Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2 study Efficacy and safety of once-daily QVA149 compared with the free combination of once-daily tiotropium plus twice-daily formoterol in patients with moderate-to-severe COPD (QUANTIFY): a randomised, non-inferiority study Efficacy and safety of once-daily fluticasone furoate/vilanterol (100/25 mcg) versus twice-daily fluticasone propionate/salmeterol (250/50 mcg) in COPD patients. LANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPD Enhancing exercise tolerance and physical activity in COPD with combined pharmacological and non-pharmacological interventions: PHYSACTO randomised, placebo-controlled study design Concurrent use of indacaterol plus tiotropium in patients with COPD provides superior bronchodilation compared with tiotropium alone: a randomised, double-blind comparison Safety and Efficacy of Fluticasone Propionate/Salmeterol Hydrofluoroalkane 134a Metered-Dose-Inhaler Compared with Fluticasone Propionate/Salmeterol Diskus in Patients with Chronic Obstructive Pulmonary Disease Efficacy and Safety of a 12-week Treatment with Twice-daily Aclidinium Bromide in COPD Patients (ACCORD COPD I) Once-daily inhaled fluticasone furoate and vilanterol versus vilanterol only for prevention of exacerbations of COPD: two replicate double-blind, parallel-group, randomised controlled trials. Long-Term Maintenance Bronchodilation With Indacaterol/Glycopyrrolate Versus Indacaterol in Moderate-to-Severe COPD Patients: The FLIGHT 3 Study. A randomised double-blind, placebo-controlled, long-term extension study of the efficacy, safety and tolerability of fixed-dose combinations of aclidinium/formoterol or monotherapy in the treatment of chronic obstructive pulmonary disease. Long-term safety and efficacy of glycopyrrolate/formoterol metered dose inhaler using novel Co-Suspension™ Delivery Technology in patients with chronic obstructive pulmonary disease. Umeclidinium/vilanterol as step-up therapy from tiotropium in patients with moderate COPD: a randomized, parallel-group, 12-week study A multicenter, randomized, double-blind dose-ranging study of glycopyrrolate/formoterol fumarate fixed-dose combination metered dose inhaler compared to the monocomponents and open-label tiotropium dry powder inhaler in patients with moderate-to-severe COPD. Effect of 12 weeks of once-daily tiotropium/olodaterol on exercise endurance during constant work-rate cycling and endurance shuttle walking in chronic obstructive pulmonary disease A randomized, blinded study to evaluate the efficacy and safety of umeclidinium 62.5 μg compared with tiotropium 18 μg in patients with COPD A phase III randomised controlled trial of single-dose triple therapy in COPD: the IMPACT protocol Tiotropium and olodaterol in the prevention of chronic obstructive pulmonary disease exacerbations (DYNAGITO): a double-blind, randomised, parallel-group, active-controlled trial. Efficacy and Tolerability of Budesonide/Formoterol in One Hydrofluoroalkane Pressurized Metered-Dose Inhaler in Patients with Chronic Obstructive Pulmonary Disease Once‐Daily Single‐Inhaler Triple versus Dual Therapy in Patients with COPD The effect of aclidinium bromide on daily respiratory symptoms of COPD, measured using the Evaluating Respiratory Symptoms in COPD (E-RS: COPD) diary: pooled analysis of two 6-month Phase III studies Lung function efficacy and symptomatic benefit of olodaterol once daily delivered via Respimat® versus placebo and formoterol twice daily in patients with GOLD 2–4 COPD: results from two replicate 48-week studies The prevention of chronic obstructive pulmonary disease exacerbations by salmeterol/fluticasone propionate or tiotropium bromide. Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: the 24-week, randomized, placebo-controlled AUGMENT COPD study Once-daily indacaterol versus twice-daily salmeterol for COPD: a placebo-controlled comparison Outcomes in COPD patients receiving tiotropium or salmeterol plus treatment with inhaled corticosteroids Combining tiotropium and salmeterol in COPD: Effects on airflow obstruction and symptoms. Effect of Fluticasone Propionate/Salmeterol (250/50) on COPD Exacerbations and Impact on Patient Outcomes Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomised controlled trials. Effects of Tiotropium and Salmeterol/Fluticasone Propionate on Airway Wall Thickness in Chronic Obstructive Pulmonary Disease Efficacy and safety of fluticasone furoate/vilanterol or tiotropium in subjects with COPD at cardiovascular risk Budesonide/formoterol via Turbuhaler® versus formoterol via Turbuhaler® in patients with moderate to severe chronic obstructive pulmonary disease: phase III multinational study results. A randomised, open-label study of umeclidinium versus glycopyrronium in patients with COPD Formoterol and Tiotropium Compared With Tiotropium Alone for Treatment of COPD Effects of indacaterol/glycopyrronium (QVA149) on lung hyperinflation and physical activity in patients with moderate to severe COPD: a randomised, placebo-controlled, crossover study (The MOVE Study) Efficacy of a new once-daily long-acting inhaled β2-agonist indacaterol versus twice-daily formoterol in COPD Effect of budesonide/formoterol pMDI on COPD exacerbations: a double-blind, randomized study. Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study. INSTEAD: a randomised switch trial of indacaterol versus salmeterol/fluticasone in moderate COPD Comparison of registered and published primary outcomes in randomized controlled trials. Magnitude of umeclidinium/vilanterol lung function effect depends on monotherapy responses: Results from two randomised controlled trials. Acute effects of indacaterol on lung hyperinflation in moderate COPD: a comparison with tiotropium. A randomised trial of fluticasone furoate/vilanterol (50/25 μg; 100/25 μg) on lung function in COPD. Umeclidinium/vilanterol versus fluticasone propionate/salmeterol in COPD: a randomised trial Long-acting bronchodilators and arterial stiffness in patients with COPD: a comparison of fluticasone furoate/vilanterol with tiotropium. Dual bronchodilation with QVA149 reduces patient-reported dyspnoea in COPD: the BLAZE study The lung function profile of once-daily tiotropium and olodaterol via Respimat® is superior to that of twice-daily salmeterol and fluticasone propionate via Accuhaler® (ENERGITO® study) A blinded evaluation of the efficacy and safety of glycopyrronium, a once-daily long-acting muscarinic antagonist, versus tiotropium, in patients with COPD: the GLOW5 study Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial Efficacy and safety of coadministration of once-daily indacaterol and glycopyrronium versus indacaterol alone in COPD patients: the GLOW6 study Maintenance therapy with budesonide and formoterol in chronicobstructive pulmonary disease Safety and tolerability of once-daily umeclidinium/vilanterol 125/25 mcg and umeclidinium 125 mcg in patients with chronic obstructive pulmonary disease: results from a 52-week, randomized, double-blind, placebo-controlled study Efficacy and safety of inhaled formoterol 4.5 and 9 μg twice daily in Japanese and European COPD patients: Phase III study results Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2–4) Fluticasone propionate/salmeterol 250/50 μg versus salmeterol 50 μg after chronic obstructive pulmonary disease exacerbation Dual Bronchodilator Therapy with Umeclidinium/Vilanterol Versus Tiotropium plus Indacaterol in Chronic Obstructive Pulmonary Disease: A Randomized Controlled Trial Blinded 12-week comparison of once-daily indacaterol and tiotropium in COPD Anti-inflammatory effects of salmeterol/fluticasone, tiotropium/fluticasone or tiotropium in COPD Efficacy and safety of once-daily inhaled umeclidinium/vilanterol in Asian patients with COPD: results from a randomized, placebo-controlled study Effects of indacaterol versus tiotropium on exercise tolerance in patients with moderate COPD: a pilot randomized crossover study Efficacy and safety of QVA149 compared to the concurrent administration of its monocomponents indacaterol and glycopyrronium: the BEACON study Efficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study Efficacy and safety of combining olodaterol Respimat® and tiotropium HandiHaler® in patients with COPD: results of two randomized, double-blind, active-controlled studies Tiotropium + olodaterol shows clinically meaningful improvements in quality of life. Analysis of chronic obstructive pulmonary disease exacerbations with the dual bronchodilator QVA149 compared with glycopyrronium and tiotropium (SPARK): a randomised, double-blind, parallel-group study. Profiling the effects of indacaterol on dyspnoea and health status in patients with COPD. [Combination of inhaled salmeterol/fluticasone and tiotropium in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial]. Withdrawal of fluticasone propionate from combined salmeterol/fluticasone treatment in patients with COPD causes immediate and sustained disease deterioration: a randomised controlled trial Efficacy and safety of olodaterol once daily delivered via Respimat® in patients with GOLD 2–4 COPD: results from two replicate 48-week studies Fluticasone propionate/formoterol for COPD management: a randomized controlled trial Effect of budesonide/formoterol pressurized metered-dose inhaler on exacerbations versus formoterol in chronic obstructive pulmonary disease: The 6-month, randomized RISE (Revealing the Impact of Symbicort in reducing Exacerbations in COPD) study. Improvements in lung function with umeclidinium/vilanterol versus fluticasone propionate/salmeterol in patients with moderate-to-severe COPD and infrequent exacerbations. Changes in lung function and health status in patients with COPD treated with tiotropium or salmeterol plus fluticasone. Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium. Formoterol mono- and combination therapy with tiotropium in patients with COPD: a 6-month study. Integrating indacaterol dose selection in a clinical study in COPD using an adaptive seamless design. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Tolerance to bronchodilating effects of salmeterol in COPD. Effect of combination treatment on lung volumes and exercise endurance time in COPD. Improved daytime spirometric efficacy of tiotropium compared with salmeterol in patients with COPD. Efficacy and Safety of Glycopyrrolate/Formoterol Metered Dose Inhaler Formulated Using Co‐Suspension Delivery Technology in Patients With COPD Impact of salmeterol/fluticasone propionate versus salmeterol on exacerbations in severe chronic obstructive pulmonary disease. Tiotropium in Combination with Placebo, Salmeterol, or FluticasoneSalmeterol for Treatment of Chronic Obstructive Pulmonary Disease FLIGHT1 and FLIGHT2: Efficacy and Safety of QVA149 (Indacaterol/Glycopyrrolate) versus Its Monocomponents and Placebo in Patients with Chronic Obstructive Pulmonary Disease. Assessing efficacy of indacaterol in moderate and severe COPD patients: a 12-week study in an Asian population. One-Year Extension Study of ACCORD COPD I: Safety and Efficacy of Two Doses of Twice-daily Aclidinium Bromide in Patients with COPD Effect of tiotropium vs. salmeterol on exacerbations: GOLD II and maintenance therapy naïve patients. Efficacy and safety of direct switch to indacaterol/glycopyrronium in patients with moderate COPD: the CRYSTAL open-label randomised trial Compare the efficacy and safety of long-acting anticholinergic and a combination of inhaled steroids and long-acting beta-2 agonist in moderate chronic obstructive pulmonary disease. Influence of salmeterol/fluticasone via single versus separate inhalers on exacerbations in severe/very severe COPD. Effect of fluticasone propionate/salmeterol (250/50 microg) or salmeterol (50 microg) on COPD exacerbations. Efficacy and safety of aclidinium/formoterol versus salmeterol/fluticasone: a phase 3 COPD study Fluticasone furoate/vilanterol (100/25; 200/25 μg) improves lung function in COPD: a randomised trial. A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol. Effect of once-daily indacaterol in a predominantly Chinese population with chronic obstructive pulmonary disease: a 26-week Asia-Pacific study. ACCORD COPD II: A Randomized Clinical Trial to Evaluate the 12-Week Efficacy and Safety of Twice-Daily Aclidinium Bromide in Chronic Obstructive Pulmonary Disease Patients A randomised, phase III trial of once-daily fluticasone furoate/vilanterol 100/25 μg versus once-daily vilanterol 25 μg to evaluate the contribution on lung function of fluticasone furoate in the combination in patients with COPD. 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. Comparison of a combination of tiotropium plus formoterol to salmeterol plus fluticasone in moderate COPD. Efficacy and safety of once-daily QVA149 compared with twice-daily salmeterol-fluticasone in patients with chronic obstructive pulmonary disease (ILLUMINATE): a randomised, double-blind, parallel group study. Extrafine beclomethasone/formoterol in severe COPD patients with history of exacerbations. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. Quality of life changes in COPD patients treated with salmeterol. Beclomethasone/formoterol in the management of COPD: a randomised controlled trial. Long-term safety and efficacy of twice-daily aclidinium bromide in patients with COPD. Safety and tolerability of NVA237, a once-daily long-acting muscarinic antagonist, in COPD patients. Comparison of airway dimensions with once daily tiotropium plus indacaterol versus twice daily Advair(®) in chronic obstructive pulmonary disease. Computed tomography assessment of airway dimensions with combined tiotropium and indacaterol therapy in COPD patients. Once-daily umeclidinium/vilanterol 125/25 mcg in COPD: a randomized, controlled study. AMPLIFY: a randomized, Phase III study evaluating the efficacy and safety of aclidinium/formoterol vs monocomponents and tiotropium in patients with moderate-to-very severe symptomatic COPD Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Effect of QVA149 on lung volumes and exercise tolerance in COPD patients: the BRIGHT study. Long-term safety of glycopyrrolate: A randomized study in patients with moderate-to-severe COPD (GEM3). Long-term safety of aclidinium bromide/formoterol fumarate fixed-dose combination: Results of a randomized 1-year trial in patients with COPD. Tiotropium versus salmeterol for the prevention of exacerbations of COPD. Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD.
We investigated the efficacy and safety of dual bronchodilation with QVA149 versus its monocomponents indacaterol and glycopyrronium , tiotropium and placebo in patients with moderate-to-severe chronic obstructive pulmonary disease ( COPD ) . This was a multicentre , r and omised , double-blind , placebo- and active-controlled , 26-week trial . Patients ( n = 2144 ) were r and omised ( 2:2:2:2:1 ) to receive once-daily QVA149 ( indacaterol 110 & mgr;g/glycopyrronium 50 & mgr;g ) , indacaterol 150 & mgr;g , glycopyrronium 50 & mgr;g , open-label tiotropium 18 & mgr;g or placebo . The primary end-point was trough forced expiratory volume in 1 s ( FEV1 ) at week 26 for QVA149 versus its monocomponents . Secondary end-points included dyspnoea , health status , rescue medication use and safety . Trough FEV1 at week 26 was significantly improved ( p<0.001 ) with QVA149 compared with indacaterol and glycopyrronium ( least squares mean ( LSM ) differences 0.07 L and 0.09 L , respectively ) , tiotropium and placebo ( LSM differences 0.08 L and 0.20 L , respectively ) ; these beneficial effects were sustained throughout the 26-week study . QVA149 significantly improved dyspnoea and health status versus placebo ( p<0.001 and p = 0.002 , respectively ) and tiotropium ( p = 0.007 and p = 0.009 , respectively ) at week 26 . All treatments were well tolerated . Dual bronchodilation with once-daily QVA149 demonstrated superior and clinical ly meaningful outcomes versus placebo and superiority versus treatment with a single bronchodilator , with a safety and tolerability profile similar to placebo , supporting the concept of fixed-dose long-acting muscarinic antagonist/long-acting & bgr;2-agonist combinations for the treatment of COPD . Dual indacaterol/glycopyrronium therapy was safe and more efficacious than monotherapy in moderate-to-severe COPD NVA237 ( glycopyrronium bromide ) is a once-daily long-acting muscarinic antagonist ( LAMA ) in development for chronic obstructive pulmonary disease ( COPD ) . The GLycopyrronium bromide in COPD airWays clinical Study 2 ( GLOW2 ) evaluated the efficacy and safety of NVA237 in moderate-to-severe COPD over 52 weeks . Patients were r and omised 2:1:1 to NVA237 50 μg , placebo or open-label tiotropium 18 μg for 52 weeks . Primary end-point was trough forced expiratory volume in 1 s ( FEV1 ) at 12 weeks . 1,066 patients were r and omised , 810 completed the study . At week 12 , trough FEV1 increased significantly by 97 mL with NVA237 ( 95 % CI 64.6–130.2 ; p<0.001 ) and 83 mL with tiotropium ( 95 % CI 45.6–121.4 ; p<0.001 ) . Compared with placebo , NVA237 produced significant improvements in dyspnoea ( Transition Dyspnoea Index at week 26 ; p=0.002 ) and health status ( St George 's Respiratory Question naire at week 52 ; p<0.001 ) . NVA237 significantly reduced the risk of moderate-to-severe COPD exacerbations by 34 % ( p=0.001 ) and the use of rescue medication ( p=0.039 ) , versus  placebo  . NVA237-placebo and tiotropium-placebo differences were comparable for all outcomes . Safety profiles were similar across groups . NVA237 50 μg provided significant improvements in lung function , dyspnoea , health status , exacerbations and rescue medication use , versus placebo , and was comparable to tiotropium . NVA237 can potentially be an alternative choice of LAMA for COPD patients Background QVA149 is a once-daily ( o.d . ) inhaled dual bronchodilator containing a fixed-dose combination of the long-acting β2-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium for the treatment of COPD . The QUANTIFY study compared QVA149 with a free-dose bronchodilator combination of tiotropium plus formoterol ( TIO+FOR ) in improving health-related quality of life ( HRQoL ) of patients with COPD . Methods This multicentre , blinded , triple-dummy , parallel-group , non-inferiority study r and omised patients aged ≥40 years with moderate-to-severe COPD ( post-bronchodilator forced expiratory volume in 1 s ( FEV1 ) ≥30 % to < 80 % predicted ) to QVA149 110/50 µg o.d . or TIO 18 µg o.d.+ FOR 12 µg twice daily ( 1:1 ) for 26 weeks . The primary endpoint was to demonstrate non-inferiority in HRQoL assessed using St George 's Respiratory Question naire- COPD ( SGRQ-C ) . The prespecified non-inferiority margin was 4 units . Secondary endpoints included Transition Dyspnoea Index ( TDI ) score , pre-dose FEV1 , forced vital capacity ( FVC ) and safety . Results Of the 934 patients r and omised ( QVA149=476 and TIO+FOR=458 ) , 87.9 % completed the study . At week 26 , non-inferiority was met for SGRQ-C ( QVA149 vs TIO+FOR ; difference : –0.69 units ; 95 % CI −2.31 to 0.92 ; p=0.399 ) . A significantly higher percentage of patients achieved a clinical ly relevant ≥1 point improvement in TDI total score with QVA149 ( 49.6 % ) versus TIO+FOR ( 42.4 % ; p=0.033 ) . QVA149 significantly increased pre-dose FEV1 ( + 68 mL , 95 % CI 37 mL to 100 mL ; p<0.001 ) and FVC ( + 74 mL , 95 % CI 24 mL to 125 mL ; p=0.004 ) compared with TIO+FOR at week 26 . The incidence of adverse events was comparable between both treatments ( QVA149=43.7 % and TIO+FOR=42.6 % ) . Conclusions QVA149 is non-inferior to TIO+FOR in improving HRQoL , with clinical ly meaningful and significant improvements in breathlessness and lung function in patients with COPD . Trial registration number NCT01120717 BACKGROUND Fluticasone furoate/vilanterol ( FF/VI ) is an inhaled corticosteroid/long-acting beta2-agonist ( ICS/LABA ) , recently approved as once-daily maintenance therapy for COPD . We compared the lung function effects of FF/VI with those of twice-daily fluticasone propionate/salmeterol ( FP/SAL ) . METHODS Three 12 week studies comparing FF/VI and FP/SAL were conducted . Patients aged ≥40 years with moderate-to-very severe COPD were r and omized to receive double-blind , double-dummy FF/VI 100/25 mcg once-daily , or FP/SAL 250/50 mcg twice-daily for 12 weeks following a 2 week placebo run-in period . The primary endpoint of each study was change from baseline trough in 0 - 24 h weighted mean FEV(1 ) ( wmFEV(1 ) ) on Day 84 . Safety was also assessed . RESULTS In Study 1 ( HZC113109 ) ( intent-to-treat n : FF/VI = 260 ; FP/SAL = 259 ) , the increase from baseline in 0 - 24 h wmFEV(1 ) was significantly greater with FF/VI than FP/SAL ( Δ80 mL , P < 0.001 ) . In Study 2 ( HZC112352 ) ( intent-to-treat n : FF/VI = 259 ; FP/SAL = 252 ) and Study 3 ( RLV116974 ) ( intent-to-treat n : FF/VI = 412 ; FP/SAL = 416 ) , the increase from baseline in 0 - 24 h wmFEV(1 ) was not significantly greater with FF/VI than FP/SAL ( Δ29 mL , P = 0.267 ; Δ25 mL , P = 0.137 ) . The treatment difference was statistically but not clinical ly significant in a pooled analysis ( Δ41 mL , P < 0.001 ) . Pooled adverse events ( FF/VI 27 % ; FP/SAL 28 % ) and serious adverse events ( FF/VI 2 % ; FP/SAL 3 % ) were similar between treatments . CONCLUSIONS Our data suggest that once-daily FF/VI 100/25 mcg provides FEV(1 ) improvement in COPD that is at least comparable with that conferred by twice-daily FP/SAL 250/50 mcg , although interpretation is limited by differences in individual study outcomes . The safety profiles of FF/VI 100/25 mcg and FP/SAL 250/50 mcg are similar . CLINICAL TRIAL REGISTRATION clinical trials.gov : NCT01323634 ; NCT01323621 ; NCT01706328 . GlaxoSmithKline study codes : HZC113109 ; HZC112352 ; RLV116974 Background The current Global initiative for chronic Obstructive Lung Disease ( GOLD ) treatment strategy recommends the use of one or more bronchodilators according to the patient ’s airflow limitation , their history of exacerbations , and symptoms . The LANTERN study evaluated the effect of the long-acting β2-agonist (LABA)/long-acting muscarinic antagonist ( LAMA ) dual bronchodilator , QVA149 ( indacaterol/glycopyrronium ) , as compared with the LABA/inhaled corticosteroid , salmeterol/fluticasone ( SFC ) , in patients with moderate-to-severe COPD with a history of ≤1 exacerbation in the previous year . Methods In this double-blind , double-dummy , parallel-group study , 744 patients with moderate-to-severe COPD with a history of ≤1 exacerbations in the previous year were r and omized ( 1:1 ) to QVA149 110/50 μg once daily or SFC 50/500 μg twice daily for 26 weeks . The primary endpoint was noninferiority of QVA149 versus SFC for trough forced expiratory volume in 1 second ( FEV1 ) at week 26 . Results Overall , 676 patients completed the study . The primary objective of noninferiority between QVA149 and SFC in trough FEV1 at week 26 was met . QVA149 demonstrated statistically significant superiority to SFC for trough FEV1 ( treatment difference [Δ]=75 mL ; P<0.001 ) . QVA149 demonstrated a statistically significant improvement in st and ardized area under the curve ( AUC ) from 0 hours to 4 hours for FEV1 ( FEV1 AUC0–4h ) at week 26 versus SFC ( Δ=122 mL ; P<0.001 ) . QVA149 and SFC had similar improvements in transition dyspnea index focal score , St George Respiratory Question naire total score , and rescue medication use . However , QVA149 significantly reduced the rate of moderate or severe exacerbations by 31 % ( P=0.048 ) over SFC . Overall , the incidence of adverse events was comparable between QVA149 ( 40.1 % ) and SFC ( 47.4 % ) . The incidence of pneumonia was threefold lower with QVA149 ( 0.8 % ) versus SFC ( 2.7 % ) . Conclusion These findings support the use of the LABA/LAMA , QVA149 as an alternative treatment , over LABA/inhaled corticosteroid , in the management of moderate-to-severe COPD patients ( GOLD B and GOLD D ) with a history of ≤1 exacerbation in the previous year Introduction Chronic obstructive pulmonary disease ( COPD ) is associated with exercise limitation and physical inactivity , which are believed to have significant long-term negative health consequences for patients . While a number of COPD treatments and exercise training programmes increase exercise capacity , there is limited evidence for their effects on physical activity levels , with no clear association between exercise capacity and physical activity in clinical trials . Physical activity depends on a number of behaviour , environmental and physiological factors . We describe the design of the PHYSACTO trial , which is investigating the effects of bronchodilators , either alone or with exercise training , in combination with a st and ardised behaviour-change self-management programme , on exercise capacity and physical activity in patients with COPD . It is hypothesised that bronchodilators in conjunction with a behaviour-change self-management programme will improve physical activity and that this effect will be amplified by the addition of exercise training . Methods and analysis Patients are being recruited from 34 sites in Australia , New Zeal and , the USA , Canada and Europe . Patients receiving a multicomponent intervention design ed to support behaviour change related to physical activity are r and omised to four treatment arms : placebo , tiotropium , tiotropium+olo date rol , and tiotropium+olo date rol+exercise training . The primary outcome is improvement in exercise capacity after 8 weeks , measured by endurance time during a shuttle walk test . The secondary outcome is improvement in physical activity , including objective accelerometer assessment and patient-reported functioning using the Functional Performance Inventory — Short Form and the novel hybrid PROactive instrument . Additionally , the influence of moderating variables ( ie , factors influencing a patient 's choice to be physically active ) on increases in physical activity is also explored . Ethics and dissemination The study has been approved by the relevant Institutional Review Boards , Independent Ethics Committee and Competent Authority according to national and international regulations . The findings of the trial will be disseminated through relevant peer- review ed journals and international conference presentations . Trial registration number NCT02085161 Background Current guidelines recommend treatment with one or more long-acting bronchodilators for patients with moderate or more severe chronic obstructive pulmonary disease ( COPD ) . The authors investigated the approach of dual bronchodilation using indacaterol , a once-daily long-acting β2 agonist , and the long-acting muscarinic antagonist tiotropium , compared with tiotropium alone . Methods In two identically design ed , double-blind , 12-week studies , patients with moderate to severe COPD were r and omised to indacaterol 150 μg once daily or matching placebo . All patients concurrently received open-label tiotropium 18 μg once daily . The primary outcome was st and ardised area under the curve of forced expiratory volume in 1 s ( FEV1 ) from 5 min to 8 h post dose at week 12 . The key secondary outcome was 24 h post-dose ( ‘ trough ’ ) FEV1 at week 12 . Resting inspiratory capacity ( IC ) was measured in a subgroup . Results 1134 and 1142 patients were r and omised in studies 1 and 2 ; 94 % and 94 % completed . Compared with monotherapy , concurrent therapy increased FEV1 ( area under the curve by 130 and 120 ml , trough by 80 and 70 ml ; all p<0.001 ) and trough IC ( by 130 and 100 ml , p<0.01 ) . Cough was more common with indacaterol plus tiotropium ( 10 % and 9 % ) than with tiotropium alone ( 4 % and 4 % ) . Most cases ( ∼90 % ) of cough were mild . Other adverse events were similar for the treatment groups . Conclusions Compared with tiotropium monotherapy , indacaterol plus tiotropium  provided greater bronchodilation and lung deflation ( reflected by increased resting IC ) . Adverse events were similar between treatments apart from mild cough being more common with indacaterol plus tiotropium . These results support COPD guideline recommendations to combine bronchodilators with different mechanisms of action . Trial registration numbers NCT00846586 and NCT00877383 Purpose : To provide information on the efficacy and safety of Fluticasone Propionate/Salmeterol Hydrofluoroalkane 134a Metered-Dose-Inhaler 230/42mcg ( FSC MDI ) and its comparable dose of Fluticasone Propionate/Salmeterol DISKUS 250/50mcg ( FSC DISKUS ) in patients with COPD . Methods : This multicenter , r and omized , double-blind , 12 week study was design ed to evaluate FSC MDI treatment responses as compared with FSC DISKUS . The primary comparison of interest was non-inferiority between the FSC MDI treatment group and the FSC DISKUS treatment group assessed in terms of 2-hour post-dose FEV1 change from baseline at endpoint . The non-inferiority criterion bound was 75mL ( lower confidence limit of -75mL ) . Inclusion criteria : Male or female aged ≥ 40 , post-bronchodilator FEV1 ≤ 70 % predicted normal , FEV1/FVC ≤ 70 % and ≥ 10 pack years smoking history . Adverse events were recorded by patients throughout the study on daily diary cards . Adverse events were collected in eCRFs at all clinic visits and during a final follow-up phone call . Results : Patients ( N=247 ) were r and omized to FSC MDI ( FEV1 % 49.3 ± 12.3 , FEV1/FVC 50.5 ± 10.0 ) and FSC DISKUS ( FEV1 % 48.4 ± 11.0 , FEV1/FVC 50.3 ± 10.3 ) . From an ANCOVA model the least squares ( LS ) mean difference ( FSC MDI– FSC DISKUS ) for the 2-hour post dose FEV1 at endpoint was -2.0mL ( 95 % CI -64mL , 59mL ) . Pre-dose FEV1 , FVC , PEF , and albuterol use were also similar between the two formulations . The most common adverse events ( AE ) during treatment were headache ( 8 % and 6 % of patients ) , nasopharyngitis ( 4 % and 6 % ) , cough ( 3 % and 4 % ) , and sinusitis ( 2 % and 5 % ) for FSC MDI and FSC DISKUS , respectively . Pneumonia was recorded as an AE for 2 ( 2 % ) patients in the FSC DISKUS arm . Conclusion : This is the first study to demonstrate that FSC MDI has a similar efficacy and safety profile to FSC DISKUS in COPD patients Abstract Background : This Phase III study evaluated the efficacy and safety of twice-daily aclidinium 200 μg and 400 μg versus placebo in the treatment of moderate-to-severe COPD . Methods : In this 12-week , double-blind , multicenter trial , patients were r and omized ( 1:1:1 ) to inhaled twice-daily aclidinium 200 μg , aclidinium 400 μg , or placebo . Primary and secondary endpoints were changes from baseline in trough FEV1 and peak FEV1 at Week 12 , respectively . Health status ( St. George 's Respiratory Question naire [ SGRQ ] ) , COPD symptoms ( Transitional Dyspnea Index [ TDI ] , night and early morning symptoms ) , and safety were also assessed . Results : A total of 561 patients ( mean age , 64 ± 9 years ) with a mean baseline FEV1 of 1.36 ± 0.54 L ( 47.2 % of predicted value ) were r and omized . At Week 12 , aclidinium 200 μg and 400 μg showed significant improvements from baseline in mean ( 95 % CI ) trough FEV1 compared with placebo by 86 ( 45 , 127 ) mL and 124 ( 83,164 ) mL , respectively , and in peak FEV1 by 146 ( 101 , 190 ) mL and 192 ( 148 , 236 ) mL , respectively ( p ≤ 0.0001 for all ) . Both aclidinium doses also provided significant improvements in SGRQ , TDI and almost all COPD symptom scores compared with placebo ( p < 0.05 for all ) . Incidences of adverse events ( AEs ) were similar across treatment groups . The incidence of anticholinergic AEs was low and similar across groups ( dry mouth : 0.5%–1.6 % ; constipation : 0%-1.1 % ) . Conclusions : Treatment of moderate-to-severe COPD patients with twice-daily aclidinium 200 μg and 400 μg was associated with significant improvements in bronchodilation , health status , and COPD symptoms . Both doses were well tolerated and had safety profiles similar to placebo . Trial Registration : This ACCORD I study ( AClidinium in Chronic Obstructive Respiratory Disease I ) was registered on clinical trials.gov ( NCT00891462 ) as “ Efficacy and Safety of Aclidinium Bromide for Treatment of Moderate to Severe Chronic Obstructive Pulmonary Disease ( COPD ) ” BACKGROUND Whether the combination of a once-daily inhaled corticosteroid with a once-daily longacting β(2 ) agonist is more protective than a once-daily longacting β(2 ) agonist alone against exacerbations of chronic obstructive pulmonary disease ( COPD ) is unknown . We hypothesised that fluticasone furoate and vilanterol would prevent more exacerbations than would vilanterol alone . METHODS We did two replicate double-blind parallel-group 1 year trials . Both studies began on Sept 25 , 2009 . Study 1 ended on Oct 31 , 2011 , and study 2 on Oct 17 , 2011 . Eligible patients were aged 40 years or older , had a history of COPD , a smoking history of 10 or more pack-years , a ratio of forced expiratory volume in 1 s ( FEV(1 ) ) to forced vital capacity of 0·70 or less after bronchodilators ( and an FEV(1 ) of 70 % or less of predicted ) , and a documented history of one or more moderate or severe disease exacerbations in the year before screening . Patients were r and omly assigned ( 1:1:1:1 ) on the basis of the Registration and Medication Ordering System to 25 μg vilanterol alone or 25 μg vilanterol combined with either 50 μg , 100 μg , or 200 μg fluticasone furoate once daily . Our primary endpoint was the yearly rate of moderate and severe exacerbations . The trials were analysed separately and a pooled analysis was also done . These trials are registered with Clinical Trials.gov ( NCT01009463 and NCT01017952 ) . FINDINGS 1622 patients in study 1 and 1633 patients in study 2 were r and omly assigned . In study 1 , no significant difference in exacerbation rate was noted between the 200/25 μg fluticasone furoate/vilanterol group and the vilanterol only group ( mean 0·90 events vs 1·05 events per year ; ratio 0·9 [ 95 % CI 0·7 - 1·0 ] ) . Because of the statistical hierarchy used , we could not infer significance for the 50 μg and 100 μg groups . In study 2 , significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group ( p=0·0398 for the 50 μg group , 0·0244 for the 100 μg group , and 0·0004 for the 200 μg group ) . In the pooled analysis , significantly fewer moderate and severe exacerbations were noted in all fluticasone furoate/vilanterol groups than in the vilanterol only group ( 0·0141 for the 50 μg group , < 0·0001 for the 100 μg group , and 0·0003 for the 200 μg group ) . Nasopharyngitis was the most frequently reported adverse event in both studies . Pneumonia and fractures were reported more frequently with fluticasone furoate and vilanterol than with vilanterol alone . Eight deaths from pneumonia were noted in the fluticasone furoate/vilanterol groups compared with none in the vilanterol only group . INTERPRETATION Addition of fluticasone furoate to vilanterol was associated with a decreased rate of moderate and severe exacerbations of COPD  in patients with a history of exacerbation , but was also associated with an increased pneumonia risk . FUNDING GlaxoSmithKline Background : The objective of the FLIGHT3 study was to evaluate the long-term safety and efficacy of indacaterol/glycopyrrolate * ( IND/GLY ) versus an active comparator , IND , in patients with moderate-to-severe chronic obstructive pulmonary disease ( COPD ) over 52 weeks . Method : FLIGHT3 was a multicenter , r and omized , double-blind , parallel-group , 52-week study . Patients were r and omized ( 1:1:1 ) to IND/GLY ( 27.5/15.6 or 27.5/31.2 µg twice daily [ b.i.d . ] ) or IND ( 75 µg once daily [ o.d . ] ) , delivered via the Neohaler ® device . The primary objective was to evaluate the long-term safety and tolerability of IND/GLY versus IND in terms of adverse event (AE)-reporting rates in patients with moderate-to-severe COPD over 52 weeks . The secondary objective was to evaluate the long-term efficacy of IND/GLY versus IND in terms of pre-dose trough forced expiratory volume in 1 second ( FEV1 ) and post-dose 1-h FEV1 over 52 weeks . Results : A total of 85.2 % patients completed the study treatment .  The overall incidence of AEs ( and SAEs ) was similar between treatments . Major adverse cardiovascular events ( MACE ) and /or cardiovascular ( CV ) events were comparable between treatment groups . The rate of discontinuation of the study treatment due to AEs was lower for IND/GLY than IND . Improvements in pre-dose trough FEV1 and post-dose 1-h FEV1 were consistently superior with IND/GLY than with IND over 52 weeks , demonstrating long-term maintenance of lung function . Conclusions : IND/GLY demonstrated a favorable long-term safety and tolerability profile and provided effective bronchodilation , with maintenance of lung function over 52 weeks in patients with moderate-to-severe COPD . These data support the safety and efficacy of IND/GLY as a treatment option for COPD . Trial registration : ClinTrials.gov identifier NCT01682863 * Glycopyrrolate 15.6 µg ( excluding the bromide salt ) is equivalent to 12.5 µg glycopyrronium INTRODUCTION Aclidinium bromide/formoterol fumarate ( AB/FF ) 400/12 μg efficacy and safety was demonstrated in two 6-month Phase III studies ( AUGMENT and ACLIFORM ) and a 12-month study in patients with moderate to severe chronic obstructive pulmonary disease ( COPD ) . This Phase III , double-blind , placebo-controlled , 6-month AUGMENT extension investigated the long-term safety and tolerability of AB/FF 400/12 μg ( NCT01572792 ) . METHODS Patients were r and omised in AUGMENT  ( 1:1:1:1:1 ) to twice-daily AB/FF 400/12 μg , AB/FF 400/6 μg , AB 400 μg , FF 12 μg or placebo . Patients completing AUGMENT were invited to continue the same treatment in the extension . Adverse events ( AEs ) , major adverse cardiovascular events ( MACE ) , laboratory tests , electrocardiograms and vital signs were recorded . Efficacy was assessed . RESULTS Of 1322 patients completing AUGMENT , 921 enrolled and 780 completed the extension .  AE incidence was low and comparable across treatment groups ; most common were nasopharyngitis ( range 4.8%-9.3 % ) , urinary tract infection ( range 4.1%-8.8 % ) and upper respiratory tract infection ( range 2.7%-5.5 % ) . Serious AEs ( SAEs ) and MACE were low ( ranges 6.8%-7.7 % and 0.5%-1.5 % , respectively ) . Significant improvements in bronchodilation and dyspnoea were maintained over 52 weeks versus placebo . Trends towards improvements in other symptoms and health status were observed versus placebo and monotherapies . AB/FF combinations increased the time to first exacerbation by approximately 30 % versus placebo ( p < 0.05 ) . CONCLUSION AB/FF 400/12 μg was well tolerated over 52 weeks with low incidences of AEs , SAEs and MACE that were comparable across treatment groups . Improvements in bronchodilation , symptoms and health status were maintained across 52 weeks BACKGROUND The long-term safety and efficacy of a novel Co-Suspension ™ Delivery Technology glycopyrrolate (GP)/formoterol fumarate ( FF ) 18/9.6 μg fixed-dose combination metered dose inhaler ( GFF MDI ) were investigated in a 28-week safety extension study ( PINNACLE-3 , NCT01970878 ) of two r and omized controlled Phase III trials ( PINNACLE-1 and -2 ; NCT01854645 and NCT01854658 ) in subjects with moderate-to-very severe chronic obstructive pulmonary disease ( COPD ) . METHODS Subjects completing 24 weeks ' treatment with GFF MDI , GP MDI , FF MDI ( all twice-daily ) or open-label tiotropium 18 μg ( once-daily ) in PINNACLE-1 or -2 were r and omly selected to continue treatment for 28 weeks . The target enrollment for PINNACLE-3 was 850 subjects . Safety and efficacy were evaluated over 52 weeks . RESULTS Of 3274 subjects r and omized to active treatment in PINNACLE-1 or -2 , 892 entered PINNACLE-3 . Incidences of adverse events , serious adverse events and major adverse cardiovascular events were similar across treatment groups with no unexpected safety findings . For change from baseline in morning pre-dose trough forced expiratory volume in 1 s ( FEV1 ) , treatment differences for GFF MDI versus GP MDI , FF MDI and open-label tiotropium over 52 weeks were 57 , 65 and 25 mL , respectively ( p ≤ 0.0117 ) . Average daily rescue medication use was significantly reduced for GFF MDI versus GP MDI and open-label tiotropium ( p ≤ 0.0002 ) . Statistically significant improvements were observed with GFF MDI versus monocomponents in Self-Administered Computerized Transition Dyspnea Index focal score , and in St George 's Respiratory Question naire total score versus GP MDI . CONCLUSIONS Results confirmed the long-term safety and tolerability  of GFF MDI 18/9.6 μg twice-daily in subjects with moderate-to-very severe COPD . Improvements in efficacy endpoints were also sustained over 52 weeks Introduction Patients with COPD who remain symptomatic on long-acting bronchodilator monotherapy may benefit from step-up therapy to a long-acting bronchodilator combination . This study evaluated the efficacy and safety of umeclidinium (UMEC)/vilanterol ( VI ) in patients with moderate COPD who remained symptomatic on tiotropium ( TIO ) . Methods In this r and omized , blinded , double-dummy , parallel-group study ( NCT01899742 ) , patients ( N=494 ) who were prescribed TIO for ≥3 months at screening ( forced expiratory volume in 1 s [ FEV1 ] : 50%–70 % of predicted ; modified Medical Research Council [ mMRC ] score ≥1 ) and completed a 4-week run-in with TIO were r and omized to UMEC/VI 62.5/25 µg or TIO 18 µg for 12 weeks . Efficacy assessment s included trough FEV1 at Day 85 ( primary end point ) , 0–3 h serial FEV1 , rescue medication use , Transition Dyspnea Index ( TDI ) , St George ’s Respiratory Question naire ( SGRQ ) , and COPD Assessment Test ( CAT ) . Safety evaluations included adverse events ( AEs ) . Results Compared with TIO , UMEC/VI produced greater improvements in trough FEV1 ( least squares [ LS ] mean difference : 88 mL at Day 85 [ 95 % confidence interval { CI } : 45–131 ] ; P<0.001 ) and FEV1 after 5 min on Day 1 ( 50 mL [ 95 % CI : 27–72 ] ; P<0.001 ) . Reductions in rescue medication use over 12 weeks were greater with UMEC/VI versus TIO ( LS mean change : −0.1 puffs/d [ 95 % CI : −0.2–0.0 ] ; P≤0.05 ) . More patients achieved clinical ly meaningful improvements in TDI score ( ≥1 unit ) with UMEC/VI ( 63 % ) versus TIO ( 49 % ; odds ratio at Day 84=1.78 [ 95 % CI : 1.21–2.64 ] ; P≤0.01 ) . Improvements in SGRQ and CAT scores were similar between treatments . The incidence of AEs was similar with UMEC/VI ( 30 % ) and TIO ( 31 % ) . Conclusion UMEC/VI step-up therapy provides clinical benefit over TIO monotherapy in patients with moderate COPD who are symptomatic on TIO alone BACKGROUND This study formed part of the dose selection for a glycopyrrolate (GP)/formoterol fumarate ( FF ) fixed-dose combination formulated using novel Co-Suspension ™ Delivery Technology and delivered via a metered dose inhaler ( GFF MDI ) . The study aim ed to confirm the optimal dose of GP to formulate with FF 9.6 μg in the fixed-dose combination product , GFF MDI . METHODS This multicenter , r and omized , double-blind , chronic-dosing , balanced incomplete block , crossover study ( NCT01587079 ) compared five doses of GFF MDI ( 18/9.6 , 9/9.6 , 4.6/9.6 , 2.4/9.6 and 1.2/9.6 μg , twice daily [ BID ] ) with its monocomponents FF MDI 9.6 μg and GP MDI 18 μg ( both BID ) and open-label tiotropium ( 18 μg once daily ) as the active control . The primary efficacy endpoint was change from baseline in forced expiratory volume in 1 s area under the curve from 0 to 12 h ( FEV1 AUC0 - 12 ) on Day 7 . RESULTS In total , 159 patients were r and omized to treatment and 132 patients ( 52.2 % male , mean age 62.8 years ) were included in the intent-to-treat population . All doses of GFF MDI ( except 1.2/9.6 μg ) result ed in statistically significant improvements in FEV1 AUC0 - 12 versus monocomponents and open-label tiotropium . GFF MDI 18/9.6 μg consistently showing the greatest improvement over monocomponents and open-label tiotropium . Adverse events for each GFF MDI dose were similar versus GP MDI 18 μg , FF MDI 9.6 μg and open-label tiotropium . CONCLUSIONS These findings further support selection of GP 18 μg as the optimal dose to combine with FF MDI 9.6 μg for advancement into Phase III clinical trials of GFF MDI Background : The TORRACTO ® study evaluated the effects of tiotropium/olo date rol versus placebo on endurance time during constant work-rate cycling and constant speed shuttle walking in patients with chronic obstructive pulmonary disease ( COPD ) after 12 weeks of treatment . Methods : The effects of once-daily tiotropium/olo date rol ( 2.5/5 and 5/5 μg ) on endurance time during constant work-rate cycle ergometry ( CWRCE ) after 6 and 12 weeks of treatment were compared with placebo in patients with COPD in a r and omized , double-blind , placebo-controlled , parallel-group clinical trial . Endurance time during the endurance shuttle walk test ( ESWT ) after 6 and 12 weeks of treatment was also evaluated in a subset of patients . Results : A total of 404 patients received treatment , with 165 participating in the ESWT sub study . A statistically significant improvement in endurance time during CWRCE was observed after 12 weeks ( primary endpoint ) with tiotropium/olo date rol 5/5 µg [ 14 % ( p = 0.02 ) ] but not with tiotropium/olo date rol 2.5/5 µg [ 9 % ( p = 0.14 ) ] versus placebo . In the ESWT sub study , a trend to improvement in endurance time during ESWT after 12 weeks ( key secondary endpoint ) was observed with tiotropium/olo date rol 5/5 µg [ 21 % ( p = 0.055 ) ] and tiotropium/olo date rol 2.5/5 µg [ 21 % ( p = 0.056 ) ] versus placebo . Conclusion : Tiotropium/olo date rol 5/5 µg improved endurance time during cycle ergometry versus placebo , with a strong tendency to also improve walking endurance time . [ Clinical Trials.gov identifier : NCT01525615 . Background The long-acting muscarinic antagonists umeclidinium ( UMEC ) and tiotropium ( TIO ) are approved once-daily maintenance therapies for COPD . This study investigated the efficacy and safety of UMEC versus TIO in COPD . Methods This was a 12-week , multicenter , r and omized , blinded , double-dummy , parallel-group , non-inferiority study . Patients were r and omized 1:1 to UMEC 62.5 μg plus placebo or TIO 18 μg plus placebo .  The primary end point was trough forced expiratory volume in 1 second ( FEV1 ) at day 85 ( non-inferiority margin −50 mL ; per- protocol [ PP ] population ) . Other end points included weighted mean FEV1 over 0–24 and 12–24 hours post-dose . Patient-reported outcomes comprised Transition Dyspnea Index score , St George ’s Respiratory Question naire total score , and COPD Assessment Test score . Adverse events were also assessed . Results In total , 1,017 patients were r and omized to treatment . In the PP population , 489 and 487 patients received UMEC and TIO , respectively . In the PP population , change from baseline in trough FEV1 was greater with UMEC versus TIO at day 85 , meeting non-inferiority and superiority margins ( difference : 59 mL ; 95 % confidence interval [ CI ] : 29–88 ; P<0.001 ) . Similar results were observed in the intent-to-treat analysis of trough FEV1 at day 85 ( 53 mL , 95 % CI : 25–81 ; P<0.001 ) . Improvements in weighted mean FEV1 over 0–24 hours post-dose at day 84 were similar with UMEC and TIO but significantly greater with UMEC versus TIO over 12–24 hours post-dose ( 70 mL ; P=0.015 ) . Clinical ly meaningful improvements in Transition Dyspnea Index and St George ’s Respiratory Question naire were observed with both treatments at all time points . No differences were observed between UMEC and TIO in patient-reported outcomes . Overall incidences of adverse events were similar for UMEC and TIO . Conclusion UMEC 62.5 μg demonstrated superior efficacy to TIO 18 μg on the primary end point of trough FEV1 at day 85 . Safety profiles were similar for both treatments Patients with symptomatic advanced chronic obstructive pulmonary disease ( COPD ) who experience recurrent exacerbations are particularly at risk of poor outcomes and present a significant burden on healthcare systems . The relative merits of treating with different inhaled combination therapies e.g. inhaled corticosteroids (ICS)/long-acting β2-agonist ( LABA ) , LABA/long-acting muscarinic antagonists ( LAMA ) , ICS/LABA/LAMA , in this patient group are poorly understood , as is reflected in current guidelines . The InforMing the PAthway of COPD Treatment ( IMPACT ) study will evaluate the efficacy and safety of fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol ( VI ) versus FF/VI or UMEC/VI over a 52-week treatment period . The study has been design ed with a focus on underst and ing the comparative merits of each treatment modality in different phenotypes/endotypes . This is a phase III , r and omised , double-blind , three-arm , parallel-group , global multicentre study comparing the rate of moderate and severe exacerbations between FF/UMEC/VI and FF/VI or UMEC/VI over a 52-week treatment period . The study aims to recruit 10 000 patients from approximately 1070 centres . Eligible patients are aged ≥40 years , with symptomatic advanced COPD ( Global initiative for chronic Obstructive Lung Disease ( GOLD ) group D ) and an exacerbation in the previous 12 months . The first patients were recruited to the IMPACT study ( Clinical Trials.gov : NCT02164513 ) in June 2014 and the anticipated completion date is July 2017 . Treatment choices between LABA/LAMA versus ICS/LABA versus ICS/LABA/LAMA in GOLD group D subjects with COPD BACKGROUND Combinations of long-acting bronchodilators are recommended to reduce the rate of chronic obstructive pulmonary disease ( COPD )  exacerbations . It is unclear whether combining olo date rol , a long-acting beta-agonist , with tiotropium , a long-acting anti-muscarinic , reduces the rate of exacerbations compared with tiotropium alone . METHODS This 52-week , double-blind , r and omised , parallel-group , active-controlled trial r and omly assigned ( 1:1 ) patients with COPD with a history of exacerbations using a r and omised block design to receive tiotropium-olo date rol 5 μg-5 μg or tiotropium 5 μg once daily . Patients using inhaled corticosteroids  continued this therapy . Treatment was masked to patients , investigators , and those involved in analysing the data . The primary endpoint was the rate of moderate and severe COPD exacerbations from the first dose of medication until 1 day after last drug administration . The primary analysis included all r and omly assigned patients who received any dose of study medication but were not from a site excluded due to on-site protocol violations . The trial is registered with Clinical Trials.gov , number NCT02296138 . FINDINGS Overall , 9009 patients were screened from 818 centres in 51 countries . We recruited 7880 patients between Jan 22 , 2015 and March 7 , 2016 ( mean age 66·4 years [ SD 8·5 ] , 5626 [ 71 % ] were men , mean FEV1 percent predicted 44·5 % [ SD 27·7 ] ) : 3939 received tiotropium-olo date rol and 3941 tiotropium . The rate of moderate and severe exacerbations was lower with tiotropium-olo date rol than tiotropium ( rate ratio [ RR ] 0·93 , 99 % CI 0·85 - 1·02 ; p=0·0498 ) , not meeting the targeted 0·01 significance level . The proportion of patients reporting adverse events was similar between treatments . INTERPRETATION Combining tiotropium and olo date rol did not reduce exacerbation rate as much as expected compared with tiotropium alone . FUNDING Boehringer Ingelheim International Background : Combination therapy with a long-acting bronchodilator and an inhaled corticosteroid ( ICS ) is recommended in patients with chronic obstructive pulmonary disease ( COPD ) who have frequent exacerbations . The efficacy and tolerability of the combination of budesonide/formoterol have been demonstrated in patients with COPD when administered via the dry powder inhaler ( DPI ) in a 1-year study and when administered via the hydrofluoroalkane ( HFA ) pressurized metered-dose inhaler ( pMDI ) in a 6-month study . Objective : This study assessed the long-term efficacy and tolerability of budesonide/formoterol HFA pMDI in patients with moderate to very severe COPD . Methods : This was a 12-month , r and omized , double-blind , double-dummy , parallel-group , active- and placebo-controlled , multicentre study ( NCT00206167 ) of 1964 patients aged ≥40 years with moderate to very severe COPD conducted from 2005 to 2007 at 237 sites in the US , Europe and Mexico . After 2 weeks of treatment based on previous therapy ( ICSs , short-acting bronchodilators allowed ) , patients received one of the following treatments twice daily : budesonide/formoterol pMDI 160/4.5 μg × two inhalations ( 320/9 μg ) ; budesonide/formoterol pMDI 80/4.5 μg × two inhalations ( 160/9 μg ) ; formoterol DPI 4.5 μg × two inhalations ( 9 μg ) ; or placebo . Main outcome measures : The co- primary efficacy variables were pre-dose forced expiratory volume in 1 second ( FEV1 ) and 1-hour post-dose FEV1 . Results : Budesonide/formoterol 320/9 μg demonstrated greater improvements in pre-dose FEV1  versus formoterol ( p = 0.008 ) , and both budesonide/formoterol doses demonstrated greater improvements in 1-hour post-dose FEV1  versus placebo ( p < 0.001 ) . The rate of COPD exacerbations was lower in both budesonide/formoterol groups compared with formoterol and placebo ( p ≤ 0.004 ) . Both budesonide/formoterol doses were more effective  than placebo ( p ≤ 0.006 ) for controlling dyspnoea and improving health status ( St George ’s Respiratory Question naire ) . All treatments were generally well tolerated . The incidence of pneumonia was not different for active ( 3.4–4.0 % ) and placebo ( 5.0 % ) groups . Conclusions : Budesonide/formoterol pMDI ( 320/9 μg and 160/9 μg ) improved pulmonary function and reduced symptoms and exacerbations over 1 year in patients with moderate to very severe COPD .  Only budesonide/formoterol pMDI 320/9 μg demonstrated greater efficacy for both co- primary variables compared with formoterol DPI 9 μg . Both budesonide/formoterol pMDI dosages were well tolerated relative to formoterol and placebo 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 Reducing the severity of respiratory symptoms is a key goal in the treatment of chronic obstructive pulmonary disease ( COPD ) . We evaluated the effect of aclidinium bromide 400 μg twice daily ( BID ) on respiratory symptoms , assessed using the Evaluating Respiratory Symptoms in COPD ( E-RS ™ : COPD ) scale ( formerly EXACT-RS ) . Methods Data were pooled from the aclidinium 400 μg BID and placebo arms of two 24-week , double-blind , r and omized Phase III studies evaluating aclidinium monotherapy ( ATTAIN ) or combination therapy ( AUGMENT COPD I ) in patients with moderate to severe airflow obstruction . Patients were stratified by Global initiative for chronic Obstructive Lung Disease ( GOLD ) Groups A – D. Change from baseline in E-RS scores , proportion of responders ( patients achieving pre-defined improvements in E-RS scores ) , and net benefit ( patients who improved minus patients who worsened ) were analyzed . Results Of 1210 patients , 1167 had data available for GOLD classification . Mean ( st and ard deviation ) age was 63.2 ( 8.6 ) years , 60.7 % were male , and mean post-bronchodilator forced expiratory volume in 1 s was 54.4 % predicted .  Compared with placebo , aclidinium 400 μg BID significantly improved RS-Total ( 2.38 units vs 0.79 units , p < 0.001 ) and domain scores ( all p < 0.001 ) at Week 24 , and doubled the likelihood of being an RS-Total score responder ( p < 0.05 ) , irrespective of GOLD group . The net benefit for RS-Total ( Overall : 56.9 % vs 19.4 % ; A + C : 65.7 % vs 6.3 % ; B + D : 56.0 % vs 20.8 % , for aclidinium 400 μg BID and placebo respectively ; all p < 0.05 ) and domain scores ( all p < 0.05 ) was significantly greater with aclidinium compared with placebo , in both GOLD Groups A + C and B + D. Conclusions Aclidinium 400 μg BID significantly improved respiratory symptoms regardless of the patients ’ level of symptoms at baseline . Net treatment benefit was similar in patients with low or high levels of symptoms . Trial registration ATTAIN ( Clinical Trials.gov identifier : NCT01001494 ) and AUGMENT COPD I ( Clinical Trials.gov identifier : NCT01437397 ) Two replicate , multicenter , r and omized , double-blind , placebo-controlled , parallel-group , Phase III studies investigated the long-term efficacy and safety of once-daily olo date rol via Respimat ® versus placebo and formoterol over 48 weeks in patients with moderate to very severe chronic obstructive pulmonary disease receiving usual-care background therapy . Patients received once-daily olo date rol 5 or 10 μg , twice-daily formoterol 12 μg , or placebo . Co- primary end points were forced expiratory volume in 1 second ( FEV1 ) area under the curve from 0–3 hours response , FEV1 trough response , and Mahler transition dyspnea index total score after 24 weeks ; secondary end points included St George ’s Respiratory Question naire . Overall , 904 ( Study 1222.13 ) and 934 ( Study 1222.14 ) patients received treatment . Olo date rol significantly improved FEV1 area under the curve from 0–3 hours versus placebo in both studies ( with olo date rol 5 μg , 0.151 L and 0.129 L ; with olo date rol 10 μg , 0.165 L and 0.154 L ; for all comparisons P<0.0001 ) and FEV1 trough responses versus placebo ( 0.053–0.085 L ; P<0.01 ) , as did formoterol . Primary analysis revealed no significant difference in transition dyspnea index focal score for any active treatment versus placebo . Post hoc analysis using pattern mixture modeling ( accounting for discontinuations ) demonstrated statistical significance for olo date rol versus placebo . St George ’s Respiratory Question naire total score was significantly improved with olo date rol , but not formoterol , versus placebo . No safety signals were identified from adverse-event or other safety data . Once-daily olo date rol 5 μg and 10 μg is efficacious in patients with moderate to very severe chronic obstructive pulmonary disease on usual-care maintenance therapy , with a satisfactory safety profile 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 ) Background Combining two long-acting bronchodilators with complementary mechanisms of action may provide treatment benefits to patients with chronic obstructive pulmonary disease ( COPD ) that are greater than those derived from either treatment alone . The efficacy and safety of a fixed-dose combination ( FDC ) of aclidinium bromide , a long-acting muscarinic antagonist , and formoterol fumarate , a long-acting β2-agonist , in patients with moderate to severe COPD are presented . Methods In this 24-week double-blind study , 1692 patients with stable COPD were equally r and omized to twice-daily treatment with FDC aclidinium 400μg/formoterol 12μg ( ACL400/FOR12 FDC ) , FDC aclidinium 400μg/formoterol 6μg ( ACL400/FOR6 FDC ) , aclidinium 400μg , formoterol 12μg , or placebo administered by a multidose dry powder inhaler (Genuair ® /Pressair ® )*. Co primary endpoints were change from baseline to week 24 in 1-hour morning postdose FEV1 ( FDCs versus aclidinium ) and change from baseline to week 24 in morning predose ( trough ) FEV1 ( FDCs versus formoterol ) . Secondary endpoints were change from baseline in St. George ’s Respiratory Question naire ( SGRQ ) total score and improvement in Transition Dyspnea Index ( TDI ) focal score at week 24 . Safety and tolerability were also assessed . Results At study end , improvements from baseline in 1-hour postdose FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC or ACL400/FOR6 FDC compared with aclidinium ( 108 mL and 87 mL , respectively ; p < 0.0001 ) . Improvements in trough FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC versus formoterol ( 45 mL ; p = 0.0102 ) , a numerical improvement of 26 mL in trough FEV1 over formoterol was observed with ACL400/FOR6 FDC . Significant improvements in both SGRQ total and TDI focal scores were observed in the ACL400/FOR12 FDC group at study end ( p < 0.0001 ) , with differences over placebo exceeding the minimal clinical ly important difference of ≥4 points and ≥1 unit , respectively . All treatments were well tolerated , with safety profiles of the FDCs similar to those of the monotherapies . Conclusions Treatment with twice-daily aclidinium 400μg/formoterol 12μg FDC provided rapid and sustained bronchodilation that was greater than either monotherapy ; clinical ly significant improvements in dyspnea and health status were evident compared with placebo . Aclidinium/formoterol FDC may be an effective and well tolerated new treatment option for patients with COPD .Trial registration Clinical trials.gov NCT01437397.*Registered trademarks of Almirall S.A. , Barcelona , Spain ; for use within the US as Pressair ® and Genuair ® within all other licensed territories Indacaterol is a novel , inhaled , once-daily , ultra-long-acting & bgr;2-agonist bronchodilator recently approved in Europe for the treatment of chronic obstructive pulmonary disease ( COPD ) . The aim of the present study was to investigate the efficacy and safety of indacaterol compared with placebo and the twice-daily & bgr;2-agonist , salmeterol , as an active control . Patients with moderate-to-severe COPD were r and omised to 6 months double-blind treatment with indacaterol ( 150 & mgr;g once daily ) , salmeterol ( 50 & mgr;g twice daily ) or placebo . The primary efficacy end-point was trough ( 24 h post-dose ) forced expiratory volume in 1 s ( FEV1 ) after 12 weeks . 1,002 patients were r and omised and 838 ( 84 % ) completed the study .  Indacaterol increased trough FEV1 at week 12 by 170 mL over placebo ( p<0.001 ) and by 60 mL over salmeterol ( p<0.001 ) . Both active treatments improved health status ( St George 's Respiratory Question naire ) and dyspnoea ( transition dyspnoea index ) compared with placebo , with differences between them favouring indacaterol .  Safety profiles were similar across the treatment groups , and both indacaterol and salmeterol were well tolerated . Once-daily treatment with 150 & mgr;g indacaterol had a significant and clinical ly relevant bronchodilator effect over 24 h post-dose and improved health status and dyspnoea to a greater extent than twice-daily 50 & mgr;g salmeterol . Indacaterol should prove a useful additional treatment for patients with COPD Patients with COPD are frequently prescribed inhaled corticosteroids ( ICS ) ; however , it is unclear whether the treatment with ICS might modify responses to inhaled bronchodilators . Two 6-month , r and omized , placebo-controlled , double-blind , double-dummy , parallel-group studies of tiotropium 18 μg once daily , compared with salmeterol , 50 μg bid , had been conducted in patients with moderate-to-severe COPD . Efficacy was assessed by spirometry , transition dyspnea index ( TDI ) , St. George ’s Respiratory Question naire ( SGRQ ) , and exacerbations . Data from both studies were combined to form subgroups with regard to concurrent use of ICS .  796 patients receiving ICS were separately analyzed from 390 patients not receiving ICS . Mean age was 64 years , and pre-bronchodilator FEV1 was 1.06 L ( ICS group ) and 1.13 L ( non-ICS group ) . Both bronchodilators increased morning mean ± SE pre-dose FEV1 compared with placebo ( ICS groups : tiotropium 110 ± 20 mL , salmeterol 80 ± 20 mL ; non-ICS groups : tiotropium 150 ± 30 mL , salmeterol 110 ± 30 mL ; p > 0.05 for tiotropium vs salmeterol ) . Improvements in TDI and SGRQ and frequency of exacerbations also tended to be more profound for tiotropium . Treatment with tiotropium in patients with moderate-to-severe COPD was superior to salmeterol in lung function , irrespective of concurrent use of ICS BACKGROUND Clinical information on 24-h spirometric efficacy of combining tiotropium and salmeterol compared to single-agent therapy is lacking in patients with COPD . METHODS A r and omized , double-blind , four-way crossover study of 6-week treatment periods comparing combination therapy of tiotropium 18 microg plus qd or bid salmeterol 50 microg versus single-agent therapy . Serial 24-h spirometry ( FEV(1 ) , FVC ) , effects on dyspnea ( TDI focal score ) and rescue salbutamol use were evaluated in 95 patients . RESULTS Tiotropium plus qd salmeterol was superior to tiotropium or salmeterol alone in average FEV(1 ) ( 0 - 24h ) by 72 mL and 97 mL ( p<0.0001 ) , respectively . Compared to this qd regimen , combination therapy including bid salmeterol provided comparable daytime ( 0 - 12h : 12 mL , p=0.38 ) bronchodilator effects , but significantly more bronchodilation during the night-time ( 12 - 24h : 73 mL , p<0.0001 ) . Clinical ly relevant improvements in TDI focal score were achieved with bronchodilator combinations including salmeterol qd or bid ( 2.56 and 2.71 ; p<0.005 versus components ) . Symptom benefit of combination therapies was also reflected in less need for reliever medication . All treatments were well tolerated . CONCLUSION Compared to single-agent therapy , combination therapy of tiotropium plus salmeterol in COPD provided clinical ly meaningful improvements in airflow obstruction and dyspnea as well as a reduction in reliever medication Prevention and treatment of COPD exacerbations are recognized as key goals in disease management . This r and omized , double-blind , parallel-group , multicenter study evaluated the effect of fluticasone propionate/salmeterol 250 mcg/50 mcg ( FSC 250/50 ) and salmeterol 50 mcg ( SAL ) twice-daily on moderate/severe exacerbations . Subjects received treatment with FSC 250/50 during a one month run-in , followed by r and omization to FSC 250/50 or SAL for 52 weeks . Moderate/severe exacerbations were defined as worsening symptoms of COPD requiring antibiotics , oral corticosteroids and /or hospitalization . In 797 subjects with COPD ( mean FEV1 = 0.98L , 34 % predicted normal ) , treatment with FSC 250/50 significantly reduced the annual rate of moderate/severe exacerbations by 30.4 % compared with SAL ( 1.10 and 1.59 per subject per year , respectively , p < 0.001 ) , the annual rate of exacerbations requiring oral corticosteroids by 34 % ( p < 0.001 ) and the annual rate of moderate/severe exacerbations requiring hospitalization by 36 % ( p = 0.043 ) . Clinical improvements observed during run-in treatment with FSC 250/50 were better maintained over 52 weeks with FSC 250/50 compared to SAL . Statistically significant reductions in albuterol use , dyspnea scores , and nighttime awakenings and numerical benefits on quality of life were seen with FSC 250/50 compared with SAL . The incidence of adverse events was similar across groups . Pneumonia was reported more frequently with FSC 250/50 compared with SAL ( 7 % vs. 2 % ) . FSC 250/50 is more effective than SAL at reducing the rate of moderate/severe exacerbations . These data confirm the beneficial effect of FSC on the management of COPD exacerbations and support the use of FSC in patients with COPD BACKGROUND Combination long-acting bronchodilator treatment might be more effective than long-acting bronchodilator monotherapy for the treatment of chronic obstructive pulmonary disease ( COPD ) . We aim ed to compare the efficacy and safety of umeclidinium ( UMEC ) plus vilanterol ( VI ) with tiotropium ( TIO ) monotherapy , UMEC monotherapy , or VI monotherapy in patients with moderate to very severe COPD . METHODS In two multicentre , r and omised , blinded , double-dummy , parallel-group , active-controlled trials , eligible patients ( current or former smokers aged 40 years or older with an established clinical history of COPD ) were r and omly assigned in 1:1:1:1 ratio to UMEC 125 μg plus VI 25 μg , UMEC 62·5 μg plus VI 25 μg , TIO 18 μg , and either VI 25 μg ( study 1 ) or UMEC 125 μg ( study 2 ) . All study drugs were used once daily for 24 weeks . TIO was delivered via the H and iHaler inhaler and all other active treatments were delivered via the ELLIPTA dry powder inhaler . R and om assignment ( by a vali date d computer-based system ) was done by centre and was not stratified . All patients and physicians were masked to assigned treatment during the studies . The primary efficacy endpoint of both studies was trough forced expiratory volume in 1 s ( FEV1 ) on day 169 , which was analysed in the intention-to-treat population . Both studies are registered with Clinical Trials.gov , numbers NCT01316900 ( study 1 ) and NCT01316913 ( study 2 ) . FINDINGS 1141 participants were recruited in study 1 , and 1191 in study 2 . For study 1 , after exclusions , 208 , 209 , 214 , and 212 patients were included in the intention-to-treat analyses for TIO monotherapy , VI monotherapy , UMEC 125 μg plus VI 25 μg , and UMEC 62·5 μg plus VI 25 μg , respectively . For study 2 , 215 , 222 , 215 , and 217 patients were included in the intention-to-treat analyses  for TIO monotherapy , UMEC monotherapy , UMEC 125 μg plus VI 25 μg , and UMEC 62·5 μg plus VI 25 μg , respectively . In both studies , we noted improvements in trough FEV1 on day 169 for both doses of UMEC plus VI compared with TIO monotherapy ( study 1 , UMEC 125 μg plus VI 25 μg : 0·088 L [ 95 % CI 0·036 to 0·140 ; p=0·0010 ] ; study 1 , UMEC 62·5 μg plus VI 25 μg : 0·090 L [ 0·039 to 0·141 ; p=0·0006 ] ; study 2 , UMEC 125 μg plus VI 25 μg : 0·074 L [ 0·025 to 0·123 ; p=0·0031 ] ; study 2 , UMEC 62·5 μg plus VI 25 μg : 0·060 L [ 0·010 to 0·109 ; nominal p=0·0182 ] ) . Both doses of UMEC plus VI also improved trough FEV1 compared with VI monotherapy ( UMEC 125 μg plus VI 25 μg : 0·088 L [ 0·036 to 0·140 ; p=0·0010 ] ; UMEC 62·5 μg plus VI 25 μg : 0·090 L [ 0·039 to 0·142 ; p=0·0006 ] , but not compared with UMEC 125 μg monotherapy ( UMEC 125 μg plus VI 25 μg : 0·037 L [ -0·012 to 0·087 ; p=0·14 ] ; UMEC 62·5 μg plus VI 25 μg : 0·022 L [ -0·027 to 0·072 ; p=0·38 ] ) . All treatments produced improvements in dyspnoea and health-related quality of life ; we noted no significant differences in symptoms , health status , or risk of exacerbation between UMEC plus VI and TIO . The most common on-treatment , severe-intensity adverse event in both studies was acute exacerbation of COPD ( 1 - 4 [ < 1 - 2 % ] patients across treatment groups in study 1 and 1 - 6 [ < 1 - 3 % ] patients in study 2 ) . We recorded five to 15 ( 2 - 7 % ) on-treatment serious adverse events across treatment groups in study 1 , and nine to 22 ( 4 - 10 % ) in study 2 . We noted no substantial changes from baseline in vital signs , clinical laboratory findings , or electrocardiography findings in any of the treatment groups . INTERPRETATION Combination treatment with once-daily UMEC plus  VI improved lung function compared with VI monotherapy and TIO monotherapy in patients with COPD . Overall our results suggest that the combination of UMEC plus VI could be beneficial for the treatment of moderate to very severe COPD . FUNDING GlaxoSmithKline 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 Background Fluticasone furoate/vilanterol ( FF/VI ) is a novel , once-daily , inhaled corticosteroid/long-acting β2-agonist combination approved for the treatment of COPD and asthma . We compared the safety and efficacy of FF/VI and tiotropium ( TIO ) in subjects with moderate-to-severe COPD with greater risk for comorbid cardiovascular disease ( CVD ) . Methods This r and omized , blinded , double-dummy , parallel-group study compared a once-daily morning dose of FF/VI 100/25 mcg delivered via ELLIPTA ™ with TIO 18 mcg via H and iHaler ® for 12 weeks in subjects with diagnosed COPD , forced expiratory volume in 1 second ( FEV1 ) 30%–70 % predicted , and CVD or CVD risk . The primary endpoint was change from baseline in 24-hour weighted mean FEV1 on Day 84 . Other efficacy endpoints included time to onset of bronchodilation , trough FEV1 , other spirometry measures , rescue medication use , symptoms , quality of life ( St George ’s Respiratory Question naire- COPD [ SGRQ-C ] ) , and health status ( COPD Assessment Tests [ CAT ] ) measures . Safety endpoints included cardiovascular monitoring , cortisol excretion , COPD exacerbations , and adverse events , including prespecified drug effects . Results Both FF/VI and TIO improved the 24-hour weighted mean FEV1 from baseline after 12 weeks with no significant difference between treatments . Other endpoints favored FF/VI for time to onset of bronchodilation , rescue medication use , dyspnea , SGRQ-C and CAT scores , or favored TIO for change from baseline in forced vital capacity and inspiratory capacity . Pneumonia occurred more frequently in the FF/VI group , and two TIO-treated subjects died following cardiovascular events . Other safety measures were similar between groups , and cardiovascular monitoring did not reveal increased CVD risk . Conclusion Both FF/VI and TIO were efficacious in improving lung function  in subjects with COPD and comorbid CVD or CVD risk factors , with minor differences in efficacy and safety profiles BACKGROUND AND OBJECTIVE The efficacy and tolerability of budesonide/formoterol versus formoterol in patients with moderate to severe chronic obstructive pulmonary disease ( COPD ) was evaluated . METHODS In this r and omized , double-blind , parallel-group , phase III study ( NCT01069289 ) , patients with moderate to severe COPD for ≥2 years received either budesonide/formoterol 160/4.5 μg two inhalations twice daily via Turbuhaler ® or formoterol 4.5 μg two inhalations twice daily via Turbuhaler ® for 12 weeks . Salbutamol was available as reliever medication . Primary outcome variable : change from baseline to average during treatment in pre-dose forced expiratory volume in 1 s ( FEV1 ) . RESULTS One thous and two hundred ninety-three patients were r and omized  ( budesonide/formoterol n = 636 ; formoterol n = 657 ) .  Both budesonide/formoterol and formoterol increased pre-dose FEV1 versus baseline ( improvements of 4.6 % and 1.5 % over baseline , respectively ) , with the increase from baseline being significantly greater with budesonide/formoterol versus formoterol ( budesonide/formoterol : formoterol ratio 1.032 ; 95 % confidence interval : 1.013 - 1.052 ; P = 0.0011 ) . The budesonide/formoterol group had a significantly prolonged time to first exacerbation versus the formoterol group ( hazard ratio : 0.679 ; 95 % confidence interval : 0.507 - 0.909 ; P = 0.0094 ) and significantly greater improvements in many secondary outcome measures . Both treatments were well tolerated ; the incidence and type of adverse events were similar : most commonly reported ( budesonide/formoterol vs formoterol ) : COPD ( 8.0 % vs 9.4 % ) and nasopharyngitis ( 5.5 % vs 4.9 % ) . CONCLUSIONS Budesonide/formoterol 160/4.5 μg two inhalations twice daily was effective and well tolerated in patients with moderate to severe COPD , offering benefits over formoterol alone in terms of improved lung function and reduced risk of exacerbation This study compared the efficacy and safety of once-daily umeclidinium 62.5 µg with once-daily glycopyrronium 50 µg in patients with moderate-to-severe chronic obstructive pulmonary disease . This was a 12-week , multicentre , r and omised , open-label , parallel-group study ( Clinical trials.gov : NCT02236611 ) . Patients were r and omised 1:1 to umeclidinium 62.5 µg or glycopyrronium 50 µg administered via Ellipta or Breezhaler dry powder inhaler , respectively . The primary endpoint was trough forced expiratory volume in 1 s ( FEV1 ) at day 85 in the per- protocol population . Other endpoints included : weighted mean FEV1 over 0–24 h and patient-reported outcomes ( transition dyspnoea index score and St George 's Respiratory Question naire total score ) . Adverse events were also assessed . A total of 1037 patients were r and omised to treatment . Umeclidinium was non-inferior ( margin : −50 mL ) to glycopyrronium ( trough FEV1 at day 85 treatment difference : 24 mL , 95 % confidence intervals : −5–54 ) . Improvements in other endpoints were similar between treatments . Adverse event incidences were similar for umeclidinium ( 37 % ) and glycopyrronium ( 36 % ) . Once-daily umeclidinium was non-inferior to once-daily glycopyrronium in patients with chronic obstructive pulmonary disease  in trough FEV1 at day 85 . Patient-reported outcomes and safety profiles were similar for both treatments . Once-daily umeclidinium is non-inferior to once-daily glycopyrronium in patients with COPD by trough FEV1 at day 85 Combined use of β2-agonists and anticholinergic bronchodilators may have complementary benefits in patients with chronic obstructive pulmonary disease ( COPD ) . The objective of this study was to compare combination treatment with formoterol ( FORM ) plus tiotropium ( TIO ) versus treatment with TIO alone in patients with COPD . In this active-controlled , double-blind , multicenter trial , a total of 255 subjects with diagnosed COPD were r and omized to 12 weeks of either a combination of FORM 12 μ g twice-daily plus TIO 18 μ g once-daily in the morning ( QD AM ) or monotherapy with TIO 18 μ g QD AM . The primary efficacy variable was the area under the curve for forced expiratory volume in 1 second measured 0 to 4 hours after AM dosing ( FEV1 AUC0−4h ) . Significantly greater improvements in the FEV1 AUC0−4h were seen with FORM + TIO ( n = 116 ) versus TIO ( n = 124 ) at all time points . The increase in FEV1 5 minutes after the first dose was 180 mL with FORM + TIO versus 40 mL with TIO ( p < 0.001 ) . At endpoint , FEV1 AUC0−4h increased 340 mL with FORM + TIO versus 170 mL with TIO ( p < 0.001 ) . Improvements in trough FEV1 with FORM + TIO versus TIO were 180 mL and 100 mL , respectively ( p < 0.01 ) . Significantly greater reductions from baseline in symptom scores ( p < 0.05 ) and daytime albuterol use ( p < 0.04 ) were seen at endpoint with combination FORM + TIO versus TIO monotherapy . Both treatments were well tolerated . This study demonstrated that concurrent treatment with FORM + TIO results in greater therapeutic benefits than TIO alone Background Physical activity limitation is common in chronic obstructive pulmonary disease ( COPD ) , and is associated with worse health status , and increased hospitalisation and mortality . Long-acting bronchodilators , either alone or in combination , have been shown to improve exercise intolerance . However , none of these studies were design ed with physical activity as primary outcome .This study assessed the effect of indacaterol/glycopyrronium fixed dose combination ( IND/GLY ) 110/50 μg once daily ( OD ) versus placebo on lung hyperinflation ( inspiratory capacity [ IC ] ) and physical activity in patients with moderate-to-severe COPD . Methods In this multicentre , r and omised , double-blind , placebo-controlled crossover study , patients received IND/GLY or placebo OD in two 21-day treatment periods ( 14-day washout between periods ) . Eligible patients were ≥40 years of age , current or ex-smokers ( smoking history ≥10 pack-years ) , with post-salbutamol forced expiratory volume in 1 s ( FEV1 ) 40–80 % predicted , and FEV1:forced vital capacity < 0.70.The co- primary endpoints were peak IC after 21 days and average daily activity-related energy expenditure . Key secondary endpoints were average number of steps per day and the duration of at least moderate activity per day . Peak IC and FEV1 on Day 1 , and trough IC and FEV1 after 21 days were other secondary endpoints . Results A total of 194 patients were r and omised ( 65.5 % male , mean age 62.8 years , mean FEV1 61.6 % predicted ) , with 183 ( 94.3 % ) completing the study .Compared  with placebo , IND/GLY significantly increased peak IC after 21 days ( difference 202 mL , p < 0.0001 ) , activity-related energy expenditure ( difference 36.7 kcal/day , p = 0.040 ) , and the average number of steps per day ( difference 358 , p = 0.029 ) , with a trend towards an improvement in the duration of at least moderate activity ( difference 4.4 min , p = 0.264 ) . IND/GLY was associated with statistically significant improvements versus placebo in peak IC and FEV1 on Day 1 , and trough IC and FEV1 after 21 days . The incidence of treatment-emergent adverse events was 22.8 % with IND/GLY and 22.9 % with placebo . Conclusions In this study , compared with  placebo , IND/GLY reduced hyperinflation , and , despite no patient education or lifestyle advice , improved daily physical activity levels . This suggests that IND/GLY has the potential to impact two of the main clinical concerns in the care of patients with COPD .Trial registration Clinical Trials.gov number : NCT01996319 Background Indacaterol is a long-acting inhaled β2-agonist ( LABA ) for the treatment of chronic obstructive pulmonary disease ( COPD ) . In previous studies , indacaterol provided 24 h bronchodilation on once-daily dosing with a fast onset of action . This study compared the efficacy and safety of indacaterol with the twice-daily LABA formoterol and placebo over 1 year . Methods Patients with moderate to severe COPD were r and omised to receive once-daily indacaterol 300 μg ( n=437 ) or 600 μg ( n=428 ) , twice-daily formoterol 12 μg ( n=435 ) or placebo ( n=432 ) for 52 weeks in a double-blind double-dummy parallel group study . The primary efficacy variable was forced expiratory volume in 1 s ( FEV1 ) measured 24 h postdose after 12 weeks ( indacaterol vs placebo ) . Other outcomes included dyspnoea ( transition dyspnoea index , TDI ) , use of as-needed salbutamol , symptom-based measures recorded on diary cards , exacerbations , health status ( St George 's Respiratory Question naire ) , BODE index ( body mass index , obstruction , dyspnoea , exercise ) , safety and tolerability . Results Indacaterol  increased 24 h postdose FEV1 after 12 weeks by 170 ml ( both doses ) versus placebo and by 100 ml versus formoterol ( all p<0.001 ) . These significant differences were maintained at 52 weeks . Symptomatic outcomes were improved compared with placebo with all active treatments , and indacaterol was more effective than formoterol in improving TDI score and reducing the need for as-needed salbutamol . Indacaterol was well tolerated and had a good overall safety profile , including minimal impact on QTc interval and systemic β2-mediated events . Conclusions Once-daily indacaterol is an effective 24 h bronchodilator that improves symptoms and health status and confers clinical improvements over a twice-daily 12 h LABA as a treatment for patients with moderate to severe COPD . Trial registration number NCT 00393458 BACKGROUND Treatment with an inhaled corticosteroid ( ICS ) and long-acting bronchodilator is recommended for severe/very severe chronic obstructive pulmonary disease ( COPD ) patients with repeated exacerbations . This r and omized , double-blind , double-dummy , parallel-group , 12-month multicenter study evaluated the effect of budesonide/formoterol pressurized metered-dose inhaler ( pMDI ) on COPD exacerbations . METHODS Following a 2-week run-in during which COPD patients aged ≥40 years with an exacerbation history discontinued medications except ICSs , 1219 patients were r and omized 1:1:1 to twice-daily budesonide/formoterol pMDI 320/9 μg , budesonide/formoterol pMDI 160/9 μg , or formoterol dry powder inhaler 9 μg . An exacerbation was defined as COPD worsening requiring oral corticosteroids and /or hospitalization . A post hoc analysis , with antibiotic treatment added to the exacerbation definition , was also performed . RESULTS Budesonide/formoterol 320/9 and 160/9 reduced exacerbation rates ( number per patient-treatment year ) by 34.6 % and 25.9 % , respectively , versus formoterol ( p ≤ 0.002 ) . Budesonide/formoterol 320/9 prolonged time to first exacerbation versus formoterol , corresponding to a 21.2 % reduction in hazard ratio ( 0.788 [ 95 % CI : 0.639 , 0.972 ] ; p = 0.026 ) . Exacerbation rates ( number per patient-treatment year ) including antibiotic treatment ( post hoc analysis ) were reduced by 25.9 % and 18.7 % with budesonide/formoterol 320/9 and 160/9 , respectively , versus formoterol ( p ≤ 0.023 ) . Both budesonide/formoterol doses were well tolerated with safety profiles similar to formoterol . Pneumonia adverse events occurred in 6.4 % , 4.7 % , and 2.7 % of patients in the budesonide/formoterol 320/9 , 160/9 , and formoterol groups . CONCLUSIONS Over 12 months , both budesonide/formoterol doses reduced the exacerbation rate ( defined with or without antibiotic treatment ) versus formoterol . Budesonide/formoterol pMDI is an appropriate treatment for reducing exacerbations in COPD patients with a history of exacerbations . ( NCT00419744 ) BACKGROUND We compared the efficacy and safety of indacaterol and tiotropium in patients with severe chronic obstructive pulmonary disease ( COPD ) and a history of at least one moderate to severe exacerbation in the previous 12 months . METHODS In this multicentre , r and omised , blinded , double-dummy , parallel group study , we enrolled patients aged 40 years or older with severe COPD and at least one exacerbation within the previous year . We used a computer-generated sequence to r and omly allocate patients ( 1:1 ; stratified by baseline inhaled corticosteroid use , with the balance of treatments maintained at country level ) to receive either indacaterol ( 150 μg ) or tiotropium ( 18 μg ) once-daily for 52 weeks . Our primary and key secondary objectives were to investigate whether indacaterol was non-inferior to tiotropium  for trough forced expiratory volume in 1 s ( FEV1 ) at week 12 ( primary endpoint ) , and for rate of exacerbations at week 52 ( secondary endpoint ) . Analysis population s for the primary and key secondary endpoints were per- protocol sets . The safety set included all patients who received at least one dose of study drug . This study is registered with Clinical Trials.gov , number NCT00845728 . FINDINGS Between March 16 , 2009 , and July 5 , 2012 , we enrolled and r and omly allocated 3444 patients : 1723 to indacaterol and 1721 to tiotropium . At week 12 , the estimated least squares mean trough FEV1 difference between the groups was -0.011 L ( least squares mean with indacaterol [ n=1450 ] 1.134 L [ SE 0.008 ] vs tiotropium [ n=1467 ] 1.145 L [ 0.008 ] ; one-sided 97.5 % CI lower limit -0.026 L ; p<0.0001 ) . The lower limit of the 97.5 % CI was above the prespecified non-inferiority margin of -0.055 L , suggesting that indacaterol was non-inferior to tiotropium . Indacaterol did not show non-inferiority in terms of annualised exacerbation rates : 0.79 ( indacaterol , n=1529 ) versus 0.61 ( tiotropium , n=1543 ) ; ratio 1.29 ( one-sided 97.5 % CI upper limit 1.44 ) . In the safety set , we recorded no between-group difference in the number of patients who had adverse events  ( indacaterol 1119 [ 65 % ] of 1721 patients vs tiotropium 1065 [ 62 % ] of 1718 patients ) or serious adverse events  ( indacaterol , 263 [ 15 % ] of 1721 patients vs tiotropium , 255 [ 15 % ] of 1718 patients ) . Respiratory disorders , particularly worsening of COPD , were the most common adverse events ( COPD : indacaterol , 747 [ 43 % ] of 1721 patients and tiotropium , 665 [ 39 % ] of 1718 patients ) and serious adverse events ( COPD : indacaterol , 147 [ 9 % ] of 1721 patients and tiotropium , 121 [ 7 % ] of 1718 patients ) . INTERPRETATION Indacaterol and tiotropium provided clinical ly relevant improvements in lung function with comparable safety profiles . Tiotropium afforded greater protection from exacerbations , although the absolute number of events was small and the difference between treatments is of uncertain clinical importance . The present data offer evidence consistent with current guidelines . FUNDING Novartis Pharma AG The Indacaterol : Switching Non-exacerbating Patients with Moderate COPD From Salmeterol/Fluticasone to Indacaterol ( INSTEAD ) study investigated the effect of switching patients at low risk of chronic obstructive pulmonary disease ( COPD ) exacerbations from salmeterol/fluticasone ( SFC ;  inhaled corticosteroid  ( ICS ) regimen ) to indacaterol monotherapy ( non-ICS regimen ) . This 26-week , double-blind , double-dummy , parallel-group , phase IV study , r and omised 581 patients with moderate COPD to indacaterol 150 μg once daily or SFC 50/500 μg twice daily . Patients had been receiving SFC 50/500 μg for ≥3 months , with no COPD exacerbations for more than a year before the study ( patients for whom ICS is not recommended ) . The primary objective was to demonstrate non-inferiority of indacaterol to SFC , measured by trough forced expiratory volume in 1 second ( FEV1 ) after 12 weeks ( non-inferiority margin of 0.06 L ) . The primary objective was met , with a mean treatment difference of 9 mL ( 95 % CI -45–26 mL ) . There were no significant differences between treatments in terms of breathlessness ( transition dyspnoea index ) or health status ( Saint George ’s Respiratory Question naire ) at weeks 12 or 26 , or rescue medication use or COPD exacerbation rates over 26 weeks . Safety profiles of both treatments were as expected . This study demonstrated that patients with moderate COPD and no exacerbations in the previous year can be switched from SFC to indacaterol 150 μg with no efficacy loss . Moderate COPD patients can switch from salmeterol/fluticasone to indacaterol with no efficacy loss CONTEXT As of 2005 , the International Committee of Medical Journal Editors required investigators to register their trials prior to participant enrollment as a precondition for publishing the trial 's findings in member journals . OBJECTIVE To assess the proportion of registered trials with results recently published in journals with high impact factors ; to compare the primary outcomes specified in trial registries with those reported in the published articles ; and to determine whether primary outcome reporting bias favored significant outcomes . DATA SOURCES AND STUDY SELECTION MEDLINE via PubMed was search ed for reports of r and omized controlled trials ( RCTs ) in 3 medical areas ( cardiology , rheumatology , and gastroenterology ) indexed in 2008 in the 10 general medical journals and specialty journals with the highest impact factors . DATA EXTRACTION For each included article , we obtained the trial registration information using a st and ardized data extraction form . RESULTS Of the 323 included trials , 147 ( 45.5 % ) were adequately registered ( ie , registered before the end of the trial , with the primary outcome clearly specified ) . Trial registration was lacking for 89 published reports ( 27.6 % ) , 45 trials ( 13.9 % ) were registered after the completion of the study , 39 ( 12 % ) were registered with no or an unclear description of the primary outcome , and 3 ( 0.9 % ) were registered after the completion of the study and had an unclear description of the primary outcome . Among articles with trials adequately registered , 31 % ( 46 of 147 ) showed some evidence of discrepancies between the outcomes registered and the outcomes published . The influence of these discrepancies could be assessed in only half of them and in these statistically significant results were favored in 82.6 % ( 19 of 23 ) . CONCLUSION Comparison of the primary outcomes of RCTs registered with their subsequent publication indicated that selective outcome reporting is prevalent 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 Evidence has been provided that high-dose indacaterol ( 300 μg ) can reduce lung hyperinflation in moderate-to-severe chronic obstructive pulmonary disease ( COPD ) . AIM To study whether low-dose indacaterol ( 150 μg ) also reduces lung hyperinflation in comparison with the recommended dose of tiotropium ( 18 μg ) in moderate COPD . METHODS This was a multicenter , r and omized , blinded , 3-period cross-over , placebo-controlled study . Spirometry and lung volumes were measured before and 30 , 60 , 120 , 180 and 240 min after the administration of single-doses of indacaterol , tiotropium , or placebo . The primary end-point was the change in peak inspiratory capacity ( IC ) . The area under the 4-h curve ( AUC(0 - 4 ) ) for IC , 1-s forced expiratory volume ( FEV(1 ) ) and forced vital capacity ( FVC ) were secondary variables . RESULTS 49 patients completed the study . On average , peak IC and AUC(0 - 4 ) for IC were significantly greater after indacaterol than placebo by 177 mL ( p = 0.007 ) and 142 mL ( p = 0.001 ) , respectively . Differences in peak IC and AUC(0 - 4 ) for IC between tiotropium and placebo were 120 mL ( p = 0.07 ) and 85 mL ( p = 0.052 ) , respectively . Differences between indacaterol and tiotropium were statistically insignificant . Peak IC increased by > 20 % in 12 patients with indacaterol and 9 with tiotropium ( p = 0.001 ) , and by > 30 % in 8 patients with indacaterol and 3 with tiotropium ( p = 0.001 ) . The effects of indacaterol and tiotropium on FEV(1 ) and FVC were statistically significant vs placebo . CONCLUSIONS Low-dose indacaterol has a bronchodilator effect that is similar to the recommended dose of tiotropium , but it is slightly superior in reducing lung hyperinflation . TRIAL REGISTRATION Clinical Trials.gov number : NCT00999908 BACKGROUND Fluticasone furoate (FF)/vilanterol ( VI ) is a novel once-daily inhaled corticosteroid/long-acting β2-agonist combination therapy for COPD . We aim ed to assess the efficacy and safety of two strengths of FF/VI ( 100/25 μg ; 50/25 μg ) vs. individual components ( FF 100 μg , VI 25 μg ) and placebo over 24 weeks . METHODS Multicentre , r and omised , placebo-controlled , double-blind , parallel-group study of patients ( N = 1030 ) with moderate-to-severe COPD . All medication was administered once daily in the morning . Co- primary efficacy endpoints were : ( 1 ) weighted mean ( wm ) FEV1 ( 0 - 4 h post-dose on day 168 ) to assess acute lung function effects ; and ( 2 ) trough FEV1 ( 23 - 24 h post-dose on day 169 ) to assess long-lasting effects . Symptom-related outcomes were analysed and adverse events ( AEs ) assessed . RESULTS Main findings were : ( 1 ) the combination of FF/VI at a strength of 100/25 μg significantly ( p < 0.001 ) improved wm FEV1 ( 173 ml ) and trough FEV1 ( 115 ml ) vs. placebo . Similar effects were observed with FF/VI 50/25 μg ; ( 2 ) no significant difference was seen between FF/VI 100/25 μg and VI 25 μg for trough FEV1 ( 48 ml , p = 0.082 ) , while an effect was observed between FF/VI 100/25 μg and FF 100 μg for wm FEV1 ( 120 ml , p < 0.001 ) ; ( 3 ) VI 25 μg over 24 weeks improved lung function  vs. placebo significantly for wm FEV1 ( 103 ml , p < 0.001 ) and trough FEV1 ( 67 ml , p = 0.017 ) ; and ( 4 ) no safety signal was observed . CONCLUSIONS In subjects with moderate-to-severe COPD , FF/VI 100/25 μg provides rapid and significant sustained bronchodilation at 24 weeks . Lung function is improved to a similar extent with FF/VI 50/25 μg and to a somewhat lesser extent with VI 25 μg . All treatments were well tolerated . GSK study number : HZC112206 . Clinical Trials.gov : NCT01053988 Background Umeclidinium ( UMEC ; long-acting muscarinic antagonist ) plus vilanterol ( VI ; long-acting beta2 agonist [ LABA ] ) and the LABA/inhaled corticosteroid fluticasone propionate/salmeterol ( FP/SAL ) are approved maintenance treatments for chronic obstructive pulmonary disease ( COPD ) . This 12-week , multicentre , double-blind , parallel-group , double-dummy study compared the efficacy and safety of these treatments in symptomatic patients with moderate-to-severe COPD with no exacerbations in the year prior to enrolment . Methods Patients ( n = 717 ) were r and omised 1:1 to once-daily UMEC/VI 62.5/25 mcg or twice-daily FP/SAL 500/50 mcg . Endpoints included 0–24 h weighted mean ( wm ) forced expiratory volume in 1 s ( FEV1 ) ( Day 84 ; primary ) , trough FEV1 ( Day 85 ; secondary ) , other lung function endpoints , symptoms , quality of life ( QoL ) and safety . Results Improvements with UMEC/VI versus FP/SAL were 0.080 L ( 95 % confidence interval : 0.046–0.113 ; wmFEV1 ) and 0.090 L ( 0.055–0.125 ; trough FEV1 ) ( both p < 0.001 ) . UMEC/VI statistically significantly improved all other lung function measures versus FP/SAL . Both treatments demonstrated a clinical ly meaningful improvement in symptoms ( Transition Dyspnoea Index ≥1 unit ) and QoL ( St George ’s Respiratory Question naire Total score ≥4 unit decrease from baseline ) over 12 weeks . The incidence of adverse events was 28 % ( UMEC/VI ) and 29 % ( FP/SAL ) ; nasopharyngitis and headache were most common . Conclusions Once-daily UMEC/VI 62.5/25 mcg over 12 weeks result ed in significant and sustained improvements in lung function versus twice-daily FP/SAL 500/50 mcg in patients with moderate-to-severe COPD and with no exacerbations in the year prior to enrolment . Trial Registration NCT01822899 Registration date : March 28 , BACKGROUND Increased arterial stiffness as measured by aortic pulse wave velocity ( aPWV ) predicts cardiovascular events and mortality and is elevated in patients with COPD . Prior investigation suggests that a long-acting β-agonist (LABA)/inhaled corticosteroid ( ICS ) lowers aPWV in patients with baseline aPWV ≥ 11 m/s . This study compared the effect of the ICS/LABA fluticasone furoate/vilanterol ( FF/VI ) , 100/25 μg , delivered via the ELLIPTA dry powder inhaler , with tiotropium bromide ( TIO ) , 18 μg , on aPWV . METHODS This multicenter , r and omized , blinded , double-dummy , parallel-group , 12-week study compared FF/VI and TIO , both administered once daily . The primary end point was aPWV change from baseline at 12 weeks . Safety end points included adverse events ( AEs ) , vital signs , and clinical laboratory tests . RESULTS Two hundred fifty-seven patients with COPD and aPWV ≥ 11 m/s were r and omized ; 87 % had prior cardiovascular events and /or risk . The mean difference in aPWV between FF/VI and TIO at week 12 was not significant ( P = .484 ) . Because the study did not contain a placebo arm , a post hoc analysis was performed to show that both treatments lowered aPWV by an approximate difference of 1 m/s compared with baseline . The proportion of patients reporting AEs was similar with FF/VI ( 24 % ) and TIO ( 18 % ) . There were no changes in clinical concern for vital signs or clinical laboratory tests . CONCLUSIONS No differences on aPWV were observed between FF/VI and TIO . However , further studies with a placebo arm are required to establish definitively whether long-acting bronchodilators lower aPWV . Both treatments demonstrated an acceptable tolerability profile . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT01395888 ; URL : www . clinical trials.gov We evaluated the effect of QVA149 , a dual bronchodilator combining indacaterol and glycopyrronium , on direct patient-reported dyspnoea in patients with moderate-to-severe chronic obstructive pulmonary disease . In this multicentre , blinded , double-dummy , three-period crossover study , 247 patients were r and omised to once-daily QVA149 110/50 μg , placebo or tiotropium 18 μg . Superiority of QVA149 versus placebo ( primary objective ) and tiotropium ( secondary objective ) was assessed for improvement in dyspnoea via the self-administered computerised ( SAC ) version of the Baseline and Transition Dyspnoea Index after 6 weeks . Secondary end-points included lung function , rescue medication use and safety . After 6 weeks , the SAC Transition Dyspnoea Index total score was significantly higher with QVA149 versus placebo ( least squares mean ( LSM ) treatment difference 1.37 , p<0.001 ) and tiotropium ( LSM treatment difference 0.49 , p=0.021 ) . QVA149 provided significant improvements in lung function , with higher forced expiratory volume in 1 s area under the curve from 0–4 h post-dose versus placebo and tiotropium at day 1 and week 6 ( all p<0.001 ) . Rescue medication use was significantly lower with QVA149 versus placebo ( p<0.001 ) and tiotropium ( p=0.002 ) . All treatments were well tolerated . Once-daily QVA149 provided superior improvements in patient-reported dyspnoea and lung function versus placebo and tiotropium . These benefits were associated with improvements in other symptoms and reduced use of rescue medication . Two different bronchodilators in a single inhaler were effective in relieving  patient-reported dyspnoea in COPD Background Tiotropium + olo date rol has demonstrated improvements beyond lung function benefits in a large Phase III clinical program as a once-daily maintenance treatment for COPD and may be a potential option for the initiation of maintenance treatment in COPD . Despite guideline recommendations that combined long-acting β2-agonists and inhaled corticosteroids should only be used in individuals at high risk of exacerbation , there is substantial use in individuals at lower risk . This raises the question of the comparative effectiveness of this combination as maintenance treatment in this group compared to other combination regimens . Objective The study aim ed to assess the effect on lung function of once-daily tiotropium + olo date rol versus twice-daily salmeterol + fluticasone propionate in all participants with Global initiative for chronic Obstructive Lung Disease 2 or 3 ( moderate to severe ) COPD . Methods This was a r and omized , double-blind , double-dummy , four-treatment , complete crossover study in which participants received once-daily tiotropium + olo date rol ( 5/5 µg and 2.5/5 µg ) via Respimat ® and twice-daily salmeterol + fluticasone propionate ( 50/500 µg and 50/250 µg ) via Accuhaler ® for 6 weeks . The primary end point was change in forced expiratory volume in 1 second ( FEV1 ) area under the curve from 0 hour to 12 hours ( AUC0–12 ) relative to the baseline after 6 weeks . Results Tiotropium + olo date rol 5/5 µg and 2.5/5 µg demonstrated statistically significant improvements in FEV1 AUC0–12 compared to salmeterol + fluticasone propionate ( improvements from baseline were 317 mL and 295 mL with tiotropium + olo date rol 5/5 µg and 2.5/5 µg , and 188 mL and 192 mL with salmeterol + fluticasone propionate 50/500 µg and 50/250 µg , respectively ) . Tiotropium + olo date rol was  superior to salmeterol + fluticasone propionate  in lung function secondary end points , including FEV1 area under the curve from 0 hour to 24 hours ( AUC0–24 ) . Conclusion Once-daily tiotropium + olo date rol in participants with moderate-to-severe COPD provided superior lung function improvements to twice-daily salmeterol + fluticasone propionate . Dual bronchodilation can be considered to optimize lung function in individuals requiring maintenance treatment for COPD Background Two once-daily long-acting muscarinic antagonists ( LAMAs ) are currently available for the treatment of chronic obstructive pulmonary disease ( COPD ) – tiotropium and glycopyrronium . Previous studies have compared glycopyrronium with open-label tiotropium . In the GLOW5 study , we compare glycopyrronium with blinded tiotropium . Methods In this blinded , double-dummy , parallel group , 12-week study , patients with moderate-to-severe COPD were r and omized 1:1 to glycopyrronium 50 μg once daily or tiotropium 18 μg once daily  . The primary objective was to demonstrate the non-inferiority of glycopyrronium versus blinded tiotropium with respect to trough forced expiratory volume in 1 second ( FEV1 ) following 12 weeks of treatment ( non-inferiority margin : –50 mL ) . Secondary objectives were to evaluate glycopyrronium versus tiotropium for other spirometric outcomes , breathlessness ( Transition Dyspnea Index ; TDI ) , health status ( St George ’s Respiratory Question naire ; SGRQ ) , daily rescue medication use , COPD exacerbations and COPD symptoms over 12 weeks of treatment . Results 657 patients were r and omized ( glycopyrronium : 327 ; tiotropium : 330 ) ; 96 % ( 630 patients ) completed the study .  Least squares mean trough FEV1  for both glycopyrronium and tiotropium was 1.405 L at Week 12 , meeting the criterion for non-inferiority ( mean treatment difference : 0 mL , 95 % CI : –32 , 31 mL ) . Glycopyrronium demonstrated rapid bronchodilation following first dose on Day 1 , with significantly higher FEV1 at all time points from 0–4 h post-dose versus tiotropium ( all p < 0.001 ) . FEV1 area under the curve from 0–4 h ( AUC0–4h ) post-dose with glycopyrronium was significantly superior to tiotropium on Day 1 ( p < 0.001 ) and was comparable to tiotropium at Week 12 . Glycopyrronium demonstrated comparable improvements to tiotropium  in TDI focal score , SGRQ total score , rescue medication use and the rate of COPD exacerbations ( all p = not significant ) . Patients on glycopyrronium also had a significantly lower total COPD symptom score versus patients on tiotropium after 12 weeks ( p = 0.035 ) . Adverse events were reported by a similar percentage of patients receiving glycopyrronium ( 40.4 % ) and tiotropium ( 40.6 % ) . Conclusion In patients with moderate-to-severe COPD , 12-week blinded treatment with once-daily glycopyrronium 50 μg or tiotropium 18 μg , provided similar efficacy and safety , with glycopyrronium having a faster onset of action on Day 1 versus tiotropium . Trial registration Clinical Trial.gov , The efficacy and safety of budesonide/formoterol in a single inhaler compared with placebo , budesonide and formoterol were evaluated in patients with moderate-to-severe chronic obstructive pulmonary disease ( COPD ) . In a 12-month , r and omised , double-blind , placebo-controlled , parallel-group study in 812 adults ( mean age 64 yrs , mean forced expiratory volume in one second ( FEV1 ) 36 % predicted normal ) , patients received two inhalations twice daily of either budesonide/formoterol ( Symbicort ® ) 160/4.5 µg ( delivered dose ) , budesonide 200 µg ( metered dose ) , formoterol 4.5 µg or placebo . Severe exacerbations and FEV1 ( primary variables ) , peak expiratory flow ( PEF ) , COPD symptoms , health-related quality of life ( HRQL ) , mild exacerbations , use of reliever β2‐agonist and safety variables were recorded .  Budesonide/formoterol reduced the mean number of severe exacerbations per patient per year by 24 % versus placebo and 23 % versus formoterol . FEV1 increased by 15 % versus placebo and 9 % versus budesonide . Morning PEF improved significantly on day 1 versus placebo and budesonide ; after 1 week , morning PEF was improved versus placebo , budesonide and formoterol . Improvements in morning and evening PEF versus comparators were maintained over 12 months . Budesonide/formoterol decreased all symptom scores and use of reliever β2‐agonists significantly versus placebo and budesonide , and improved HRQL versus placebo . All treatments were well tolerated . These results suggest a role for budesonide/formoterol in the long-term management of moderate-to-severe chronic obstructive pulmonary disease BACKGROUND Inhaled long-acting beta2 agonists improve lung function and health status in symptomatic chronic obstructive pulmonary disease ( COPD ) , whereas inhaled corticosteroids reduce the frequency of acute episodes of symptom exacerbation and delay deterioration in health status . We postulated that a combination of these treatments would be better than each component used alone . METHODS 1465 patients with COPD were recruited from outpatient departments in 25 countries . They were treated in a r and omised , double-blind , parallel-group , placebo-controlled study with either 50 microg salmeterol twice daily ( n=372 ) , 500 microg fluticasone twice daily ( n=374 ) , 50 microg salmeterol and 500 microg fluticasone twice daily ( n=358 ) , or placebo ( n=361 ) for 12 months . The primary outcome was the pretreatment forced expiratory volume in 1s ( FEV1 ) after 12 months treatment ' and after patients had abstained from all bronchodilators for at least 6h and from study medication for at least 12h . Secondary outcomes were other lung function measurements , symptoms and rescue treatment use , the number of exacerbations , patient withdrawals , and disease-specific health status . We assessed adverse events , serum cortisol concentrations , skin bruising , and electrocardiograms . Analysis was as predefined in the study protocol . FINDINGS All active treatments improved lung function , symptoms , and health status and reduced use of rescue medication and frequency of exacerbations . Combination therapy improved pretreatment FEV1 significantly more than did placebo ( treatment difference 133 mL , 95 % CI 105 - 161 , p<0.0001 ) , salmeterol ( 73 mL , 46 - 101 , p<0.0001 ) , or fluticasone alone ( 95 mL , 67 - 122 , p<0.0001 ) . Combination treatment produced a clinical ly significant improvement in health status and the greatest reduction in daily symptoms . All treatments were well tolerated with no difference in the frequency of adverse events , bruising , or clinical ly significant falls in serum cortisol concentration . INTERPRETATION Because inhaled long-acting beta2 agonists and corticosteroid combination treatment produces better control of symptoms and lung function , with no greater risk of side-effects than that with use of either component alone , this combination treatment should be considered for patients with COPD Background Addition of a second bronchodilator from a different pharmacological class may benefit patients with moderate-to-severe chronic obstructive pulmonary disease ( COPD ) whose symptoms are insufficiently controlled by bronchodilator monotherapy . GLOW6 evaluated the efficacy and safety of once-daily coadministration of the long-acting β2-agonist indacaterol ( IND ) and the long-acting muscarinic antagonist glycopyrronium ( GLY ) versus IND alone in patients with moderate-to-severe COPD . Material s and methods In this r and omized , double-blind , parallel group , placebo-controlled , 12-week study , patients were r and omized 1:1 to IND 150 μg and GLY 50 μg daily ( IND + GLY ) or IND 150 μg daily and placebo ( IND + PBO ) ( all delivered via separate Breezhaler ® devices ) . The primary objective was to demonstrate the superiority of IND + GLY versus IND + PBO  for trough forced expiratory volume in 1 second ( FEV1 ) at week 12 . Other end points included trough FEV1 at day 1 , FEV1 area under the curve from 30 minutes to 4 hours ( AUC30min–4h ) , peak FEV1 , inspiratory capacity and trough forced vital capacity ( FVC ) at day 1 and week 12 , and transition dyspnea index ( TDI ) focal score , COPD symptoms , and rescue medication use over 12 weeks . Results A total of 449 patients were r and omized ( IND + GLY , 226 ; IND + PBO , 223 ) ; 94 % completed the study . On day 1 and at week 12 , IND + GLY significantly improved trough FEV1  versus IND + PBO , with treatment differences of 74 mL ( 95 % CI 46–101 mL ) and 64 mL ( 95 % CI 28–99 mL ) , respectively ( both P<0.001 ) . IND + GLY  significantly improved postdose peak FEV1 , FEV1 AUC30min–4h , and trough FVC at day 1 and week 12 versus IND + PBO ( all P<0.01 ) . TDI focal score and COPD symptoms ( percentage of days able to perform usual daily activities and change from baseline in mean daytime respiratory score ) were significantly improved with IND + GLY versus IND + PBO ( P<0.05 ) . The incidence of adverse events was similar for the two treatment groups . Conclusion In patients with moderate-to-severe COPD , once-daily coadministration of IND and GLY provides significant and sustained improvement in bronchodilation versus IND alone from day 1 , with significant improvements in patient-centered outcomes Lung function in chronic obstructive pulmonary disease ( COPD ) can be improved acutely by oral corticosteroids and bronchodilators . Whether clinical improvement can be maintained by subsequent inhaled therapy is unknown . COPD patients ( n=1,022 , mean prebronchodilator forced expiratory volume in one second ( FEV1 ) 36 % predicted ) initially received formoterol ( 9 µg b.i.d . ) and oral prednisolone ( 30 mg o.d . ) for 2 weeks . After this time , patients were r and omised to b.i.d . inhaled budesonide/formoterol 320/9 µg , budesonide 400 µg , formoterol 9 µg or placebo for 12 months . Postmedication FEV1 improved by 0.21 L and health-related quality of life using the St George 's Respiratory Question naire ( SGRQ ) by 4.5 units after run-in . Fewer patients receiving budesonide/formoterol withdrew from the study than those receiving budesonide , formoterol or placebo . Budesonide/formoterol patients had a prolonged time to first exacerbation ( 254 versus 96 days ) and maintained higher FEV1 ( 99 % versus 87 % of baseline ) , both primary variables versus placebo . They had fewer exacerbations ( 1.38 versus 1.80 exacerbations per patient per year ) , had higher prebronchodilator peak expiratory flow , and showed clinical ly relevant improvements in SGRQ versus placebo ( −7.5 units ) . Budesonide/formoterol was more effective than either monocomponent in both primary variables . Budesonide/formoterol in a single inhaler ( Symbicort ® ) maintains the benefit of treatment optimisation , stabilising lung function and delaying exacerbations more effectively than either component drug alone or placebo Background The long-acting muscarinic antagonist ( LAMA ) umeclidinium ( UMEC ) and the combination of UMEC with the long-acting β2-agonist ( LABA ) vilanterol ( UMEC/VI ) are approved maintenance treatments for chronic obstructive pulmonary disease ( COPD ) in the US and EU . They are not indicated for the treatment of asthma . Methods In this 52-week , double-blind , placebo-controlled , parallel-group safety study ( GSK study DB2113359 ; NCT01316887 ) , patients were r and omized 2:2:1 to UMEC/VI 125/25 mcg , UMEC 125 mcg , or placebo .  Study endpoints included adverse events ( AEs ) , clinical chemistry and hematology parameters , vital signs , 12-lead , and 24-hour Holter electrocardiograms . COPD exacerbations and rescue medication use were assessed as safety parameters ; lung function was also evaluated . Results The incidence of on-treatment AEs , serious AEs ( SAEs ) , and drug-related AEs was similar between treatment groups ( AEs : 52–58 % ; SAEs : 6–7 % ; drug-related AEs : 12–13 % ) . Headache was the most common AE in each treatment group ( 8–11 % ) . AEs associated with the LAMA and LABA pharmacologic classes occurred at a low incidence across treatment groups . No clinical ly meaningful effects on vital signs or laboratory assessment s were reported for active treatments versus placebo . The incidences of atrial arrhythmias with UMEC/VI 125/25 mcg were similar to placebo ; for UMEC 125 mcg , the incidences of ectopic supraventricular beats , sustained supraventricular tachycardia , and ectopic supraventricular rhythm were ≥2 % greater than placebo . With active treatments , COPD exacerbations were fewer ( 13–15 % of patients reporting ≥1 exacerbation ) and on average less rescue medication was required ( 1.6–2.2 puffs/day ) versus placebo ( 24 % reporting ≥1 exacerbation , 2.6 puffs/day ) . Both active treatments improved lung function  versus placebo . Conclusion UMEC/VI 125/25 mcg and UMEC 125 mcg were well tolerated over 12 months in patients with COPD Background This study evaluated the efficacy and safety of the long-acting β2-agonist formoterol in patients with moderate-to-severe COPD . Methods This double-blind , placebo-controlled , parallel-group , multinational phase III study r and omized patients ≥ 40 years of age with moderate-to-severe COPD to inhaled formoterol 4.5 or 9 μg twice daily ( bid ) via Turbuhaler ® or placebo for 12 weeks . Salbutamol 100 μg/actuation via pMDI was permitted as reliever medication . The primary outcome variable was change ( ratio ) from baseline to treatment period in FEV1 60-min post-dose . Results 613 patients received treatment ( formoterol 4.5 μg n = 206 ; 9 μg n = 199  ; placebo n = 208 ) ; 539 ( 87.9 % ) male ; 324 ( 52.9 % ) Japanese and 289 ( 47.1 % ) European . End of study increases in FEV1 60-min post-dose were significantly greater ( p < 0.001 for both ) with formoterol 4.5 and 9 μg bid ( 113 % of baseline for both ) than with placebo , as were all secondary outcome measures . The proportion of patients with an improvement in St George 's Respiratory Question naire score of ≥ 4 was 50.2 % for formoterol 4.5 μg ( p = 0.0682 vs. placebo ) , 59.2 % ( p = 0.0004 ) for 9 μg , and 41.3 % for  placebo . Reduction in reliever medication use was significantly greater with formoterol vs. placebo ( 9 μg : -0.548 , p < 0.001 ; 4.5 μg : -0.274 , p = 0.027 ) , with 9 μg being significantly superior to 4.5 μg ( -0.274 ,  p = 0.029 ) . Formoterol was well tolerated with the incidence and type of adverse events not being different for the three groups . Conclusions Formoterol 4.5 μg and 9 μg bid was effective and well tolerated in patients with COPD ; there was no difference between formoterol doses for the primary endpoint ; however , an added value of formoterol 9 μg over 4.5 μg bid was observed for some secondary endpoints . Trial registration NCT00628862 ( Clinical Trials.gov ) ; D5122C00001 ( AstraZeneca Study code ) Efficacy and safety of tiotropium+olo date rol fixed-dose combination ( FDC ) compared with the mono-components was evaluated in patients with moderate to very severe chronic obstructive pulmonary disease ( COPD ) in two replicate , r and omised , double-blind , parallel-group , multicentre , phase III trials . Patients received tiotropium+olo date rol FDC 2.5/5 μg or 5/5 μg , tiotropium 2.5 μg or 5 μg , or olo date rol 5 μg delivered once-daily via Respimat inhaler over 52 weeks . Primary end points were forced expiratory volume in 1 s ( FEV1 ) area under the curve from 0 to 3 h ( AUC0–3 ) response , trough FEV1 response and St George 's Respiratory Question naire ( SGRQ ) total score at 24 weeks . In total , 5162 patients ( 2624 in Study 1237.5 and 2538 in Study 1237.6 ) received treatment . Both FDCs significantly improved FEV1 AUC0–3 and trough FEV1 response versus the mono-components in both studies . Statistically significant improvements in SGRQ total score versus the mono-components were only seen for tiotropium+olo date rol FDC 5/5 μg . Incidence of adverse events was comparable between the FDCs and the mono-components . These studies demonstrated significant improvements in lung function and health-related quality of life with once-daily tiotropium+olo date rol FDC versus mono-components over 1 year in patients with moderate to very severe COPD . Lung function/symptomatic benefits of daily tiotropium+olo date rol fixed-dose combination in moderate-very severe COPD Background Inhaled long-acting beta2agonists used alone and in combination with an inhaled corticosteroid reduce the risk of exacerbations in patients with stable COPD . However , the relative efficacy of these agents in preventing recurrent exacerbations in those recovering from an initial episode is not known . This study compared the rate of COPD exacerbations over the 26 weeks after an initial exacerbation in patients receiving the combination of fluticasone propionate and salmeterol ( FP/SAL ) or SAL alone . Methods Patients ( n = 639 ) aged ≥40 years were r and omized to either twice-daily inhaled FP/SAL 250/50 μg or SAL 50 μg . Primary , and secondary , endpoints were rates of recurrent severe , and moderate/severe , exacerbations of COPD . Lung function , health outcomes and levels of biomarkers of systemic inflammation were also assessed . Results There was no statistically significant treatment difference in rates of recurrent severe exacerbations ( treatment ratio 0.92 [ 95 % CI : 0.58 , 1.45 ] ) and moderate/severe exacerbations ( 0.82 [ 0.64 , 1.06 ] ) between FP/SAL and SAL in the intent-to-treat population . Pre-dose morning FEV1change from baseline was greater ( 0.10 L [ 0.04 , 0.16 ] ) with FP/SAL than SAL . No treatment difference was seen for other endpoints including patient-reported health outcomes and biomarker levels for the full cohort . Conclusions No significant treatment difference between FP/SAL and SAL was seen in COPD exacerbation recurrence for the complete cohort . Treatment benefit with FP/SAL over SAL ( treatment ratio 0.68 [ 0.47 , 0.97 ] ) was seen in patients having FEV1≥ 30 % and prior exposure to ICS . No unexpected safety issues were identified with either treatment . Patients with the most severe COPD may be more refractory to treatment . Trial registration Clinical Trials.gov ( identifier http:// clinical trials.gov/show/NCT01110200 ) . This study was funded by GlaxoSmithKline ( study number ADC113874 ) Introduction The fixed-dose , long-acting bronchodilator combination of umeclidinium/vilanterol ( UMEC/VI ) has not previously been compared with a combination of a long-acting muscarinic antagonist and long-acting β2-agonist in patients with chronic obstructive pulmonary disease ( COPD ) . Methods This 12-week , r and omized , blinded , triple-dummy , parallel-group , non-inferiority study compared once-daily UMEC/VI 62.5/25 mcg with once-daily tiotropium ( TIO ) 18 mcg + indacaterol ( IND ) 150 mcg in patients with moderate-to-very-severe COPD . The primary endpoint was the trough forced expiratory volume in 1 s ( FEV1 ) on day 85 ( predefined non-inferiority margin −50 mL ) , and the secondary endpoint was the 0- to 6-h weighted mean ( WM ) FEV1 on day 84 . Other efficacy endpoints [ including rescue medication use , the Transition Dyspnea Index ( TDI ) focal score , and the St. George ’s Respiratory Question naire ( SGRQ ) score ] and safety endpoints [ adverse events ( AEs ) , vital signs , and COPD exacerbations ] were also assessed . Results Trough FEV1 improvements were comparable between treatment groups [ least squares ( LS ) mean changes from baseline to day 85 : UMEC/VI 172 mL ; TIO + IND 171 mL ; treatment difference 1 mL ; 95 % confidence interval ( CI ) −29 to 30 mL ] , demonstrating non-inferiority between UMEC/VI and TIO + IND . The treatments produced similar improvements in the trough FEV1 at other study visits and the 0- to 6-h WM FEV1 ( LS mean changes at day 84 : UMEC/VI 235 mL ; TIO + IND 258 mL ; treatment difference −23 mL ; 95 % CI −54 to 8 mL ) . The results for patient-reported measures ( rescue medication use , TDI focal score , and SGRQ score ) were comparable ; both treatments produced clinical ly meaningful improvements in TDI and SGRQ scores . The incidence of AEs and COPD exacerbations , and changes in vital signs were similar for the two treatments . Conclusion UMEC/VI and TIO + IND , given once daily , provided similar improvements in lung function and patient-reported outcomes over 12 weeks in patients with COPD , with comparable tolerability and safety profiles . Trial numbers Clinical Trials.gov study ID NCT02257385 ; GSK study no. 116961 Two , once daily ( q.d . ) inhaled bronchodilators are available for the treatment of chronic obstructive pulmonary disease ( COPD ): the & bgr;2-agonist indacaterol and the anticholinergic tiotropium . This blinded study compared the efficacy of these two agents and assessed their safety and tolerability . Patients with moderate-to-severe COPD were r and omised to treatment with indacaterol 150 μg q.d . ( n=797 ) or tiotropium 18 μg q.d . ( n=801 ) for 12 weeks . After 12 weeks , the two treatments had similar overall effects on “ trough ” ( 24 h post-dose ) forced expiratory volume in 1 s.  Indacaterol-treated patients had greater improvements in transition dyspnoea index ( TDI ) total score ( least squares means 2.01 versus 1.43 ; p<0.001 ) and St George ’s Respiratory Question naire ( SGRQ ) total score ( least squares means 37.1 versus 39.2 ; p<0.001 ; raw mean change from baseline -5.1 versus -3.0 ) , and were significantly more likely to achieve clinical ly relevant improvements in these end-points ( indacaterol versus tiotropium odds ratios of 1.49 for TDI and 1.43 for SGRQ , both p<0.001 ) . Adverse events were recorded for 39.7 % and 37.2 % of patients in the indacaterol and tiotropium treatment groups , respectively . The most frequent adverse events were COPD worsening , cough and nasopharyngitis . Both bronchodilators demonstrated spirometric efficacy . The two treatments were well tolerated with similar adverse event profiles . Compared with tiotropium , indacaterol provided significantly greater improvements in clinical outcomes The anti-inflammatory effects of salmeterol/fluticasone ( SFP ) , tiotropium/fluticasone ( Tio+FP ) and tiotropium ( Tio ) alone were investigated on the inflammatory cells and mediators in sputum induced from chronic obstructive pulmonary disease patients . Subjects were either newly diagnosed or had not taken any medication for 3 months prior to the study . Subjects ( n = 99 ) were r and omised ( not double blinded ) and received either SFP ( 100/1,000 μg daily ) , Tio+FP ( 18/1,000 μg daily ) or Tio ( 18 μg daily ) for 12 weeks . Induced sputum and serum C-reactive protein ( CRP ) were analysed prior to and at the end of treatment . The results showed that treatment with SFP caused a significant reduction in interleukin (IL)-8 and matrix metalloprotease (MMP)-9 in induced sputum , compared with treatment with Tio alone . There were no treatment differences between the SFP and Tio+FP groups in decreasing IL-8 and MMP-9 levels . The reduction in IL-8 showed significant association with the reduction in MMP-9 . All treatment groups failed to significantly reduce the numbers of total cells , neutrophils , macrophages and eosinophils in induced sputum ; in addition , there were no treatment differences in terms of improvement of forced expiratory volume in one second , forced vital capacity , CRP or quality of life between the three groups . The anti-inflammatory effects of salmeterol/fluticasone probably contribute to the clinical benefits seen in chronic obstructive pulmonary disease patients Background Combination of the inhaled long-acting muscarinic antagonist umeclidinium ( UMEC ; GSK573719 ) with the long-acting β2-agonist vilanterol ( VI ) is an approved maintenance treatment for COPD in the US and EU . We compared the efficacy and safety of UMEC/VI with placebo in patients with COPD of Asian ancestry . Patients and methods In this 24-week , Phase III , multicenter , r and omized , double-blind , placebo-controlled , parallel-group study , patients were r and omized 1:1:1 to UMEC/VI 125/25 μg , UMEC/VI 62.5/25 μg , or placebo . The primary efficacy end point was trough forced expiratory volume in 1 second ( FEV1 ) on day 169 ; secondary end points were Transition Dyspnea Index ( TDI ) focal score at week 24 and weighted mean ( WM ) FEV1 over 0–6 hours postdose on day 1 . Additional end points and safety were also assessed . Results Both UMEC/VI 125/25 μg and UMEC/VI 62.5/25 μg statistically significantly improved trough FEV1 at day 169 versus placebo ( UMEC/VI 125/25 μg , 0.216 L , [ 95 % confidence interval [ CI ] 0.175–0.257 ] ; UMEC/VI 62.5/25 μg , 0.151 L , 95 % CI 0.110–0.191 ; both P<0.001 ) . Statistically significant improvements in TDI score were observed for both UMEC/VI groups versus placebo ( UMEC/VI 125/25 μg , 0.9 , 95 % CI 0.3–1.4 , P=0.002 ; UMEC/VI 62.5/25 μg , 0.7 , 95 % CI 0.1–1.2 , P=0.016 ) . On day 1 , both UMEC/VI groups improved 0–6-hour WM FEV1  versus placebo ( UMEC/VI 125/25 μg , 0.182 L 95 % CI 0.161–0.203 ; UMEC/VI 62.5/25 μg , 0.160 L , 95 % CI 0.139–0.181 ; both P<0.001 ) . Statistically significant improvements for UMEC/VI groups versus placebo were observed for rescue albuterol use at weeks 1–24 ( puffs/day , both P<0.001 ) . The incidence of adverse events was similar across groups . Conclusion In Asian patients with COPD , once-daily UMEC/VI 125/25 μg and UMEC 62.5/25 μg result ed in clinical ly meaningful and statistically significant improvements in lung-function end points versus placebo . Symptomatic and quality of life measures also improved . The safety profile of UMEC/VI was consistent with previous studies Abstract Objective : To compare a once-daily long-acting β2 agonist ( indacaterol 150 µg ) with a once-daily long-acting anticholinergic ( tiotropium 5 µg ) in terms of their effects on exercise endurance ( limit of tolerance , Tlim ) in patients with moderate COPD . Secondary endpoints were their effects on lung hyperinflation , exercise-related dyspnea , and daily-life dyspnea . Methods : This was a r and omized , single-blind , crossover pilot study involving 20 patients ( mean age , 60.9 ± 10.0 years ; mean FEV1 , 69 ± 7 % of predicted ) . Spirometric parameters , Transition Dyspnea Index scores , Tlim , and exertional dyspnea were compared after three weeks of each treatment ( with a one-week washout period between treatments ) . Results : Nineteen patients completed the study ( one having been excluded because of COPD exacerbation ) . Improvement in Tlim from baseline tended to be greater after treatment with tiotropium than after treatment with indacaterol ( 96 ± 163 s vs. 8 ± 82 s ; p = 0.06 ) . Tlim significantly improved from baseline after treatment with tiotropium ( having increased from 396 ± 319 s to 493 ± 347 s ; p = 0.010 ) but not after treatment with indacaterol ( having increased from 393 ± 246 to 401 ± 254 s ; p = 0.678 ) . There were no differences between the two treatments regarding improvements in Borg dyspnea scores and lung hyperinflation at " isotime " and peak exercise . There were also no significant differences between treatments regarding Transition Dyspnea Index scores ( 1.5 ± 2.1 vs. 0.9 ± 2.3 ; p = 0.39 ) . Conclusions : In patients with moderate COPD  , tiotropium tends to improve Tlim in comparison with indacaterol . No significant differences were observed between the two treatments regarding their effects on lung hyperinflation , exercise-related dyspnea , and daily-life dyspnea . Future studies , including a larger number of patients , are required in order to confirm our findings and explore mechanistic explanations . ( Clinical Trials.gov identifier : NCT01693003 [ http://www . clinical trials.gov/ ] Introduction The BEACON study evaluated the efficacy and safety of QVA149 , a once-daily dual bronchodilator containing a fixed-dose combination of the long-acting β2-agonist ( LABA ) indacaterol and long-acting muscarinic antagonist ( LAMA ) glycopyrronium ( NVA237 ) , in development for the treatment of patients with chronic obstructive pulmonary disease ( COPD ) , compared with the free-dose concurrent administration of indacaterol plus glycopyrronium ( IND+GLY ) . Methods In this multicenter , double-blind , parallel group study , patients with stage II or stage III COPD ( Global initiative for chronic Obstructive Lung Disease [ GOLD ] 2010 ) were r and omized ( 1:1 ) to once-daily QVA149  ( 110 μg indacaterol/50 μg glycopyrronium ) or concurrent administration of indacaterol ( 150 μg ) and glycopyrronium ( 50 μg ) via the Breezhaler ® device ( Novartis AG , Basel , Switzerl and ) for 4 weeks . The primary endpoint was to evaluate the noninferiority of QVA149  as compared with concurrent administration of IND+GLY , for trough forced expiratory volume in 1 second ( FEV1 ) after 4 weeks of treatment . The other assessment s included FEV1 area under the curve from 0 to 4 hours ( AUC0–4 hours ) at day 1 and week 4 , symptom scores , rescue medication use , safety , and tolerability over the 4-week study period . Results Of 193 patients r and omized , 187 ( 96.9 % ) completed the study . Trough FEV1 at week 4 for QVA149 and IND+GLY was 1.46 L ± 0.02 and 1.46 L ± 0.18 , respectively . The FEV1 AUC0–4 hours at day 1 and week 4 were similar between the two treatment groups . Both treatment groups had a similar reduction in symptom scores and rescue medication use for the 4-week treatment period . Overall , 25.6 % of patients in QVA149 group and 25.2 % in the IND+GLY group experienced an adverse event , with the majority being mild-to-moderate in severity . No deaths were reported during the study or during the 30 days follow-up period . Conclusion The BEACON study demonstrated that once-daily QVA149 provides an efficacy and safety profile similar to the concurrent administration of its monocomponents indacaterol and glycopyrronium Background Aclidinium/formoterol is a twice-daily ( BID ) fixed-dose combination ( FDC ) in development for chronic obstructive pulmonary disease ( COPD ) . The efficacy and safety of aclidinium/formoterol versus monotherapy and placebo in patients with COPD was assessed . Methods In this 24-week double-blind , parallel-group , active- and placebo-controlled , multicentre Phase III study , patients ( ≥40 years , post-bronchodilator forced expiratory volume in 1 second [FEV1]/forced vital capacity < 70 % and FEV1 ≥30 % but < 80 % predicted normal ) were r and omised 2:2:2:2:1 to aclidinium/formoterol 400/12 μg ( n = 385 ) or 400/6 μg ( n = 381 ) , aclidinium 400 μg ( n = 385 ) , formoterol 12 μg ( n = 384 ) or placebo ( n = 194 ) BID via Genuair ® /Pressair ® a . Results At Week 24 , aclidinium/formoterol 400/12 μg and 400/6 μg lead to significant improvements from baseline in 1-hour post-dose FEV1  versus aclidinium ( 125 mL [ 95 % CI : 90 , 160 ; p < 0 · 001 ] and 69 mL [ 95 % CI : 34 , 105 ; p < 0.001 ] , respectively ) and trough FEV1 versus formoterol ( 85 mL [ 95 % CI : 51 , 119 ; p < 0.001 ] and 53 mL [ 95 % CI : 19 , 87 ; p < 0.01 ] , respectively ; co- primary endpoints ) . Additionally , aclidinium/formoterol 400/12 μg and 400/6 μg provided significant improvements in Transition Dyspnoea Index ( TDI ) focal score versus placebo ( 1.29 units [ 95 % CI : 0.73 , 1.86 ; p < 0.001 ] and 1.16 units [ 95 % CI : 0.59 , 1.73 ; p < 0.001 ] , respectively ; secondary endpoint ) . All treatments were well tolerated , with safety profiles of the FDCs similar to those of placebo and monotherapy . Conclusions Both aclidinium/formoterol BID doses significantly improved bronchodilation versus monotherapy , and dyspnoea versus placebo , with no increase in safety risk . Aclidinium/formoterol may be an effective treatment for patients with COPD .Trial registration Clinical Trials.gov : NCT01462942 Background Combining bronchodilators with different mechanisms of action may improve efficacy and reduce risk of side effects compared to increasing the dose of a single agent in chronic obstructive pulmonary disease ( COPD ) . We investigated this by combining two long-acting bronchodilators : once-daily muscarinic antagonist tiotropium and once-daily β2-agonist olo date rol . Methods Two replicate , double-blind , r and omized , 12-week studies ( ANHELTO 1 [ NCT01694771 ] and ANHELTO 2 [ NCT01696058 ] ) evaluated the efficacy and safety of olo date rol 5 μg once daily ( via Respimat ® ) combined with tiotropium 18 μg once daily ( via H and iHaler ® ) versus tiotropium 18 μg once daily ( via H and iHaler ® ) combined with placebo ( via Respimat ® ) in patients with moderate to severe COPD .  Primary efficacy end points were area under the curve from 0–3 hours of forced expiratory volume in 1 second ( FEV1 AUC0–3 ) and trough FEV1 after 12 weeks ( for the individual trials ) . A key secondary end point was health status by St George ’s Respiratory Question naire ( SGRQ ) total score ( combined data set ) . Results Olo date rol + tiotropium result ed in significant improvements  over tiotropium + placebo  in FEV1 AUC0–3 ( treatment differences : 0.117 L [ P<0.001 ] , ANHELTO 1 ; 0.106 L [ P<0.001 ] , ANHELTO 2 ) and trough FEV1 ( treatment differences : 0.062 L [ P<0.001 ] , ANHELTO 1 ; 0.040 L [ P=0.0029 ] , ANHELTO 2 ) ; these were supported by secondary end points . These effects translated to improvements in SGRQ total scores ( treatment difference −1.85 ; P<0.0001 ) . The tolerability  profile of olo date rol + tiotropium was similar to tiotropium monotherapy . Conclusion These studies demonstrated that olo date rol ( Respimat ® ) and tiotropium ( H and iHaler ® ) provided bronchodilatory effects above tiotropium alone in patients with COPD . In general , both treatments were well tolerated BACKGROUND Tiotropium + olo date rol improves lung function and symptoms compared to monotherapies in chronic obstructive pulmonary disease ( COPD ) . The OTEMTO 1 and 2 studies investigated the effects of tiotropium + olo date rol on lung function and health-related quality of life compared to placebo in patients with moderate to severe COPD . METHODS In these two replicate , double-blind , parallel-group , placebo-controlled trials , patients were r and omised to receive tiotropium + olo date rol 5/5 μg , 2.5/5 μg , tiotropium 5 μg or placebo for 12 weeks , via the Respimat ( ® ) inhaler . Primary end points were St George 's Respiratory Question naire ( SGRQ ) total score , forced expiratory volume in 1 s ( FEV1 ) area under the curve from 0 to 3 h ( AUC0 - 3 ) response and trough FEV1 response . RESULTS In OTEMTO 1 and 2 , tiotropium + olo date rol 5/5 μg improved SGRQ total score by 4.89 ( 95 % confidence interval [ CI ] -6.90 , -2.88 ) and 4.56 ( 95 % CI -6.50 , -2.63 ) units versus placebo ( both p < 0.0001 ) , and 2.49 ( 95 % CI -4.47 , -0.51 ; p < 0.05 ) and 1.72 ( 95 % CI -3.63 , 0.19 ) units versus tiotropium 5 μg . Tiotropium + olo date rol 2.5/5 μg significantly improved SGRQ score compared to placebo . Both doses significantly improved FEV1 AUC0 - 3 response compared to placebo and tiotropium 5 μg . Tiotropium + olo date rol 5/5 and 2.5/5 μg also significantly improved trough FEV1 response compared to placebo ( both studies ) and separated from tiotropium 5 μg in OTEMTO 2 . Adverse-event incidence was similar between treatment groups . CONCLUSION Tiotropium + olo date rol improved lung function and quality of life compared to placebo and tiotropium 5 μg . TRIAL REGISTRATION Clinical Trials.gov : NCT01964352 and NCT02006732 BACKGROUND We evaluated the effect of dual , longacting inhaled bronchodilator treatment on exacerbations in patients with severe and very severe chronic obstructive pulmonary disease ( COPD ) . METHODS In this parallel-group study , 2224 patients ( aged ≥40 years , Global Initiative for Chronic Obstructive Lung Disease stages III-IV , and one or more moderate COPD exacerbation in the past year ) were r and omly assigned ( 1:1:1 ; via interactive voice response or web system ; stratified for smoking status ) to once-daily QVA149 ( fixed-dose combination of indacaterol 110 μg and glycopyrronium 50 μg ) , glycopyrronium 50 μg , or tiotropium 18 μg for 64 weeks . Assignment to QVA149 and glycopyrronium was double-blind ; tiotropium was open-label . Efficacy was assessed in all patients r and omly assigned to treatment groups who received at least one dose of study drug ; safety was assessed in all patients who received at least one dose whether or not they were assigned to a group . The primary objective was to show superiority  of QVA149 versus glycopyrronium for rate of moderate to severe COPD exacerbations ( defined by worsening symptoms and categorised by treatment requirements ) during treatment . This completed trial is registered at Clinical Trials.gov , NCT01120691 . FINDINGS Between April 27 , 2010 , and July 11 , 2012 , 741 patients were r and omly assigned to receive QVA149 , 741 to receive glycopyrronium , and 742 to receive tiotropium ( 729 , 739 , and 737 patients , respectively , analysed for efficacy ) . QVA149 significantly reduced the rate of moderate to severe exacerbations  versus glycopyrronium by 12 % ( annualised rate of exacerbations 0·84 [ 95 % CI 0·75 - 0·94 ] vs 0·95 [ 0·85 - 1·06 ] ; rate ratio 0·88 , 95 % CI 0·77 - 0·99 , p=0·038 ) . Adverse events ( including exacerbations ) were reported for 678 ( 93 % ) of 729 patients on QVA149 , 694 ( 94 % ) of 740 on glycopyrronium , and 686 ( 93 % ) of 737 on tiotropium . Incidence of serious adverse events was similar between groups ( 167 [ 23 % ] patients on QVA149 , 179 [ 24 % ] on glycopyrronium , and 165 [ 22 % ] on tiotropium ) ; COPD worsening was the most frequent serious adverse event ( 107 [ 15 % ] patients on QVA149 , 116 [ 16 % ] on glycopyrronium , 87 [ 12 % ] on tiotropium ) . INTERPRETATIONS The dual bronchodilator QVA149 was superior in preventing moderate to severe COPD exacerbations compared with the single longacting antimuscarinic bronchodilator glycopyrronium , with concomitant improvements in lung function and health status . These results indicate the potential of dual bronchodilation as a treatment option for patients with severe and very severe COPD . FUNDING Novartis Pharma AG BACKGROUND Indacaterol is a novel , inhaled , ultra-long-acting β(2)-agonist bronchodilator for maintenance use in patients with COPD . The aim of this paper is to assess the effect of indacaterol on dyspnoea and health status , using pooled study data to evaluate the relative efficacy of indacaterol and existing bronchodilators . METHODS Individual patient data were pooled from three r and omized , placebo-controlled studies ( NCT00393458 ; NCT00567996 ; NCT00463567 ) , conducted in patients with moderate-to-severe COPD . Treatments were double-blind indacaterol 150 μg ( n = 746 ) or 300 μg ( n = 853 ) once-daily , formoterol 12 μg twice-daily ( n = 556 ) , salmeterol 50 μg twice-daily ( n = 333 ) and placebo ( n = 1185 ) ; and open-label tiotropium 18 μg once-daily ( n = 415 ) . Evaluation after 6 months ' treatment was by transition dyspnoea index ( TDI ; minimum clinical ly important difference [ MCID ] ≥1 point ) , and St George 's Respiratory Question naire ( SGRQ ; MCID ≥4 units ) . RESULTS Differences from placebo in TDI total score were 1.01 ( indacaterol 150 μg ) 1.28 ( indacaterol 300 μg ) , 0.74 ( formoterol ) , 0.92 ( salmeterol ) and 0.88 ( tiotropium ) ( all p < 0.05 ) , with corresponding odds ratios versus placebo for exceeding the MCID from baseline of 1.91 , 2.69 , 2.02 , 1.79 and 1.49 ( all p < 0.05 ) . Differences versus placebo in SGRQ total score were -4.4 ( indacaterol 150 μg ) , -3.4 ( indacaterol 300 μg ) , -2.8 ( formoterol ) , -4.0 ( salmeterol ) and -1.7 ( tiotropium ) ( all p < 0.05 ) , with corresponding odds ratios versus placebo for exceeding the MCID of 1.95 , 1.63 , 1.54 , 1.82 and 1.29 ( all p < 0.05 apart from tiotropium ) . CONCLUSIONS Indacaterol provided clinical ly important improvements in dyspnoea and health status that were at least as good as and often better than those observed with existing bronchodilator treatments for COPD OBJECTIVE To observe the efficacy of combination therapy with inhaled salmeterol/fluticasone and tiotropium in reducing the frequency of acute episodes of symptom exacerbation and improving lung function and health status in chronic obstructive pulmonary disease ( COPD ) . METHODS One hundred and twenty-six patients ( M/F : 92/34 ) with COPD were treated in a r and omised , parallel-group , controlled study with salmeterol/fluticasone ( 50/250 microg ) twice daily and tiotropium 18 microg once daily ( n = 33 , M/F : 23/10 ) ; salmeterol/fluticasone ( 50/250 microg ) twice daily ( n = 32 , M/F : 24/8 ) ; or tiotropium 18 microg once daily ( n = 32 , M/F : 23/9 ) for 12 months . Patients in the blank control group ( n = 29 , M/F : 22/7 ) did not receive any inhaled anticholinergic drugs , long-acting beta(2 ) agonists or glucocorticoid therapy . Intention-to-treat analysis ( n = 161 ) and per- protocol analysis ( n = 126 , age 45 - 71 years ) were performed . RESULTS Three active treatments significantly improved symptoms and health status . The use of rescue medication in the combination group [ 1 ( 0 - 7 ) time , 95 % CI ] was significantly decreased compared with those in the blank group [ 2 ( 0 - 29 ) times ] , salmeterol/fluticasone alone [ 2 ( 0 - 13 ) times ] , tiotropium alone [ 1 ( 0 - 11 ) time ] , F = 4.914 , P < 0.01 . The frequency of exacerbations in the combination group was ( 0.7 + /- 0.5 ) time , significantly lower than that in the blank group [ ( 1.5 + /- 0.9 ) times ] , salmeterol/fluticasone alone [ ( 1.2 + /- 0.6 ) times ] , and tiotropium alone [ ( 1.1 + /- 0.5 ) times ] , F = 8.513 , P < 0.01 . The FEV(1 ) in the combination group after the trial was ( 1.19 + /- 0.03 ) L , significantly improved compared to that before treatment ( 1.09 + /- 0.04 ) L , a 9.5 % increase , which was greater than the blank ( 0.9 % ) , tiotropium alone ( 8.2 % ) and salmeterol/fluticasone alone ( 6.3 % ) , t = -5.024 to -15.58 , P < 0.01 . CONCLUSION Combination therapy with salmeterol/fluticasone and tiotropium leads to better control of symptoms and improved lung function , with no greater risk of side-effects , as compared to salmeterol/fluticasone or tiotropium alone in the treatment of COPD Background : Guidelines recommend inhaled corticosteroids ( ICS ) as maintenance treatment for patients with chronic obstructive pulmonary disease ( COPD ) with a post-bronchodilator forced expiratory volume in 1 second ( FEV1 ) < 50 % predicted and frequent exacerbations , although they have only a small preventive effect on the accelerated decline in lung function . Combined treatment with ICS and long acting β2 agonists ( LABA ) may provide benefit to the stability of COPD , but it is unknown if withdrawal of ICS will result in disease deterioration . Methods : The effects of 1 year withdrawal of the ICS fluticasone propionate ( FP ) after a 3 month run-in treatment period with FP combined with the LABA salmeterol ( S ) ( 500 μg FP + 50 μg S twice daily ; SFC ) were investigated in patients with COPD in a r and omised , double blind study . 497 patients were enrolled from 39 centres throughout the Netherl and s ; 373 were r and omised and 293 completed the study . Results : The drop out rate after r and omisation was similar in the two groups . Withdrawal of FP result ed in a sustained decrease in FEV1 : mean ( SE ) change from baseline −4.4 (0.9)% ( S ) v −0.1 (0.9)% ( SFC ) ; adjusted difference 4.1 ( 95 % CI 1.6 to 6.6 ) percentage points ( p<0.001 ) . Corresponding figures for the FEV1/FVC ratio were −3.7 (0.8)% ( S ) v 0.0 (0.8)% ( SFC ) ( p = 0.002 ) . The annual moderate to severe exacerbation rate was 1.6 and 1.3 in the S and SFC groups , respectively ( adjusted rate ratio 1.2 ; 95 % CI 0.9 to 1.5 ; p = 0.15 ) . The mean annual incidence rate of mild exacerbations was 1.3 ( S ) v 0.6 ( SFC ) , p = 0.020 . An immediate and sustained increase in dyspnoea score ( scale 0–4 ; mean difference between groups 0.17 ( 0.04 ) , p<0.001 ) and in the percentage of disturbed nights ( 6 ( 2 ) percentage points , p<0.001 ) occurred after withdrawal of fluticasone . Conclusions : Withdrawal of FP  in COPD patients using SFC result ed in acute and persistent deterioration in lung function and dyspnoea and in an increase in mild exacerbations and percentage of disturbed nights . This study clearly indicates a key role for ICS in the management of COPD as their discontinuation leads to disease deterioration , even under treatment with a LABA Background Olo date rol is a long-acting β2-agonist with a 24-hour bronchodilator profile . Two replicate , r and omized , double-blind , placebo-controlled , parallel-group , Phase III trials were performed as part of a comprehensive clinical program to investigate the long-term safety and efficacy of olo date rol in patients with moderate to very severe chronic obstructive pulmonary disease ( COPD ) receiving usual-care background therapy . Methods Patients received olo date rol 5 μg or 10 μg or placebo once daily for 48 weeks . Co primary end points were forced expiratory volume in 1 second ( FEV1 ) area under the curve from 0 to 3 hours ( AUC0–3 ) response ( change from baseline ) , and trough FEV1 response at 12 weeks . Secondary end points included additional lung function assessment s , use of rescue medications , FEV1 AUC response from 0 to 12 hours , and Patient Global Rating over 48 weeks . Results Overall , 624 and 642 patients were evaluated in studies 1222.11 and 1222.12 , respectively . In both studies , olo date rol 5 μg and 10 μg significantly improved the FEV1 AUC0–3 response ( P<0.0001 ) and trough FEV1 ( study 1222.11 , P<0.0001 ; study 1222.12 , P<0.05 , post hoc ) at week 12 , with an incidence of adverse events comparable with that of placebo . Secondary end points supported the efficacy of olo date rol . Conclusion These studies demonstrate the long-term efficacy and safety of once-daily olo date rol 5 μg and 10 μg in patients with moderate to very severe COPD continuing with usual-care maintenance therapy Purpose To evaluate fluticasone propionate/formoterol ( FP/FORM ) in COPD . Patients and methods COPD patients with forced expiratory volume in 1 s ( FEV1 ) ≤50 % predicted and ≥1 moderate/severe COPD exacerbation in the last 12 months were r and omized to FP/FORM 500/20 or 250/10 µg bid , or formoterol ( FORM ) 12 µg bid for 52 weeks . The primary outcome was the annualized rate of moderate/severe COPD exacerbations . Results In total , 1,765 patients were r and omized . There were fewer discontinuations with FP/FORM 500/20 µg ( 20.6 % ) and 250/10 µg ( 24.0 % ) compared with FORM ( 26.1 % ) . None of the two FP/FORM doses reduced the moderate/severe exacerbation rate versus FORM ( rate ratios [ RR ] : 0.93 ; P≤0.402 ) . There was a trend toward a lower moderate/severe exacerbation rate with FP/FORM 500/20 µg versus FORM in patients with ≥2 exacerbations in the preceding year ( RR : 0.79 ; P=0.084 ) . Pre- and post-dose FEV1 and forced vital capacity were greater with FP/FORM 500/20 µg versus FORM ( P≤0.039 ) . There was a trend toward a lower EXAcerbations of Chronic pulmonary disease Tool ( EXACT ) exacerbation rate with FP/FORM 500/20 µg versus FORM ( RR : 0.87 ; P=0.077 ) . There were more St George ’s Respiratory Question naire for COPD ( SGRQ-C ) responders with FP/FORM 500/20 µg than FORM ( odds ratios [ OR ] at weeks 6 , 23 and 52 ≥1.28 ; P≤0.054 ) . EXACT-respiratory symptoms total and breathlessness scores were lower with both FP/FORM 500/20 µg and 250/10 µg versus FORM ( P≤0.066 ) . Acute β2-agonist-induced effects and 24-hour Holter findings were similar for all treatments . Mean 24-hour urinary cortisol was similarly reduced with both FP/FORM doses . Radiologically confirmed pneumonia was seen in 2.4 % , 3.2 % and 1.5 % of FP/FORM 500/20 µg , FP/FORM 250/10 µg and FORM-treated patients , respectively . Adverse events were otherwise similar across treatment groups . Conclusion FP/FORM did not reduce exacerbation rates versus FORM . Numerical benefits were observed with FP/FORM 500/20 µg versus FORM for secondary variables , including lung function , EXACT exacerbations , SGRQ-C and EXACT-respiratory symptoms total and breathlessness scores . Few efficacy differences were evident between FP/FORM 250/10 µg and FORM . Pneumonia was more frequent in FP/FORM-treated patients , although the absolute difference was low . Adverse events were otherwise similar between treatments BACKGROUND Prevention of exacerbations is a primary goal for chronic obstructive pulmonary disease ( COPD ) therapy . This r and omized , double-blind , double-dummy , parallel-group , multicenter study evaluated the effect of budesonide/formoterol pressurized metered-dose inhaler ( pMDI ) versus formoterol dry powder inhaler ( DPI ) on reducing COPD exacerbations . METHODS 1219 patients aged ≥40 years with moderate-to-very-severe COPD ( per lung function ) and a history of ≥1 COPD exacerbation received budesonide/formoterol pMDI 320/9 μg twice daily ( BID ) during a 4-week run-in . Patients were then r and omized 1:1 to receive budesonide/formoterol pMDI 320/9 μg BID ( n = 606 ) or formoterol DPI 9 μg BID ( n = 613 ) for 26 weeks . Exacerbations were identified using predefined criteria for symptom worsening and treatment with systemic corticosteroids and /or antibiotics and /or hospitalization . The primary endpoint was annual rate of exacerbations . RESULTS Budesonide/formoterol pMDI result ed in a 24 % reduction in annual rate of exacerbations ( 0.85 vs 1.12 ; rate ratio : 0.76 [ 95 % CI : 0.62 , 0.92 ] ; P = 0.006 ) , and a significant risk reduction for time to first exacerbation ( hazard ratio : 0.78 [ 95 % CI : 0.64 , 0.96 ] ; P = 0.016 ) versus formoterol DPI . The most commonly reported adverse events ( AEs ; ≥3 % ) in budesonide/formoterol and formoterol groups were COPD ( 4.5 % vs 8.6 % ) and nasopharyngitis ( 5.0 % vs 5.2 % ) . Pneumonia AEs were reported in 0.5 % and 1.0 % of budesonide/formoterol-treated and formoterol-treated patients , respectively . CONCLUSIONS Budesonide/formoterol pMDI is an effective treatment option for reducing exacerbation rates in COPD patients with moderate-to-very-severe airflow limitation and history of exacerbations . No increase in pneumonia was observed with budesonide/formoterol ; safety data were consistent with its established profile BACKGROUND Umeclidinium ( UMEC ; long-acting muscarinic antagonist [LAMA])/vilanterol ( VI ; long-acting beta2-agonist [ LABA ] ) and fluticasone propionate/salmeterol ( FP/SAL ) ( inhaled corticosteroid/LABA ) are approved maintenance therapies for chronic obstructive pulmonary disease ( COPD ) . Two studies compared efficacy and safety of UMEC/VI with FP/SAL in patients with moderate-to-severe COPD with no exacerbations in the previous year . METHODS In these 12-week , multicenter , double-blind , parallel-group , double-dummy trials , r and omized ( 1:1 ) patients received once-daily UMEC/VI 62.5/25 mcg or twice-daily FP/SAL 250/50 mcg ( DB2114930 n = 353 and 353 ; DB2114951 n = 349 and 348 , respectively ; intent-to-treat ) . Endpoints included 0 - 24 h weighted mean ( wm ) forced expiratory volume in 1 s ( FEV1 ) ( Day 84 ; primary ) , trough FEV1 ( Day 85 ; secondary ) , other lung function endpoints , dyspnea , quality of life ( QoL ) and safety . RESULTS UMEC/VI demonstrated statistically significant , clinical ly meaningful improvements in lung function measures versus FP/SAL . For 0 - 24 h wmFEV1 ( Day 84 ) , improvements with UMEC/VI versus FP/SAL were 74 mL ( 95 % confidence interval [ CI ] : 38 - 110 ; DB2114930 ) and 101 mL ( 63 - 139 ; DB2114951 ) ( both p < 0.001 ) . Trough FEV1 improvements were 82 mL ( 45 - 119 ) and 98 mL ( 59 - 137 ) ( both p < 0.001 ) for UMEC/VI versus FP/SAL , respectively . Both treatments demonstrated similar , clinical ly meaningful improvements from baseline in dyspnea ( Transition Dyspnea Index focal score > 1 unit ) and QoL ( St George 's Respiratory Question naire Total score > 4-unit decrease ) in both studies with no statistical differences between treatments . Adverse event rates were similar : 26 and 30 % UMEC/VI ; 27 and 31 % FP/SAL . CONCLUSIONS Once-daily UMEC/VI 62.5/25 mcg over 12 weeks result ed in statistically significant , clinical ly meaningful improvements in lung function versus twice-daily FP/SAL 250/50 mcg in patients with moderate-to-severe COPD with infrequent exacerbations . Both treatments improved dyspnea and QoL. CLINICAL TRIAL REGISTRATION DB2114930/NCT01817764 ; DB2114951/NCT01879410 BACKGROUND AND OBJECTIVE The effects of tiotropium , a long-acting anticholinergic drug , were compared with those of the combination of salmeterol , a long-acting beta(2)-agonist , and fluticasone , an inhaled corticosteroid , in patients with COPD . METHODS A 4-month , r and omized , open cross-over study of tiotropium , 18 microg once daily , versus salmeterol , 50 microg , plus fluticasone , 200 microg , twice daily , was conducted in patients with COPD .  Efficacy was assessed by spirometry and responses to the St George 's Respiratory Question naire ( SGRQ ) . After 4 months , patients were asked to select their subsequent therapy and indicate the reasons for their selection . RESULTS A total of 78 patients completed the study . There were no significant differences in the improvements in FEV(1 ) or SGRQ scores between the therapies . Similar numbers of patients selected tiotropium ( 42.3 % ) and salmeterol plus fluticasone ( 57.7 % ) . However , those who preferred one of the therapies demonstrated greater improvements in SGRQ scores with that therapy . One subgroup of patients ( 30.8 % ) showed greater improvements in dyspnoea and FEV(1 ) in response to tiotropium , and the other subgroup of patients ( 35.9 % ) showed greater improvements in dyspnoea and FEV(1 ) in response to salmeterol plus fluticasone . Some patients ( 14.1 % ) selected salmeterol plus fluticasone because of positive effects on sputum expectoration . CONCLUSIONS The study was unblinded and the results need to be interpreted with caution . However , tiotropium and salmeterol plus fluticasone had similar overall effects on pulmonary function and SGRQ scores in patients with COPD . Responses to the two therapies were heterogeneous , and the patients who showed greater improvements in FEV(1 ) or SGRQ scores with one of the therapies preferred it for their subsequent treatment RATIONALE Indacaterol is the first once-daily , long-acting inhaled beta(2)-agonist bronchodilator studied in patients with chronic obstructive pulmonary disease ( COPD ) . OBJECTIVES To demonstrate greater efficacy of indacaterol versus placebo on FEV(1 ) at 24 hours post dose ( trough ) after 12 weeks , to compare efficacy with placebo and tiotropium , and to evaluate safety and tolerability over 26 weeks . MEASUREMENTS Patients with moderate-to-severe COPD were r and omized to double-blind indacaterol 150 or 300 microg or placebo , or open-label tiotropium 18 microg , all once daily , for 26 weeks . The primary efficacy outcome was trough FEV(1 ) at 12 weeks . Additional analyses ( not adjusted for multiplicity ) included transition dyspnea index ( TDI ) , health status ( St George 's Respiratory Question naire [ SGRQ ] ) , and exacerbations . Serum potassium , blood glucose , and QTc interval were measured . RESULTS A total of 1,683 patients ( age , 63.3 yr ; post-bronchodilator FEV(1 ) , 56 % predicted ; FEV(1)/FVC , 0.53 ) were r and omized to the four treatment arms . Trough FEV(1 ) at Week 12 increased versus placebo by 180 ml with both indacaterol doses and by 140 ml with tiotropium ( all P < 0.001 vs. placebo ) . At Week 26 , for indacaterol 150/300 microg , respectively , versus placebo , TDI increased ( 1.00/1.18 , P < 0.001 ) and SGRQ total score decreased ( -3.3/-2.4 , P < 0.01 ) ; corresponding results with tiotropium were 0.87 ( P < 0.001 ) for TDI and ( -1.0 , P = not significant ) for SGRQ total score . The incidence of adverse events , low serum potassium , high blood glucose , and prolonged QTc interval was similar across treatments . CONCLUSIONS Indacaterol was an effective once-daily bronchodilator and was at least as effective as tiotropium in improving clinical outcomes for patients with COPD . Clinical trial registered with clinical trials.gov ( NCT 00463567 ) Although guidelines recommend combining long-acting bronchodilators in COPD , data are limited . We examined the clinical efficacy and safety of formoterol , tiotropium and the combination in patients with COPD . Eight hundred and forty-seven patients with COPD ( mean FEV(1 ) 52 % predicted ; FEV(1)/FVC 53 % ) were r and omized to receive one of the following four treatments for 24 weeks : formoterol 10 microg b.i.d . plus tiotropium 18 microg o.d . ; formoterol 10 microg b.i.d . ; tiotropium 18 microg o.d . , or placebo . The study was partially blinded ( formoterol and placebo ) . For the primary endpoint , FEV(1 ) 2h post-dose after 24 weeks , there were small differences in favour of the combination therapy versus formoterol ( 0.07 L , p=0.044 ) or tiotropium ( 0.06 L , p=0.066 ) . All three treatments were superior to placebo ( p<0.001 ) . The combination was statistically superior to monotherapy for : the primary endpoint ( p=0.044 vs. formoterol ) ; FEV(1 ) 5 min after the first dose ( p<0.001 ) and at 12 weeks ( p<0.05 vs. tiotropium ) ; and peak expiratory flow averaged over the first 6 weeks ( p<0.001 vs. both ) . The three active treatments were significantly more effective than placebo for secondary endpoints : COPD -related ' bad days ' , symptoms , use of rescue medication and peak expiratory flow , and aspects of health-related quality of life . The overall incidence of adverse events was similar with all active treatments , although COPD -related adverse events were more common with tiotropium . Combined bronchodilator therapy may be a valuable treatment option for patients with COPD BACKGROUND The drug development process can be streamlined by combining the traditionally separate stages of dose-finding ( Phase IIb ) and confirmation of efficacy and safety ( Phase III ) using an adaptive seamless design . This approach was used in a clinical study of indacaterol , a novel once-daily ( od ) inhaled long-acting beta(2)-adrenoreceptor agonist bronchodilator for the treatment of COPD ( chronic obstructive pulmonary disease ) . METHODS The study comprised a dose-finding stage with dose selection after 14 days of treatment , and a second stage evaluating efficacy and safety during 26 weeks of treatment . The dose-finding stage included seven r and omized treatment arms : double-blind indacaterol 75 microg , 150 microg , 300 microg or 600 microg od , the beta(2)-adrenoceptor agonist formoterol 12 microg twice-daily or placebo , or the anticholinergic tiotropium 18 microg od open-label . An independent data monitoring committee selected two indacaterol doses based on unblinded results of an interim analysis performed by an independent statistician . The sponsor , investigators and patients remained blinded to the results . The indacaterol doses were selected using pre-set efficacy criteria for trough ( 24-h post-dose ) and early ( 1 - 4 h post-dose ) bronchodilator effect after 14 days , and all safety data . To qualify for selection , the doses had to exceed a threshold for clinical relevance or be superior to either tiotropium or formoterol , whichever was the highest value . Selected doses were continued into the second , 26-week stage . The two other indacaterol doses not selected , and formoterol , were discontinued following dose selection . RESULTS 801 patients with moderate-to-severe COPD were evaluated . Indacaterol 150 microg was the lowest effective dose , exceeding criteria for trough FEV(1 ) ( reference value 140 mL vs placebo ) and FEV(1 ) AUC(1 - 4 h ) ( reference value 220 mL vs placebo ) . No safety signal was observed with any dose of indacaterol . Thus , indacaterol 150 and 300 microg were selected to continue into the second , 26-week stage . CONCLUSION The adaptive seamless design is a novel and efficient way to combine dose selection with efficacy evaluation and safety confirmation in a single trial This r and omized controlled trial examined the benefits of combining an inhaled corticosteroid , fluticasone propionate ( F ) , with an inhaled long-acting beta(2)-agonist , salmeterol ( S ) , to treat the inflammatory and bronchoconstrictive components of chronic obstructive pulmonary disease ( COPD ) . A total of 691 patients with COPD received the combination of F and S ( FSC ) , S ( 50 mcg ) , F ( 500 mcg ) , or placebo twice daily via the Diskus device for 24 weeks . A significantly greater increase in predose FEV(1 ) at the endpoint was observed after FSC ( 156 ml ) compared with S ( 107 ml , p = 0.012 ) and placebo ( -4 ml , p < 0.0001 ) . A significantly greater increase in 2-hour postdose FEV(1 ) at the endpoint was observed after treatment with FSC ( 261 ml ) compared with F ( 138 ml , p < 0.001 ) and placebo ( 28 ml , p < 0.001 ) . There were greater improvements in the Transition Dyspnea Index with FSC ( 2.1 ) compared with F ( 1.3 , p = 0.033 ) , S ( 0.9 , p < 0.001 ) , and placebo ( 0.4 , p < 0.0001 ) . The incidence of adverse effects ( except for an increase in oral c and idiasis with FSC and F ) was similar among the treatment groups . We conclude that FSC improved lung function and reduced the severity of dyspnea compared with individual components and placebo Loss of bronchodilator effectiveness or tolerance has been observed with inhaled beta-agonists but not with inhaled anticholinergic medications . Initially , tolerance is reflected in loss of bronchial protection against stimuli followed by loss of bronchodilator properties . However , generally such observations have been reported in asthma . A 6-month r and omized , double-dummy placebo-controlled trial comparing tiotropium to salmeterol provided the opportunity to examine spirometric tolerance to long-acting beta-agonists in patients with COPD .  Spirometry was measured over 12h at baseline and at days 15 , 57 , 116 and 169 . Changes over time from baseline were compared relative to changes observed with placebo .  A total of 623 patients participated ( tiotropium = 209 , salmeterol = 213 , placebo = 201 ) . The groups were similar in age ( mean = 65 years ) , gender ( 75 % men ) , and baseline FEV1 ( mean = 1.08 + /- 0.37l [ 40 + /- 12 % predicted ] ) . Relative to placebo , both active drugs improved morning pre-drug , peak and average FEV1 and FVC throughout the trial . However , from day 1 to 169 , salmeterol was associated with a higher decline in average FEV1 and FVC ( 0 - 12h ) ( difference from placebo : -36 and -115 ml , P < 0.05 ) , which was most prominent over the 8 - 12 h period ( difference from placebo : -45 and -138 ml , P < 0.01 ) . Significant declines in peak FVC relative to placebo ( -83 ml , P < 0.05 ) but not FEV1 ( -12ml ) were observed with salmeterol . Tiotropium was associated with further improvements in spirometry from days 1 to 15 and no evidence of tolerance from day 15 to the end of the trial . In conclusion , tolerance to pharmacologic bronchodilation occurs with long-acting beta-agonists such as salmeterol and not with inhaled anticholinergics BACKGROUND Data comparing two bronchodilators vs. one bronchodilator plus inhaled corticosteroid ( ICS ) on hyperinflation and exercise endurance in chronic obstructive pulmonary disease ( COPD ) are scarce , though these therapeutic strategies are widely used in clinical practice . METHODS We performed a r and omized , crossover clinical trial of two × 8 weeks comparing tiotropium ( 18 μg once daily ) + salmeterol ( 50 μg twice daily ) ( T + S ) to salmeterol + fluticasone ( 50/500 μg twice daily ) ( S + F ) in COPD ( forced expiratory volume in 1 s ( FEV(1 ) ) ≤65 % predicted , and thoracic gas volume ( TGV ) ≥120 % predicted ) . Co primary endpoints were postbronchodilator TGV and exercise endurance time ( EET ) . RESULTS In 309 patients , at baseline , prebronchodilator FEV(1 ) was 1.36 L ( 46 % predicted ) , TGV was 5.42 L ( 165 % predicted ) , and EET = 458 s. Relative to S + F , T + S lowered postdose TGV by 182 ± 44 ml after 4 weeks ( p < 0.0001 ) and 87 ± 44 ml after 8 weeks ( p < 0.05 ) . EET was nonsignificantly increased following T + S treatment ( 20 ± 15 s at 4 weeks , 15 ± 13 s at 8 weeks ) vs. S + F. BORG dyspnea score at exercise isotime was reduced in favor of T + S. CONCLUSION The two bronchodilators decreased hyperinflation significantly more than one bronchodilator and ICS . This difference was not reflected in EET . ( Clinical Trials.gov number , NCT00530842 ) BACKGROUND The Global Initiative for Chronic Obstructive Lung Disease ( GOLD ) recommends long-acting bronchodilators as first-line maintenance treatment for patients with chronic obstructive pulmonary disease ( COPD ) . A study was conducted comparing the long-acting anticholinergic tiotropium with the long-acting beta-agonist salmeterol to confirm the significant improvements in daytime bronchodilator efficacy seen with tiotropium in previous studies . METHODS R and omized , double-blind , double-dummy , parallel-group study , comparing daytime bronchodilator efficacy of tiotropium 18 mcg once daily with salmeterol 50 mcg twice daily in patients with COPD . Serial spirometry was performed over 12 h after 12 weeks of treatment . Co- primary endpoints were average ( over 12 h ) and peak FEV1 at 12 weeks . RESULTS 653 patients were r and omized ( 328 tiotropium , 325 salmeterol ) : mean age 64 years ; 66 % male ; mean baseline FEV1 1.05 l ( 37.7 % predicted ) . After 12 weeks , the average post-dose FEV1 over 12 h was significantly higher with tiotropium compared with salmeterol ( 167 vs. 130 mL , respectively , p=0.03 ) , as was peak FEV1 ( 262 vs. 216 ml , respectively , p=0.01 ) . The average FEV1 responses from 0 - 6 h and 6 - 12 h were higher in the tiotropium group compared with salmeterol ( p<0.05 ) . Peak and average FVC were significantly higher with tiotropium compared with salmeterol ( p<0.01 ) . Morning pre-dose FEV1 responses were not significantly different ; however , tiotropium demonstrated a significantly higher pre-dose FVC than salmeterol ( p<0.05 ) . CONCLUSION Tiotropium demonstrated significantly greater post-dose improvements in spirometric parameters compared with salmeterol . These improvements were sustained over 12 Background : Long‐acting muscarinic antagonist (LAMA)/long‐acting & bgr;2‐agonist ( LABA ) combinations are a treatment option for patients with COPD who continue to have symptoms despite treatment with a LAMA or a LABA alone . The Efficacy and Safety of PT003 , PT005 , and PT001 in Subjects with Moderate‐to‐Very Severe COPD ( PINNACLE‐1 ) ( NCT01854645 ) and the Multi‐Center Study to Assess the Efficacy and Safety of PT003 , PT005 , and PT001 in Subjects with Moderate‐to‐Very Severe COPD ( PINNACLE‐2 ) ( NCT01854658 ) trials investigated the efficacy and safety of a novel glycopyrrolate [GP]/formoterol [ FF ] 18/9.6‐&mgr;g ( GFF ) metered dose inhaler ( MDI ) formulated using the Co‐Suspension Delivery Technology in patients with moderate‐to‐very severe COPD . Methods : These two phase III trials took place over 24 weeks and were r and omized , double blind , and placebo controlled ; 2,103 and 1,615 patients ( 40–80 years of age ) , respectively , were r and omized . Patients received GFF MDI , GP MDI 18 & mgr;g , FF MDI 9.6 & mgr;g , or placebo MDI ( all twice daily ) , or tiotropium 18 & mgr;g dry powder inhaler ( once daily in PINNACLE‐1 only [ open‐label active comparator ] ) . Efficacy and safety were assessed . Results : At week 24 , differences in change from baseline in the morning predose trough FEV1 for GFF MDI vs placebo MDI , GP MDI , and FF MDI were 150 mL , 59 mL , and 64 mL in PINNACLE‐1 ( all P < .0001 ) and 103 mL , 54 mL , and 56 mL in PINNACLE‐2 ( all P < .001 ) , respectively . There were no significant safety findings ( incidence of adverse events was similar between treatment arms ) . Conclusions : We conclude that GFF MDI 18/9.6 & mgr;g demonstrated superiority over placebo and monocomponent MDIs and was well tolerated , thus providing an additional treatment option for patients with moderate‐to‐very severe COPD . Trial Registry : Clinical Trials.gov ; No. : NCT01854645 and No. NCT01854658 ; URL : www . clinical trials.gov RATIONALE Exacerbations of chronic obstructive pulmonary disease ( COPD ) greatly contribute to declining health status and the progression of the disease , thereby incurring significant direct and indirect health care costs . The prevention of exacerbations , therefore , is an important treatment goal . OBJECTIVES To assess the impact of combination therapy with salmeterol/fluticasone propionate compared with salmeterol alone on moderate and severe exacerbations in patients with severe COPD and a history of repeated exacerbations . METHODS R and omized , double-blind , parallel-group study . After a 4-wk run-in period , 994 clinical ly stable patients were r and omized to one of two treatment groups : 507 patients received the salmeterol/fluticasone combination 50/500 micro g twice daily and 487 received salmeterol 50 micro g twice daily for 44 wk . MAIN RESULTS The total number of exacerbations was 334 in the combination therapy and 464 in the salmeterol group ( p < 0.0001 ) . The annualized rate of moderate and severe exacerbations per patient was 0.92 in the combination therapy and 1.4 in the salmeterol group , corresponding to a 35 % decrease . In addition , the mean time to first exacerbation in the combination therapy group was significantly longer compared with that of the salmeterol group ( 128 vs. 93 d , p < 0.0001 ) . Other endpoints , including health-related quality of life , peak expiratory flow , and use of rescue medication , were significantly improved in the combination therapy group . Both treatments were well tolerated . CONCLUSIONS This study demonstrates that combination therapy with salmeterol/fluticasone compared with salmeterol monotherapy significantly reduces the frequency of moderate/severe exacerbations in patients with severe COPD Context Physicians use multiple medications to treat chronic obstructive pulmonary disease ( COPD ) . Contribution In this multicenter trial , 449 adults with moderate or severe COPD were r and omly assigned to receive tiotropium and placebo , tiotropium and salmeterol , or tiotropium and fluticasonesalmeterol for 1 year . About 63 % , 65 % , and 60 % of patients , respectively , had exacerbations . The third group , but not the second group , had better lung function and fewer hospitalizations than the first group . Caution Many patients discontinued assigned medications . Implication s Adding fluticasonesalmeterol to tiotropium may improve lung function and decrease hospitalizations , but it does not affect reduce exacerbations in patients with moderate or severe COPD . The Editors Most patients with moderate or severe chronic obstructive pulmonary disease ( COPD ) experience chronic progressive dyspnea that is not alleviated by short-acting bronchodilators . It is therefore not surprising that many patients are treated with multiple inhaled medications to optimize their lung function and minimize symptoms ( 1 ) . Published guidelines on COPD state that the goals of pharmacologic therapy should be to control symptoms , improve health status , and reduce the frequency of COPD exacerbations ( 2 , 3 ) , and many published guidelines advocate combining different classes of long-acting bronchodilators or inhaled steroids to achieve these goals ( 2 , 3 ) . In the past several years , several studies have shown that treatment of COPD with the long-acting anticholinergic tiotropium ( 47 ) ; the long-acting 2-agonist salmeterol ( 810 ) ; or products that combine inhaled steroids and long-acting 2-agonists , such as fluticasonesalmeterol or budesonideformoterol ( 1114 ) , improve dyspnea and quality of life and decrease exacerbation rates compared with placebo . However , no studies have assessed whether therapy with a combination of these products provides greater clinical benefit than does therapy with these agents used alone . 2-Agonists and anticholinergics work by different mechanisms to cause bronchodilation ( 15 ) , and inhaled corticosteroids may have an anti-inflammatory effect in COPD ( 16 ) . Thus , it makes theoretical and intuitive sense that combining these therapies might be more beneficial than therapy with 1 agent alone . However , safety concerns , such as side effects associated with long-term use of long-acting 2-agonists and inhaled corticosteroids , and economic issues related to the additional costs of these medications may argue against routine use of inhaled medication polypharmacy without evidence of efficacy . We therefore conducted a r and omized , double-blind , placebo-controlled clinical trial to determine whether combining tiotropium with salmeterol or fluticasonesalmeterol produces greater improvements in clinical outcomes for adults with moderate or severe COPD compared with tiotropium therapy alone . Methods Design We design ed a parallel-group , 3-group , r and omized , double-blind , placebo-controlled trial in patients with moderate or severe COPD that was conducted from October 2003 to January 2006 . The study protocol has been published elsewhere ( 17 ) . The research ethics boards of all participating centers approved the study , and all trial participants provided written informed consent . Setting and Participants We enrolled patients with diagnosed moderate or severe COPD from 27 Canadian medical centers . Twenty centers were academic hospitalbased pulmonary clinics , 5 were community-based pulmonary clinics , and 2 were community-based primary care clinics . Eligible patients had to have had at least 1 exacerbation of COPD that required treatment with systemic steroids or antibiotics within the 12 months before r and omization . Additional inclusion criteria were age older than 35 years ; a history of 10 pack-years or more of cigarette smoking ; and documented chronic airflow obstruction , with an FEV1FVC ratio less than 0.70 and a postbronchodilator FEV1 less than 65 % of the predicted value . We excluded patients with a history of physician-diagnosed asthma before 40 years of age ; those with a history of physician-diagnosed chronic congestive heart failure with known persistent severe left ventricular dysfunction ; those receiving oral prednisone ; those with a known hypersensitivity or intolerance to tiotropium , salmeterol , or fluticasonesalmeterol ; those with a history of severe glaucoma or severe urinary tract obstruction , previous lung transplantation or lung volume reduction surgery , or diffuse bilateral bronchiectasis ; and those who were pregnant or were breastfeeding . Persons with a recent COPD exacerbation requiring oral or intravenous antibiotics or steroids were required to wait until treatment with these agents had been discontinued for 28 days before entering the study . R and omization and Interventions We r and omly assigned patients to 1 of 3 treatment groups for 52 weeks : tiotropium ( Spiriva [ Boehringer Ingelheim Pharma , Ingelheim , Germany ] ) , 18 g once daily , plus placebo inhaler , 2 puffs twice daily ; tiotropium , 18 g once daily , plus salmeterol ( Serevent [ GlaxoSmithKline , Research Triangle Park , North Carolina ] ) , 25 g/puff , 2 puffs twice daily ; or tiotropium , 18 g once daily , plus fluticasonesalmeterol ( Advair [ GlaxoSmithKline ] ) , 250/25 g/puff , 2 puffs twice daily . R and omization was done through central allocation of a r and omization schedule that was prepared from a computer-generated r and om listing of the 3 treatment allocations , blocked in variable blocks of 9 or 12 and stratified by site . Neither research staff nor patients were aware of the treatment assignment before or after r and omization . All study patients were provided with inhaled albuterol and were instructed to use it when necessary to relieve symptoms . Any treatment with inhaled corticosteroids , long-acting 2-agonists , and anticholinergics that the patient may have been using before entry was discontinued on entry into the study . Therapy with other respiratory medications , such as oxygen , antileukotrienes , and methylxanthines , was continued in all patient groups . Tiotropium was administered by using a H and ihaler device ( Boehringer Ingelheim ) . Study drugs were administered through a pressurized metered-dose inhaler using a spacer device ( Aerochamber Plus , Trudell Medical , London , Ontario , Canada ) , and patients were taught the correct inhalation technique to ensure adequate drug delivery . The metered-dose inhalers containing placebo , salmeterol , and fluticasonesalmeterol were identical in taste and appearance , and they were enclosed in identical tamper-proof blinding devices . The medication canisters within the blinding devices were stripped of any identifying labeling . Adherence to therapy was assessed by weighing the returned inhaler canisters . Measurements and Outcomes The primary outcome was the proportion of patients in each treatment group who experienced a COPD exacerbation within 52 weeks of r and omization . Respiratory exacerbations were defined , according to the 2000 Aspen Lung Conference Consensus definition , as a sustained worsening of the patient 's respiratory condition , from the stable state and beyond normal day-to-day variations , necessitating a change in regular medication in a patient with underlying COPD ( 18 ) . An acute change in regular COPD medications was defined as physician-directed , short-term use of oral or intravenous steroids , oral or intravenous antibiotics , or both therapies . Secondary outcomes were the mean number of COPD exacerbations per patient-year ; the total number of exacerbations that result ed in urgent visits to a health care provider or emergency department ; the number of hospitalizations for COPD ; the total number of hospitalizations for all causes ; and changes in health-related quality of life , dyspnea , and lung function . Health-related quality of life was assessed by using the St. George 's Respiratory Question naire ( 19 ) , dyspnea was assessed by using the Transitional Dyspnea Index ( 20 ) and the dyspnea domain of the Chronic Respiratory Disease Question naire ( 21 ) , and lung function was assessed by measuring the FEV1 according to established criteria of the American Thoracic Society . Follow-up Procedures Patients were monitored for exacerbations by monthly telephone calls . Exacerbations and all secondary outcomes were also assessed through patient visits at baseline and at 4 , 20 , 36 , and 52 weeks after r and omization . For every suspected exacerbation , we contacted both the patient and the patient 's treating physician to ensure that the medical encounter had been prompted by acute respiratory symptoms and a full report , including physician , emergency department , and hospital records that described the circumstances of each suspected exacerbation , was prepared . The assembled data from the visit for the suspected exacerbation were presented to a blinded adjudication committee for review , and the committee confirmed whether the encounter met the study definition of COPD exacerbation . For the purpose s of the trial , we considered that a patient had experienced a new COPD exacerbation if he or she had not been receiving oral steroids and antibiotics for at least 14 days after the previous exacerbation . Patients were followed for the full 52-week duration of the trial , and primary and secondary outcomes were recorded throughout the 1-year period regardless of whether patients had experienced an exacerbation or discontinued treatment with study medications . We did not break the study blinding for patients who prematurely discontinued treatment with study medications . Adverse events were captured by the research coordinators through monthly patient telephone interviews and at scheduled patient visits by using checklists of potential side effects . Physicians rated events as expected or unexpected , and they were asked to rate event severity and attribute causality of adverse events to the study drugs . Statistical Analysis We design ed the study to detect an 18 % absolute RATIONALE Current Global Initiative for Chronic Obstructive Lung Disease ( GOLD ) strategy recommends the combination of two long-acting bronchodilators of different pharmacologic classes for the management of chronic obstructive pulmonary disease ( COPD ) if symptoms are not adequately controlled by a single bronchodilator . OBJECTIVES The FLIGHT1 and FLIGHT2 studies evaluated the efficacy and safety of QVA149 ( indacaterol/glycopyrrolate ) , a fixed-dose combination of a long-acting β2-agonist ( indacaterol ) and a long-acting muscarinic antagonist ( glycopyrrolate ) , compared with its monocomponents and placebo in patients with moderate-to-severe COPD . METHODS FLIGHT1 and FLIGHT2 were 12-week , identical , multicenter , r and omized , double-blind , parallel-group , placebo- and active-controlled studies . Patients were r and omized ( 1:1:1:1 ) to indacaterol/glycopyrrolate ( 27.5/15.6 μg twice daily ) , indacaterol ( 27.5 μg twice daily ) , glycopyrrolate ( 15.6 μg twice daily ) , or placebo , all delivered via the Neohaler device . The primary objective was to demonstrate the superiority of indacaterol/glycopyrrolate versus its monocomponents for st and ardized area under the curve from 0 - 12 hours for FEV1 at Week 12 . Secondary objectives included St. George 's Respiratory Question naire total score and transition dyspnea index total score and reduction in daily rescue medication use with indacaterol/glycopyrrolate versus placebo . MEASUREMENTS AND MAIN RESULTS In total , 2,038 patients were included in the pooled analysis . Indacaterol/glycopyrrolate was statistically superior in terms of FEV1 area under the curve from 0 - 12 hours compared with its monocomponents ( P < 0.001 ) . Statistically and clinical ly meaningful improvements in St. George 's Respiratory Question naire total score , transition dyspnea index total score , and reduction in rescue medication use were observed with indacaterol/glycopyrrolate compared with placebo ( P < 0.001 ) . The safety profile was comparable across the treatment groups . CONCLUSIONS Indacaterol/glycopyrrolate twice daily can be an alternative treatment option for the management of symptomatic patients with moderate-to-severe COPD . Clinical trial registered with www . clinical trials.gov ( NCT 01727141 and NCT 0171251 ) INTRODUCTION This post hoc analysis evaluated the efficacy of indacaterol , a novel inhaled once-daily long-acting β(2)-agonist , by disease severity ( GOLD 2005 ) in patients with moderate-to-severe COPD from six Asian countries/ areas ( Hong Kong , India , Japan , Korea , Singapore , Taiwan ) . METHODS Data from a 12-week , double-blind , placebo-controlled , parallel-group study in patients r and omized to indacaterol 150 μg , indacaterol  300 μg or placebo  once daily were analyzed based on baseline disease severity ( moderate or severe ) . Endpoints were : trough FEV(1 ) ( average of 23 h 10 min and 23 h 45 min post-dose values ) , transition dyspnoea index ( TDI ) and St George 's Respiratory Question naire ( SGRQ ) at Week 12 . Safety data were collected . RESULTS Of 347 patients r and omized , 59.7 % had moderate , and 40.3 % had severe COPD . Least squares means ( LSMs ) indacaterol-placebo differences in trough FEV(1 ) at Week 12 exceeded the pre-specified minimal clinical ly important difference ( MCID ) of 0.12L and were statistically superior ( p < 0.001 ) for indacaterol ( 150 μg , 300 μg ) versus placebo in the two subgroups [ 0.19L , 0.20L ( moderate ) ; 0.15L , 0.19L ( severe ) respectively ] . LSM TDI scores for both indacaterol doses versus placebo in both subgroups were statistically superior ( p < 0.05 ) and clinical ly meaningful ( ≥1 unit ) . Both indacaterol doses showed improvements in LSM SGRQ total scores at Week 12 which exceeded the MCID ( 4 units ) versus placebo in both subgroups , with indacaterol 300 μg-placebo difference in the severe subgroup being statistically significant ( p < 0.01 ) . Overall incidence of adverse events was lower with indacaterol than with placebo across both subgroups . CONCLUSIONS Indacaterol demonstrated clinical ly relevant improvements versus placebo in lung function , dyspnea and health status in Asian COPD patients irrespective of disease severity . CLINICAL TRIALS IDENTIFIER NCT00794157 Abstract This was a 52-week , double-blind , extension study in which COPD patients previously treated with twice-daily ( BID ) aclidinium bromide 200 μg or 400 μg during a 12-week lead-in study ( ACCORD COPD I ) continued the same treatment , while patients previously receiving placebo  were rer and omized ( 1:1 ) to aclidinium 200 μg or 400 μg BID . The primary objective of this study was to evaluate the long-term safety and tolerability of aclidinium  treatment . Efficacy outcomes included bronchodilation , health status , and rescue medication use . A total of 467 patients completed the lead-in study and 291 patients consented to participate in the extension . At study end , the percentages of patients who reported a treatment-emergent adverse event ( TEAE ) were similar for both treatments ( 200 μg , 77.4 % ; 400 μg , 73.7 % ) . Incidence of anticholinergic TEAEs was low and similar for both treatments , with dry mouth reported in only 1 patient ( 400 μg ) . Cardiac TEAEs were reported by a similarly low percentage of patients ( < 5 % for any event in any group ) with no apparent dose dependence . Improvements from baseline in lung function were greatest for patients who received continuous aclidinium treatment and those who were rer and omized from placebo to aclidinium 400 μg ; these improvements were generally sustained throughout the study . Health status and overall rescue medication use was improved from baseline for both treatments . The safety profile of twice-daily aclidinium and sustained improvements in lung function and health status throughout the 52-week extension study support its use as a long-term maintenance treatment for patients with COPD . ( Clinical trial registration number NCT00970268 ) The objective of this study was to investigate the effect of tiotropium compared with salmeterol on exacerbations in patients with moderate ( Global Initiative for Chronic Obstructive Lung Disease [ GOLD ] stage II ) chronic obstructive pulmonary disease ( COPD ) and those naïve to maintenance respiratory therapy  in the 1-year Prevention Of Exacerbations with Tiotropium in COPD ( POET- COPD ( ® ) ) trial ( NCT00563381 ) . Time to first exacerbation ( primary endpoint ) and rates of exacerbations were analyzed using exploratory Cox and Poisson regression ( adjusting for time on treatment ) . Of 7376 r and omized patients , 3614 were GOLD stage II ( tiotropium n = 1781 ;  salmeterol n = 1833 ) and 1343 were maintenance therapy naïve ( tiotropium  n = 672 ; salmeterol n = 671 )  . Tiotropium significantly increased time to first exacerbation vs. salmeterol in GOLD stage II patients ( hazard ratio [ HR ] , 0.88 ; 95 % confidence interval [ CI ] : 0.79 - 0.99 ; p = 0.028 ) and maintenance therapy naïve patients ( HR , 0.79 ; 95 % CI , 0.65 - 0.97 ; p = 0.028 ) . Annual exacerbation rates were also significantly lower with tiotropium in the maintenance naïve subgroup compared with salmeterol ( rate ratio [ RR ] , 0.77 ; 95 % CI , 0.63 - 0.94 ; p = 0.012 ) . In the GOLD stage II subgroup , the rate of hospitalized exacerbations per year was significantly lower with tiotropium than with salmeterol ( RR , 0.70 ; 95 % CI , 0.57 - 0.85 ; p < 0.001 ) ; tiotropium also significantly prolonged time to first hospitalized exacerbation  versus salmeterol in this subgroup ( HR , 0.66 ; 95 % CI , 0.48 - 0.91 ; p = 0.012 ) . In conclusion , results from this prespecified subgroup analysis support the selection of tiotropium as first-choice maintenance therapy for patients with GOLD stage II COPD Background Dual bronchodilation combining a long-acting β2-agonist ( LABA ) and a long-acting muscarinic antagonist ( LAMA ) is the preferred choice of treatment recommended by the Global Initiative for Chronic Obstructive Lung Disease ( GOLD ) 2017 guidelines for the management of patients with moderate-to-severe chronic obstructive pulmonary disease ( COPD ) . The once-daily ( q.d . ) fixed-dose combination ( FDC ) of LABA , indacaterol 110 μg and LAMA , glycopyrronium 50 μg ( IND/GLY 110/50 μg q.d . ) demonstrated superior improvements in lung function , dyspnoea and overall health status and better tolerability against LABA or LAMA monotherapies and combination of LABA and inhaled corticosteroid ( ICS ) in more than 11,000 patients with moderate-to-severe COPD in several r and omised controlled clinical trials . Methods The CRYSTAL study was the first , 12-week , r and omised , open-label trial that evaluated the efficacy and safety of a direct switch from previous treatments to IND/GLY 110/50 μg q.d . on lung function and dyspnoea in patients with moderate COPD and a history of up to one exacerbation in the previous year . Patients were divided into 2 groups according to their background therapy and symptom scores and were r and omised ( 3:1 ) to IND/GLY or to continue with their previous treatments . Results The study included 4389 r and omised patients , of whom 2160 were in groups switched to IND/GLY ( intention-to-treat population ) . The effect of IND/GLY was superior to LABA + ICS on trough forced expiratory volume in 1 s ( FEV1 ; treatment difference , Δ = + 71 mL ) and transition dyspnoea index ( TDI ; [ Δ = 1.09 units ] ) , and to LABA or LAMA on trough FEV1 ( Δ = + 101 mL ) and a TDI ( Δ = 1.26 units ) . Improvements in health status and lower rescue medication use were also observed with IND/GLY . The safety profile of the study medication was similar to that observed in previous studies . Conclusions IND/GLY demonstrated superior improvements in lung function and dyspnoea after direct switch from previous treatments . Trial registration Clinical Trials.gov number : NCT01985334 INTRODUCTION The treatment of COPD ( Chronic Obstructive Pulmonary Disease ) aims to improve the patients 's well-being and to reduce mortality , morbidity and the development of exacerbations . This study was thus design ed to compare the efficacy and tolerability of salmeterol/fluticasone combination with tiotropium in patients with moderate COPD . MATERIAL S AND METHODS This was an open , prospect i ve , r and omized trial in COPD patients whose FEV1 ( forced expiratory volume in 1 second ) levels were between 80 % and 50 % predicted . A total of 44 patients who met the inclusion and exlusion criteria and who gave written informed consent were included in the study . At the end of the two week wash-out period , the patients were r and omized to receive either salmeterol 50 µg/fluticasone 500 µg combination as dry powder inhaler twice daily ( SF Group ) or tiotropium dry powder inhaler 18 µg once daily ( T Group ) for one year . These were equally distributed in the two groups ( 22 patients in each study group ) . At follow-up , the patients were required to come to the outpatient clinic at the third , sixth , ninth and twelfth months . RESULT There were no statistically significant difference between the two groups with regards to demographic features and baseline measurements . There were 1.2 ± 1.7 exacerbations in SF Group and 2.1 ± 2.2 exacerbations in T Group ( p= 0.070 ) . The time to the first exacerbation was 4.2 ± 4.0 and 4.2 ± 3.3 months , respectively ( p= 0.697 ) . The number of severe exacerbations that result ed in admission to the emergency department or hospital was 0.6 ± 1.0 and 1.1 ± 1.4 , respectively ( p= 0.245 ) . Significant improvements were observed in CAT ( CPOD Assessment Test ) scores in both groups during the treatment period ( p < 0.0001 ) ; but there was no difference between the two groups . CONCLUSIONS This study has shown that in patients with moderate COPD , treatment with combined corticosteroid and long-acting beta-2 agonist provides similar improvements in pulmonary function tests , patient-reported outcomes and exercise capacity as compared a long-acting anticholinergics BACKGROUND Patients with severe or very severe chronic obstructive pulmonary disease ( COPD ) frequently suffer repeated exacerbations generating high health care utilization costs . Combined corticosteroid and bronchodilator treatment using a single inhaler might - via improved compliance - reduce exacerbation rates . OBJECTIVES Our aim was to obtain descriptive data on exacerbation rates in patients with severe or very severe COPD ( GOLD Stages III and IV as per GOLD 2009 classification ) receiving salmeterol xinafoate/fluticasone propionate via a single inhaler ( SFC ) or via separate inhalers ( Sal/FP ) in addition to individual existing therapy in order to investigate the potential benefit of a fixed combination device as compared with two separate devices due to potentially improved patients ' compliance . METHODS This prospect i ve , r and omized , open-label , parallel-group , multi-center , exploratory study was conducted in Germany in 2007 - 2009 . Patients were required to have suffered ≥ 2 moderate/severe exacerbations in the preceding year . RESULTS 213 patients ( SFC : 108 patients , Sal/FP : 105 patients ) from 23 centers were evaluated . Approximately 25 % of patients showed COPD Stage IV . On average patients had suffered 2.3 ± 0.6 moderate/severe exacerbations in the preceding year . The annual rate of moderate/severe exacerbations observed in the study was similar in both treatment groups ( SFC : 0.86 ± 0.13 ; Sal/FP : 0.86 ± 0.14 ; exacerbation rate ratio SFC/Sal/FP : 1.00 ; p = 0.73 ; negative binomial model ) . Compliance was high and comparable in both groups . Besides COPD exacerbations , pneumonia ( 5.6 % ) and nasopharyngitis ( 5.2 % ) were the most common adverse events . CONCLUSION Observed exacerbation rates were lower than those reported at baseline . No substantial difference was observed between administration of salmeterol xinafoate/fluticasone propionate via a single inhaler and separate inhalers . Treatment was safe and well tolerated . Clinical Trials.gov Identifier : NCT00527826 OBJECTIVES COPD exacerbations are associated with significant morbidity and mortality . This r and omized , double-blind , parallel-group , multicenter study evaluated the effect of fluticasone propionate/salmeterol 250/50 and salmeterol 50 microg twice daily on moderate to severe exacerbations . METHODS Patients received st and ardized treatment with fluticasone propionate/salmeterol 250/50 during a 1-month run-in , followed by r and omization to fluticasone propionate/salmeterol 250/50 or salmeterol for 12 months . Moderate to severe exacerbations were defined as worsening symptoms of COPD requiring treatment with oral corticosteroids , antibiotics , or hospitalization . RESULTS In 782 patients with COPD ( mean FEV(1)=0.94+/-0.36 L , 33 % predicted normal ) , treatment with fluticasone propionate/salmeterol 250/50 significantly reduced ( 1 ) the annual rate of moderate to severe exacerbations by 30.5 % compared with salmeterol ( 1.06 and 1.53 per subject per year , respectively , p<0.001 ) , ( 2 ) the risk of time to first exacerbation by 25 % ( hazard ratio=0.750 , p=0.003 ) and ( 3 ) the annual rate of exacerbations requiring oral corticosteroids by 40 % ( p<0.001 ) . Clinical improvements observed during run-in treatment with fluticasone propionate/salmeterol 250/50 were better maintained over 12 months with fluticasone propionate/salmeterol 250/50 than salmeterol .  Adverse events were reported for a similar percentage of subjects across groups . A higher reporting of pneumonia was observed with fluticasone propionate/salmeterol 250/50 than salmeterol ( 7 % vs. 4 % ) . CONCLUSIONS We conclude that fluticasone propionate/salmeterol 250/50 is more effective than salmeterol at reducing the rate of moderate to severe exacerbations over 1 year . The benefits of this reduction relative to the risk of a higher incidence of reported pneumonia should be considered . This study supports the use of fluticasone propionate/salmeterol 250/50 for the reduction of COPD exacerbations in patients with COPD The efficacy and safety of twice-daily aclidinium bromide/formoterol fumarate was compared with that of salmeterol/fluticasone propionate in patients with stable , moderate-to-severe chronic obstructive pulmonary disease ( COPD ) . AFFIRM COPD ( Aclidinium and Formoterol Findings in Respiratory Medicine COPD ) was a 24-week , double-blind , double-dummy , active-controlled study . Patients were  r and omised ( 1:1 ) to aclidinium/formoterol 400/12 µg twice-daily via Genuair/Pressair or salmeterol/fluticasone 50/500 µg twice-daily via Accuhaler . The primary end-point was peak forced expiratory volume in 1 s ( FEV1 ) at week 24 . Other end-points included Transition Dyspnoea Index ( TDI ) focal score at week 24 , TDI and St George 's Respiratory Question naire ( SGRQ ) responders , COPD Assessment Test and SGRQ scores , assessment of COPD symptoms and exacerbations , use of reliever medication , and device preference . Adverse events were monitored throughout . In total , 933 patients were eligible ( mean age 63.4 years , 65.1 % male ) . Aclidinium/formoterol was superior to salmeterol/fluticasone in peak FEV1 and noninferior in TDI . Health status and reduction in exacerbation risk were similar in both groups . While both treatments were well tolerated , pneumonia occurred less frequently with aclidinium/formoterol than salmeterol/fluticasone . In stable COPD , aclidinium/formoterol  significantly improved bronchodilation versus salmeterol/fluticasone , with equivalent benefits in symptom control and reduction in exacerbation risk . Both treatments were well tolerated and treatment-related adverse events were less common with aclidinium/formoterol . Aclidinium/formoterol achieves significantly greater bronchodilation than salmeterol/fluticasone in stable COPD BACKGROUND Once-daily combination treatment is an attractive maintenance therapy for COPD . However , the dose of inhaled corticosteroid to use in a once-daily combination is unknown . We compared two strengths of fluticasone furoate ( FF ) plus vilanterol ( VI ) , the same strengths of the individual components , and placebo . METHODS Multicentre , r and omised , 24-week , double-blind , placebo-controlled , parallel-group study in stable , moderate-to-severe COPD subjects ( N = 1224 ) . Subjects were r and omised to FF/VI ( 200/25 μg ; 100/25 μg ) , FF ( 200 μg ; 100 μg ) , VI 25 μg , or placebo , once daily in the morning . Co- primary efficacy endpoints ; 0 - 4 h weighted mean ( wm ) FEV(1 ) on day 168 , and change from baseline in trough ( 23 - 24 h post-dose ) FEV(1 ) on day 169 . The primary safety objective was adverse events ( AEs ) . RESULTS There was a statistically significant ( p < 0.001 ) increase in wm FEV(1 ) ( 209 ml ) and trough FEV(1 ) ( 131 ml ) for FF/VI 200/25 μg vs. placebo ; similar changes were seen for FF/VI 100/25 μg vs. placebo . Whereas the difference between FF/VI 200/25 μg and VI 25 μg in change from baseline trough FEV(1 ) ( 32 ml ) was not statistically significant ( p = 0.224 ) , the difference between FF/VI 200/25 μg and FF 200 μg for wm FEV(1 ) ( 168 ml ) was significantly different ( p < 0.001 ) . VI 25 μg significantly improved wm and trough FEV(1 ) vs. placebo ( 185 ml and 100 ml , [ corrected ] respectively ) . No increase was seen in on-treatment AEs or serious AEs ( SAEs ) , with active therapy vs. placebo . CONCLUSIONS FF/VI provides rapid and significant sustained improvement in FEV(1 ) in subjects with moderate-to-severe COPD , which was not influenced by the dose of FF . These data suggest that FF/VI may offer clinical efficacy in COPD and warrants additional study . GSK study number : HZC112207 . Clinical Trials.gov : NCT01054885 BACKGROUND Tiotropium , a once-daily anticholinergic , and salmeterol represent two inhaled , long-acting bronchodilators from different pharmacologic classes . A trial was design ed to examine the efficacy and safety of both compounds with multiple outcome measures , including lung function , dyspnea , and health-related quality of life ( HRQoL ) in patients with COPD . METHODS A 6-month , r and omized , placebo-controlled , double-blind , double-dummy , parallel-group study of tiotropium , 18 microg once daily via dry-powder inhaler , compared with salmeterol , 50 microg bid via metered-dose inhaler , was conducted in patients with COPD .  Efficacy was assessed by 12-h monitoring of spirometry , transition dyspnea index ( TDI ) , and the St. George 's Respiratory Question naire ( SGRQ ) . RESULTS A total of 623 patients participated ( tiotropium , n= 209 ; salmeterol , n = 213 ; and  placebo , n = 201 ) . The groups were similar in age ( mean , 65 years ) , gender ( 75 % men ) , and baseline FEV(1 ) ( mean , 1.08 + /- 0.37 L ; percent predicted , 40 + /- 12 % [ + /- SD ] ) . Compared with placebo treatment , the mean predose morning FEV(1 ) following 6 months of therapy increased significantly more for the tiotropium group ( 0.14 L ) than the salmeterol group ( 0.09 L ; p < 0.01 ) . The average FEV(1 ) ( 0 to 12 h ) for tiotropium was statistically superior to salmeterol ( difference , 0.08 L ; p < 0.001 ) . Tiotropium improved TDI focal score by 1.02 U compared with placebo ( p = 0.01 ) , whereas there was no significant change in TDI focal score with salmeterol ( 0.24 U ) . Tiotropium was superior to salmeterol in improving TDI focal score ( p < 0.05 ) . At 6 months , the mean improvement in SGRQ total score vs baseline was tiotropium , - 5.14 U ( p < 0.05 vs placebo ) ; salmeterol , - 3.54 U ( p = 0.4 vs placebo ) ; and placebo , - 2.43 U. A statistically higher proportion of patients receiving tiotropium achieved at least a 4-U change in SGRQ score compared to patients receiving placebo . Both active drugs reduced the need for rescue albuterol ( p < 0.0001 ) . CONCLUSIONS Tiotropium once daily produces superior bronchodilation , improvements in dyspnea , and proportion of patients achieving meaningful changes in HRQoL compared to twice-daily salmeterol in patients with COPD BACKGROUND AND OBJECTIVE This study , in a predominantly Chinese population , investigated the efficacy and safety of a once-daily ( o.d . ) inhaled ultra-long-acting β2 -agonist indacaterol for the treatment of moderate-to-severe chronic obstructive pulmonary disease ( COPD ) . METHODS This is a 26-week , double-blind study on r and omized patients who received indacaterol 150 μg or 300 μg or placebo o.d .  The primary variable was trough forced expiratory volume in 1 s ( FEV1 , average of 23 h 10 min and 23 h 45 min post-dose values ) at Week 12 . Health status ( St George 's Respiratory Question naire , SGRQ ) , dyspnoea ( transition dyspnoea index , TDI ) and safety were evaluated over 26 weeks . RESULTS Of the 563 patients r and omized , 561 ( 89.8 % Chinese ) received treatment and 482 completed . At Week 12 , trough FEV1 improved significantly for indacaterol 150 and 300 μg versus placebo ( 1.32 , 1.29 vs 1.17 ; P < 0.001 for both comparisons ) , with differences exceeding the pre-specified minimal clinical ly important difference of 0.12 L. At Week 26 , TDI score was superior to placebo for indacaterol 150 and 300 μg ( 0.82 , 1.15 ; P < 0.01 ) , as was the percentage of patients with a clinical ly relevant improvement ( ≥1 point ) ( 74.1 % , 78.6 % vs 55.5 % ; P < 0.05 ) . Both doses provided ≥4-point improvements from baseline in SGRQ score at Week 26 that were numerically greater than placebo ( unadjusted means : -9.6 , -8.8 vs -7.0 ) , with a similar pattern in percentage of patients with clinical ly relevant improvements in SGRQ score ( 65.0 % , 61.5 % vs 60.6 % ) . Incidences of adverse events were comparable across treatment groups . CONCLUSIONS Indacaterol delivered effective bronchodilation with significant improvements in breathlessness and health status in this predominantly Chinese population Background and Objectives Aclidinium bromide is a long-acting muscarinic antagonist approved for the long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease ( COPD ) . This 12-week phase III study evaluated efficacy and tolerability of aclidinium 200 or 400 μg in patients with moderate-to-severe COPD . Methods In this double-blind study , 544 patients with COPD were r and omized to placebo or twice-daily aclidinium 200 or 400 μg administered by Genuair ® /Pressair ® . Lung function , health status [ measured by the St. George ’s Respiratory Question naire ( SGRQ ) ] , dyspnea [ measured using the Transition Dyspnea Index ( TDI ) ] , and safety were assessed throughout the study . Results Mean changes from baseline in morning trough forced expiratory volume in 1 s ( FEV1 ) at week 12 ( primary endpoint ) were significantly higher for aclidinium than for placebo ( 200 μg , 51 mL ; 400 μg , 72 mL ; both p < 0.05 ) . Aclidinium also significantly improved other lung function outcomes . At week 12 , improvements from baseline were observed with aclidinium  in SGRQ total score ( 200 μg , −6.0 ; 400 μg , −5.4 ) and TDI focal score ( 200 μg , 1.0 ; 400 μg , 1.3 ) . Furthermore , clinical ly important improvements in SGRQ total and TDI focal scores were achieved by 45 and 51 % of patients , respectively , who received aclidinium 400 μg , with a significant difference versus placebo for TDI ( p < 0.05 ) . Anticholinergic-related adverse events ( e.g. , dry mouth ) were infrequent , occurring < 2 % for any event in any treatment group . Both aclidinium doses were well tolerated . Conclusion This study demonstrates efficacy and safety  of aclidinium in COPD patients . Unexpected baseline imbalances between treatment groups may have impacted the aclidinium treatment benefit in this study BACKGROUND The contribution of fluticasone furoate ( FF ) on lung function in the FF/vilanterol ( VI ) 100/25 μg combination has been demonstrated numerically , but not statistically . METHODS This multicentre , r and omised , double-blind , controlled trial ( GlaxoSmithKline study number 200820 ; clinical trials.gov NCT02105974 ) enrolled ≥40-year-old patients with chronic obstructive pulmonary disease ( COPD ) , a ≥10-pack-year smoking history , a post-bronchodilator forced expiratory volume in 1 s ( FEV1 ) 30 - 70 % of the predicted value , a FEV1/forced vital capacity ratio of ≤0.70 , ≥1 COPD exacerbation in the previous 12 months requiring corticosteroids , antibiotics and /or hospitalisation , and current COPD symptoms . Participants received FF/VI 100/25 μg or VI 25 μg once daily . The primary endpoint was the change from baseline in trough FEV1 at day 84 . FINDINGS 1620 patients were r and omised and received at least one dose of FF/VI 100/25 μg ( n = 806 ) or VI 25 μg ( n = 814 ) . At day 84 , the FF/VI 100/25 μg group showed an adjusted mean treatment difference of 34 mL over VI 25 μg in change from baseline trough FEV1 ( 95 % confidence interval [ CI ] 14 - 55 ; p = 0.001 ) . There was no significant difference between the groups in the percentage of rescue medication-free 24-h periods . The FF/VI 100/25 μg group demonstrated a 42 % risk reduction compared with the VI 25 μg group in time to first moderate/severe COPD exacerbation ( 95 % CI 22 - 57 ; nominal p < 0.001 ) . The incidence of on-treatment adverse events was similar between the groups . INTERPRETATION The contribution of FF in the FF/VI 100/25 μg combination on lung function in COPD was statistically significant . FUNDING GlaxoSmithKline 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 A 6-week , multicenter , r and omized , double-blind , parallel-group study was conducted in patients with COPD to compare lung function improvements of tiotropium , 18 microg qd , plus formoterol , 12 microg bid , to salmeterol , 50 microg bid , plus fluticasone , 500 microg bid . METHODS Following a screening visit , subjects entered a run-in period in which they received regular ipratropium . At r and omization , patients were assigned to either tiotropium plus formoterol or salmeterol plus fluticasone . After 6 weeks of treatment , a 12-h lung function profile was obtained . The co primary end points were FEV(1 ) area under the curve for the time period 0 to 12 h ( AUC(0 - 12 ) ) and peak FEV(1 ) . RESULTS A total of 729 patients were screened , and 605 patients were r and omized and treated . A total of 592 patients ( baseline FEV(1 ) , 1.32 + /- 0.43 L/min [ + /-SD ] ) were included in the analysis . After 6 weeks , the 12-h lung function profiles in the group receiving tiotropium plus formoterol were superior to those in the group receiving salmeterol plus fluticasone ( mean difference in FEV(1 ) AUC(0 - 12 ) , 78 mL [ p = 0.0006 ] ; mean difference in FVC AUC(0 - 12 ) , 173 mL , p < 0.0001 ) . Also , peak responses were in favor of tiotropium plus formoterol ( difference in peak FEV(1 ) , 103 mL [ p < 0.0001 ] ; difference in peak FVC , 214 mL [ p < 0.0001 ] ) , as were FEV(1 ) and FVC at each individual time point after dose ( p < 0.05 ) . Predose FVC was significantly higher with the bronchodilator combination , while predose FEV(1 ) and rescue medication use did not differ significantly between groups . Both treatments were well tolerated . CONCLUSIONS Tiotropium plus formoterol was superior in lung function over the day compared to salmeterol plus fluticasone in patients with moderate COPD . Long-term studies in patients with severe COPD are warranted to assess the relative efficacy of different treatment combinations . TRIAL REGISTRATION Clinical trials.gov Identifier : NCT00239421 BACKGROUND QVA149 is an inhaled fixed-dose combination therapy under development for the treatment of chronic obstructive pulmonary disease ( COPD ) . It combines indacaterol ( a longacting β2-agonist ) with glycopyrronium ( a longacting muscarinic antagonist ) as a dual bronchodilator . We aim ed to compare the efficacy , safety , and tolerability of QVA149 versus salmeterol-fluticasone ( SFC ) over 26 weeks in patients with moderate-to-severe COPD . METHODS In this multicentre double-blind , double-dummy , parallel-group study , 523 patients ( age 40 years or older , Global Initiative for Chronic Obstructive Lung Disease [ GOLD ] stages II-III , without exacerbations in the previous year ) were r and omly assigned ( 1:1 ; via automated , interactive response technology and stratified for smoking status ) to once-daily QVA149 110/50 μg or twice-daily SFC 50/500 μg for 26 weeks . Efficacy was assessed in the full analysis set ( r and omised patients who received at least one dose of study drug ) ; safety was assessed in all patients who received at least one dose of study drug . The primary endpoint was to demonstrate the superiority of QVA149 compared with SFC for the st and ardised area under the curve from 0 to 12 h post dose for forced expiratory volume in 1 second ( FEV1 AUC0 - 12h ) after 26 weeks of treatment . This trial was registered at Clinical Trial.gov , NCT01315249 . FINDINGS Between March 25 , 2011 , and March 12 , 2012 , 259 patients were r and omly assigned to receive QVA149 and 264 to receive SFC . At week 26 , FEV1 AUC0 - 12h was significantly higher with QVA149 than with SFC ( treatment difference 0·138 L ; 95 % CI 0·100 - 0·176 ; p<0·0001 ) . Overall incidence of adverse events ( including COPD exacerbations ) was 55·4 % ( 143 of 258 ) for the QVA149 group and 60·2 % ( 159 of 264 ) for the SFC group . Incidence of serious adverse events was similar between treatment groups ( QVA149 , 13 of 258 [ 5·0 % ] ; SFC 14 of 264 [ 5·3 % ] ) ; COPD worsening was the most frequent serious adverse event ( one of 13 [ 0·4 % ] and three of 14 [ 1·1 % ] , respectively ) . INTERPRETATION Once-daily QVA149 provides significant , sustained , and clinical ly meaningful improvements in lung function versus twice-daily SFC , with significant symptomatic benefit . These results indicate the potential of dual bronchodilation as a treatment option for non-exacerbating symptomatic COPD patients . FUNDING Novartis Pharma AG The FORWARD study is a r and omised , double-blind trial that compares the efficacy and safety of 48 weeks treatment with extrafine beclomethasone dipropionate/formoterol fumarate ( BDP/FOR ) , 100/6 μg pMDI , 2 inhalations BID , vs. FOR 12 μg pMDI , 1 inhalation BID , in severe COPD patients with a history of exacerbations . Co- primary endpoints were exacerbation rate over 48 weeks and pre-dose morning FEV(1 ) at 12 weeks . The ITT population included 1186 patients ( 69 % males , mean age 64 years ) with severe airflow limitation ( mean post-bronchodilator FEV(1 ) 42 % predicted ) . Salbutamol as rescue therapy , theophylline and tiotropium ( if stable regimen prior to screening ) were allowed . Compared to FOR , BDP/FOR : ( 1 ) reduced the exacerbation rate ( rate ratio : 0.72 [ 95 % confidence interval 0.62 - 0.84 ] , p < 0.001 ) ; ( 2 ) improved pre-dose morning FEV(1 ) ( mean difference : 0.069 L [ 0.043 - 0.095 ] p < 0.001 ) ; ( 3 ) prolonged the time to first exacerbation ; ( 4 ) improved the SGRQ total score . The percentage of patients with adverse events was similar ( 52.1 % with BDP/FOR and 49.2 % with FOR ) . Pneumonia incidence was low , slightly higher with BDP/FOR ( 3.8 % ) than with FOR ( 1.8 % ) . No difference for laboratory values , ECG or vital signs . Extrafine BDP/FOR significantly reduces the exacerbation rate and improves lung function of  patients with severe COPD and history of exacerbations as compared to FOR alone BACKGROUND Long-acting beta-agonists and inhaled corticosteroids are used to treat chronic obstructive pulmonary disease ( COPD ) , but their effect on survival is unknown . METHODS We conducted a r and omized , double-blind trial comparing salmeterol at a dose of 50 microg plus fluticasone propionate at a dose of 500 microg twice daily ( combination regimen ) , administered with a single inhaler , with placebo , salmeterol alone , or fluticasone propionate alone for a period of 3 years . The primary outcome was death from any cause for the comparison between the combination regimen and placebo ; the frequency of exacerbations , health status , and spirometric values were also assessed . RESULTS Of 6112 patients in the efficacy population , 875 died within 3 years after the start of the study treatment .  All-cause mortality rates were 12.6 % in the combination-therapy group , 15.2 % in the placebo group , 13.5 % in the salmeterol group , and 16.0 % in the fluticasone group . The hazard ratio for death in the combination-therapy group , as compared with the placebo group , was 0.825 ( 95 % confidence interval [ CI ] , 0.681 to 1.002 ; P=0.052 , adjusted for the interim analyses ) , corresponding to a difference of 2.6 percentage points or a reduction in the risk of death of 17.5 % . The mortality rate for salmeterol alone or fluticasone propionate alone did not differ significantly from that for placebo . As compared with placebo , the combination regimen reduced the annual rate of exacerbations from 1.13 to 0.85 and improved health status and spirometric values ( P<0.001 for all comparisons with placebo ) . There was no difference in the incidence of ocular or bone side effects . The probability of having pneumonia reported as an adverse event was higher among patients receiving medications containing fluticasone propionate ( 19.6 % in the combination-therapy group and 18.3 % in the fluticasone group ) than in the placebo group ( 12.3 % , P<0.001 for comparisons between these treatments and placebo ) . CONCLUSIONS The reduction in death from all causes among patients with COPD in the combination-therapy group did not reach the predetermined level of statistical significance . There were significant benefits in all other outcomes among these patients . ( Clinical Trials.gov number , NCT00268216 [ Clinical Trials.gov ] . ) Changes in health-related quality of life ( HRQoL ) were evaluated in patients with chronic obstructive pulmonary disease ( COPD ) following treatment with placebo , salmeterol 50 microg twice a day or 100 microg twice a day by metered-dose inhaler . Patients completed the disease-specific St. George 's Respiratory Question naire ( SGRQ ) and the Medical Outcomes Study Short Form 36 ( SF-36 ) at baseline and after 16 wk of treatment . Data from 283 patients ( 95 patients in the placebo group and 94 in each salmeterol group ) were available for HRQoL analysis . Apart from a small difference in ages , all treatment groups were well matched at baseline in terms of forced expiratory volume in one second ( FEV1 ) and HRQoL scores . Compared with placebo , salmeterol 50 microg twice a day was associated with significant improvements in SGRQ " Total " and " Impacts " scores which exceeded the threshold for a clinical ly significant change . This was not seen with salmeterol 100 microg twice a day . Changes in SGRQ and SF-36 scores correlated . They also showed a weak but significant relationship with FEV1 . This study has shown that a modest change in lung function may be associated with clinical ly significant gain in health and well-being in COPD patients OBJECTIVES To evaluate the effect of beclomethasone/formoterol versus budesonide/formoterol ( non-inferiority ) and versus formoterol ( superiority ) in patients with severe stable chronic obstructive pulmonary disease ( COPD ) . METHODS A double-blind , double-dummy , r and omised , active-controlled , parallel-group study . After 4 weeks run-in with ipratropium/salbutamol ( 40/200 μg , three times daily ) patients were r and omised to receive beclomethasone/formoterol ( 200/12 μg pressurised metered dose inhaler ) , budesonide/formoterol ( 400/12 μg dry powder inhaler ) or formoterol ( 12 μg dry powder inhaler ) twice daily for 48 weeks . Co- primary efficacy variables were change from baseline to 48 weeks in pre-dose morning forced expiratory volume in 1 s ( FEV(1 ) ) and mean rate of COPD exacerbations . RESULTS Of 718 patients r and omised , 703 ( 232 beclomethasone/formoterol , 238 budesonide/formoterol , 233 formoterol ) were in the ITT analysis .  Improvement in pre-dose morning FEV(1 ) was 0.077 L , 0.080 L and 0.026 L for beclomethasone/formoterol , budesonide/formoterol and formoterol respectively ( LS mean from the ANCOVA model ) . Beclomethasone/formoterol was not inferior to budesonide/formoterol ( 95 % CI of the difference -0.052 , 0.048 ) and superior to formoterol ( p = 0.046 ) . The overall rate of COPD exacerbations/patient/year was similar and not statistically significantly different among treatments ( beclomethasone/formoterol 0.414 , budesonide/formoterol 0.423 and formoterol 0.431 ) . Quality of life and COPD symptoms improved in all groups and use of rescue medication decreased . Safety profiles were as expected and treatments well-tolerated . CONCLUSIONS Beclomethasone/formoterol ( 400/24 μg ) treatment for 48 weeks improved pulmonary function , reduced symptoms compared to formoterol , was safe and well-tolerated in patients with severe stable COPD . Neither of the long-acting β2-agonist/inhaled corticosteroid combinations affected the low exacerbation rate seen in this population BACKGROUND Aclidinium is a novel , long-acting muscarinic antagonist indicated for maintenance treatment of COPD . METHODS In this 52-week , parallel-group , double-blind study , patients with moderate-to-severe COPD were r and omized ( 1:1 ) to receive aclidinium twice-daily ( BID ) 200 μg or 400 μg via a novel , dry powder inhaler ( Genuair( ® )/Pressair ( ® ) ) [ Registered trademarks of Almirall , SA , Barcelona , Spain for use within the European Union , Icel and , Norway , and Switzerl and as Genuair ( ® ) and within the United States as Pressair ( ® ) ] . Safety , the primary objective , was assessed via adverse events ( AEs ) , clinical laboratory tests , vital signs , and 12-lead electrocardiograms . Efficacy was evaluated using spirometry , SGRQ , and rescue medication use . RESULTS A total of 605 patients were r and omized in the study . The percentage of patients reporting any treatment-emergent AE ( TEAE ) was comparable between groups ; most TEAEs were mild or moderate . Anticholinergic TEAEs were reported by low percentages of patients in either treatment group ( dry mouth : 200 μg , 1.3 % ; 400 μg , 2.7 % ; constipation : 200 μg , 2.9 % ; 400 μg , 1.7 % ) . Cardiac TEAEs were also reported by a low percentage of patients ( < 2 % for any event in any group ) and did not appear to be dose dependent . There were no clinical ly relevant abnormalities in other safety outcomes . Both aclidinium 200 μg and 400 μg result ed in improvements from baseline to Week 52 in FEV1 , with numerically greater increases observed with the higher dose . Clinical ly important improvements in SGRQ scores and a reduction in rescue medication use were observed throughout the study for both doses . CONCLUSIONS Long-term treatment with aclidinium 200 μg or 400 μg BID was well tolerated , with sustained benefits in lung function and health status in patients with COPD throughout the 1-year study NVA237 is a novel once-daily inhaled long-acting muscarinic antagonist administered via a dry powder inhaler . This r and omized , double-blind , placebo-controlled study evaluated the safety , tolerability and bronchodilator efficacy of two doses of NVA237 ( 100 and 200 microg ) , versus placebo , in patients with moderate-to-severe COPD ( forced expiratory volume in 1s [FEV(1)]>or=30 % and < 80 % predicted and FEV(1)/forced vital capacity [FVC]<0.7 , 30 min after inhalation of 80 microg ipratropium bromide )  . After appropriate washout periods , patients were r and omized to treatment with NVA237 100 microg ( n=92 ) , NVA237 200 microg ( n=98 ) or placebo ( n=91 ) for 28 days . The primary objective was evaluation of safety , with efficacy measures included as secondary objectives . NVA237 was generally well tolerated and associated with a frequency and distribution of adverse events similar to placebo .  Serious adverse events were uncommon and there was no evidence of adverse cardiovascular effects or unexpected events . Trough FEV(1 ) was significantly higher in those receiving NVA237 compared with placebo . For NVA237 100 microg the differences were 131 and 161 mL on Days 1 and 28 , respectively ( p<0.05 ) , and for NVA237 200 microg the differences were 146 and 151 mL on Days 1 and 28 , respectively ( p<0.05 ) . Peak FEV(1 ) , FEV(1 ) at all timepoints up to 24h after dosing , and FEV(1 ) area under the curve during 5 min-5 h post-dosing were also significantly higher in both NVA237 groups , compared with placebo . Patients receiving NVA237 required fewer daily puffs of rescue medication and had a higher percentage of days on which rescue medication was not required . Overall , the present study provides further evidence of the safety , tolerability and bronchodilator efficacy of once-daily treatment with NVA237 100 and 200 microg in patients with moderate-to-severe COPD BACKGROUND Current guidelines recommend combining long-acting bronchodilators with different modes of action in patients with moderate-to-severe chronic obstructive pulmonary disease ( COPD ) . We evaluated the effects of airway dimensions and pulmonary function with tiotropium plus indacaterol versus Advair ( ® ) . METHODS Subjects ( n = 46 ) were r and omized to receive tiotropium ( 18 μg once daily ) plus indacaterol ( 150 μg once daily ) or Advair ( ® ) ( 50/250 μg twice daily ) for 16 weeks . Airway geometry was determined by quantitative computed tomography ( luminal area , Ai ; total area of the airway , Ao ; wall area , WA ; and percentage wall area , WA/Ao and wall thickness , T ) . Spirometry ( forced expiratory volume in 1 s , FEV1 ; forced vital capacity , FVC and inspiratory capacity , IC ) and St. George 's Respiratory Question naire ( SGRQ ) were evaluated . RESULTS Tiotropium plus indacaterol significantly increased CT-indices including Ai corrected for body surface area ( Ai/BSA ) , and decreased WA/BSA , WA/Ao and T/√BSA compared with Advair ( ® ) ( p < 0.05 , respectively ) . In physiological parameters , mean difference in IC was significantly higher under treatment with tiotropium plus indacaterol than Advair ( ® ) ( p < 0.05 ) . The changes in Ai/BSA , WA/BSA , WA/Ao and T/√BSA were significantly correlated with changes in IC ( r = 0.535 , p = 0.011 ; r = -0.688 , p < 0.001 ; r = -0.555 , p = 0.002 and r = -0.542 , p = 0.007 ; respectively ) . There were more significant improvements in SGRQ scores after treatment with tiotropium plus indacaterol than Advair ( ® ) . CONCLUSIONS These findings suggest that dual bronchodilation with tiotropium plus indacaterol is superior in airway geometry and lung function compared with Advair ( ® ) in COPD BACKGROUND AND OBJECTIVE Combining a long-acting muscarinic antagonist with a long-acting β₂-agonist has been shown to be pharmacologically useful in patients with chronic obstructive pulmonary disease ( COPD ) . The aim of the present study was to evaluate the effectiveness of the dual bronchodilator therapy on airway dimensions in COPD . METHODS Patients ( n = 54 ) were r and omly assigned to receive tiotropium ( 18 μg once daily ) , indacaterol ( 150 μg once daily ) or tiotropium plus indacaterol for 16 weeks . Quantitative computed tomography ( CT ) , pulmonary function and health status ( St. George 's Respiratory Question naire ) were measured . RESULTS Compared with tiotropium or indacaterol alone , combination therapy result ed in a significant decrease in percentage wall area ( WA% ) and wall thickness , corrected for body surface area , and an increase in luminal area ( Ai/BSA ) . Concurrent treatment was superior to monotherapy in physiological indices , including forced vital capacity , forced expiratory volume in 1 s ( FEV₁ ) and inspiratory capacity . The changes in WA% and Ai/BSA were significantly correlated with changes in FEV₁ ( r = -0.44 , P < 0.01 and r = 0.37 , P < 0.01 ) . There were more significant improvements in SGRQ scores after treatment with combined therapy than with either treatment alone . CONCLUSIONS Concurrent therapy with tiotropium and indacaterol is effective for COPD patients to promote reduction in airway wall thickness , bronchodilation , and improvements in lung function compared with a single inhaler BACKGROUND Combination long-acting bronchodilator therapy may be more effective than long-acting bronchodilator monotherapy in chronic obstructive pulmonary disease ( COPD ) . OBJECTIVES To compare the efficacy and safety of once-daily umeclidinium/vilanterol ( UMEC/VI ) 125/25 mcg with placebo and UMEC or VI monotherapy in COPD . METHODS This was a double-blind , placebo-controlled , parallel-group study . A total of 1493 patients were r and omized ( 3:3:3:2 ) to 24 weeks of treatment with UMEC/VI 125/25 mcg , UMEC 125 mcg , VI 25 mcg , or placebo once-daily via dry powder inhaler . RESULTS Primary efficacy endpoint was trough forced expiratory volume in one second ( FEV1 ) on Day 169 ( 23 - 24 h post-dose ) . Additional lung-function , symptomatic and health-related quality of life endpoints were also assessed . Safety evaluations included : adverse events , vital signs , electrocardiography and clinical laboratory measurements . All active treatments significantly improved trough FEV1 vs placebo ( 0.124 - 0.238 L , all p<0.001 ) . Improvements with UMEC/VI 125/25 mcg were significantly greater than for UMEC 125 mcg or VI 25 mcg ( 0.079 L and 0.114 L ; both p≤0.001 ) . Improvements for UMEC/VI 125/25 mcg vs placebo were observed for the transition dyspnea index ( 1.0 unit ; p<0.001 ) , rescue albuterol use at Weeks 1 - 24 ( -1.5 puffs/day ) and St. George 's Respiratory Question naire ( -3.60 units , p<0.001 ) . No safety signals were observed . CONCLUSIONS Once-daily UMEC/VI 125/25 mcg was well tolerated and provided greater improvements in lung function , health status , and dyspnea scores compared with monotherapy components and placebo over 24 weeks . This study supports the use of UMEC/VI 125/25 mcg for the maintenance treatment of COPD . CLINICAL TRIAL REGISTRATION protocol number : DB2113361 ; Clinical Trials.gov identifier : NCT01313637 Background AMPLIFY assessed the efficacy and safety of aclidinium bromide/formoterol fumarate ( AB/FF ) vs its monocomponents and tiotropium ( TIO ) in patients with moderate-to-very severe symptomatic COPD ( NCT02796677 ) . Methods In this 24-week , Phase III , double-dummy , active-controlled study , symptomatic patients ( COPD Assessment Test score ≥10 ) were r and omized to twice-daily AB/FF 400/12 µg , AB 400 µg , or FF 12 µg , or once-daily TIO 18 µg . Co- primary endpoints were change from baseline at week 24 in 1-hour morning post-dose FEV1 ( AB/FF vs AB ) and in pre-dose ( trough ) FEV1 ( AB/FF vs FF ) . Non-inferiority of AB vs TIO in pre-dose FEV1 was also an objective . Normalized area under the curve (AUC)0–3/3 h FEV1 and nighttime and early morning symptoms were also assessed . A subgroup participated in a 24-hour serial spirometry sub- study . Results A total of 1,594 patients were r and omized ; 566 entered the sub- study . At week 24 , 1-hour post-dose FEV1 significantly improved with AB/FF vs AB , FF , and TIO ( 84 , 84 , and 92 mL ; all P<0.0001 ) . AB/FF significantly improved trough FEV1 vs FF ( 55 mL , P<0.001 ) and AB was non-inferior to TIO . AB/FF significantly improved AUC0–3/3 h FEV1 vs all comparators ( P<0.0001 ) and provided significant improvements in early morning symptoms vs TIO . The 24-hour spirometry demonstrated significantly greater improvements with AB/FF in AUC12–24/12 h vs all comparators , and in AUC0–24/24 h vs FF or TIO at week 24 . Conclusion In patients with moderate-to-very severe symptomatic COPD , twice-daily AB/FF significantly improved lung function vs monocomponents and TIO , and early morning symptom control vs TIO STUDY OBJECTIVE To examine the efficacy and safety of the once-daily , inhaled , long-acting muscarinic antagonist/β2-agonist combination umeclidinium/vilanterol ( UMEC/VI ) compared with UMEC and VI monotherapies in patients with chronic obstructive pulmonary disease ( COPD ) . METHODS In this 24-week , double-blind , placebo-controlled , parallel-group study ( Clinical Trials.gov : NCT01313650 ) eligible patients were r and omised 3:3:3:2 to treatment with  UMEC/VI 62.5/25 mcg , UMEC 62.5 mcg , VI 25 mcg or placebo administered once daily via dry powder inhaler ( N = 1532 ; intent-to-treat population ) . Primary endpoint was trough forced expiratory volume in one second ( FEV1 ) on Day 169 ( 23 - 24 h post-dose ) . Additional lung-function , symptomatic , and health-related quality -of-life endpoints were assessed , including 0 - 6 h weighted-mean FEV1 , rescue salbutamol use , Transition Dyspnoea Index ( TDI ) , Shortness Of Breath With Daily Activity ( SOBDA ) and St. George 's Respiratory Question naire ( SGRQ ) scores . Safety evaluations included adverse events ( AEs ) , vital signs , 12-lead/24-h Holter electrocardiography parameters and clinical laboratory/haematology measurements . RESULTS All active treatments produced statistically significant improvements in trough FEV1 compared with placebo on Day 169 ( 0.072 - 0.167 L , all p < 0.001 ) ; increases with UMEC/VI 62.5/25 mcg were significantly greater than monotherapies ( 0.052 - 0.095 L , p ≤ 0.004 ) . Improvements were observed for UMEC/VI 62.5/25 mcg vs placebo for weighted-mean FEV1 on Day 168 ( 0.242 L , p < 0.001 ) , rescue salbutamol use during Weeks 1 - 24 ( -0.8 puffs/day , p = 0.001 ) , TDI ( 1.2 units , p < 0.001 ) , SOBDA ( -0.17 units , p < 0.001 ) and SGRQ ( -5.51 units , p < 0.001 ) scores . No clinical ly-significant changes in vital signs , electrocardiography , or laboratory parameters were observed . CONCLUSION Once-daily UMEC/VI 62.5/25 mcg was well tolerated and provided clinical ly-significant improvements in lung function and symptoms in patients with COPD INTRODUCTION QVA149 is a novel , inhaled , once-daily dual bronchodilator containing a fixed-dose combination of the long-acting β2-agonist indacaterol and the long-acting muscarinic antagonist glycopyrronium ( NVA237 ) , for the treatment of chronic obstructive pulmonary disease ( COPD ) . This study evaluated the effects of QVA149 on exercise tolerance , hyperinflation , lung function and lung volumes versus placebo and tiotropium . METHODS Patients with moderate-to-severe COPD were r and omized to QVA149 110/50 μg , placebo or tiotropium 18 μg once daily in a blinded , 3-period crossover study for 3 weeks . The primary endpoint was exercise endurance time at Day 21 for QVA149 versus placebo . RESULTS Eighty-five patients were r and omized ; 86 % completed the study . QVA149 significantly improved exercise endurance time at Day 21 compared with placebo ( least squares mean treatment difference 60 s [ p = 0.006 ] ) . No significant improvements in exercise endurance time at Day 21 between QVA149 and tiotropium were found . Dynamic inspiratory capacity ( IC ) at exercise isotime , trough forced expiratory volume in 1 s , residual volume and functional residual capacity showed significant improvements with QVA149 from Day 1 of treatment that were maintained throughout the study . The safety profiles were similar across groups . CONCLUSIONS In patients with moderate-to-severe COPD , once-daily QVA149 significantly improved exercise endurance time compared with placebo which was associated with sustained reductions of lung hyperinflation as indicated by significant improvement in IC at rest and during exercise . TRIAL REGISTRATION Clinical Trials.gov NCT01294787 . TAKE HOME MESSAGE Dual bronchodilation with QVA149 decreases lung hyperinflation and improves exercise tolerance and lung function in patients with moderate-to-severe COPD BACKGROUND Chronic obstructive pulmonary disease ( COPD ) is one of the leading causes of death in the United States . Long-acting muscarinic antagonists ( LAMAs ) are a class of medications used as maintenance therapy for COPD . The GEM3 ( Glycopyrrolate Effect on syMptoms and lung function ) study assessed the long-term safety and efficacy of a LAMA , glycopyrrolate ( GLY ) 15.6 μg twice daily ( b.i.d . ) , compared with an approved long-acting β2-agonist ( LABA ) , indacaterol ( IND ) 75 μg once daily ( q.d . ) in patients with stable , symptomatic COPD with moderate-to-severe airflow limitation . METHODS This 52-week , multicenter , double-blind , parallel-group study r and omized patients ( 1:1 ) of the United States to receive GLY 15.6 μg b.i.d . or IND 75 μg q.d . both delivered via the Neohaler ( ® ) device . The primary objective was to assess the safety and tolerability in terms of adverse event ( AE ) reporting rates over 52 weeks . Safety was also determined by evaluating multiple secondary endpoints , including vital signs , electrocardiograms ( ECGs ) , and time to first moderate or severe exacerbation . Efficacy-related secondary endpoints included pre-dose forced expiratory volume in one second ( FEV1 ) and forced vital capacity ( FVC ) . RESULTS Of the 511 r and omized patients ( GLY , n = 254 ; IND , n = 257 ) , 81.6 % completed the study . The overall incidences of AEs ( GLY , 77.3 % ; IND , 77.0 % ) and serious AEs ( GLY , 13.1 % ; IND , 13.3 % ) were comparable between the groups . The incidence of major adverse cardiovascular events was low and comparable between the groups . No clinical ly relevant differences for vital signs or ECG parameters were observed between the treatment groups . The three sudden deaths reported within 30 days of the treatment ( GLY , n = 2 ; IND , n = 1 ) were adjudicated as unrelated to the study medication . In terms of efficacy , GLY 15.6 μg b.i.d . showed improvements in pre-dose FEV1 and FVC from baseline , which was comparable to those with IND 75 μg q.d . , with no statistically significant differences . No significant differences were observed between the treatment groups in the time to first moderate or severe COPD exacerbation . CONCLUSION GLY 15.6 μg b.i.d . showed a long-term safety profile comparable to that of IND 75 μg q.d . and provided rapid and sustained bronchodilation over 52 weeks in patients with COPD with moderate-to-severe airflow limitation . CLINICAL TRIAL REGISTRATION NUMBER NCT01697696 TRIAL DESIGN This was a one-year , Phase III r and omized , double-blind , parallel-group , active-control study investigating the long-term safety and tolerability of twice-daily aclidinium 400 μg/formoterol 12 μg versus formoterol 12 μg . METHODS Eligible patients were male or female , current or ex-smokers ( history of ≥10 pack-years ) aged ≥40 years with a diagnosis of moderate to severe chronic obstructive pulmonary disease ( COPD ): post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity ( FVC ) ratio < 70 % , and post-bronchodilator FEV1≥30 % and < 80 % predicted . Patients were r and omized 2:1 to twice-daily aclidinium 400 μg/formoterol 12 μg or formoterol 12 μg , administered via a multidose dry powder inhaler ( Genuair ™ /Pressair( ® ))(1 ) . The objective was to evaluate the one-year safety of aclidinium 400 μg/formoterol 12 μg versus formoterol 12 μg . RESULTS All 590 patients were included in the safety population ; 392 patients received aclidinium 400 μg/formoterol 12 μg and 198 patients received formoterol 12 μg . Of these , 581 patients were included in the intent-to-treat ( ITT ) population ( 385 patients received aclidinium 400 μg/formoterol 12 μg ; 196 patients received formoterol 12 μg ) . In the safety population , the percentage of patients with ≥1 treatment-emergent adverse event was similar between aclidinium 400 μg/formoterol 12 μg ( 71.4 % ) and formoterol 12 μg ( 65.7 % ) . Mean baseline post-bronchodilator FEV1 was 51.3 % of predicted ( ITT population ) . Aclidinium 400 μg/formoterol 12 μg significantly improved morning pre-dose ( trough ) FEV1 and trough FVC versus formoterol 12 μg at each assessment , with improvements at Week 1 ( least squares mean difference [ LSMD ] : 87.4 mL and 157.8 mL , respectively ) maintained at study end ( LSMD : 81.5 mL and 185.4 mL , respectively ) . CONCLUSIONS Aclidinium 400 μg/formoterol 12 μg was well tolerated , with a safety profile similar to formoterol 12 μg and consistent with that seen in two Phase III studies . Additionally , aclidinium 400 μg/formoterol 12 μg improved lung function versus formoterol 12 μg , with a sustained effect over one year BACKGROUND Treatment guidelines recommend the use of inhaled long-acting bronchodilators to alleviate symptoms and reduce the risk of exacerbations in patients with moderate-to-very-severe chronic obstructive pulmonary disease ( COPD ) but do not specify whether a long-acting anticholinergic drug or a β(2)-agonist is the preferred agent . We investigated whether the anticholinergic drug tiotropium is superior to the β(2)-agonist salmeterol in preventing exacerbations of COPD . METHODS In a 1-year , r and omized , double-blind , double-dummy , parallel-group trial , we compared the effect of treatment with 18 μg of tiotropium once daily with that of 50 μg of salmeterol twice daily on the incidence of moderate or severe exacerbations in patients with moderate-to-very-severe COPD and a history of exacerbations in the preceding year . RESULTS A total of 7376 patients were r and omly assigned to and treated with tiotropium ( 3707 patients ) or salmeterol ( 3669 patients ) . Tiotropium , as compared with salmeterol , increased the time to the first exacerbation ( 187 days vs. 145 days ) , with a 17 % reduction in risk ( hazard ratio , 0.83 ; 95 % confidence interval [ CI ] , 0.77 to 0.90 ; P<0.001 ) . Tiotropium also increased the time to the first severe exacerbation ( hazard ratio , 0.72 ; 95 % CI , 0.61 to 0.85 ; P<0.001 ) , reduced the annual number of moderate or severe exacerbations ( 0.64 vs. 0.72 ; rate ratio , 0.89 ; 95 % CI , 0.83 to 0.96 ; P=0.002 ) , and reduced the annual number of severe exacerbations ( 0.09 vs. 0.13 ; rate ratio , 0.73 ; 95 % CI , 0.66 to 0.82 ; P<0.001 ) . Overall , the incidence of serious adverse events and of adverse events leading to the discontinuation of treatment was similar in the two study groups . There were 64 deaths ( 1.7 % ) in the tiotropium group and 78 ( 2.1 % ) in the salmeterol group . CONCLUSIONS These results show that , in patients with moderate-to-very-severe COPD  , tiotropium is more effective than salmeterol in preventing exacerbations . ( Funded by Boehringer Ingelheim and Pfizer ; Clinical Trials.gov number , NCT00563381 . ) BACKGROUND Most guidelines recommend either a long-acting beta-agonist ( LABA ) plus an inhaled glucocorticoid or a long-acting muscarinic antagonist ( LAMA ) as the first-choice treatment for patients with chronic obstructive pulmonary disease ( COPD ) who have a high risk of exacerbations . The role of treatment with a LABA-LAMA regimen in these patients is unclear . METHODS We conducted a 52-week , r and omized , double-blind , double-dummy , noninferiority trial . Patients who had COPD with a history of at least one exacerbation during the previous year were r and omly assigned to receive , by inhalation , either the LABA indacaterol ( 110 μg ) plus the LAMA glycopyrronium ( 50 μg ) once daily or the LABA salmeterol ( 50 μg ) plus the inhaled glucocorticoid fluticasone ( 500 μg ) twice daily . The primary outcome was the annual rate of all COPD exacerbations . RESULTS A total of 1680 patients were assigned to the indacaterol-glycopyrronium group , and 1682 to the salmeterol-fluticasone group .  Indacaterol-glycopyrronium showed not only noninferiority but also superiority to salmeterol-fluticasone in reducing the annual rate of all COPD exacerbations ; the rate was 11 % lower in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group ( 3.59 vs. 4.03 ; rate ratio , 0.89 ; 95 % confidence interval [ CI ] , 0.83 to 0.96 ; P=0.003 ) . The indacaterol-glycopyrronium group had a longer time to the first exacerbation than did the salmeterol-fluticasone group ( 71 days [ 95 % CI , 60 to 82 ] vs. 51 days [ 95 % CI , 46 to 57 ] ; hazard ratio , 0.84 [ 95 % CI , 0.78 to 0.91 ] , representing a 16 % lower risk ; P<0.001 ) . The annual rate of moderate or severe exacerbations was lower in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group ( 0.98 vs. 1.19 ; rate ratio , 0.83 ; 95 % CI , 0.75 to 0.91 ; P<0.001 ) , and the time to the first moderate or severe exacerbation was longer in the indacaterol-glycopyrronium group than in the salmeterol-fluticasone group ( hazard ratio , 0.78 ; 95 % CI , 0.70 to 0.86 ; P<0.001 ) , as was the time to the first severe exacerbation ( hazard ratio , 0.81 ; 95 % CI , 0.66 to 1.00 ; P=0.046 ) . The effect of indacaterol-glycopyrronium versus salmeterol-fluticasone on the rate of COPD exacerbations was independent of the baseline blood eosinophil count . The incidence of adverse events and deaths was similar in the two groups . The incidence of pneumonia was 3.2 % in the indacaterol-glycopyrronium group and 4.8 % in the salmeterol-fluticasone group ( P=0.02 ) . CONCLUSIONS Indacaterol-glycopyrronium was more effective than salmeterol-fluticasone in preventing COPD exacerbations in patients with a history of exacerbation during the previous year . ( Funded by Novartis ; FLAME Clinical Trials.gov number , NCT01782326 . )
BACKGROUND Long-acting bronchodilators such as long-acting β-agonist ( LABA ) , long-acting muscarinic antagonist ( LAMA ) , and LABA/inhaled corticosteroid ( ICS ) combinations have been used in people with moderate to severe chronic obstructive pulmonary disease ( COPD ) to control symptoms such as dyspnoea and cough , and prevent exacerbations .
A number of LABA/LAMA combinations are now available for clinical use in COPD .
However , it is not clear which group of above mentioned inhalers is most effective or if any specific formulation works better than the others within the same group or class .
OBJECTIVES To compare the efficacy and safety of available formulations from four different groups of inhalers ( i.e. LABA/LAMA combination , LABA/ICS combination , LAMA and LABA ) in people with moderate to severe COPD .
The review will up date previous systematic review s on dual combination inhalers and long-acting bronchodilators to answer the questions described above using the strength of a network meta- analysis ( NMA ) .