Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study LANTERN: a randomized study of QVA149 versus salmeterol/fluticasone combination in patients with COPD Effect of tiotropium and olodaterol on symptoms and patient-reported outcomes in patients with COPD: results from four randomised, double-blind studies 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. Extrafine inhaled triple therapy versus dual bronchodilator therapy in chronic obstructive pulmonary disease (TRIBUTE): a double-blind, parallel group, randomised controlled trial 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 Effects of combined tiotropium/olodaterol on inspiratory capacity and exercise endurance in COPD Once‐Daily Single‐Inhaler Triple versus Dual Therapy in Patients with COPD Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: the 24-week, randomized, placebo-controlled AUGMENT COPD study 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. Once-daily indacaterol versus tiotropium for patients with severe chronic obstructive pulmonary disease (INVIGORATE): a randomised, blinded, parallel-group study. Umeclidinium/vilanterol versus fluticasone propionate/salmeterol in COPD: a randomised trial Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2–4) 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 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. Searching for the synergistic effect between aclidinium and formoterol: From bench to bedside. Efficacy and Safety of Glycopyrrolate/Formoterol Metered Dose Inhaler Formulated Using Co‐Suspension Delivery Technology in Patients With COPD Efficacy and safety of umeclidinium/vilanterol 62.5/25 mcg and tiotropium 18 mcg in chronic obstructive pulmonary disease: results of a 24-week, randomized, controlled trial. Efficacy and safety of direct switch to indacaterol/glycopyrronium in patients with moderate COPD: the CRYSTAL open-label randomised trial Efficacy and safety of aclidinium/formoterol versus salmeterol/fluticasone: a phase 3 COPD study 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. Effects of a combination of umeclidinium/vilanterol on exercise endurance in patients with chronic obstructive pulmonary disease: two randomized, double-blind clinical trials Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. Association of Cardiovascular Risk With Inhaled Long-Acting Bronchodilators in Patients With Chronic Obstructive Pulmonary Disease: A Nested Case-Control Study 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 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 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 Chronic obstructive pulmonary disease is associated with significant morbidity and mortality . Trials of maintenance chronic obstructive pulmonary disease treatments focus on improvement in lung function and reductions in exacerbations , while patients are much more concerned about symptoms and health status . Our aim was to investigate the effects of tiotropium + olo date rol on  patient-reported health outcomes , breathlessness and night-time rescue medication use in patients with chronic obstructive pulmonary disease , compared to placebo , tiotropium or olo date rol monotherapy . Two pairs of replicate , phase III studies of 12 ( OTEMTO 1 + 2 ) and 52 weeks ’ ( TONADO 1 + 2 ) duration were evaluated , in which patients received either tiotropium + olo date rol 2.5/5 or 5/5 μg , tiotropium 2.5 or 5 μg , olo date rol 5 μg or placebo , all delivered once daily via Respimat inhaler . Patient-reported outcomes included breathlessness assessed by transition dyspnoea index focal score , health status assessed by St George ’s Respiratory Question naire total score and night-time rescue medication use at 12 or 24 weeks . Outcomes from the pooled study data are reported . Overall , 1621 and 5162 patients were treated in the OTEMTO and TONADO trials , respectively . Significantly larger improvements in St George ’s Respiratory Question naire and transition dyspnoea index focal scores were observed and a greater proportion of patients were responders to therapy ( based on minimum clinical ly important differences in St George ’s Respiratory Question naire and transition dyspnoea index ) with tiotropium + olo date rol compared to either monotherapy or to placebo . Tiotropium + olo date rol 5/5 µg significantly reduced night-time rescue medication usage . Chronic obstructive pulmonary disease : Combined inhaler proves effective Results from four in-depth studies show that a combined inhaler is very effective for treatment of moderate to severe chronic lung disease . Alleviating the symptoms of chronic obstructive pulmonary disease ( COPD ) , particularly sleep disturbance , is crucial to enhancing patients ’ quality of life . Gary Ferguson at the Pulmonary Research Institute of Southeast Michigan , together with other scientists across the USA and Germany , analysed data from four large-scale studies to evaluate the efficacy of STIOLTO Respimat , a combination of two bronchodilators — tiotropium , and olo date rol , which tackle airway obstruction and breathlessness , improving long-term lung function . They found that the new drug combination triggered significant improvements in patients ’ quality of life and levels of breathlessness . Use of night-time rescue medication in patients on STIOLTO  Respimat was considerably reduced . A greater number of patients responded positively to the combined inhaler than to monotherapy 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 Evidence is scarce on the relative risk-benefit of inhaled triple therapy , consisting of inhaled corticosteroid , long-acting muscarinic antagonist , and long-acting β2-agonist , versus dual bronchodilation for chronic obstructive pulmonary disease ( COPD ) . We aim ed to compare a single-inhaler triple combination of beclometasone dipropionate , formoterol fumarate , and glycopyrronium ( BDP/FF/G ) versus a single-inhaler dual bronchodilator combination of indacaterol plus glycopyrronium ( IND/GLY ) in terms of the rate of moderate-to-severe COPD exacerbations over 52 weeks of treatment . METHODS This r and omised , parallel-group , double-blind , double-dummy study was done at 187 sites across 17 countries . Eligible patients had symptomatic COPD , severe or very severe airflow limitation , at least one moderate or severe exacerbation in the previous year , and were receiving inhaled maintenance medication . After a 2 week run-in period with one inhalation per day of IND/GLY ( 85 μg/43 μg ) , patients were r and omly assigned ( 1:1 ) , via an interactive response technology system , to receive 52 weeks of treatment with two inhalations of extrafine BDP/FF/G ( 87 μg/5 μg/9 μg ) twice per day or one inhalation of IND/GLY ( 85 μg/43 μg ) per day . R and omisation was stratified by country and severity of airflow limitation . The primary endpoint was the rate of moderate-to-severe COPD exacerbations across 52 weeks of treatment in all r and omised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment . Safety was assessed in all patients who received at least one dose of study drug . This study is registered with Clinical Trials.gov , number NCT02579850 . FINDINGS Between May , 29 2015 , and July 10 , 2017 , 1532 patients received BDP/FF/G ( n=764 ) or IND/GLY ( n=768 ) . Moderate-to-severe exacerbation rates were 0·50 per patient per year ( 95 % CI 0·45 - 0·57 ) for BDP/FF/G and 0·59 per patient per year ( 0·53 - 0·67 ) for IND/GLY , giving a rate ratio of 0·848 ( 0·723 - 0·995 , p=0·043 ) in favour of BDP/FF/G. Adverse events were reported by 490 ( 64 % ) of 764 patients receiving BDP/FF/G and 516 ( 67 % ) of 768 patients receiving IND/GLY . Pneumonia occurred in 28 ( 4 % ) patients receiving BDP/FF/G versus 27 ( 4 % ) patients receiving IND/GLY . One treatment-related serious adverse event occurred in each group : dysuria in a patient receiving BDP/FF/G and atrial fibrillation in a patient receiving IND/GLY . INTERPRETATION In patients with symptomatic COPD , severe or very severe airflow limitation , and an exacerbation history despite maintenance therapy , extrafine BDP/FF/G significantly reduced the rate of moderate-to-severe exacerbations compared with IND/GLY , without increasing the risk of pneumonia . FUNDING Chiesi Farmaceutici BACKGROUND The 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 Two replicate , double-blind , 6-week , incomplete-crossover studies ( MORACTO 1 and 2 ) assessed the effects of tiotropium/olo date rol on inspiratory capacity and exercise endurance time in patients with moderate to severe chronic obstructive pulmonary disease . For each patient , four of five treatments were administered once daily for 6 weeks , with a 21-day washout between treatments : tiotropium/olo date rol 2.5/5 µg or 5/5 µg , tiotropium 5 µg , olo date rol 5 µg or placebo , all via the Respimat inhaler . Primary outcomes were inspiratory capacity prior to exercise and exercise endurance time during constant work-rate cycle ergometry to symptom limitation at 75 % of peak incremental work rate after 6 weeks ( 2 h post-dose ) . 295 and 291 patients were treated in MORACTO 1 and 2 , respectively . Tiotropium/olo date rol 2.5/5 and 5/5 µg provided significant improvements in inspiratory capacity versus placebo and monotherapies ( p<0.0001 ) , and significant improvements in exercise endurance time versus placebo ( p<0.0001 ) . Intensity of breathing discomfort was reduced following both doses of tiotropium/olo date rol versus placebo ( p<0.0001 ) . Once-daily tiotropium/olo date rol yielded improvements in lung hyperinflation versus placebo and statistically significant improvements versus monotherapies . Tiotropium/olo date rol also showed improvements in dyspnoea and exercise tolerance versus placebo but not consistently versus monotherapies . T/O reduces lung hyperinflation in COPD versus T , O or placebo and increases exercise endurance versus 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 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 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 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 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 , 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 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 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 Aim of our study was to underst and if the interaction between aclidinium and formoterol administered at therapeutic doses leads to a synergistic rather than additive broncholytic effect . We tested the type of effect ex vivo on isolated human bronchi and then in vivo in COPD patients . The analysis of the interaction between aclidinium and formoterol in vitro was measured by applying the Unified Theory , whereas that in COPD patients was measured by applying the Bliss Independence criterion . Aclidinium and formoterol administered alone completely relaxed human isolated bronchial tissues sub-maximally pre-contracted with ACh in a concentration-dependent manner with similar potency ( EC50 : aclidinium 4.64 ± 0.78 nM , formoterol 2.71 ± 0.21 ) , whereas the interaction of aclidinium plus formoterol produced moderate to strong synergism . Changes in FEV1 values showed that inhaled aclidinium and formoterol induced a significant and time-dependent bronchodilatory effect during the study time . The inhalation of aclidinium and formoterol  in combination significantly anticipated at 5 min post-administration the bronchodilatory effect of FEV1 , compared with the effect of drugs administered alone . There was a synergistic interaction for FEV1 at 5 min and from 120 min to 240 min post-inhalation , whereas from 30 min to 60 min post-administration the drug interaction was additive . This study shows that aclidinium and formoterol can produce a significant synergistic interaction that may have a role also in the clinic setting 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 BACKGROUND Combinations of inhaled long-acting bronchodilator therapies such as muscarinic antagonists and β2-agonists may be more effective than monotherapy in the treatment of chronic obstructive pulmonary disease ( COPD ) . METHODS This study was a 24-week , Phase III , multicenter , r and omized , blinded , double-dummy , parallel-group study of the once-daily , inhaled , fixed-dose combination of the long-acting muscarinic antagonist umeclidinium bromide and the long-acting β2-agonist vilanterol ( UMEC/VI 62.5/25 mcg ) versus tiotropium ( TIO , 18 mcg ) . The primary endpoint was trough forced expiratory volume in 1 s ( FEV1 ) at Day 169 . The secondary endpoint was weighted mean FEV1 over 0–6 h post-dose at Day 168 . For key endpoints , a step-down closed testing hierarchy was applied to account for multiplicity . Other efficacy and safety endpoints were assessed . RESULTS Statistically significant improvements in trough FEV1 at Day 169 ( 0.112 L , 95 % confidence interval [ CI ] : 0.081 , 0.144 ; p < 0.001 ) and weighted mean FEV1 over 0–6 h post-dose at Day 168 ( 0.105 L , 95 % CI : 0.071 , 0.140 ; p < 0.001 ) were observed for UMEC/VI versus TIO . In addition UMEC/VI improved health-related quality of life , and reduced requirement for the use of rescue medication compared with TIO . The incidence of adverse events was similar between treatment groups . CONCLUSIONS UMEC/VI was associated with statistically significant and clinical ly meaningful improvements in lung function versus TIO . UMEC/VI was well tolerated . UMEC/VI 62.5/25 mcg could provide an effective new treatment option for patients with moderate-to-very severe 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 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 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 Objective : Exercise intolerance is a hallmark of chronic obstructive pulmonary disease ( COPD ) . Methods : Patients with COPD were r and omized in two multicentre , double-blind , incomplete block crossover studies . Patients received two of six treatments in sequence ( 12 weeks each ) : placebo , umeclidinium (UMEC)/vilanterol ( VI ) ( 125/25 mcg or 62.5/25 mcg ) , VI ( 25 mcg ) or UMEC ( 62.5 mcg or 125 mcg ) . Exercise endurance time ( EET ) and trough forced expiratory volume in 1 second ( FEV1 ) ( Week 12 ) were co- primary endpoints . Safety was monitored throughout . Results : Both studies showed similar 3-hour post-dose EET improvements from baseline for UMEC/VI ( Week 12 ) . Significant EET improvements were observed with both UMEC/VI doses versus placebo at Week 12 in Study 418 ( UMEC/VI 125/25 mcg : 65.8 s ; p = 0.005 ; UMEC/VI 62.5/25 mcg : 69.4 s ; p = 0.003 ) , but not in Study 417 , where a placebo effect was evident . Post hoc integrated data analysis showed significant but smaller EET improvements for both UMEC/VI doses versus placebo at Week 12 ( UMEC/VI 125/25 mcg : 47.5 s ; p = 0.002 ; UMEC/VI 62.5/25 mcg : 43.7 s ; p = 0.001 ) . Both studies showed trough FEV1 improvements at Week 12 for both UMEC/VI doses . The incidence of adverse events was similar between treatment groups within each study . Conclusions : UMEC/VI improved lung function and EET 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 ] . ) Importance The associations between cardiovascular disease ( CVD ) and inhaled long-acting & bgr;2-agonists ( LABAs ) or long-acting antimuscarinic antagonists ( LAMAs ) in chronic obstructive pulmonary disease ( COPD ) are greatly debated . Pivotal and relevant r and omized clinical trials included prior LABA or LAMA users and excluded patients with baseline CVD ; therefore , cardiovascular events arising from first-time LABA or LAMA use , if any , could not be observed . There is an urgent need to examine whether new use of and duration since initiating LABAs and LAMAs could act as important determinants of cardiovascular events . Objective To investigate risk of CVD associated with LABAs and LAMAs , focusing on the initiation and duration of LABA and LAMA therapies . Design , Setting , and Participants This nested case-control study included 284 220 LABA-LAMA – naïve patients with COPD at least 40 years old ( mean age , 71.4 years ; 68.9 % men ) , retrieved from the Taiwan National Health Insurance Research Data base for health care cl aims from 2007 to 2011 . Exposure LABA or LAMA use was measured in the year preceding the event or index date , stratified by duration since initiation of LABA or LAMA treatment , new and prevalent users , concomitant COPD medications , and individual agents . Main Outcomes and Measures Cases with inpatient or emergency care visits for coronary artery disease , heart failure , ischemic stroke , or arrhythmia were identified and individually matched to 4 r and omly selected controls . Conditional logistic regressions were performed to estimate odds ratios of CVD from LABA and LAMA treatment . Results During a mean follow-up of 2.0 years , 37 719 patients with CVD ( mean age , 75.6 years ; 71.6 % men ) and 146 139 matched controls ( mean age , 75.2 years ; 70.1 % men ) were identified .  New LABA and LAMA use in COPD was associated with a 1.50-fold ( 95 % CI , 1.35 - 1.67 ; P < .001 ) and a 1.52-fold ( 95 % CI , 1.28 - 1.80 ; P < .001 ) increased cardiovascular risk within 30 days of initiation , respectively , whereas the risk was absent , or even reduced with prevalent use . Individual LABA agents , LAMA dosage forms , and concomitant COPD regimens did not differ in the CVD risks . The risk persisted in an alternative case-crossover study and remained across subgroups without CVD history or prior exacerbations . Conclusions and Relevance New initiation of LABAs or LAMAs in patients with COPD is associated with an approximate 1.5-fold increased severe cardiovascular risk , irrespective of prior CVD status and history of exacerbations 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 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 . )
Objectives The aim of this study was to assess the current evidence for long-acting β2-agonist (LABA)/long-acting muscarinic antagonist ( LAMA ) fixed-dose combinations ( FDCs ) in the treatment of COPD .