophils ( –1.75 % ) after fluticasone compared with placebo . No significant changes were observed in the smoking asthmatic patients for any of these parameters . Conclusions : Active cigarette smoking impairs the efficacy of short term inhaled corticosteroid treatment in mild asthma . This finding has important implication s for the management of patients with mild asthma who smoke Introduction We report the results of the first direct comparison of the once-daily fixed-dose long-acting muscarinic antagonist/long-acting β2-agonist ( LAMA/LABA ) combinations umeclidinium/vilanterol ( UMEC/VI ) and tiotropium/olo date rol ( TIO/OLO ) in patients with COPD . Methods This was a r and omized , two-period crossover open-label study in symptomatic patients with COPD [ age 40 years or older , postbronchodilator forced expiratory volume in 1 s ( FEV1 ) of 70 % or less and 50 % or more of predicted normal values , and modified Medical Research Council Dyspnoea Scale score of 2 or greater ] not receiving inhaled corticosteroid therapy . Patients were r and omized to receive UMEC/VI ( 62.5/25 µg once daily ) via a multidose dry powder inhaler ( ELLIPTA ) followed by TIO/OLO ( 5/5 µg once daily ) via a soft mist inhaler ( Respimat ) , each for 8 weeks with an interim 3-week washout or vice versa . The primary end point was the change from baseline in trough FEV1 at week 8 with a noninferiority margin of − 50 mL in the per- protocol ( PP ) population . The incidence of adverse events was also assessed . Results In total , 236 patients ( mean age 64.4 years , 60 % male ) were included in the intent-to-treat population and 227 were included in the PP population . UMEC/VI treatment was noninferior in the PP population and superior in the intent-to-treat population to TIO/OLO treatment with regard to trough FEV1 at week 8 [ FEV1 change from baseline 180 mL vs 128 mL ; difference 52 mL ( 95 % confidence interval 28–77 mL ) ; p < 0.001 ] . Patients receiving UMEC/VI had twofold increased odds of experiencing a clinical ly meaningful increase ( 100 mL or more ) from baseline in trough FEV1 at week 8 compared with patients receiving TIO/OLO ( odds ratio 2.05 ; 95 % confidence interval 1.34–3.14 ) . Adverse events occurred in 25 % of patients in the UMEC/VI group and in 31 % of patients in the TIO/OLO group . Conclusion In this first direct comparison of two once-daily fixed-dose LAMA/LABA combinations , superiority was observed for the primary end point of trough FEV1 at week 8 with UMEC/VI compared with TIO/OLO  in patients with symptomatic COPD . Both treatments had similar safety profiles . These findings confirm the results of previous indirect LAMA/LABA comparisons , and show that an efficacy gradient exists within the LAMA/LABA class . Trial Registration Clinical Trials.gov identifier NCT02799784 . Funding GlaxoSmithKline BACKGROUND The peripheral blood eosinophil count might help identify those patients with chronic obstructive pulmonary disease ( COPD ) who will experience fewer exacerbations when taking inhaled corticosteroids ( ICS ) . Previous post-hoc analyses have proposed eosinophil cutoffs that are both arbitrary and limited in evaluating complex interactions of treatment response . We modelled eosinophil count as a continuous variable to determine the characteristics that determine both exacerbation risk and clinical response to ICS in patients with COPD . METHODS We analysed data from three AstraZeneca r and omised controlled trials of budesonide-formoterol in patients with COPD with a history of exacerbations and available blood eosinophil counts . Patients with any history of asthma were excluded . Negative binomial regression analysis was done using splines for modelling of continuous variables to study the primary outcome of annual exacerbation rate adjusted for exposure time and study design . The trials are registered with Clinical Trials.gov , NCT00206167 , NCT00206154 , and NCT00419744 . FINDINGS 4528 patients were studied . A non-linear increase in exacerbations occurred with increasing eosinophil count in patients who received formoterol alone . At eosinophil counts of 0·10 × 109 cells per L or more , a significant treatment effect was recorded for exacerbation reduction  with budesonide-formoterol compared with formoterol alone ( rate ratio 0·75 , 95 % CI 0·57 - 0·99 ; pinteraction=0·015 ) . Interactions were observed between eosinophil count and the treatment effects  of budesonide-formoterol over formoterol on St George 's Respiratory Question naire ( pinteraction=0·0043 ) and pre-bronchodilator FEV1 ( linear effect p<0·0001 , pinteraction=0·067 ) . Only eosinophil count and smoking history were independent predictors of response to budesonide-formoterol in reducing exacerbations ( eosinophil count , pinteraction=0·013 ; smoking history , pinteraction=0·015 ) . INTERPRETATION In patients with COPD  treated with formoterol  , blood eosinophil count predicts exacerbation risk and the clinical response to ICS . FUNDING AstraZeneca Background A thorough evaluation of the adequacy of clinical practice in a design ated health care setting and temporal context is key for clinical care improvement . This study aim ed to perform a clinical audit of primary care to evaluate clinical care delivered to patients with COPD in routine clinical practice . Methods The Community Assessment of COPD Health Care ( COACH ) study was an observational , multicenter , nationwide , non-interventional , retrospective , clinical audit of r and omly selected primary care centers in Spain . Two different data bases were built : the re sources and organization data base and the clinical data base . From January 1 , 2015 to December 31 , 2016 consecutive clinical cases of COPD in each participating primary care center ( PCC ) were audited . For descriptive purpose s , we collected data regarding the age at diagnosis of COPD and the age at audit , gender , the setting of the PCC ( rural/urban ) , and comorbidities for each patient . Two guidelines widely and uniformly used in Spain were carefully review ed to establish a benchmark of adequacy for the audited cases . Clinical performance was analyzed at the patient , center , and regional levels . The degree of adequacy was categorized as excellent ( > 80 % ) , good ( 60–80 % ) , adequate ( 40–59 % ) , inadequate ( 20–39 % ) , and highly inadequate ( < 20 % ) . Results During the study 4307 cases from 63 primary care centers in 6 regions of the country were audited . Most evaluated parameters were judged to fall in the inadequate performance category . A correct diagnosis based on previous exposure plus spirometric obstruction was made in an average of 17.6 % of cases , ranging from 9.8 to 23.3 % depending on the region . During the audited visit , only 67 ( 1.6 % ) patients had current post-bronchodilator obstructive spirometry ;  184 ( 4.3 % ) patients had current post-bronchodilator obstructive spirometry  during either the audited or initial diagnostic visit . Evaluation of dyspnea was performed in 11.1 % of cases . Regarding treatment , 33.6 % received no maintenance inhaled therapies ( ranging from 31.3 % in GOLD A to 7.0 % in GOLD D ) . The two most frequently registered items were exacerbations in the previous year ( 81.4 % ) and influenza vaccination ( 87.7 % ) . Conclusions The results of this audit revealed a large variability in clinical performance across centers , which was not fully attributable to the severity of the disease Purpose Current COPD management recommendations indicate that pharmacological treatment can be stepped up or down , but there are no recommendations on how to make this adjustment . We aim ed to describe pharmacological prescriptions during a routine clinical visit for COPD and study the determinants of changing therapy . Methods EPOCONSUL is a Spanish nationwide observational cross-sectional clinical audit with prospect i ve case recruitment including 4,508 COPD patients from outpatient respiratory clinics for a period of 12 months ( May 2014–May 2015 ) .  Prescription patterns were examined in 4,448 cases and changes analyzed in stepwise backward , binomial , multivariate , logistic regression models . Results Patterns of prescription of inhaled therapy groups were no treatment prescribed , 124 ( 2.8 % ) cases ; one or two long-acting bronchodilators ( LABDs ) alone , 1,502 ( 34.6 % ) cases ; LABD with inhaled corticosteroids ( ICSs ) , 389 ( 8.6 % ) cases ; and triple therapy cases , 2,428 ( 53.9 % ) cases . Incorrect prescriptions of inhaled therapies were observed in 261 ( 5.9 % ) cases . After the clinical visit was audited , 3,494 ( 77.5 % ) cases did not modify their therapeutic prescription , 307 ( 6.8 % ) cases had a step up , 238 ( 5.3 % ) cases had a change for a similar scheme , 182 ( 4.1 % ) cases had a step down , and 227 ( 5.1 % ) cases had other nonspecified change . Stepping-up strategies were associated with clinical presentation ( chronic bronchitis , asthma-like symptoms , and exacerbations ) , a positive bronchodilator test , and specific inhaled medication groups . Stepping down was associated with lung function impairment , ICS containing regimens , and nonexacerbator phenotype . Conclusion The EPOCONSUL study shows a comprehensive evaluation of pharmacological treatments in COPD care , highlighting strengths and weaknesses , to help us underst and how physicians use available drugs BACKGROUND Inhaled corticosteroids have been used in patients with chronic obstructive pulmonary disease ( COPD ) , but the potential benefits of their use in triple therapy are not well known . We aim ed to compare the efficacy of a triple therapy with corresponding dual therapies in symptomatic patients with moderate to very severe COPD , without a requirement for a history of exacerbations . METHODS In this double-blind , parallel-group , multicentre phase 3 r and omised controlled trial , we recruited patients from hospitals and care centres in Canada , China , Japan , and the USA . Eligible patients were 40 - 80 years of age , were current or former smokers ( with a smoking history of ≥10 pack-years ) , had an established clinical history of COPD , and were symptomatic for COPD , despite receiving two or more inhaled maintenance therapies for at least 6 weeks before screening . We r and omly assigned patients ( 2:2:1:1 ) using an interactive web response system to receive budesonide/glycopyrrolate/formoterol fumarate metered-dose inhaler 320/18/9·6 μg ( BGF MDI ) , glycopyrrolate/ formoterol fumarate metered-dose inhaler 18/9·6 μg ( GFF MDI ) , budesonide/formoterol fumarate metered-dose inhaler 320/9·6 μg ( BFF MDI ) , or open-label budesonide/formoterol fumarate dry-powder inhaler 400/12 μg ( BUD/ FORM DPI ) . Primary endpoints for the Europe/Canada statistical analysis approach were FEV1 area under the curve from 0 - 4 h ( AUC0 - 4 ) for BGF MDI versus BFF MDI and BGF MDI versus BUD/FORM DPI over 24 weeks ; and change from baseline in morning pre-dose trough FEV1 for BGF MDI versus GFF MDI and non-inferiority of BFF MDI versus BUD/FORM DPI ( margin of -50 mL from lower bound of 95 % CI ) over 24 weeks . Comparisons with BUD/FORM DPI were made for the Europe/Canada statistical analysis approach only . This study is registered with Clinical Trials.gov , number NCT02497001 . FINDINGS Between Aug 20 , 2015 , and Jan 5 , 2018 , 3047 patients were screened from 215 sites , and 1902 were r and omly assigned to receive BGF MDI ( n=640 ) , GFF MDI ( n=627 ) , BFF MDI ( n=316 ) , or BUD/FORM DPI ( n=319 ) . Over 24 weeks , BGF MDI  significantly improved FEV1 AUC0 - 4 versus BFF MDI ( least squares mean difference 104 mL , 95 % CI 77 to 131 ; p<0·0001 ) and BUD/FORM DPI ( 91 mL , 64 to 117 ; p<0·0001  ) . BGF MDI also significantly improved pre-dose trough FEV1 versus GFF MDI ( 22 mL , 4 to 39 ; p=0·0139 ) and was non-inferior to BUD/FORM DPI ( -10 mL , -36 to 16 ; p=0·4390 ) . At week 24 , patients in the BGF MDI group had a significantly improved FEV1 AUC0 - 4 compared with patients receiving BFF MDI ( 116 mL , 95 % CI 80 to 152 ; p<0·0001 ) ; there was a non-significant improvement in the change from baseline in morning pre-dose trough FEV1 at week 24 versus GFF MDI ( 13 mL , -9 to 36 mL ; p=0·2375 ) . The most common treatment-emergent adverse events were nasopharyngitis ( n=49 [ 8 % ] in the BGF MDI group ; n=41 [ 7 % ] in the GFF MDI group ; n=26 [ 8 % ] in the BFF MDI group ; and n=30 [ 9 % ] in the BUD/FORM DPI group ) and upper respiratory tract infection ( n=65 [ 10 % ] ; n=38 [ 6 % ] ; n=18 [ 6 % ] ; and n=22 [ 7 % ] ) . Pneumonia incidence was low ( < 2 % ) and similar across treatments . There were two treatment-related deaths , both in the GFF MDI group . INTERPRETATION BGF MDI was efficacious , well tolerated , and could be a more appropriate treatment than the corresponding dual therapies for symptomatic patients with moderate to very severe COPD , irrespective of exacerbation history . FUNDING Pearl-a member of the AstraZeneca Group Background Run-in periods are occasionally used in r and omized clinical trials to exclude patients after inclusion , but before r and omization . In theory , run-in periods increase the probability of detecting a potential treatment effect , at the cost of possibly affecting external and internal validity . Adequate reporting of exclusions during the run-in period is a prerequisite for judging the risk of compromised validity . Our study aims were to assess the proportion of r and omized clinical trials with run-in periods , to characterize such trials and the types of run-in periods and to assess their reporting . Material s and methods This was an observational study of 470 PubMed -indexed r and omized controlled trial publications from 2014 . We compared trials with and without run-in periods , described the types of run-in periods and evaluated the completeness of their reporting by noting whether publications stated the number of excluded patients , reasons for exclusion and baseline characteristics of the excluded patients . Results Twenty-five trials reported a run-in period ( 5 % ) . These were larger than other trials ( median number of r and omized patients 217 vs 90 , P=0.01 ) and more commonly industry trials ( 11 % vs 3 % , P<0.01 ) . The run-in procedures varied in design and purpose . In 23 out of 25 trials ( 88 % ) , the run-in period was incompletely reported , mostly due to missing baseline characteristics . Conclusion Approximately 1 in 20 trials used run-in periods , though much more frequently in industry trials . Reporting of the run-in period was often incomplete , precluding a meaningful assessment of the impact of the run-in period on the validity of trial results . We suggest that current trials with run-in periods are interpreted with caution and that up date s of reporting guidelines for r and omized trials address the issue Background In patients with chronic obstructive pulmonary disease , all efforts should be made to prevent exacerbations because each event modifies the trajectory of the disease . Treatment recommendations are mostly built on results from r and omized controlled trials ( RCTs ) whose methodology ensure internal validity . However , their relevance may be compromised by the lack of generalizability , due to poor representability of study population s compared to real-life patients .In order to delimit to whom the results of studies on current and future treatments apply , we sought to identify and characterize the fraction of COPD population that would be eligible for inclusion into RCTs aim ing at decreasing exacerbation risk . Methods We used the Initiatives-BPCO data base , a French cohort of 1309 real-life COPD patients monitored in academic centers . We identified  industry-sponsored phase III and IV trials that enrolled more than 500 patients , lasted at least one year and used exacerbations related endpoints . Eligibility criteria were extracted from each trial and applied to the patients . Results The eligibility criteria of 16 RCTs were applied to the 1309 patients . The most discriminating eligibility criteria were FEV1 , minimum exacerbation rate in the previous year and smoking history , responsible for the exclusion of 39.9 , 36.7 and 16.8 % of patients , respectively . Altogether , 2.3 to 46.7 % of our patients would have satisfied all eligibility criteria . Conclusion These analyses confirm that an important gap exists between real-life patients and clinical trials population s in COPD , which limits the relevance of results and therefore should be considered when grading levels of evidence and design ing future studies BACKGROUND Limited 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 compared treatment with extrafine beclometasone dipropionate , formoterol fumarate , and glycopyrronium bromide ( BDP/FF/GB ; fixed triple ) with tiotropium , and BDP/FF plus tiotropium ( open triple ) . METHODS For this double-blind , parallel-group , r and omised , controlled trial , eligible patients had COPD , post-bronchodilator forced expiratory volume in 1 s ( FEV1 ) of less than 50 % , at least one moderate-to-severe COPD exacerbation in the previous 12 months , and a COPD Assessment Test total score of at least 10 . After a 2-week run-in period receiving one inhalation per day via single-dose dry-powder inhaler of open-label 18 μg tiotropium , patients were r and omised ( 2:2:1 ) using a interactive response technology system to 52 weeks treatment with tiotropium , fixed triple , or open triple . R and omisation was stratified by country and severity of airflow limitation . The primary endpoint was moderate-to-severe COPD exacerbation rate . The key secondary endpoint was change from baseline in pre-dose FEV1 at week 52 . The trial is registered with Clinical Trials.gov , number NCT01911364 . FINDINGS Between Jan 21 , 2014 , and March 18 , 2016 , 2691 patients received fixed triple ( n=1078 )  , tiotropium ( n=1075 ) , or open triple ( n=538 ) . Moderate-to-severe exacerbation rates were 0·46 ( 95 % CI 0·41 - 0·51 ) for fixed triple , 0·57 ( 0·52 - 0·63 ) for tiotropium , and 0·45 ( 0·39 - 0·52 ) for open triple ; fixed triple  was superior to tiotropium ( rate ratio 0·80 [ 95 % CI 0·69 - 0·92 ] ; p=0·0025 ) . For week 52 pre-dose FEV1 , fixed triple was superior to tiotropium ( mean difference 0·061 L [ 0·037 to 0·086 ] ; p<0·0001 ) and non-inferior to open triple ( -0·003L [ -0·033 to 0·027 ] ; p=0·85 ) . Adverse events were reported by 594 ( 55 % ) patients with fixed triple , 622 ( 58 % ) with tiotropium , and 309 ( 58 % ) with open triple . INTERPRETATION In our TRINITY study , treatment with extrafine fixed triple therapy  had clinical benefits compared with tiotropium  in patients with symptomatic COPD , FEV1 of less than 50 % , and a history of exacerbations . FUNDING Chiesi Farmaceutici Rationale : R and omized data comparing triple therapy with dual inhaled corticosteroid (ICS)/long‐acting & bgr;2‐agonist ( LABA ) therapy in patients with chronic obstructive pulmonary disease ( COPD ) are limited . Objectives : We compared the effects of once‐daily triple therapy on lung function and health‐related quality of life with twice‐daily ICS/LABA therapy in patients with COPD . Methods : The FULFIL ( Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy ) trial was a r and omized , double‐blind , double‐dummy study comparing 24 weeks of once‐daily triple therapy ( fluticasone furoate/umeclidinium/vilanterol 100 & mgr;g/62.5 & mgr;g/25 & mgr;g ; ELLIPTA inhaler ) with twice‐daily ICS/LABA therapy ( budesonide/formoterol 400 & mgr;g/12 & mgr;g ; Turbuhaler ) . A patient subgroup remained on blinded treatment for up to 52 weeks . Co‐ primary endpoints were change from baseline in trough FEV1 and in St. George ’s Respiratory Question naire ( SGRQ ) total score at Week 24 . Measurements and Main Results : In the intent‐to‐treat population ( n = 1,810 ) at Week 24 for triple therapy ( n = 911 ) and ICS/LABA therapy ( n = 899 ) , mean changes from baseline in FEV1 were 142 ml ( 95 % confidence interval [ CI ] , 126 to 158 ) and −29 ml ( 95 % CI , −46 to −13 ) , respectively , and mean changes from baseline in SGRQ scores were −6.6 units ( 95 % CI , −7.4 to −5.7 ) and −4.3 units ( 95 % CI , −5.2 to −3.4 ) , respectively . For both endpoints , the between‐group differences were statistically significant ( P < 0.001 ) . There was a statistically significant reduction in moderate/severe exacerbation  rate with triple therapy versus dual ICS/LABA therapy ( 35 % reduction ; 95 % CI , 14‐51 ; P = 0.002 ) . The safety profile of triple therapy reflected the known profiles of the components . Conclusions : These results support the benefits of single‐inhaler triple therapy compared with ICS/LABA therapy in patients with advanced COPD . Clinical trial registered with www . clinical trials.gov ( NCT02345161 )
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