Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study A randomized, parallel-group study to evaluate the efficacy of umeclidinium/vilanterol 62.5/25 μg on health-related quality of life in patients with COPD A 4-year trial of tiotropium in chronic obstructive pulmonary disease. Enhancing exercise tolerance and physical activity in COPD with combined pharmacological and non-pharmacological interventions: PHYSACTO randomised, placebo-controlled study design Efficacy of Tiotropium + Olodaterol in Patients with Chronic Obstructive Pulmonary Disease by Initial Disease Severity and Treatment Intensity: A Post Hoc Analysis 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. Behaviour-change intervention in a multicentre, randomised, placebo-controlled COPD study: methodological considerations and implementation Umeclidinium/vilanterol versus fluticasone propionate/salmeterol in COPD: a randomised trial The lung function profile of once-daily tiotropium and olodaterol via Respimat® is superior to that of twice-daily salmeterol and fluticasone propionate via Accuhaler® (ENERGITO® study) Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2–4) Efficacy and safety of combining olodaterol Respimat® and tiotropium HandiHaler® in patients with COPD: results of two randomized, double-blind, active-controlled studies Tiotropium + olodaterol shows clinically meaningful improvements in quality of life. Efficacy and safety of olodaterol once daily delivered via Respimat® in patients with GOLD 2–4 COPD: results from two replicate 48-week studies The 24-h lung-function profile of once-daily tiotropium and olodaterol fixed-dose combination in chronic obstructive pulmonary disease. Randomized, Double-Blind, Dose-Finding Study for Tiotropium when Added to Olodaterol, Administered via the Respimat® Inhaler in Patients with Chronic Obstructive Pulmonary Disease Long-term general and cardiovascular safety of tiotropium/olodaterol in patients with moderate to very severe chronic obstructive pulmonary disease. 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 [Pharmacological treatment of stable chronic obstructive pulmonary disease].
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 the inhaled muscarinic antagonist umeclidinium ( UMEC ) with the long-acting β2-agonist vilanterol ( VI ) has been shown to provide significant improvements in lung function compared with UMEC , VI , or placebo ( PBO ) in patients with chronic obstructive pulmonary disease ( COPD ) . This study was specifically design ed to support these findings by assessing health-related quality of life and symptomatic outcomes in a similar population . Methods This was a 12-week multicenter , r and omized , double-blind , parallel-group , placebo-controlled study . Eligible patients were r and omized 1:1 to receive once-daily UMEC/VI 62.5/25 μg ( via ELLIPTA ® dry powder inhaler ) or PBO for 12 weeks . The primary endpoint was St George ’s Respiratory Question naire ( SGRQ ) total score at day 84 . Secondary efficacy endpoints included rescue albuterol use ( puffs/day ) over weeks 1–12 and trough forced expiratory volume in 1 second on day 84 . Adverse events were also assessed . Results A total of 496 patients were included in the intent-to-treat population in the UMEC/VI ( n=248 ) and PBO ( n=248 ) treatment groups . UMEC/VI 62.5/25 μg provided a significant and clinical ly meaningful improvement in SGRQ total score at day 84 versus PBO ( difference between treatments in SGRQ total score change from baseline : −4.03 [ 95 % confidence interval { CI } : −6.28 , −1.79 ] ; P<0.001 ) . UMEC/VI 62.5/25 μg result ed in a statistically significant reduction in rescue albuterol use versus PBO ( −0.7 puffs/day [ 95 % CI : −1.1 , −0.4 ] ; P<0.001 ) . UMEC/VI 62.5/25 μg provided a significant and clinical ly meaningful improvement in trough forced expiratory volume in 1 second on day 84 versus PBO ( 122 mL [ 95 % CI : 71 , 172 ] ; P<0.001 ) . The incidence of adverse events was similar between treatments ( 32 % and 30 % of patients in the UMEC/VI 62.5/25 μg and PBO groups , respectively ) . Conclusion The results of this study demonstrate that treatment with UMEC/VI 62.5/25 μg provides clinical ly important improvements in SGRQ and rescue medication use  versus PBO in patients with moderate-to-very-severe COPD BACKGROUND Previous studies showing that tiotropium improves multiple end points in patients with chronic obstructive pulmonary disease ( COPD ) led us to examine the long-term effects of tiotropium therapy . METHODS In this r and omized , double-blind trial , we compared 4 years of therapy with either tiotropium or placebo in patients with COPD who were permitted to use all respiratory medications except inhaled anticholinergic drugs . The patients were at least 40 years of age , with a forced expiratory volume in 1 second ( FEV(1 ) ) of 70 % or less after bronchodilation and a ratio of FEV(1 ) to forced vital capacity ( FVC ) of 70 % or less . Co primary end points were the rate of decline in the mean FEV(1 ) before and after bronchodilation beginning on day 30 . Secondary end points included measures of FVC , changes in response on St. George 's Respiratory Question naire ( SGRQ ) , exacerbations of COPD , and mortality . RESULTS Of a total of 5993 patients ( mean age , 65+/-8 years ) with a mean FEV(1 ) of 1.32+/-0.44 liters after bronchodilation ( 48 % of predicted value ) , we r and omly assigned 2987 to the tiotropium group and 3006 to the placebo group . Mean absolute improvements in FEV(1 ) in the tiotropium group were maintained throughout the trial ( ranging from 87 to 103 ml before bronchodilation and from 47 to 65 ml after bronchodilation ) , as compared with the placebo group ( P<0.001 ) . After day 30 , the differences between the two groups in the rate of decline in the mean FEV(1 ) before and after bronchodilation were not significant . The mean absolute total score on the SGRQ was improved ( lower ) in the tiotropium group , as compared with the placebo group , at each time point throughout the 4-year period ( ranging from 2.3 to 3.3 units , P<0.001 ) . At 4 years and 30 days , tiotropium was associated with a reduction in the risks of exacerbations , related hospitalizations , and respiratory failure . CONCLUSIONS In patients with COPD , therapy with tiotropium was associated with improvements in lung function , quality of life , and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV(1 ) . ( Clinical Trials.gov number , NCT00144339 . Introduction Chronic obstructive pulmonary disease ( COPD ) is associated with exercise limitation and physical inactivity , which are believed to have significant long-term negative health consequences for patients . While a number of COPD treatments and exercise training programmes increase exercise capacity , there is limited evidence for their effects on physical activity levels , with no clear association between exercise capacity and physical activity in clinical trials . Physical activity depends on a number of behaviour , environmental and physiological factors . We describe the design of the PHYSACTO trial , which is investigating the effects of bronchodilators , either alone or with exercise training , in combination with a st and ardised behaviour-change self-management programme , on exercise capacity and physical activity in patients with COPD . It is hypothesised that bronchodilators in conjunction with a behaviour-change self-management programme will improve physical activity and that this effect will be amplified by the addition of exercise training . Methods and analysis Patients are being recruited from 34 sites in Australia , New Zeal and , the USA , Canada and Europe . Patients receiving a multicomponent intervention design ed to support behaviour change related to physical activity are r and omised to four treatment arms : placebo , tiotropium , tiotropium+olo date rol , and tiotropium+olo date rol+exercise training . The primary outcome is improvement in exercise capacity after 8 weeks , measured by endurance time during a shuttle walk test . The secondary outcome is improvement in physical activity , including objective accelerometer assessment and patient-reported functioning using the Functional Performance Inventory — Short Form and the novel hybrid PROactive instrument . Additionally , the influence of moderating variables ( ie , factors influencing a patient 's choice to be physically active ) on increases in physical activity is also explored . Ethics and dissemination The study has been approved by the relevant Institutional Review Boards , Independent Ethics Committee and Competent Authority according to national and international regulations . The findings of the trial will be disseminated through relevant peer- review ed journals and international conference presentations . Trial registration number NCT02085161 Introduction The once-daily long-acting muscarinic antagonist ( LAMA ) tiotropium and once-daily long-acting β2-agonist ( LABA ) olo date rol have been studied as a once-daily fixed-dose combination ( FDC ) in patients with chronic obstructive pulmonary disease ( COPD ) . Two large , 52-week , double-blind , parallel-group studies in patients with moderate – very severe COPD demonstrated that tiotropium + olo date rol significantly improved lung function and symptoms versus the monocomponents . This post hoc analysis determined effects on lung function by prior LAMA or LABA maintenance treatment and initial disease severity . Methods 5162 patients were r and omized and treated with olo date rol 5 µg , tiotropium 2.5 µg , tiotropium 5 µg , tiotropium + olo date rol 2.5/5 µg , or tiotropium + olo date rol 5/5 µg ( all once daily via Respimat ® inhaler ) . Primary efficacy ( lung-function ) end points were forced expiratory volume in 1 s ( FEV1 ) area under the curve from 0 to 3 h ( AUC0–3 ) and trough FEV1 responses ( i.e. , change from baseline ) . Pooled data are presented for the following subgroups : prior maintenance treatment with LAMA or LABA , Global initiative for chronic Obstructive Lung Disease ( GOLD ) 2 ( predicted FEV1 50 % to < 80 % ) and 3 ( 30 % to < 50%)/4 ( < 30 % ) , sex , age , and prior use of inhaled corticosteroids . Results Tiotropium + olo date rol FDC improved lung function over the monocomponents in patients with GOLD 2 and 3–4 disease , irrespective of prior LAMA or LABA maintenance therapy ; most comparisons between FDCs and their respective monocomponents were statistically significant ( P < 0.05 ) . FEV1 AUC0–3 and trough FEV1 responses for the individual treatments were generally greater in patients with less severe COPD at baseline . Conclusions Tiotropium + olo date rol 5/5 µg  significantly improved FEV1 AUC0–3 and trough FEV1 in all GOLD severity groups compared to olo date rol 5 µg and tiotropium 5 µg alone , irrespective of whether patients had received prior LAMA or LABA maintenance treatment . Improvements from baseline in lung function were generally greater in patients with less severe disease . Funding Boehringer Ingelheim . Trial registration : Clinical Trials.gov numbers , NCT01431274 and NCT01431287 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 Introduction Chronic obstructive pulmonary disease is generally progressive and associated with reduced physical activity . Both pharmacological therapy and exercise training can improve exercise capacity ; however , these are often not sufficient to change the amount of daily physical activity a patient undertakes . Behaviour-change self-management programmes are design ed to address this , including setting motivational goals and providing social support . We present and discuss the necessary method ological considerations when integrating behaviour-change interventions into a multicentre study . Methods and analysis PHYSACTO is a 12-week phase IIIb study assessing the effects on exercise capacity and physical activity of once-daily tiotropium+olo date rol 5/5 µg with exercise training , tiotropium+olo date rol 5/5 µg without exercise training , tiotropium 5 µg or placebo , with all pharmacological interventions administered via the Respimat inhaler . Patients in all intervention arms receive a behaviour-change self-management programme to provide an optimal environment for translating improvements in exercise capacity into increases in daily physical activity . To maximise the likelihood of success , special attention is given in the programme to : ( 1 ) the Site Case Manager , with careful monitoring of programme delivery ; ( 2 ) the patient , incorporating patient-evaluation/programme-evaluation measures to guide the Site Case Manager in the self-management intervention ; and ( 3 ) quality assurance , to help identify and correct any problems or shortcomings in programme delivery and ensure the effectiveness of any corrective steps . This paper documents the comprehensive methods used to optimise and st and ardise the behaviour-change self-management programme used in the study to facilitate dialogue on the inclusion of this type of programme in multicentre studies . Ethics and dissemination The study has been approved by the relevant Institutional Review Boards , Independent Ethics Committee and Competent Authority according to national and international regulations . The results of this study will be disseminated through relevant , peer- review ed journals and international conference presentations . Trial registration number NCT02085161 Background Umeclidinium ( UMEC ; long-acting muscarinic antagonist ) plus vilanterol ( VI ; long-acting beta2 agonist [ LABA ] ) and the LABA/inhaled corticosteroid fluticasone propionate/salmeterol ( FP/SAL ) are approved maintenance treatments for chronic obstructive pulmonary disease ( COPD ) . This 12-week , multicentre , double-blind , parallel-group , double-dummy study compared the efficacy and safety of these treatments in symptomatic patients with moderate-to-severe COPD with no exacerbations in the year prior to enrolment . Methods Patients ( n = 717 ) were r and omised 1:1 to once-daily UMEC/VI 62.5/25 mcg or twice-daily FP/SAL 500/50 mcg . Endpoints included 0–24 h weighted mean ( wm ) forced expiratory volume in 1 s ( FEV1 ) ( Day 84 ; primary ) , trough FEV1 ( Day 85 ; secondary ) , other lung function endpoints , symptoms , quality of life ( QoL ) and safety . Results Improvements with UMEC/VI versus FP/SAL were 0.080 L ( 95 % confidence interval : 0.046–0.113 ; wmFEV1 ) and 0.090 L ( 0.055–0.125 ; trough FEV1 ) ( both p < 0.001 ) . UMEC/VI statistically significantly improved all other lung function measures versus FP/SAL . Both treatments demonstrated a clinical ly meaningful improvement in symptoms ( Transition Dyspnoea Index ≥1 unit ) and QoL ( St George ’s Respiratory Question naire Total score ≥4 unit decrease from baseline ) over 12 weeks . The incidence of adverse events was 28 % ( UMEC/VI ) and 29 % ( FP/SAL ) ; nasopharyngitis and headache were most common . Conclusions Once-daily UMEC/VI 62.5/25 mcg over 12 weeks result ed in significant and sustained improvements in lung function versus twice-daily FP/SAL 500/50 mcg in patients with moderate-to-severe COPD and with no exacerbations in the year prior to enrolment . Trial Registration NCT01822899 Registration date : March 28 , Background Tiotropium + olo date rol has demonstrated improvements beyond lung function benefits in a large Phase III clinical program as a once-daily maintenance treatment for COPD and may be a potential option for the initiation of maintenance treatment in COPD . Despite guideline recommendations that combined long-acting β2-agonists and inhaled corticosteroids should only be used in individuals at high risk of exacerbation , there is substantial use in individuals at lower risk . This raises the question of the comparative effectiveness of this combination as maintenance treatment in this group compared to other combination regimens . Objective The study aim ed to assess the effect on lung function of once-daily tiotropium + olo date rol versus twice-daily salmeterol + fluticasone propionate in all participants with Global initiative for chronic Obstructive Lung Disease 2 or 3 ( moderate to severe ) COPD . Methods This was a r and omized , double-blind , double-dummy , four-treatment , complete crossover study in which participants received once-daily tiotropium + olo date rol ( 5/5 µg and 2.5/5 µg ) via Respimat ® and twice-daily salmeterol + fluticasone propionate ( 50/500 µg and 50/250 µg ) via Accuhaler ® for 6 weeks . The primary end point was change in forced expiratory volume in 1 second ( FEV1 ) area under the curve from 0 hour to 12 hours ( AUC0–12 ) relative to the baseline after 6 weeks . Results Tiotropium + olo date rol 5/5 µg and 2.5/5 µg demonstrated statistically significant improvements in FEV1 AUC0–12 compared to salmeterol + fluticasone propionate ( improvements from baseline were 317 mL and 295 mL with tiotropium + olo date rol 5/5 µg and 2.5/5 µg , and 188 mL and 192 mL with salmeterol + fluticasone propionate 50/500 µg and 50/250 µg , respectively ) . Tiotropium + olo date rol was  superior to salmeterol + fluticasone propionate  in lung function secondary end points , including FEV1 area under the curve from 0 hour to 24 hours ( AUC0–24 ) . Conclusion Once-daily tiotropium + olo date rol in participants with moderate-to-severe COPD provided superior lung function improvements to twice-daily salmeterol + fluticasone propionate . Dual bronchodilation can be considered to optimize lung function in individuals requiring maintenance treatment for COPD 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 Combining bronchodilators with different mechanisms of action may improve efficacy and reduce risk of side effects compared to increasing the dose of a single agent in chronic obstructive pulmonary disease ( COPD ) . We investigated this by combining two long-acting bronchodilators : once-daily muscarinic antagonist tiotropium and once-daily β2-agonist olo date rol . Methods Two replicate , double-blind , r and omized , 12-week studies ( ANHELTO 1 [ NCT01694771 ] and ANHELTO 2 [ NCT01696058 ] ) evaluated the efficacy and safety of olo date rol 5 μg once daily ( via Respimat ® ) combined with tiotropium 18 μg once daily ( via H and iHaler ® ) versus tiotropium 18 μg once daily ( via H and iHaler ® ) combined with placebo ( via Respimat ® ) in patients with moderate to severe COPD .  Primary efficacy end points were area under the curve from 0–3 hours of forced expiratory volume in 1 second ( FEV1 AUC0–3 ) and trough FEV1 after 12 weeks ( for the individual trials ) . A key secondary end point was health status by St George ’s Respiratory Question naire ( SGRQ ) total score ( combined data set ) . Results Olo date rol + tiotropium result ed in significant improvements  over tiotropium + placebo  in FEV1 AUC0–3 ( treatment differences : 0.117 L [ P<0.001 ] , ANHELTO 1 ; 0.106 L [ P<0.001 ] , ANHELTO 2 ) and trough FEV1 ( treatment differences : 0.062 L [ P<0.001 ] , ANHELTO 1 ; 0.040 L [ P=0.0029 ] , ANHELTO 2 ) ; these were supported by secondary end points . These effects translated to improvements in SGRQ total scores ( treatment difference −1.85 ; P<0.0001 ) . The tolerability  profile of olo date rol + tiotropium was similar to tiotropium monotherapy . Conclusion These studies demonstrated that olo date rol ( Respimat ® ) and tiotropium ( H and iHaler ® ) provided bronchodilatory effects above tiotropium alone in patients with COPD . In general , both treatments were well tolerated BACKGROUND Tiotropium + olo date rol improves lung function and symptoms compared to monotherapies in chronic obstructive pulmonary disease ( COPD ) . The OTEMTO 1 and 2 studies investigated the effects of tiotropium + olo date rol on lung function and health-related quality of life compared to placebo in patients with moderate to severe COPD . METHODS In these two replicate , double-blind , parallel-group , placebo-controlled trials , patients were r and omised to receive tiotropium + olo date rol 5/5 μg , 2.5/5 μg , tiotropium 5 μg or placebo for 12 weeks , via the Respimat ( ® ) inhaler . Primary end points were St George 's Respiratory Question naire ( SGRQ ) total score , forced expiratory volume in 1 s ( FEV1 ) area under the curve from 0 to 3 h ( AUC0 - 3 ) response and trough FEV1 response . RESULTS In OTEMTO 1 and 2 , tiotropium + olo date rol 5/5 μg improved SGRQ total score by 4.89 ( 95 % confidence interval [ CI ] -6.90 , -2.88 ) and 4.56 ( 95 % CI -6.50 , -2.63 ) units versus placebo ( both p < 0.0001 ) , and 2.49 ( 95 % CI -4.47 , -0.51 ; p < 0.05 ) and 1.72 ( 95 % CI -3.63 , 0.19 ) units versus tiotropium 5 μg . Tiotropium + olo date rol 2.5/5 μg significantly improved SGRQ score compared to placebo . Both doses significantly improved FEV1 AUC0 - 3 response compared to placebo and tiotropium 5 μg . Tiotropium + olo date rol 5/5 and 2.5/5 μg also significantly improved trough FEV1 response compared to placebo ( both studies ) and separated from tiotropium 5 μg in OTEMTO 2 . Adverse-event incidence was similar between treatment groups . CONCLUSION Tiotropium + olo date rol improved lung function and quality of life compared to placebo and tiotropium 5 μg . TRIAL REGISTRATION Clinical Trials.gov : NCT01964352 and NCT02006732 Background Olo date rol is a long-acting β2-agonist with a 24-hour bronchodilator profile . Two replicate , r and omized , double-blind , placebo-controlled , parallel-group , Phase III trials were performed as part of a comprehensive clinical program to investigate the long-term safety and efficacy of olo date rol in patients with moderate to very severe chronic obstructive pulmonary disease ( COPD ) receiving usual-care background therapy . Methods Patients received olo date rol 5 μg or 10 μg or placebo once daily for 48 weeks . Co primary end points were forced expiratory volume in 1 second ( FEV1 ) area under the curve from 0 to 3 hours ( AUC0–3 ) response ( change from baseline ) , and trough FEV1 response at 12 weeks . Secondary end points included additional lung function assessment s , use of rescue medications , FEV1 AUC response from 0 to 12 hours , and Patient Global Rating over 48 weeks . Results Overall , 624 and 642 patients were evaluated in studies 1222.11 and 1222.12 , respectively . In both studies , olo date rol 5 μg and 10 μg significantly improved the FEV1 AUC0–3 response ( P<0.0001 ) and trough FEV1 ( study 1222.11 , P<0.0001 ; study 1222.12 , P<0.05 , post hoc ) at week 12 , with an incidence of adverse events comparable with that of placebo . Secondary end points supported the efficacy of olo date rol . Conclusion These studies demonstrate the long-term efficacy and safety of once-daily olo date rol 5 μg and 10 μg in patients with moderate to very severe COPD continuing with usual-care maintenance therapy BACKGROUND This study investigated the effects on 24-h lung function and lung volume of a once-daily fixed-dose combination ( FDC ) of the long-acting muscarinic antagonist tiotropium and the long-acting β2-agonist olo date rol in patients with chronic obstructive pulmonary disease . METHODS This was a r and omised , double-blind , placebo-controlled , Phase III trial with an incomplete crossover design . Patients received four of the following six treatment options for 6 weeks each : placebo , olo date rol 5 μg , tiotropium 2.5 μg , tiotropium 5 μg , tiotropium + olo date rol FDC 2.5/5 μg and tiotropium + olo date rol FDC 5/5 μg , all delivered via the Respimat ( ® ) inhaler . The primary end point was forced expiratory volume in 1 s ( FEV1 ) area under the curve from 0 to 24 h ( AUC0 - 24 ) response after 6 weeks of treatment ; key secondary end points were FEV1 AUC from 0 to 12 h and AUC from 12 to 24 h , and further end points included lung-volume parameters measured using body plethysmography ( subset of patients ) , measures of peak and trough FEV1 , and incidence of adverse events . RESULTS A significant improvement in FEV1 AUC0 - 24 response was observed with tiotropium + olo date rol 5/5 μg and 2.5/5 μg versus placebo and monotherapies after 6 weeks of treatment ; mean response with tiotropium + olo date rol 5/5 μg versus placebo was 0.280 L ( p < 0.0001 ) . Differences to monotherapies with tiotropium + olo date rol 5/5 μg were 0.115 L versus olo date rol 5 μg , 0.127 L versus tiotropium 2.5 μg and 0.110 L versus tiotropium 5 μg ( p < 0.0001 for all comparisons ) . Secondary end points supported these data . No safety concerns were identified . CONCLUSIONS Overall , this study demonstrated improvements in lung function over 24 h with an FDC of tiotropium + olo date rol over tiotropium or olo date rol alone , with no observed difference in tolerability . Clinical Trials.gov number : NCT01559116 Introduction Combining long-acting muscarinic antagonists ( LAMAs ) and long-acting β2-agonists ( LABAs ) is beneficial in chronic obstructive pulmonary disease ( COPD ) , as the two classes of bronchodilator have complementary modes of action . The optimal dose for the fixed-dose combination of the LAMA tiotropium and the LABA olo date rol needed to be determined . In this phase II trial , the dose response of tiotropium on top of olo date rol was investigated in a free-dose combination , while other phase II studies have explored different doses of olo date rol on top of tiotropium , with both drugs delivered using the Respimat ® inhaler . Methods This was a double-blind incomplete crossover trial in which 233 patients with moderate or severe COPD were r and omized to receive four out of eight free-dose combinations of olo date rol ( 5 or 10 µg ) and tiotropium ( 1.25 , 2.5 , or 5 µg ) or placebo for 4 weeks each . Primary end point was trough forced expiratory volume in 1 s ( FEV1 ) change from baseline ( response ) after 4 weeks . Results Addition of tiotropium 1.25 , 2.5 , and 5 µg to olo date rol 5 µg increased mean trough FEV1 response by 0.054 , 0.065 , and 0.084 L , respectively ; addition of tiotropium 1.25 , 2.5 , and 5 µg to olo date rol 10 µg increased mean trough FEV1 response by 0.051 , 0.083 , and 0.080 L , respectively . All treatments were well tolerated and incidence of adverse events was similar with all treatments . Conclusions Overall , a dose response for tiotropium on top of both doses of olo date rol was observed , with increasing improvements in trough FEV1 compared to olo date rol alone as the tiotropium dose was increased . Funding Boehringer Ingelheim . Trial registration : Clinical Trials.gov number , NCT01040403 BACKGROUND Long-term safety , particularly cardiovascular safety , is of special interest in maintenance treatment of chronic obstructive pulmonary disease ( COPD ) with long-acting β2-agonists and long-acting muscarinic antagonists , given potential cardiovascular effects . METHODS Two 52-week Phase III trials ( TONADO ® ) investigated tiotropium/olo date rol ( 5/5 and 2.5/5 μg ) versus tiotropium 2.5 , 5 μg and olo date rol 5 μg . In a pre-specified safety analysis , investigator-reported treatment-emergent adverse events ( AEs ) , electrocardiogram and laboratory data were pooled . All serious AE ( SAE ) reports were review ed by an independent Adjudication Committee , which assessed whether deaths , hospitalisations or intubations were respiratory , cardiovascular , cerebrovascular or other disease related . Subgroup analyses investigated cardiovascular safety including major cardiac events in patients with cardiovascular co-morbidities . RESULTS This analysis comprised 3100 patients with moderate to very severe COPD , treated for ≤1 year , including 784 patients with cardiovascular co-morbidities .  AEs were balanced across treatments in the total population as well as in patient subgroups with pre-existing cardiovascular co-morbidities . The incidence and nature of events were consistent with the disease under study and a 1-year trial duration . 494/3100 patients contributed to an adjudicated analysis of SAEs : 260 had respiratory-related , 53 had cardiovascular-related and 16 had cerebrovascular-related SAEs . Incidences of these SAEs were comparable between treatments . There was no evidence of any increased risk for the combination compared to the monotherapy groups . CONCLUSIONS These data provide confidence for clinicians that tiotropium/olo date rol 5/5 μg can be safely administered once-daily to patients with moderate to very severe COPD long-term , including those with significant cardiovascular co-morbidity . TRIAL REGISTRY Clinical Trials.gov , Nos. : NCT01431274 , NCT01431287 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 The pharmacological treatment of chronic obstructive pulmonary disease ( COPD ) can significantly improve quality of life by reducing exacerbations , dyspnea and exercise intolerance , thereby limiting the degree of h and icap and improving daily activities . Recently , large r and omised trials showed that some treatments can alter the decline in FEV1 , which was previously only accessible to smoking cessation , and maybe reduce mortality . Bronchodilators are the first-line pharmacological treatment of COPD . Their clinical efficacy can not be predicted by the inconstant changes in FEV(1 . ) Their main mechanism of action is the reduction in lung hyperinflation .  Theophylline has a lower efficacy/tolerance ratio than inhaled bronchodilators . In symptomatic patients with FEV1 < 50/60 % predicted and repeated exacerbations despite bronchodilators , inhaled corticosteroids combined with long acting beta-agonists can be used . Several other approaches targeting inflammation and oxidative stress , remodelling and lung regeneration are also being studied . Medications must be associated with non-pharmacological measures ( including help towards smoking cessation , education , exercise training ... ) . Systemic manifestations of COPD must also be taken into account
Background Long-acting bronchodilators are the cornerstone of pharmacologic treatment of COPD .
The new combination of long-acting muscarinic antagonist ( LAMA ) tiotropium ( TIO ) and long acting beta-agonists ( LABA ) olo date rol ( OLO ) has been introduced as fist line therapy for COPD .
This article analyses the evidence of efficacy and safety of the TIO/OLO combination .