Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial Once‐Daily Single‐Inhaler Triple versus Dual Therapy in Patients with COPD Comparison of tiotropium plus fluticasone propionate/salmeterol with tiotropium in COPD: a randomized controlled study. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Effects of Tiotropium and Salmeterol/Fluticasone Propionate on Airway Wall Thickness in Chronic Obstructive Pulmonary Disease Once-Daily Triple Therapy in Patients with Advanced COPD: Healthcare Resource Utilization Data and Associated Costs from the FULFIL Trial 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 Efficacy and Safety of Umeclidinium Added to Fluticasone Propionate/Salmeterol in Patients with COPD: Results of Two Randomized, Double-Blind Studies Efficacy and tolerability of budesonide/formoterol added to tiotropium compared with tiotropium alone in patients with severe or very severe COPD: A randomized, multicentre study in East Asia. The effect of umeclidinium added to inhaled corticosteroid/long-acting β2-agonist in patients with symptomatic COPD: a randomised, double-blind, parallel-group study Benefits of adding fluticasone propionate/salmeterol to tiotropium in moderate to severe COPD. Single-inhaler fluticasone furoate/umeclidinium/vilanterol versus fluticasone furoate/vilanterol plus umeclidinium using two inhalers for chronic obstructive pulmonary disease: a randomized non-inferiority study Effects of adding salmeterol/fluticasone propionate to tiotropium on airway dimensions in patients with chronic obstructive pulmonary disease. A pilot study to assess the effects of combining fluticasone propionate/salmeterol and tiotropium on the airflow obstruction of patients with severe-to-very severe COPD. 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 Efficacy and tolerability of budesonide/formoterol added to tiotropium in patients with chronic obstructive pulmonary disease. FULFIL Trial: Once‐Daily Triple Therapy for Patients with Chronic Obstructive Pulmonary Disease
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 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 . BACKGROUND The combination of tiotropium and fluticasone propionate/salmeterol ( FSC ) is commonly used to treat chronic obstructive pulmonary disease ( COPD ) , but no study had evaluated the effectiveness of tiotropium plus FSC with 250 μg of fluticasone propionate . Our aim was to assess whether tiotropium ( 18 μg once daily ) plus FSC ( 250/50 μg twice daily ) provides better clinical outcomes compared to tiotropium monotherapy . METHODS In this 24-week , r and omized , open label , multicenter two-arm parallel study , 479 patients received tiotropium plus FSC ( n = 237 ) or tiotropium alone ( n = 242 ) . RESULTS After 24 weeks of treatment , the triple-inhaled treatment group had a significant improvement in pre-bronchodilator FEV(1 ) ( L ) compared to the tiotropium-only group ( 0.090 L vs. 0.038 L ; P = 0.005 ) . Regarding health-related quality of life , the mean change in total score on the St. George 's Respiratory Question naire for COPD patients ( SGRQ-C ) was -6.6 points in the tiotropium plus FSC group , but -1.5 points in the tiotropium-only group ( P = 0.001 ) . In the subgroup of GOLD stage II patients with COPD , treatment with tiotropium plus FSC also improved FEV(1 ) compared to tiotropium alone ( 0.088 L vs. 0.030 L ; P = 0.011 ) and improved the total SGRQ-C score  than tiotropium alone ( -4.5 points vs. -1.0 points , respectively ) . This triple-inhaled treatment approach did not induce more adverse events , such as pneumonia . CONCLUSION Over the course of 24 weeks , FSC ( 250/50 μg twice daily ) added to tiotropium provided greater improvement in lung function and quality of life in patients with COPD ( FEV(1 ) ≤ 65 % ) than tiotropium alone Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more 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 Introduction Chronic obstructive pulmonary disease is associated with a high healthcare re source and cost burden . Healthcare re source utilization was analyzed in patients with symptomatic chronic obstructive pulmonary disease at risk of exacerbations in the FULFIL study . Patients received either once-daily , single inhaler triple therapy ( fluticasone furoate/umeclidinium/vilanterol ) 100 µg/62.5 µg/25 µg or twice-daily dual inhaled corticosteroid/long-acting beta agonist therapy ( budesonide/formoterol ) 400 µg/12 µg . Methods FULFIL was a phase III , r and omized , double-blind , double-dummy , multicenter study . Unscheduled contacts with healthcare providers were recorded by patients in a daily electronic diary ; the costs of healthcare re source utilization were calculated post hoc using UK reference costs . Results Over 24 weeks , slightly fewer patients who received fluticasone furoate/umeclidinium/vilanterol ( 169/911 ; 18.6 % ) required contacts with healthcare providers compared with budesonide/formoterol ( 180/899 ; 20.0 % ) . Over 52 weeks in an extension population , fewer patients who received fluticasone furoate/umeclidinium/vilanterol required unscheduled contacts with healthcare providers compared with budesonide/formoterol ( 25.2 % vs. 32.7 % ) . Non-drug costs per treated patient per year were lower in the fluticasone furoate/umeclidinium/vilanterol group than the budesonide/formoterol group over 24 and 52 weeks ( £ 653.80 vs. £ 763.32 and £ 749.22 vs. £ 988.03 , respectively ) , with the total annualized cost over 24 weeks being slightly greater for fluticasone furoate/umeclidinium/vilanterol than budesonide/formoterol ( £ 1,289.35 vs. £ 1,267.45 ) . Conclusions This healthcare re source utilization evidence suggests that , in a clinical trial setting over a 24- or 52-week timeframe , non-drug costs associated with management of a single inhaler fluticasone furoate/umeclidinium/vilanterol are lower compared with twice-daily budesonide/formoterol . Trial Registration Clinical Trials.gov number : NCT02345161 . Funding 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 Abstract Combinations of drugs with distinct and complementary mechanisms of action may offer improved efficacy in the treatment of chronic obstructive pulmonary disease ( COPD ) . In two 12-week , double-blind , parallel-group studies , patients with COPD were r and omized 1:1:1 to once-daily umeclidinium ( UMEC ; 62.5 μg and 125 μg ) or placebo ( PBO ) , added to twice-daily fluticasone propionate/salmeterol ( FP/SAL ; 250/50 μg ) . In both studies , the primary efficacy measure was trough forced expiratory volume in 1 second ( FEV1 ) at Day 85 . Secondary endpoints were weighted-mean ( WM ) FEV1 over 0–6 hours post-dose ( Day 84 ) and rescue albuterol use . Health-related quality of life outcomes ( St. George 's Respiratory Question naire [ SGRQ ] and COPD assessment test [ CAT ] ) were also examined . Safety was assessed throughout . Both UMEC+FP/SAL doses provided statistically significant improvements in trough FEV1 ( Day 85 : 0.127–0.148 L ) versus PBO+FP/SAL . Similarly , both UMEC+FP/SAL doses provided statistically-significant improvements in 0–6 hours post-dose WM FEV1 versus PBO+FP/SAL ( Day 84 : 0.144–0.165 L ) . Rescue use over Weeks 1–12 decreased with UMEC+FP/SAL in both studies versus PBO+FP/SAL ( Study 1 , 0.3 puffs/day [ both doses ] ; Study 2 , 0.5 puffs/day [ UMEC 125+FP/SAL ] ) . Decreases from baseline in CAT score were generally larger for both doses of UMEC+FP/SAL versus PBO+FP/SAL ( except for Day 84 Study 2 ) . In Study 1 , no differences in SGRQ score were observed between UMEC+FP/SAL and PBO+FP/SAL ; however , in Study 2 , statistically significant improvements were observed with UMEC 62.5+FP/SAL ( Day 28 ) and UMEC 125+FP/SAL ( Days 28 and 84 ) versus PBO+FP/SAL . The incidence of on-treatment adverse events across all treatment groups was 37–41 % in Study 1 and 36–38 % in Study 2 . Overall , these data indicate that the combination of UMEC+FP/SAL can provide additional benefits over FP/SAL alone in patients with COPD BACKGROUND AND OBJECTIVE Triple combination therapy with tiotropium plus budesonide/formoterol has improved lung function and reduced exacerbation risk in patients with chronic obstructive pulmonary disease ( COPD ) in Western countries , but no such data exist for East Asian patients . This study aim ed to evaluate the efficacy and tolerability of adding budesonide/formoterol to tiotropium compared with tiotropium alone in East Asian patients with severe/very severe COPD . METHODS This 12-week , r and omized , parallel-group , multicentre , open-label study was conducted in East Asia . After a 14-day run-in period during which patients received tiotropium 18 μg once daily , patients were r and omized to tiotropium ( 18 μg once daily ) + budesonide/formoterol ( 160/4.5 μg 2 inhalations twice daily ) or tiotropium alone ( 18 μg once daily ) . The primary endpoint was change from baseline in pre-dose forced expiratory volume in 1 s ( FEV1 ) to the mean of values measured at Weeks 1 , 6 and 12 . RESULTS Pre-dose FEV1 significantly increased from baseline with tiotropium plus budesonide/formoterol ( n = 287 ) versus tiotropium alone ( n = 291 ) ( 5.0 % vs 0.6 % ; treatment difference : 4.4 % ( 95 % CI : 1.9 - 6.9 ) , P = 0.0004 ) . Triple therapy also reduced the COPD exacerbation rate by 40.7 % ( P = 0.0032 ) and prolonged time to first exacerbation ( 38.6 % risk reduction , P = 0.0167 ) versus tiotropium alone and markedly improved health-related quality of life ( HRQoL ) , measured using the St George 's Respiratory Question naire . Incidence of adverse events was 26 % for both groups . CONCLUSIONS In East Asian patients with severe/very severe COPD , adding budesonide/formoterol to tiotropium was associated with significant improvements in FEV1 and HRQoL and lower COPD exacerbation rates . Treatment was generally well tolerated . CLINICAL TRIAL REGISTRATION NCT01397890 at Clinical trials.gov Benefits of triple therapy with a long-acting muscarinic antagonist ( LAMA ) , added to inhaled corticosteroid (ICS)/long-acting β2-agonist ( LABA ) , have been demonstrated . Limited data assessing the efficacy of the LAMA umeclidinium ( UMEC ) added to ICS/LABA are available . The aim of this study is to evaluate the efficacy and safety of UMEC added to ICS/LABAs in patients with moderate-to-very-severe COPD . This is a multicentre , r and omised , double-blind , parallel-group study . Patients were symptomatic ( modified Medical Research Council Dyspnoea Scale score ⩾2 ) , despite receiving ICS/LABA ( fluticasone propionate/salmeterol ( FP/SAL , br and ed ) 500/50 mcg , budesonide/formoterol ( BD/FOR , br and ed ) 200/6 mcg or 400/12 mcg , or other ICS/LABAs ) ⩾30 days before the run-in ( 7±2 days ) . Patients were r and omised 1:1 to once-daily UMEC 62.5 mcg or placebo ( PBO ) , added to twice-daily open-label ICS/LABA for 12 weeks . Primary end point was trough forced expiratory volume in 1 s ( FEV1 ) at Day 85 ; secondary end point was weighted mean ( WM ) 0–6 h FEV1 at Day 84 ; other end points included COPD Assessment Test ( CAT ) score and Transition Dyspnoea Index ( TDI ) score . Adverse events ( AEs ) were investigated . In the UMEC+ICS/LABA and PBO+ICS/LABA groups , 119 and 117 patients were r and omised , respectively . Patients received FP/SAL ( 40 % ) , BD/FOR ( 43 % ) and other ICS/LABAs ( 17 % ) . UMEC+ICS/LABA result ed in significant improvements in trough FEV1 ( Day 85 ) and in WM 0–6 h FEV1 ( Day 84 ) versus PBO+ICS/LABA ( difference : 123 and 148 ml , respectively , both P<0.001 ) . Change from baseline for UMEC+ICS/LABA versus PBO+ICS/LABA was significantly different for CAT score at Day 84 ( −1.31 , P<0.05 ) , but not for TDI score ( 0.40 , P=0.152 ) . AE incidence was similar with UMEC+ICS/LABA ( 38 % ) and PBO+ICS/LABA ( 42 % ) . UMEC+ICS/LABA improved lung function and CAT score  in patients with symptomatic COPD versus PBO+ICS/LABA ( Clinical Trials.gov NCT02257372 ) BACKGROUND Combining maintenance medications with different mechanisms of action may improve outcomes in COPD . In this study we evaluated the efficacy and safety of fluticasone/salmeterol ( FSC ) ( 250/50 mcg twice daily ) when added to tiotropium ( 18 mcg once daily ) ( TIO ) in subjects with symptomatic moderate to severe COPD . METHODS This was a 24-week , r and omized , double-blind , parallel group , multi-center study . Subjects 40 years or older with cigarette smoking history ≥10 pack-years and with the diagnosis of COPD and post-bronchodilator FEV(1 ) ≥40 to ≤ 80 % of predicted normal and FEV(1)/FVC of ≤0.70 were enrolled . Following a 4-week treatment with open-label TIO 18 mcg once daily , subjects were r and omized in a double-blind fashion to either the addition of FSC 250/50 DISKUS twice daily or matching placebo . The primary efficacy endpoint was AM pre-dose FEV(1 ) and secondary endpoints included other measures of lung function , rescue albuterol use , health status and exacerbations . RESULTS The addition of FSC to TIO significantly improved lung function indices including AM pre-dose FEV(1 ) , 2 h post-dose FEV(1 ) , AM pre-dose FVC , 2 h post-dose FVC and AM pre-dose IC compared with TIO alone . Furthermore , this combination was superior to TIO alone in reducing rescue albuterol use . However , there were no significant differences between the treatment groups in health status or COPD exacerbations . The incidence of adverse events was similar in both groups . CONCLUSIONS The addition of FSC to subjects with COPD treated with TIO significantly improves lung function without increasing the risk of adverse events . NCT00784550 Background Single-inhaler fluticasone furoate/umeclidinium/vilanterol ( FF/UMEC/VI ) 100/62.5/25 μg has been shown to improve lung function and health status , and reduce exacerbations , versus budesonide/formoterol in patients with chronic obstructive pulmonary disease ( COPD ) . We evaluated the non-inferiority of single-inhaler FF/UMEC/VI versus FF/VI + UMEC using two inhalers . Methods Eligible patients with COPD ( aged ≥40 years ; ≥1 moderate/severe exacerbation in the 12 months before screening ) were r and omized ( 1:1 ; stratified by the number of long-acting bronchodilators [ 0 , 1 or 2 ] per day during run-in ) to receive 24-week FF/UMEC/VI 100/62.5/25 μg and placebo or FF/VI 100/25 μg + UMEC 62.5 μg ; all treatments/placebo were delivered using the ELLIPTA inhaler once-daily in the morning . Primary endpoint : change from baseline in trough forced expiratory volume in 1 s ( FEV1 ) at Week 24 . The non-inferiority margin for the lower 95 % confidence limit was set at − 50 mL. Results A total of 1055 patients ( 844 [ 80 % ] of whom were enrolled on combination maintenance therapy ) were r and omized to receive FF/UMEC/VI ( n = 527 ) or FF/VI + UMEC ( n = 528 ) . Mean change from baseline in trough FEV1 at Week 24 was 113 mL ( 95 % CI 91 , 135 ) for FF/UMEC/VI and 95 mL ( 95 % CI 72 , 117 ) for FF/VI + UMEC ; the between-treatment difference of 18 mL ( 95 % CI -13 , 50 ) confirmed FF/UMEC/VI ’s was considered non-inferior to FF/VI + UMEC . At Week 24 , the proportion of responders based on St George ’s Respiratory Question naire Total score was 50 % ( FF/UMEC/VI ) and 51 % ( FF/VI + UMEC ) ; the proportion of responders based on the Transitional Dyspnea Index focal score was similar ( 56 % both groups ) . A similar proportion of patients experienced a moderate/severe exacerbation in the FF/UMEC/VI ( 24 % ) and FF/VI + UMEC ( 27 % ) groups ; the hazard ratio for time to first moderate/severe exacerbation with FF/UMEC/VI versus FF/VI + UMEC was 0.87 ( 95 % CI 0.68 , 1.12 ) . The incidence of adverse events was comparable in both groups ( 48 % ) ; the incidence of serious adverse events was 10 % ( FF/UMEC/VI ) and 11 % ( FF/VI + UMEC ) . Conclusions Single-inhaler triple therapy ( FF/UMEC/VI ) is non-inferior to two inhalers ( FF/VI + UMEC ) on trough FEV1 change from baseline at 24 weeks . Results were similar on all other measures of efficacy , health-related quality of life , and safety . Trial registration GSK study CTT200812 ; Clinical Trials.gov NCT02729051 ( su bmi tted 31 March 2016 ) BACKGROUND AND OBJECTIVE Although salmeterol/fluticasone propionate combination ( SFC ) therapy has been widely used for the treatment of COPD , the relationship between airway dimensions and improvement in pulmonary function remains unknown . The aim of this study was to compare the effects of SFC in combination with tiotropium ( Tio ) and Tio alone , on airway dimensions and pulmonary function in COPD patients . METHODS Thirty COPD patients were r and omized to receive inhaled Tio ( 18 µg once daily ) or inhaled SFC ( 50/250 µg twice daily ) plus Tio for 12 weeks . Spirometry and CT were performed , and the St. George 's Respiratory Question naire ( SGRQ ) was completed , before and after the trial . Airway dimensions were assessed by a vali date d CT technique , and airway wall area ( WA ) corrected for body surface area ( BSA ) , percentage wall area ( WA% ) , absolute wall thickness T/√BSA , and luminal area Ai/BSA at the right apical segmental bronchus , were measured . RESULTS Treatment with SFC plus Tio significantly decreased WA/BSA ( P < 0.05 ) , WA% ( P < 0.01 ) and T/√BSA ( P < 0.01 ) , and increased Ai/BSA ( P < 0.01 ) , whereas treatment with Tio alone had no effect . The changes in WA/BSA and Ai/BSA were significantly correlated with increases in FEV1 ( r = 0.48 , P < 0.05 , and r = 0.36 , P < 0.05 , respectively ) . There were significant improvements in SGRQ scores after treatment with SFC plus Tio . CONCLUSIONS Airway wall thickening and airway narrowing decreased after treatment with SFC plus Tio , and the changes in airway dimensions were proportional to the improvements in FEV1 . These results suggest that SFC plus Tio is more effective than Tio alone in the management of COPD patients The aim of this pilot study was to explore the relative efficacy in terms of improvement in symptoms and lung function of combining fluticasone propionate/salmeterol combination ( FSC ) and tiotropium in patients with severe-to-very severe stable COPD . Ninety patients were r and omized to receive 3 months of treatment in one of three treatment groups : ( 1 ) FSC 500/50 microg Diskus , 1 inhalation twice daily+placebo H and ihaler 1 inhalation once-daily daily ; ( 2 ) tiotropium 18 microg H and ihaler , 1 inhalation once daily+placebo Diskus , 1 inhalation twice daily ; ( 3 ) FSC 500/50 microg Diskus , 1 inhalation twice daily+tiotropium 18 microg H and ihaler , 1 inhalation once-daily daily . Patients attended the clinic before and after 1 month , 2 months , and 3 months of treatment for evaluations of pulmonary function , and dyspnea , which was assessed using a visual analog scale ( VAS ) . Also the supplemental salbutamol use was measured . Eighty-one patients completed the 3-month treatment period : 26 patients receiving FSC , 26 patients receiving tiotropium , and 29 patients receiving FSC+tiotropium .  Patients were withdrawn for COPD exacerbation . Improvements in trough FEV(1 ) with all treatments medications were observed by the first month when trough FEV(1 ) had improved significantly above baseline by 74 mL ( p<0.05 ) in the tiotropium group , by 117 mL ( p<0.05 ) in the FSC group and by 115 mL ( p<0.05 ) in FSC+tiotropium group . At the end of the study , trough FEV(1 ) had improved significantly above baseline by 141 mL ( p<0.05 ) in the tiotropium group , by 140 mL ( p<0.05 ) in the FSC group and by 186 mL ( p<0.05 ) in FSC+tiotropium group . The difference between FSC and tiotropium appeared to decrease , that between FSC and FSC+tiotropium appeared to increase and that between tiotropium and FSC+tiotropium remained almost similar with study duration . Our results suggest that adding FSC and tiotropium may provide benefits in symptomatic patients with severe-to-very severe stable COPD 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 Budesonide/formoterol and tiotropium are commonly used maintenance treatments for patients with chronic obstructive pulmonary disease . Combining these medications may provide additional benefits . OBJECTIVES To assess the efficacy and tolerability of budesonide/formoterol added to tiotropium in patients eligible for inhaled corticosteroid/long-acting beta(2)-agonist combination therapy . METHODS In this 12-week , r and omized , double-blind , parallel-group , multicenter study , after a 2-week run-in , 660 subjects ( 75 % male ; mean age , 62 yr ; FEV(1 ) , 1.1 L ; 38 % predicted normal ) , 40 years of age or older , received tiotropium ( 18 microg once daily )  plus either budesonide/formoterol ( 320/9 microg ) ( n = 329 ) or placebo ( n = 331 ) twice daily . MEASUREMENTS AND MAIN RESULTS Clinic predose ( primary outcome ) and postdose FEV(1 ) , predose and postdose forced vital capacity and inspiratory capacity , and health status were measured . Other outcomes included daily measurements taken at home ( pre- and postdose morning FEV(1 ) and peak expiratory flow , morning symptoms and activities , and morning reliever use ) , severe exacerbations , and tolerability . Over the treatment period , budesonide/formoterol plus tiotropium significantly increased predose FEV(1 ) by 6 % ( 65 ml ) and postdose by 11 % ( 123 and 131 ml at 5 and 60 min postdose , respectively ) versus tiotropium alone ( both P < 0.001 ) . Other outcomes all significantly improved with budesonide/formoterol plus tiotropium versus tiotropium alone . The number of severe exacerbations decreased by 62 % ( rate ratio , 0.38 ; 95 % confidence interval , 0.25 - 0.57 ; P < 0.001 ) . Both treatments were well tolerated . CONCLUSIONS In patients with chronic obstructive pulmonary disease , budesonide/formoterol added to tiotropium versus tiotropium alone provides rapid and sustained improvements in lung function , health status , morning symptoms and activities , and reduces severe exacerbations . Clinical trial registered with www . clinical trials.gov ( NCT00496470 ) 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 )
OBJECTIVE To compare the rate of moderate to severe exacerbations between triple therapy and dual therapy or monotherapy in patients with chronic obstructive pulmonary disease ( COPD ) .