Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study Efficacy and safety of NVA237 versus placebo and tiotropium in patients with COPD: the GLOW2 study Efficacy and safety of once-daily NVA237 in patients with moderate-to-severe COPD: the GLOW1 trial A 4-year trial of tiotropium in chronic obstructive pulmonary disease. Efficacy and Safety of a 12-week Treatment with Twice-daily Aclidinium Bromide in COPD Patients (ACCORD COPD I) Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN study Absence of electrocardiographic findings and improved function with once-daily tiotropium in patients with chronic obstructive pulmonary disease. Tiotropium improves FEV1 in patients with COPD irrespective of smoking status. Effect of tiotropium in men and women with COPD: results of the 4-year UPLIFT trial. Effect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPD A blinded evaluation of the efficacy and safety of glycopyrronium, a once-daily long-acting muscarinic antagonist, versus tiotropium, in patients with COPD: the GLOW5 study Umeclidinium in patients with COPD: a randomised, placebo-controlled study A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease Efficacy and Safety of Aclidinium Bromide Compared with Placebo and Tiotropium in Patients with Moderate-to-Severe Chronic Obstructive Pulmonary Disease: Results from a 6-week, Randomized, Controlled Phase Iiib 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. The spirometric efficacy of once-daily dosing with tiotropium in stable COPD: a 13-week multicenter trial. The US Tiotropium Study Group. Once-daily bronchodilators for chronic obstructive pulmonary disease: indacaterol versus tiotropium. Formoterol mono- and combination therapy with tiotropium in patients with COPD: a 6-month study. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Efficacy of aclidinium bromide 400 μg twice daily compared with placebo and tiotropium in patients with moderate to severe COPD. A randomized controlled trial to assess the efficacy of tiotropium in Canadian patients with chronic obstructive pulmonary disease. The Effect of Tiotropium on Hyperinflation and Exercise Capacity in Chronic Obstructive Pulmonary Disease A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol. ACCORD COPD II: A Randomized Clinical Trial to Evaluate the 12-Week Efficacy and Safety of Twice-Daily Aclidinium Bromide in Chronic Obstructive Pulmonary Disease Patients Prevention of Exacerbations of Chronic Obstructive Pulmonary Disease with Tiotropium, a Once-Daily Inhaled Anticholinergic Bronchodilator Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD.
We investigated the efficacy and safety of dual bronchodilation with QVA149 versus its monocomponents indacaterol and glycopyrronium , tiotropium and placebo in patients with moderate-to-severe chronic obstructive pulmonary disease ( COPD ) . This was a multicentre , r and omised , double-blind , placebo- and active-controlled , 26-week trial . Patients ( n = 2144 ) were r and omised ( 2:2:2:2:1 ) to receive once-daily QVA149 ( indacaterol 110 & mgr;g/glycopyrronium 50 & mgr;g ) , indacaterol 150 & mgr;g , glycopyrronium 50 & mgr;g , open-label tiotropium 18 & mgr;g or placebo . The primary end-point was trough forced expiratory volume in 1 s ( FEV1 ) at week 26 for QVA149 versus its monocomponents . Secondary end-points included dyspnoea , health status , rescue medication use and safety . Trough FEV1 at week 26 was significantly improved ( p<0.001 ) with QVA149 compared with indacaterol and glycopyrronium ( least squares mean ( LSM ) differences 0.07 L and 0.09 L , respectively ) , tiotropium and placebo ( LSM differences 0.08 L and 0.20 L , respectively ) ; these beneficial effects were sustained throughout the 26-week study . QVA149 significantly improved dyspnoea and health status versus placebo ( p<0.001 and p = 0.002 , respectively ) and tiotropium ( p = 0.007 and p = 0.009 , respectively ) at week 26 . All treatments were well tolerated . Dual bronchodilation with once-daily QVA149 demonstrated superior and clinical ly meaningful outcomes versus placebo and superiority versus treatment with a single bronchodilator , with a safety and tolerability profile similar to placebo , supporting the concept of fixed-dose long-acting muscarinic antagonist/long-acting & bgr;2-agonist combinations for the treatment of COPD . Dual indacaterol/glycopyrronium therapy was safe and more efficacious than monotherapy in moderate-to-severe COPD NVA237 ( glycopyrronium bromide ) is a once-daily long-acting muscarinic antagonist ( LAMA ) in development for chronic obstructive pulmonary disease ( COPD ) . The GLycopyrronium bromide in COPD airWays clinical Study 2 ( GLOW2 ) evaluated the efficacy and safety of NVA237 in moderate-to-severe COPD over 52 weeks . Patients were r and omised 2:1:1 to NVA237 50 μg , placebo or open-label tiotropium 18 μg for 52 weeks . Primary end-point was trough forced expiratory volume in 1 s ( FEV1 ) at 12 weeks . 1,066 patients were r and omised , 810 completed the study . At week 12 , trough FEV1 increased significantly by 97 mL with NVA237 ( 95 % CI 64.6–130.2 ; p<0.001 ) and 83 mL with tiotropium ( 95 % CI 45.6–121.4 ; p<0.001 ) . Compared with placebo , NVA237 produced significant improvements in dyspnoea ( Transition Dyspnoea Index at week 26 ; p=0.002 ) and health status ( St George 's Respiratory Question naire at week 52 ; p<0.001 ) . NVA237 significantly reduced the risk of moderate-to-severe COPD exacerbations by 34 % ( p=0.001 ) and the use of rescue medication ( p=0.039 ) , versus  placebo  . NVA237-placebo and tiotropium-placebo differences were comparable for all outcomes . Safety profiles were similar across groups . NVA237 50 μg provided significant improvements in lung function , dyspnoea , health status , exacerbations and rescue medication use , versus placebo , and was comparable to tiotropium . NVA237 can potentially be an alternative choice of LAMA for COPD patients Background NVA237 is a once-daily dry-powder formulation of the long-acting muscarinic antagonist glycopyrronium bromide in development for the treatment of chronic obstructive pulmonary disease ( COPD ) . The glycopyrronium bromide in COPD airways clinical study 1 ( GLOW1 ) evaluated the efficacy , safety and tolerability of NVA237 in patients with moderate-to-severe COPD . Methods Patients with COPD with a smoking history of ≥ 10 pack-years , post-bronchodilator forced expiratory volume in 1 second ( FEV1 ) < 80 % and ≥ 30 % predicted normal and FEV1/forced vital capacity < 0.70 were enrolled . Patients were r and omized to double-blind treatment with NVA237 50 μg once daily or placebo for 26 weeks with inhaled/intranasal corticosteroids or H1 antagonists permitted in patients stabilized on them prior to study entry . The primary outcome measure was trough FEV1 at Week 12 . Results A total of 822 patients were r and omized to NVA237 ( n = 552 ) or placebo ( n = 270 ) . Least squares mean ( ± st and ard error ) trough FEV1 at Week 12 was significantly higher in patients receiving NVA237 ( 1.408 ± 0.0105 L ) , versus placebo ( 1.301 ± 0.0137 L ; treatment difference 108 ± 14.8 mL , p < 0.001 ) . Significant improvements in trough FEV1 were apparent at the end of Day 1 and sustained through Week 26 . FEV1 was significantly improved in the NVA237 group versus placebo throughout the 24-hour periods on Day 1 and at Weeks 12 and 26 , and at all other visits and timepoints . Transition dyspnoea index focal scores and St. George 's Respiratory Question naire scores were significantly improved with NVA237 versus placebo at Week 26 , with treatment differences of 1.04 ( p < 0.001 ) and -2.81 ( p = 0.004 ) , respectively  . NVA237 significantly reduced the risk of first moderate/severe COPD exacerbation by 31 % ( p = 0.023 ) and use of rescue medication by 0.46 puffs per day ( p = 0.005 ) , versus placebo . NVA237 was well tolerated and had an acceptable safety profile , with a low frequency of cardiac and typical antimuscarinic adverse effects . Conclusions Once-daily NVA237 was safe and well tolerated and provided rapid , sustained improvements in lung function , improvements in dyspnoea , and health-related quality of life , and reduced the risk of exacerbations and the use of rescue medication . Trial registration Clinical Trials.gov : 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 . Abstract Background : This Phase III study evaluated the efficacy and safety of twice-daily aclidinium 200 μg and 400 μg versus placebo in the treatment of moderate-to-severe COPD . Methods : In this 12-week , double-blind , multicenter trial , patients were r and omized ( 1:1:1 ) to inhaled twice-daily aclidinium 200 μg , aclidinium 400 μg , or placebo . Primary and secondary endpoints were changes from baseline in trough FEV1 and peak FEV1 at Week 12 , respectively . Health status ( St. George 's Respiratory Question naire [ SGRQ ] ) , COPD symptoms ( Transitional Dyspnea Index [ TDI ] , night and early morning symptoms ) , and safety were also assessed . Results : A total of 561 patients ( mean age , 64 ± 9 years ) with a mean baseline FEV1 of 1.36 ± 0.54 L ( 47.2 % of predicted value ) were r and omized . At Week 12 , aclidinium 200 μg and 400 μg showed significant improvements from baseline in mean ( 95 % CI ) trough FEV1 compared with placebo by 86 ( 45 , 127 ) mL and 124 ( 83,164 ) mL , respectively , and in peak FEV1 by 146 ( 101 , 190 ) mL and 192 ( 148 , 236 ) mL , respectively ( p ≤ 0.0001 for all ) . Both aclidinium doses also provided significant improvements in SGRQ , TDI and almost all COPD symptom scores compared with placebo ( p < 0.05 for all ) . Incidences of adverse events ( AEs ) were similar across treatment groups . The incidence of anticholinergic AEs was low and similar across groups ( dry mouth : 0.5%–1.6 % ; constipation : 0%-1.1 % ) . Conclusions : Treatment of moderate-to-severe COPD patients with twice-daily aclidinium 200 μg and 400 μg was associated with significant improvements in bronchodilation , health status , and COPD symptoms . Both doses were well tolerated and had safety profiles similar to placebo . Trial Registration : This ACCORD I study ( AClidinium in Chronic Obstructive Respiratory Disease I ) was registered on clinical trials.gov ( NCT00891462 ) as “ Efficacy and Safety of Aclidinium Bromide for Treatment of Moderate to Severe Chronic Obstructive Pulmonary Disease ( COPD ) ” The efficacy and safety of two doses of aclidinium bromide were evaluated in patients with moderate to severe chronic obstructive pulmonary disease ( COPD ) . In this 24-week , double-blind trial , patients were r and omised to twice-daily aclidinium ( 200 μg or 400 μg ) or placebo . The primary efficacy end-point was change in trough forced expiratory volume in 1 s ( FEV1 ) at week 24 . Other end-points included peak FEV1 , health status ( St George 's Respiratory Question naire ; SGRQ ) and dyspnoea ( Transitional Dyspnoea Index ; TDI ) . Overall , 828 patients were r and omised . At week 24 , significant improvements from baseline were observed with aclidinium 200 μg and 400 μg versus placebo for trough FEV1 ( 99 and 128 mL ; both p<0.0001 ) and peak FEV1 ( 185 and 209 mL ; both p<0.0001 ) . Peak FEV1 improvements on day 1 were comparable with week 24 . Aclidinium 200 μg and 400 μg produced significant improvements over placebo in baseline-adjusted mean SGRQ total score ( -3.8 and -4.6 units ; p<0.001 and p<0.0001 ) and TDI focal score ( 0.6 and 1.0 units ; p<0.05 and p<0.001 ) at week 24 . With both aclidinium doses , the incidence of anticholinergic adverse events was low , and similar to placebo . Twice-daily aclidinium significantly improved bronchodilation , health status and dyspnoea , and was well tolerated in patients with COPD STUDY OBJECTIVES To examine electrocardiographic findings after short- and long-term tiotropium therapy in patients with chronic obstructive pulmonary disease ( COPD ) , and to establish previously reported symptomatic efficacy . DESIGN R and omized , double-blind , placebo-controlled , parallel-group study . SETTING Twelve outpatient investigational centers in the United States . PATIENTS One hundred ninety-six patients with COPD . INTERVENTIONS Patients received either tiotropium 18 mug once/day or placebo , delivered by the H and iHaler device . MEASUREMENTS AND MAIN RESULTS Electrocardiography ( predose and 5 min postdose ) and 24-hour Holter monitoring were performed at baseline and after 8 and 12 weeks of treatment with tiotropium 18 microg once/day or placebo . Efficacy measures ( spirometry , global COPD ratings , scores on the EuroQol Health Question naire [ EQ-5D ] , albuterol inhaler as needed ) were included to demonstrate that the study population exhibited the characteristic improvements observed in previous tiotropium studies . Mean baseline forced expiratory volume in 1 second ( FEV1 ) was 1.03 L. Mean changes in heart rate from baseline were similar in both groups . No differences were noted in the percentage of patients developing rhythm or conduction abnormalities detected with electrocardiography or Holter monitoring . Frequency of premature beats and mean maximal changes in PR , QRS , QT , QTcB , and QTcF intervals were similar in both groups . No patients developed new-onset QT or QTc intervals greater than 500 msec , and no differences were noted in the percentage of patients developing new QT prolongation less than 30 msec , 30 - 60 msec , or greater than 60 msec . At 12 weeks , predose and postdose improvements in FEV1 were 184 and 265 ml , respectively , with tiotropium versus placebo ( p<0.001 ) . Physician and patient global COPD ratings and the EQ-5D visual analog scale scores were improved with tiotropium ( p<0.05 ) ; as-needed albuterol was reduced by 25 % relative to placebo ( p<0.05 ) . CONCLUSION Tiotropium provided spirometric and symptomatic benefits in patients with COPD and was not associated with evidence of electrocardiographic changes in heart rate , rhythm , QT intervals , or conduction This study evaluated whether the effect of tiotropium on the change in trough forced expiratory volume in 1s ( FEV1 ) , vs. placebo , is affected by smoking status . In a 3-month , double-blind study in 31 centres in Portugal , 311 ( 289 completed ) patients were r and omised to tiotropium 18 microg once daily or placebo .  Baseline mean ( st and ard deviation ( SD ) ) FEV1 was 1.11 ( 0.39 ) l in the tiotropium group and 1.13 ( 0.39 ) l in the placebo group . Patients had an average smoking history of 55 ( 25.7 ) pack-years ; 80 ( 26 % ) were smokers and 224 ( 74 % ) were ex-smokers . The primary end-point was change in morning pre-dose ( i.e. trough ) FEV1 after 12 weeks . Trough FEV1 at 12 weeks was significantly improved with tiotropium vs. placebo : the difference in means was 102 ml , P=0.0011 , 95 % confidence interval ( CI ) ( 41 , 164 ) . The difference in means in smokers was 138 ml , P=0.0105 , CI ( 32 , 244 ) ; in ex-smokers it was 66 ml , P=0.0375 , CI ( 3 , 129 ) . The difference between smokers and ex-smokers was not statistically significant ( P=0.6982 ) and may be due to greater variability and differences in disease severity . The significant improvement in lung function in patients treated with tiotropium vs. placebo in both smokers and ex-smokers suggests that tiotropium is an effective and well-tolerated therapy in chronic obstructive pulmonary disease ( COPD ) , regardless of smoking status BACKGROUND Gender differences may occur in many chronic diseases . We have examined the influence of gender in chronic obstructive pulmonary disease ( COPD ) on long-term responses to tiotropium . METHODS Subgroup analysis of data from the Underst and ing the Potential Long-term Impact of Tiotropium ( UPLIFT ) trial ( 4-year , r and omized , double-blind , placebo-controlled trial of tiotropium in patients with COPD ) . RESULTS Of 5992 patients , 75 % were men and 25 % women . Mean age was 65 and 63 years , respectively . Baseline post-bronchodilator forced expiratory volume in 1s ( FEV(1))=47 % predicted(men ) and 49 % predicted(women ) . St George 's Respiratory Question naire ( SGRQ ) total score was 44.9 and 48.7units , respectively . At 48 months , improvement in trough FEV(1 ) over control was 92mL(men ) and 77mL(women ) ( p<0.001 for both ) , with no differences in the rate of decline ( trial primary endpoint ) . Hazard ratio ( HR ) ( 95 % confidence interval [ CI ] ) for first exacerbation ( tiotropium/placebo ) was 0.87(0.81 , 0.93)(men ) and 0.83(0.74 , 0.94)(women ) . Number of exacerbations ( per patient-year ) was reduced with tiotropium in men ( from 0.82 to 0.71 ) and women ( from 0.92 to 0.77 ) ( p<0.005 for both ) . HR ( 95 % CI ) for a hospitalized exacerbation was 0.89(0.79 , 0.99 ) and 0.77(0.62 , 0.94 ) , respectively . HR ( 95 % CI ) for mortality during treatment was 0.85(0.72 , 0.99)(men ) and 0.85(0.62 , 1.18)(women ) . Improvements in SGRQ total score ( tiotropium-control ) at 1 , 2 , 3 and 4 years were : -2.8 , -2.3 , -3.6 , -2.4(men ) and -2.7 , -2.6 , -2.6 , -2.1(women ) ( p<0.05 for all ) . CONCLUSION Long-term treatment of COPD with tiotropium improves lung function , exacerbations and health status in men and women , with similar magnitudes of benefit . Boehringer Ingelheim trial 205.235 ; Clinical Trials.gov : NCT00144339 Clinical manifestations of chronic obstructive pulmonary disease ( COPD ) , including airflow limitation , dyspnea , and activity limitation , ultimately lead to impaired health-related quality of life ( HRQoL ) . This 9-month , r and omized , double-blind , multicenter study compared the effect of once-daily tiotropium 18 μg and placebo on HRQoL , spirometric parameters , and exacerbations in 554 patients with moderate-to-severe COPD .  HRQoL was assessed using the St. George ’s Respiratory Question naire ( SGRQ ) and the new 8-item Visual Simplified Respiratory Question naire ( VSRQ ) , which is currently being vali date d. The primary efficacy endpoint was the proportion of patients achieving a reduction of at least 4 units in the SGRQ total score at study end ( Month 9 ) . Mean ± SD baseline SGRQ total score was 47.4 ± 18.1 . Significantly more tiotropium-treated patients achieved a reduction of at least 4 units in the SGRQ score  vs placebo at study end ( 59.1 % vs 48.2 % , respectively ;  p = 0.029 ) . Tiotropium  significantly improved spirometric parameters ( forced expiratory volume in 1 second [ FEV1 ] : 0.11 ± 0.02 L vs 0.01 ± 0.02 L ; between-group difference : 0.10 ± 0.03 L , p = 0.0001 ) and reduced exacerbations vs placebo . Maintenance treatment with tiotropium provided significant and clinical ly relevant improvements in HRQoL , as measured by the SGRQ Background Two once-daily long-acting muscarinic antagonists ( LAMAs ) are currently available for the treatment of chronic obstructive pulmonary disease ( COPD ) – tiotropium and glycopyrronium . Previous studies have compared glycopyrronium with open-label tiotropium . In the GLOW5 study , we compare glycopyrronium with blinded tiotropium . Methods In this blinded , double-dummy , parallel group , 12-week study , patients with moderate-to-severe COPD were r and omized 1:1 to glycopyrronium 50 μg once daily or tiotropium 18 μg once daily  . The primary objective was to demonstrate the non-inferiority of glycopyrronium versus blinded tiotropium with respect to trough forced expiratory volume in 1 second ( FEV1 ) following 12 weeks of treatment ( non-inferiority margin : –50 mL ) . Secondary objectives were to evaluate glycopyrronium versus tiotropium for other spirometric outcomes , breathlessness ( Transition Dyspnea Index ; TDI ) , health status ( St George ’s Respiratory Question naire ; SGRQ ) , daily rescue medication use , COPD exacerbations and COPD symptoms over 12 weeks of treatment . Results 657 patients were r and omized ( glycopyrronium : 327 ; tiotropium : 330 ) ; 96 % ( 630 patients ) completed the study .  Least squares mean trough FEV1  for both glycopyrronium and tiotropium was 1.405 L at Week 12 , meeting the criterion for non-inferiority ( mean treatment difference : 0 mL , 95 % CI : –32 , 31 mL ) . Glycopyrronium demonstrated rapid bronchodilation following first dose on Day 1 , with significantly higher FEV1 at all time points from 0–4 h post-dose versus tiotropium ( all p < 0.001 ) . FEV1 area under the curve from 0–4 h ( AUC0–4h ) post-dose with glycopyrronium was significantly superior to tiotropium on Day 1 ( p < 0.001 ) and was comparable to tiotropium at Week 12 . Glycopyrronium demonstrated comparable improvements to tiotropium  in TDI focal score , SGRQ total score , rescue medication use and the rate of COPD exacerbations ( all p = not significant ) . Patients on glycopyrronium also had a significantly lower total COPD symptom score versus patients on tiotropium after 12 weeks ( p = 0.035 ) . Adverse events were reported by a similar percentage of patients receiving glycopyrronium ( 40.4 % ) and tiotropium ( 40.6 % ) . Conclusion In patients with moderate-to-severe COPD , 12-week blinded treatment with once-daily glycopyrronium 50 μg or tiotropium 18 μg , provided similar efficacy and safety , with glycopyrronium having a faster onset of action on Day 1 versus tiotropium . Trial registration Clinical Trial.gov , Efficacy and safety of umeclidinium administered in a dry power inhaler were evaluated in moderate-to-very-severe chronic obstructive pulmonary disease patients . This was a r and omised , placebo-controlled study assessing once-daily umeclidinium 62.5 and 125 & mgr;g over 12 weeks . The primary end-point was change from baseline in trough forced expiratory volume in 1 s ( FEV1 ) on day 85 . Secondary end-points were 0–6-h weighted mean and serial forced expiratory volume in 1 s. Other end-points were transitional dyspnoea index , health outcomes ( St George ’s Respiratory Question naire ) , pharmacokinetics and safety . 246 patients were enrolled ; 168 completed the study . On day 85 , umeclidinium 62.5 and 125 & mgr;g significantly improved least squares mean change from baseline in trough FEV1 ( 127 and 152 mL , respectively ; p<0.001 ) compared with placebo . On day 84 , umeclidinium 62.5 and 125 & mgr;g significantly improved least squares mean change from baseline in 0–6-h weighted mean ( 166 and 191 mL , respectively ; p<0.001 ) and serial FEV1 at each time point ( p≤0.003 ) . Significant improvement in least squares mean transitional dyspnoea index focal score ( 1.0 and 1.3 units , respectively ; p≤0.05 ) and change from baseline St George ’s Respiratory Question naire total score ( -7.9 and -10.87 units , respectively ; p<0.001 ) were noted compared with placebo at week 12 . The incidence of adverse events was low and similar across treatments . Umeclidinium 62.5 and 125 & mgr;g significantly improved lung function , dyspnoea and health status compared with placebo , and were well tolerated in chronic obstructive pulmonary disease patients over 12 weeks . Umeclidinium significantly improves lung function , dyspnoea and health status and is well tolerated Currently available inhaled bronchodilators used as therapy for chronic obstructive pulmonary disease ( COPD ) necessitate multiple daily dosing . The present study evaluates the long-term safety and efficacy of tiotropium , a new once-daily anticholinergic in COPD . Patients with stable COPD ( age 65.2±8.7 yrs ( mean±sd ) , n=921 ) were enrolled in two identical r and omized double-blind placebo-controlled 1-yr studies . Patients inhaled tiotropium 18 µg or placebo ( mean screening forced expiratory volume in one second ( FEV1 ) 1.01 versus 0.99 L , 39.1 and 38.1 % of the predicted value ) once daily as a dry powder . The primary spirometric outcome was trough FEV1 ( i.e. FEV1 prior to dosing ) . Changes in dyspnoea were measured using the Transition Dyspnea Index , and health status with the disease-specific St. George 's Respiratory Question naire and the generic Short Form 36 . Medication use and adverse events were recorded . Tiotropium provided significantly superior bronchodilation relative to placebo for trough FEV1 response ( ∼12 % over baseline ) ( p<0.01 ) and mean response during the 3 h following dosing ( ∼22 % over baseline ) ( p<0.001 ) over the 12-month period . Tiotropium recipients showed less dyspnoea ( p<0.001 ) , superior health status scores , and fewer COPD exacerbations and hospitalizations ( p<0.05 ) . Adverse events were comparable with placebo , except for dry mouth incidence ( tiotropium 16.0 % versus placebo 2.7 % , p<0.05 ) . Tiotropium is an effective , once-daily bronchodilator that reduces dyspnoea and chronic obstructive pulmonary disease exacerbation frequency and improves health status . This suggests that tiotropium will make an important contribution to chronic obstructive pulmonary disease therapy Abstract Background : This r and omized , double-blind , Phase IIIb study evaluated the 24-hour bronchodilatory efficacy of aclidinium bromide versus placebo and tiotropium in patients with moderate-to-severe chronic obstructive pulmonary disease ( COPD ) . Methods : Patients received aclidinium 400 μg twice daily ( morning and evening ) , tiotropium 18 μg once daily ( morning ) , or placebo for 6 weeks . The primary endpoint was change from baseline in forced expiratory volume in 1 second area under the curve for the 24-hour period post-morning dose ( FEV1 AUC0–24 ) at week 6 . Secondary and additional endpoints included FEV1 AUC12–24 , COPD symptoms ( EXAcerbations of chronic pulmonary disease Tool-Respiratory Symptoms [ E-RS ] total score and additional symptoms question naire ) , and safety . Results : Overall , 414 patients were r and omized and treated ( FEV1 1.63 L [ 55.8 % predicted ] ) . Compared with placebo  , FEV1 AUC0–24 and FEV1 AUC12–24 were significantly increased from baseline with aclidinium ( ∆ = 150 mL and 160 mL , respectively ; p < 0.0001 ) and tiotropium ( ∆ = 140 mL and 123 mL , respectively ; p < 0.0001 ) at week 6 . Significant improvements in E-RS total scores over 6 weeks were numerically greater with aclidinium ( p < 0.0001 ) than tiotropium ( p < 0.05 ) versus placebo . Only aclidinium significantly reduced the severity of early-morning cough , wheeze , shortness of breath , and phlegm , and of nighttime symptoms  versus  placebo ( p < 0.05 ) . Adverse-event ( AE ) incidence ( 28 % ) was similar between treatments . Few anticholinergic AEs ( < 1.5 % ) or serious AEs ( <3 % ) occurred in any group . Conclusions : Aclidinium provided significant 24-hour bronchodilation versus placebo from day 1 with comparable efficacy to tiotropium after 6 weeks . Improvements in COPD symptoms were consistently numerically greater with aclidinium versus tiotropium . Aclidinium was generally well tolerated 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 STUDY OBJECTIVE To compare the bronchodilator efficacy and safety of tiotropium and placebo . DESIGN A 3-month , r and omized , double-blind , placebo-controlled , multicenter trial . SETTING Outpatient . PATIENTS Four hundred seventy patients with stable COPD ( mean FEV(1 ) = 38.6 % predicted ) . INTERVENTIONS Tiotropium 18 microg ( N = 279 ) or placebo ( N = 191 ) given once daily via a lactose-based dry-powder inhaler device . MEASUREMENTS AND RESULTS Spirometry was evaluated on days 1 , 8 , 50 , and 92 . Data were expressed as the mean trough ( ie , before morning dose ; 23 to 24 h after previous dose ) and average response observed in the 3 h after the dose was received . Tiotropium produced significant improvement in trough FEV(1 ) and FVC , averaging 12 % greater than baseline on day 8 ; these improvements were maintained on days 50 and 92 . The average postdose FEV(1 ) was 16 % greater than baseline on day 1 and 20 % greater than baseline on day 92 ; FVC was 17 % greater than baseline on day 1 and 19 % greater than baseline on day 92 . Tiotropium was significantly more effective than placebo in both trough and average FEV(1 ) and FVC response ( p < 0.001 ) . These spirometric effects were corroborated by significant improvements in daily morning and evening peak expiratory flow rate , as well as a reduction in " as-needed " albuterol use . Symptoms of wheezing and shortness of breath were significantly less in patients receiving tiotropium , and the physician global assessment noted overall improvements with those treated with tiotropium relative to placebo . The most common reported adverse event after tiotropium was dry mouth ( 9.3 % vs 1.6 % relative to placebo ; p < 0.05 ) . CONCLUSIONS These data demonstrate that tiotropium is a safe and effective once-daily anticholinergic bronchodilator and should prove useful as first-line maintenance therapy in COPD RATIONALE Indacaterol is the first once-daily , long-acting inhaled beta(2)-agonist bronchodilator studied in patients with chronic obstructive pulmonary disease ( COPD ) . OBJECTIVES To demonstrate greater efficacy of indacaterol versus placebo on FEV(1 ) at 24 hours post dose ( trough ) after 12 weeks , to compare efficacy with placebo and tiotropium , and to evaluate safety and tolerability over 26 weeks . MEASUREMENTS Patients with moderate-to-severe COPD were r and omized to double-blind indacaterol 150 or 300 microg or placebo , or open-label tiotropium 18 microg , all once daily , for 26 weeks . The primary efficacy outcome was trough FEV(1 ) at 12 weeks . Additional analyses ( not adjusted for multiplicity ) included transition dyspnea index ( TDI ) , health status ( St George 's Respiratory Question naire [ SGRQ ] ) , and exacerbations . Serum potassium , blood glucose , and QTc interval were measured . RESULTS A total of 1,683 patients ( age , 63.3 yr ; post-bronchodilator FEV(1 ) , 56 % predicted ; FEV(1)/FVC , 0.53 ) were r and omized to the four treatment arms . Trough FEV(1 ) at Week 12 increased versus placebo by 180 ml with both indacaterol doses and by 140 ml with tiotropium ( all P < 0.001 vs. placebo ) . At Week 26 , for indacaterol 150/300 microg , respectively , versus placebo , TDI increased ( 1.00/1.18 , P < 0.001 ) and SGRQ total score decreased ( -3.3/-2.4 , P < 0.01 ) ; corresponding results with tiotropium were 0.87 ( P < 0.001 ) for TDI and ( -1.0 , P = not significant ) for SGRQ total score . The incidence of adverse events , low serum potassium , high blood glucose , and prolonged QTc interval was similar across treatments . CONCLUSIONS Indacaterol was an effective once-daily bronchodilator and was at least as effective as tiotropium in improving clinical outcomes for patients with COPD . Clinical trial registered with clinical trials.gov ( NCT 00463567 ) Although guidelines recommend combining long-acting bronchodilators in COPD , data are limited . We examined the clinical efficacy and safety of formoterol , tiotropium and the combination in patients with COPD . Eight hundred and forty-seven patients with COPD ( mean FEV(1 ) 52 % predicted ; FEV(1)/FVC 53 % ) were r and omized to receive one of the following four treatments for 24 weeks : formoterol 10 microg b.i.d . plus tiotropium 18 microg o.d . ; formoterol 10 microg b.i.d . ; tiotropium 18 microg o.d . , or placebo . The study was partially blinded ( formoterol and placebo ) . For the primary endpoint , FEV(1 ) 2h post-dose after 24 weeks , there were small differences in favour of the combination therapy versus formoterol ( 0.07 L , p=0.044 ) or tiotropium ( 0.06 L , p=0.066 ) . All three treatments were superior to placebo ( p<0.001 ) . The combination was statistically superior to monotherapy for : the primary endpoint ( p=0.044 vs. formoterol ) ; FEV(1 ) 5 min after the first dose ( p<0.001 ) and at 12 weeks ( p<0.05 vs. tiotropium ) ; and peak expiratory flow averaged over the first 6 weeks ( p<0.001 vs. both ) . The three active treatments were significantly more effective than placebo for secondary endpoints : COPD -related ' bad days ' , symptoms , use of rescue medication and peak expiratory flow , and aspects of health-related quality of life . The overall incidence of adverse events was similar with all active treatments , although COPD -related adverse events were more common with tiotropium . Combined bronchodilator therapy may be a valuable treatment option for patients with COPD BACKGROUND A study was undertaken to record exacerbations and health re source use in patients with COPD during 6 months of treatment with  tiotropium , salmeterol , or matching placebos . METHODS Patients with COPD were enrolled in two 6-month r and omised , placebo controlled , double blind , double dummy studies of tiotropium 18 micro g once daily via H and iHaler or salmeterol 50 micro g twice daily via a metered dose inhaler . The two trials were combined for analysis of heath outcomes consisting of exacerbations , health re source use , dyspnoea ( assessed by the transitional dyspnoea index , TDI ) , health related quality of life ( assessed by St George 's Respiratory Question naire , SGRQ ) , and spirometry . RESULTS 1207 patients participated in the study  ( tiotropium 402 , salmeterol 405 , placebo 400 ) . Compared with placebo , tiotropium but not salmeterol was associated with a significant delay in the time to onset of the first exacerbation . Fewer COPD exacerbations/patient year occurred in the tiotropium group ( 1.07 ) than in the placebo group ( 1.49 , p<0.05 ) ; the salmeterol group ( 1.23 events/year ) did not differ from placebo . The tiotropium group had 0.10 hospital admissions per patient year for COPD exacerbations compared with 0.17 for salmeterol and 0.15 for placebo ( not statistically different ) . For all causes ( respiratory and non-respiratory ) tiotropium , but not salmeterol , was associated with fewer hospital admissions while both groups had fewer days in hospital than the placebo group . The number of days during which patients were unable to perform their usual daily activities was lowest in the tiotropium group ( tiotropium 8.3 ( 0.8 ) , salmeterol 11.1 ( 0.8 ) , placebo 10.9 ( 0.8 ) , p<0.05 ) . SGRQ total score improved by 4.2 ( 0.7 ) , 2.8 ( 0.7 ) and 1.5 ( 0.7 ) units during the 6 month trial for the tiotropium , salmeterol and placebo groups , respectively ( p<0.01 tiotropium v placebo ) . Compared with placebo , TDI focal score improved in both the tiotropium group ( 1.1 ( 0.3 ) units , p<0.001 ) and the salmeterol group ( 0.7 ( 0.3 ) units , p<0.05 ) . Evaluation of morning pre-dose FEV(1 ) , peak FEV(1 ) and mean FEV(1 ) ( 0 - 3 hours ) showed that tiotropium was superior to salmeterol while both active drugs were more effective than placebo . CONCLUSIONS Exacerbations of COPD and health re source usage were positively affected by daily treatment with tiotropium . With the exception of the number of hospital days associated with all causes , salmeterol twice daily result ed in no significant changes compared with placebo . Tiotropium also improved health related quality of life , dyspnoea , and lung function in patients with COPD BACKGROUND The efficacy and safety of aclidinium bromide bid , a novel , long-acting , muscarinic antagonist , was assessed in patients with moderate to severe COPD . METHODS In this phase IIa r and omized , double-blind , double-dummy , crossover trial , patients with moderate to severe COPD received aclidinium 400 μg bid , tiotropium 8 μg once daily , and placebo for 15 days , with a 9- to 15-day washout between treatment periods . Treatments were administered through the Genuair or H and iHaler dry powder inhalers . The primary end point was mean change from baseline in FEV(1 ) AUC(0 - 12/12h ) ( area under the curve where the numbers represent the time period for which data were collected divided by the number of hours over which the data are averaged [ eg , 0 - 12 h postdose divided by 12 h ] ) on day 15 . Secondary end points were changes from baseline in FEV(1 ) AUC(12 - 24/12h ) , FEV(1 ) AUC(0 - 24/24h ) , morning predose FEV(1 ) , peak FEV(1 ) , and COPD symptom scores . RESULTS Thirty patients with COPD were r and omized , and 27 completed the study . Mean change from baseline in FEV(1 ) AUC(0 - 12/12h ) at day 15 was significantly greater for aclidinium and tiotropium over placebo ( P < .0001 ) . Mean changes from baseline in FEV(1 ) AUC(12 - 24/12h ) , FEV(1 ) AUC(0 - 24/24h ) , morning predose FEV(1 ) , and peak FEV(1 ) at day 15 were significantly greater for aclidinium and tiotropium over placebo ( P < .0001 for all except P < .001 for FEV(1 ) AUC(12 - 24/12h ) tiotropium vs placebo ) . Improvements were significantly greater with aclidinium vs tiotropium on day 1 for all of the normalized AUC values of FEV(1 ) as well as on day 15 for FEV(1 ) AUC(12 - 24/12h ) ( P < .05 for all ) . COPD symptoms were significantly improved from baseline with aclidinium vs placebo ( P < .05 ) but not with tiotropium . CONCLUSIONS In patients with COPD  , aclidinium 400 μg bid compared with placebo provided clinical ly meaningful improvements in 24-h bronchodilation that generally were comparable to tiotropium 18 μg daily but with significant differences in favor of aclidinium observed in the average nighttime period . Larger studies with longer treatment duration are ongoing to confirm the efficacy  of aclidinium 400 μg bid on bronchodilation and COPD symptoms . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT00868231 ; URL : www . clinical trials.gov BACKGROUND Patients with chronic obstructive pulmonary disease ( COPD ) who smoke have a greater annual rate of decline in forced expiratory volume in 1 s ( FEV(1 ) ) than those patients who have stopped smoking . OBJECTIVES To assess the effect of tiotropium on pre-dose ( trough ) FEV(1 ) in patients with COPD followed in Canada . METHODS A total of 913 patients were r and omly assigned to receive either tiotropium 18 mug once daily ( n=608 ) or placebo ( usual care minus inhaled anticholinergics ) ( n=305 ) for 48 weeks in the present r and omized , double-blind , parallel-group study . The effect of tiotropium on measurements of lung function ( FEV(1 ) , FEV(6 ) and forced vital capacity ) , symptoms , health-related quality of life ( St George 's Respiratory Question naire ) and exacerbations were examined . RESULTS Tiotropium improved trough FEV(1 ) in both current and ex-smokers compared with placebo .  Baseline FEV(1 ) in smokers and ex-smokers was 1.03 L and 0.93 L , respectively ( P<0.001 ) . At week 48 , the mean difference between the tiotropium and placebo groups was 0.14+/-0.04 L ( P<0.001 ) in the smoker group and 0.08+/-0.02 L ( P<0.0001 ) in the ex-smoker group . Tiotropium also significantly improved trough forced vital capacity and FEV(6 ) compared with placebo throughout the treatment period ( P<0.05 , for all ) . Furthermore , tiotropium significantly improved the St George 's Respiratory Question naire total score compared with placebo at week 48 ( 40.9 versus 43.7 units , P<0.005 ) . CONCLUSIONS Compared with the placebo group , tiotropium provides sustained improvements in lung function in patients with COPD , with improvements for smokers and ex-smokers Background : Chronic obstructive pulmonary disease ( COPD ) is characterized by airflow limitation , which results in the progressive development of dyspnea and exercise limitation . Objective and Methods : To compare the effect of tiotropium with placebo on forced vital capacity ( FVC ) in patients with moderate-to-severe COPD and lung hyperinflation , using exercise endurance , dyspnea and health-related quality of life ( HRQoL ) as secondary endpoints . One hundred patients were r and omized to receive either tiotropium 18 µg once daily or placebo for 12 weeks . Results : Trough ( predose ) FVC was significantly improved with tiotropium compared to placebo on day 42 ( 0.27 ± 0.08 liters ) and 84 ( 0.20 ± 0.08 liters ; p < 0.05 for both ) . Trough inspiratory capacity ( IC ) was also significantly improved with tiotropium compared to placebo on day 42 ( 0.16 ± 0.07 liters ) and 84 ( 0.15 ± 0.07 liters ; p < 0.05 for both ) . Tiotropium increased the mean distance walked during the shuttle walking test by 33 ± 12 ( day 42 ) and 36 ± 14 m ( day 84 ) compared to placebo ( p < 0.05 for both ) . On day 84 , 59 % of the patients in the tiotropium group and 35 % of the patients in the placebo group had significant and clinical ly meaningful improvements in the St. George ’s Respiratory Question naire total score ( p < 0.05 ) . Numerical decreases in the focal score in the Transition Dyspnea Index in patients receiving tiotropium versus placebo suggest that tiotropium also improved dyspnea during activities of daily living . Conclusion : Tiotropium 18 µg once daily reduced hyperinflation with consequent improvements in walking distance and HRQoL in patients with COPD and lung hyperinflation BACKGROUND Tiotropium , a once-daily anticholinergic , and salmeterol represent two inhaled , long-acting bronchodilators from different pharmacologic classes . A trial was design ed to examine the efficacy and safety of both compounds with multiple outcome measures , including lung function , dyspnea , and health-related quality of life ( HRQoL ) in patients with COPD . METHODS A 6-month , r and omized , placebo-controlled , double-blind , double-dummy , parallel-group study of tiotropium , 18 microg once daily via dry-powder inhaler , compared with salmeterol , 50 microg bid via metered-dose inhaler , was conducted in patients with COPD .  Efficacy was assessed by 12-h monitoring of spirometry , transition dyspnea index ( TDI ) , and the St. George 's Respiratory Question naire ( SGRQ ) . RESULTS A total of 623 patients participated ( tiotropium , n= 209 ; salmeterol , n = 213 ; and  placebo , n = 201 ) . The groups were similar in age ( mean , 65 years ) , gender ( 75 % men ) , and baseline FEV(1 ) ( mean , 1.08 + /- 0.37 L ; percent predicted , 40 + /- 12 % [ + /- SD ] ) . Compared with placebo treatment , the mean predose morning FEV(1 ) following 6 months of therapy increased significantly more for the tiotropium group ( 0.14 L ) than the salmeterol group ( 0.09 L ; p < 0.01 ) . The average FEV(1 ) ( 0 to 12 h ) for tiotropium was statistically superior to salmeterol ( difference , 0.08 L ; p < 0.001 ) . Tiotropium improved TDI focal score by 1.02 U compared with placebo ( p = 0.01 ) , whereas there was no significant change in TDI focal score with salmeterol ( 0.24 U ) . Tiotropium was superior to salmeterol in improving TDI focal score ( p < 0.05 ) . At 6 months , the mean improvement in SGRQ total score vs baseline was tiotropium , - 5.14 U ( p < 0.05 vs placebo ) ; salmeterol , - 3.54 U ( p = 0.4 vs placebo ) ; and placebo , - 2.43 U. A statistically higher proportion of patients receiving tiotropium achieved at least a 4-U change in SGRQ score compared to patients receiving placebo . Both active drugs reduced the need for rescue albuterol ( p < 0.0001 ) . CONCLUSIONS Tiotropium once daily produces superior bronchodilation , improvements in dyspnea , and proportion of patients achieving meaningful changes in HRQoL compared to twice-daily salmeterol in patients with COPD Background and Objectives Aclidinium bromide is a long-acting muscarinic antagonist approved for the long-term maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease ( COPD ) . This 12-week phase III study evaluated efficacy and tolerability of aclidinium 200 or 400 μg in patients with moderate-to-severe COPD . Methods In this double-blind study , 544 patients with COPD were r and omized to placebo or twice-daily aclidinium 200 or 400 μg administered by Genuair ® /Pressair ® . Lung function , health status [ measured by the St. George ’s Respiratory Question naire ( SGRQ ) ] , dyspnea [ measured using the Transition Dyspnea Index ( TDI ) ] , and safety were assessed throughout the study . Results Mean changes from baseline in morning trough forced expiratory volume in 1 s ( FEV1 ) at week 12 ( primary endpoint ) were significantly higher for aclidinium than for placebo ( 200 μg , 51 mL ; 400 μg , 72 mL ; both p < 0.05 ) . Aclidinium also significantly improved other lung function outcomes . At week 12 , improvements from baseline were observed with aclidinium  in SGRQ total score ( 200 μg , −6.0 ; 400 μg , −5.4 ) and TDI focal score ( 200 μg , 1.0 ; 400 μg , 1.3 ) . Furthermore , clinical ly important improvements in SGRQ total and TDI focal scores were achieved by 45 and 51 % of patients , respectively , who received aclidinium 400 μg , with a significant difference versus placebo for TDI ( p < 0.05 ) . Anticholinergic-related adverse events ( e.g. , dry mouth ) were infrequent , occurring < 2 % for any event in any treatment group . Both aclidinium doses were well tolerated . Conclusion This study demonstrates efficacy and safety  of aclidinium in COPD patients . Unexpected baseline imbalances between treatment groups may have impacted the aclidinium treatment benefit in this study Context Tiotropium , a new once-daily inhaled anticholinergic bronchodilator , has been shown to improve lung function in patients with chronic obstructive pulmonary disease ( COPD ) . Previous studies have suggested that it may also decrease the frequency of exacerbations and hospitalizations in these patients . Contribution This r and omized , parallel-group , double-blind , placebo-controlled study in patients with moderate to severe COPD showed a small but statistically significant decrease in the exacerbation rate during the 6-month study period . Caution s The study period was relatively short , and the beneficial effects were modest . The Editors Exacerbations of chronic obstructive pulmonary disease ( COPD ) can lead to costly and clinical ly significant consequences . Proven treatments for exacerbations are only modestly effective ( 1 , 2 ) . Recovery from even mild exacerbations may be protracted ( 3 ) . Frequent exacerbations are associated with impaired quality of life and a more rapid decline in lung function over time ( 4 , 5 ) . Patients with severe exacerbations commonly seek care in emergency departments , and many of these patients are hospitalized . In 2000 , COPD was responsible for 1.5 million emergency department visits and 726000 hospitalizations in the United States ( 6 ) . Economic analyses suggest that hospitalization alone consumes up to 70 % of all medical expenses for patients with COPD ( 7 , 8) . Interventions that reduce the frequency or severity of exacerbations are a highly desirable but poorly met medical need . An expert panel convened by the National Heart , Lung , and Blood Institute assigned a high priority to clinical research that might improve the management of COPD exacerbations ( 9 ) . Tiotropium is a newly developed , once-daily inhaled anticholinergic bronchodilator . Because of its very slow dissociation from muscarinic M3 receptors , 1 inhaled dose produces sustained bronchodilation for at least 24 hours ( 10 ) . In controlled clinical trials , compared with placebo or the short-acting anticholinergic bronchodilator ipratropium , tiotropium improved lung function , dyspnea , and health-related quality of life in patients with COPD ( 11 , 12 ) . An analysis of adverse event reports su bmi tted during those studies suggested that tiotropium might also reduce exacerbation and COPD -related hospitalization rates . Therefore , we design ed a clinical trial to prospect ively test the hypothesis that tiotropium reduces exacerbations and hospitalizations due to COPD . Methods Study Design Our study was a parallel-group , r and omized , double-blind , placebo-controlled trial in patients with moderate to severe COPD conducted at 26 Veterans Affairs medical centers in the United States . The sole intervention was tiotropium given by inhalation once daily . The principal outcomes were the percentage of patients experiencing at least 1 exacerbation and the percentage of patients with at least 1 hospitalization due to a COPD exacerbation during a 6-month treatment period . The protocol is consistent with the principles of Helsinki . The institutional review boards of participating medical centers approved the study . All trial participants provided written informed consent . Patients All men and women receiving medical care at participating Veterans Affairs medical centers were potential study participants . We enrolled enough participants to ensure a minimum of 1800 r and omly assigned patients . Eligibility criteria included an age of 40 years or older , a cigarette smoking history of 10 pack-years or more , a clinical diagnosis of COPD , and an FEV1 of 60 % predicted or less and 70 % or less of the FVC . Exclusion criteria were a clinical diagnosis of asthma , a myocardial infa rct ion within the previous 6 months , a serious cardiac arrhythmia or hospitalization for heart failure within the previous year , known moderate to severe renal impairment , moderate to severe symptomatic prostatic hypertrophy or bladder-neck obstruction , narrow-angle glaucoma , current radiation or chemotherapy for a malignant condition , or inability to give informed consent . We also excluded patients who took systemic corticosteroids at unstable doses , or in regular daily doses of 20 mg or more of prednisone ( or equivalent ) , or who had not fully recovered from an exacerbation for at least 30 days before the first study visit . We gathered baseline data on respiratory disease and other relevant medical history by question naire . Procedures We allocated eligible patients in equal numbers to receive tiotropium or placebo according to a central ly generated blocked r and omization list . We generated a single r and omization and assigned blocks to centers . We provided r and omly assigned patients with training and detailed instructions on the use of the dry powder inhalation device ( H and iHaler , Boehringer Ingelheim Pharma GmbH & Co. KG , Biberach , Germany ) ( 13 ) . Blinding of supplies was performed at Boehringer Ingelheim before distribution to investigational sites . The double-blind remained in place until all patients were clinical ly complete or until a serious adverse event required unblinding . Each morning during the trial , patients inhaled 1 capsule of tiotropium ( 18 g ) or 1 identical placebo capsule . Participants otherwise received usual medical care , except that they could not take any open-label anticholinergic bronchodilator . They continued taking all other respiratory medications ( including inhaled corticosteroids and long-acting -agonists ) , and primary providers were allowed to prescribe additional medications according to medical need . Primary providers also prescribed antibiotics and systemic steroid prescriptions for exacerbations without restrictions . For purpose s of recall , patients kept a daily diary throughout the treatment period , recording information about specific respiratory symptoms , medications taken for exacerbations , clinic visits , and hospitalizations . We collected information about exacerbations and health care utilization by interviews when patients made site visits at 3 and 6 months and by telephone calls at 1-month intervals between visits . We assessed study drug adherence by query and by counting returned capsules .  Participants performed spirometry before and 90 minutes after inhalation of study drug at baseline and again at the 3-month and 6-month visits . We encouraged patients to complete study visits and to provide all requested medical information even if they prematurely discontinued the study drug therapy . However , patients who discontinued the study drug therapy did not have 90-minute postinhalation spirometry testing at subsequent study visits . All open-label bronchodilators and the study drug were withheld overnight before spirometry . Study sites performed spirometry by using a common predictive nomogram with equipment and methods that conformed to American Thoracic Society recommendations ( 14 , 15 ) . Objectives We aim ed to determine whether tiotropium decreased COPD exacerbations and hospitalizations due to exacerbations . Outcome Measures The co primary outcomes were the percentage of patients with a COPD exacerbation and the percentage of patients with a hospitalization due to COPD exacerbation . We defined an exacerbation as a complex of respiratory symptoms ( increase or new-onset ) of more than 1 of the following : cough , sputum , wheezing , dyspnea , or chest tightness with a duration of at least 3 days requiring treatment with antibiotics or systemic steroids , hospitalization , or both . The study team at each site requested discharge summaries for all hospitalizations , wherever they occurred . We identified hospitalizations due to COPD exacerbations from events on case report forms that met the protocol definition of an exacerbation and where review of discharge summaries and other available medical records indicated that the event result ed in a hospitalization . We also considered an event to be a hospitalization if a patient was held and treated for an acute respiratory condition in an urgent care department or in an observation unit for longer than 24 hours . Admissions to nursing homes or other extended care facilities were not considered hospitalizations . Secondary outcomes included time to first COPD exacerbation and time to first hospitalization due to COPD exacerbation , the frequencies of exacerbations and of exacerbation-related health care utilization ( hospitalizations , hospitalization days , unscheduled clinic visits , antibiotic treatment days , and systemic corticosteroid treatment days ) , the frequencies of all-cause hospitalizations and hospitalization days , and results of spirometry . Statistical Analysis We analyzed the data by using a modified intention-to-treat principle . Therefore , we included all available data for the patients with any follow-up contact who took at least 1 capsule of study drug in the analysis up to their first event ( for the time-to-event end points ) or their withdrawal from the trial . For the time-to-event end points , we censored patients without an event at the end of their participation in the trial . Although we intended to follow all patients for the full 6 months , some patients were lost to follow-up . We h and led missing data by using longitudinal data analysis methods ( spirometry ) , analysis of observed data only ( number of events ) , or analysis methods for censored data ( time-to-event data ) . For the percentage of patients with an event , we considered that patients who discontinued the study drug therapy before having an event did not have an event . We analyzed the co primary end points by using a CochranMantelHaenszel test with center as a stratum . We used a stepwise procedure to test the percentage of patients with an exacerbation and , if rejected , to test percentage of patients with a hospitalization due to COPD exacerbation , each at a 2-sided level of 0.05 . Because of the prespecified closed testing procedure , no adjustment for multiplicity was required . We calculated that a sample size of 1800 patients would have 80 % power to 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
Background R and omized , controlled trials comparing long-acting muscarinic antagonist ( LAMA ) efficacy in COPD are limited .
This network meta- analysis ( NMA ) assessed the relative efficacy of tiotropium 18 µg once-daily ( OD ) and newer agents ( aclidinium 400 µg twice-daily , glycopyrronium 50 µg OD , and umeclidinium 62.5 µg OD ) .