Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study Aclidinium bromide and formoterol fumarate as a fixed-dose combination in COPD: pooled analysis of symptoms and exacerbations from two six-month, multicentre, randomised studies (ACLIFORM and AUGMENT) Characterisation of COPD heterogeneity in the ECLIPSE cohort 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. 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) Magnitude of umeclidinium/vilanterol lung function effect depends on monotherapy responses: Results from two randomised controlled trials. Dual bronchodilation with QVA149 reduces patient-reported dyspnoea in COPD: the BLAZE study Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2–4) Dual Bronchodilator Therapy with Umeclidinium/Vilanterol Versus Tiotropium plus Indacaterol in Chronic Obstructive Pulmonary Disease: A Randomized Controlled Trial 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 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. Cost-effectiveness of the LABA/LAMA dual bronchodilator indacaterol/glycopyrronium in a Swedish healthcare setting. Safety and efficacy of dual bronchodilation with QVA149 in COPD patients: the ENLIGHTEN study.
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 combination of aclidinium bromide , a long-acting anticholinergic , and formoterol fumarate , a long-acting beta2-agonist ( 400/12 μg twice daily ) achieves improvements in lung function greater than either monotherapy in patients with chronic obstructive pulmonary disease ( COPD ) , and is approved in the European Union as a maintenance treatment . The effect of this combination on symptoms of COPD and exacerbations is less well established . We examined these outcomes in a pre-specified analysis of pooled data from two 24-week , double-blind , parallel-group , active- and placebo-controlled , multicentre , r and omised Phase III studies ( ACLIFORM and AUGMENT ) . Methods Patients ≥40 years with moderate to severe COPD ( post-bronchodilator forced expiratory volume in 1 s [FEV1]/forced vital capacity < 70 % and FEV1 ≥30 % but < 80 % predicted normal ) were r and omised ( ACLIFORM : 2:2:2:2:1 ; AUGMENT : 1:1:1:1:1 ) to twice-daily aclidinium/formoterol 400/12 μg or 400/6 μg , aclidinium 400 μg , formoterol 12 μg or placebo via Genuair ™ /Pressair ® . Dyspnoea ( Transition Dyspnoea Index ; TDI ) , daily symptoms ( EXAcerbations of Chronic pulmonary disease Tool [EXACT]-Respiratory Symptoms [ E-RS ] question naire ) , night-time and early-morning symptoms , exacerbations ( Healthcare Re source Utilisation [ HCRU ] and EXACT definitions ) and relief-medication use were assessed . Results The pooled intent-to-treat population included 3394 patients . Aclidinium/formoterol 400/12 μg significantly improved TDI focal score versus placebo and both monotherapies at Week 24 ( all p < 0.05 ) . Over 24 weeks , significant improvements in E-RS total score , overall night-time and early-morning symptom severity and limitation of early-morning activities were observed with aclidinium/formoterol 400/12 μg versus placebo and both monotherapies ( all p < 0.05 ) . The rate of moderate or severe HCRU exacerbations was significantly reduced with aclidinium/formoterol 400/12 μg compared with placebo ( p < 0.05 ) but not monotherapies ; the rate of EXACT-defined exacerbations was significantly reduced with aclidinium/formoterol 400/12 μg versus placebo ( p < 0.01 ) and aclidinium ( p < 0.05 ) . Time to first HCRU or EXACT exacerbation was longer with aclidinium/formoterol 400/12 μg compared with placebo ( all p < 0.05 ) but not the monotherapies . Relief-medication use was reduced with aclidinium/formoterol 400/12 μg versus placebo and aclidinium ( p < 0.01 ) . Conclusions Aclidinium/formoterol 400/12 μg significantly improves 24-hour symptom control compared with placebo , aclidinium and formoterol in patients with moderate to severe COPD . Furthermore , aclidinium/formoterol 400/12 μg reduces the frequency of exacerbations compared with placebo . Trial registration NCT01462942 and NCT01437397 ( Clinical Trials.gov Background Chronic obstructive pulmonary disease ( COPD ) is a complex condition with pulmonary and extra-pulmonary manifestations . This study describes the heterogeneity of COPD in a large and well characterised and controlled COPD cohort ( ECLIPSE ) . Methods We studied 2164 clinical ly stable COPD patients , 337 smokers with normal lung function and 245 never smokers . In these individuals , we measured clinical parameters , nutritional status , spirometry , exercise tolerance , and amount of emphysema by computed tomography . Results COPD patients were slightly older than controls and had more pack years of smoking than smokers with normal lung function . Co-morbidities were more prevalent in COPD patients than in controls , and occurred to the same extent irrespective of the GOLD stage . The severity of airflow limitation in COPD patients was poorly related to the degree of breathlessness , health status , presence of co-morbidity , exercise capacity and number of exacerbations reported in the year before the study . The distribution of these variables within each GOLD stage was wide . Even in subjects with severe airflow obstruction , a substantial proportion did not report symptoms , exacerbations or exercise limitation . The amount of emphysema increased with GOLD severity . The prevalence of bronchiectasis was low ( 4 % ) but also increased with GOLD stage . Some gender differences were also identified . Conclusions The clinical manifestations of COPD are highly variable and the degree of airflow limitation does not capture the heterogeneity of the disease 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 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 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 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 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 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 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 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/glycopyrronium ( IND/GLY ) is a once-daily inhaled fixed-dose combination of indacaterol ( IND ) , a long-acting β2-adrenergic agonist ( LABA ) , and glycopyrronium ( GLY ) , a long-acting muscarinic antagonist ( LAMA ) for use as maintenance treatment to relieve symptoms of chronic obstructive pulmonary disease ( COPD ) in adults . OBJECTIVE To determine the economic benefits of IND/GLY compared with the free combination of indacaterol and glycopyrronium ( IND + GLY ) , and with the fixed-dose combination of salmeterol/fluticasone ( SFC ) , in a moderate-to-severe COPD population with low-exacerbation risk . The model-based analysis extrapolated results up to lifetime time horizon and calculated costs per quality -adjusted life year . METHODS Assuming equal efficacy , a cost-minimisation analysis compared IND/GLY vs IND + GLY using model inputs from the double-blind , r and omised SHINE trial . The double-blind , r and omised ILLUMINATE and TORCH trials were used to analyse cost-effectiveness versus SFC . To consider ICS-related pneumonia events , published odds ratio comparing an ICS-exposed group to a control group of COPD patients was used . Direct and indirect drug costs as well as drug acquisition costs ( in Swedish Krona [ SEK ] ) were derived from published Swedish sources . Cost and effects were discounted with 3 % . Uncertainty was assessed by one-way and probabilistic sensitivity analyses ( PSA ) . RESULTS IND/GLY was cost-saving vs IND + GLY with incremental savings of SEK ( EUR ) 768 ( 85 ) , and 3309 ( 368 ) per patient over one and five years . IND/GLY was found to be less costly and more effective compared to SFC with cost savings of SEK ( EUR ) 2744 ( 303 ) , 8854 ( 976 ) , 13,938 ( 1536 ) , 27,495 ( 3031 ) and 43,033 ( 4744 ) over one , three , five , ten years and lifetime . The PSA indicated that all iterations produced dominant results for IND/GLY . CONCLUSION IND/GLY is cost-minimising vs IND + GLY and dominates SFC in the maintenance treatment of COPD patients in Sweden . Encouraging dual bronchodilator therapy over an ICS-containing combination results in lower total costs and better outcomes compared to combination therapy including fluticasone in moderate-to-severe COPD patients with low exacerbation risk BACKGROUND QVA149 is an inhaled , once-daily fixed-dose dual bronchodilator combination of the long-acting β2-agonist indacaterol and long-acting muscarinic antagonist glycopyrronium ( NVA237 ) for the treatment of chronic obstructive pulmonary disease ( COPD ) . We investigated the safety and efficacy of QVA149 over 52 weeks . METHODS This 52-week , multicenter , double-blind , parallel-group ,  placebo-controlled  study r and omized ( 2:1 ) patients with moderate-to-severe COPD to once-daily  QVA149 ( 110 μg indacaterol/50 μg glycopyrronium ) or placebo delivered via the Breezhaler device . Primary endpoint was safety and tolerability for treatment-emergent adverse events ( AEs ) . Secondary endpoints included safety based on vital signs , electrocardiograms ( ECGs ) , laboratory evaluations , and pre-dose forced expiratory volume in 1 s ( FEV1 ) . RESULTS Of 339 patients r and omized , QVA149 [ n = 226 ] , placebo [ n = 113 ] ; 76.9 % male , mean age : 62.6 years , post-bronchodilator FEV1 : 57.4 % predicted , 83.5 % completed study . A smaller percentage of patients discontinued in the QVA149 group ( 14.2 % ) compared with placebo ( 21.2 % ) . Overall incidence of AEs was similar in the QVA149 ( 57.8 % ) and placebo ( 56.6 % ) groups , with most AEs being mild to moderate in severity . The numerical differences in some AEs observed could be at least in part explained by differences in baseline patient characteristics . No clinical ly relevant differences were observed between treatment groups for vital signs or ECG parameters . The five deaths reported were unrelated to study medication ( QVA149 , n = 4 [ 1.8 % ] ; placebo , n = 1 [ 0.9 % ] ) . QVA149 demonstrated rapid and clinical ly meaningful bronchodilation sustained over 52 weeks versus placebo . CONCLUSION QVA149 demonstrated a good safety and tolerability profile , providing rapid and sustained bronchodilation over 52 weeks in patients with moderate-to-severe COPD . Clinical Trials.gov identifier : NCT01120717
OBJECTIVE The combination of a long-acting muscarinic antagonist ( LAMA ) and a long-acting β2-agonist ( LABA ) in a single inhaler is a viable treatment option for patients with chronic obstructive pulmonary disease ( COPD ) .
Here , we systematic ally review the current knowledge on double bronchodilation for the treatment of COPD , with a specific focus on its efficacy versus placebo and /or monotherapy bronchodilation .