human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Background The combination of aclidinium bromide , a long-acting anticholinergic , and formoterol fumarate , a long-acting beta2-agonist ( 400/12 μg twice daily ) achieves improvements in lung function greater than either monotherapy in patients with chronic obstructive pulmonary disease ( COPD ) , and is approved in the European Union as a maintenance treatment . The effect of this combination on symptoms of COPD and exacerbations is less well established . We examined these outcomes in a pre-specified analysis of pooled data from two 24-week , double-blind , parallel-group , active- and placebo-controlled , multicentre , r and omised Phase III studies ( ACLIFORM and AUGMENT ) . Methods Patients ≥40 years with moderate to severe COPD ( post-bronchodilator forced expiratory volume in 1 s [FEV1]/forced vital capacity < 70 % and FEV1 ≥30 % but < 80 % predicted normal ) were r and omised ( ACLIFORM : 2:2:2:2:1 ; AUGMENT : 1:1:1:1:1 ) to twice-daily aclidinium/formoterol 400/12 μg or 400/6 μg , aclidinium 400 μg , formoterol 12 μg or placebo via Genuair ™ /Pressair ® . Dyspnoea ( Transition Dyspnoea Index ; TDI ) , daily symptoms ( EXAcerbations of Chronic pulmonary disease Tool [EXACT]-Respiratory Symptoms [ E-RS ] question naire ) , night-time and early-morning symptoms , exacerbations ( Healthcare Re source Utilisation [ HCRU ] and EXACT definitions ) and relief-medication use were assessed . Results The pooled intent-to-treat population included 3394 patients . Aclidinium/formoterol 400/12 μg significantly improved TDI focal score versus placebo and both monotherapies at Week 24 ( all p < 0.05 ) . Over 24 weeks , significant improvements in E-RS total score , overall night-time and early-morning symptom severity and limitation of early-morning activities were observed with aclidinium/formoterol 400/12 μg versus placebo and both monotherapies ( all p < 0.05 ) . The rate of moderate or severe HCRU exacerbations was significantly reduced with aclidinium/formoterol 400/12 μg compared with placebo ( p < 0.05 ) but not monotherapies ; the rate of EXACT-defined exacerbations was significantly reduced with aclidinium/formoterol 400/12 μg versus placebo ( p < 0.01 ) and aclidinium ( p < 0.05 ) . Time to first HCRU or EXACT exacerbation was longer with aclidinium/formoterol 400/12 μg compared with placebo ( all p < 0.05 ) but not the monotherapies . Relief-medication use was reduced with aclidinium/formoterol 400/12 μg versus placebo and aclidinium ( p < 0.01 ) . Conclusions Aclidinium/formoterol 400/12 μg significantly improves 24-hour symptom control compared with placebo , aclidinium and formoterol in patients with moderate to severe COPD . Furthermore , aclidinium/formoterol 400/12 μg reduces the frequency of exacerbations compared with placebo . Trial registration NCT01462942 and NCT01437397 ( Clinical Trials.gov The Phase IV , 8-week , r and omized , double-blind , placebo-controlled ACTIVATE study ( NCT02424344 ) evaluated the effect of aclidinium/formoterol ( AB/FF ) 400/12 μg twice daily on lung hyperinflation , exercise capacity , and physical activity in patients with moderate-to-severe COPD . Patients received AB/FF ( n=134 ) or placebo ( n=133 ) ( 1:1 ) via the Genuair ™ /Pressair ® dry powder inhaler for 8 weeks . From Weeks 5 to 8 , all patients participated in behavioral intervention ( BI ; daily messages providing step goals ) . The primary end point was trough functional residual capacity ( FRC ) at Week 4 . Exercise endurance time and physical activity were assessed at Week 4 ( pharmacotherapy only ) and at Week 8 ( 8 weeks of pharmacotherapy plus 4 weeks of BI ) . Other end points included post-dose FRC , residual volume , and inspiratory capacity ( IC ) at rest and during exercise . After 4 weeks , trough FRC improved with AB/FF versus placebo but did not reach significance ( 125 mL ; P=0.0690 ) . However , post-dose FRC , residual volume , and IC at rest improved significantly with AB/FF at Week 4 versus placebo ( all P<0.0001 ) . AB/FF significantly improved exercise endurance time and IC at isotime versus placebo at Week 4 ( P<0.01 and P<0.0001 , respectively ) and Week 8 ( P<0.05 and P<0.0001 , respectively ) . AB/FF achieved higher step counts ( P<0.01 ) with fewer inactive patients ( P<0.0001 ) at Week 4 versus placebo . Following BI , AB/FF maintained improvements in physical activity at Week 8 and nonsignificant improvements were observed with placebo . AB/FF 400/12 μg demonstrated improvements in lung hyperinflation , exercise capacity , and physical activity versus placebo that were maintained following the addition of BI . A 4-week period of BI might be too short to augment the improvements of physical activity observed with AB/FF INTRODUCTION Aclidinium bromide/formoterol fumarate ( AB/FF ) 400/12 μg efficacy and safety was demonstrated in two 6-month Phase III studies ( AUGMENT and ACLIFORM ) and a 12-month study in patients with moderate to severe chronic obstructive pulmonary disease ( COPD ) . This Phase III , double-blind , placebo-controlled , 6-month AUGMENT extension investigated the long-term safety and tolerability of AB/FF 400/12 μg ( NCT01572792 ) . METHODS Patients were r and omised in AUGMENT  ( 1:1:1:1:1 ) to twice-daily AB/FF 400/12 μg , AB/FF 400/6 μg , AB 400 μg , FF 12 μg or placebo . Patients completing AUGMENT were invited to continue the same treatment in the extension . Adverse events ( AEs ) , major adverse cardiovascular events ( MACE ) , laboratory tests , electrocardiograms and vital signs were recorded . Efficacy was assessed . RESULTS Of 1322 patients completing AUGMENT , 921 enrolled and 780 completed the extension .  AE incidence was low and comparable across treatment groups ; most common were nasopharyngitis ( range 4.8%-9.3 % ) , urinary tract infection ( range 4.1%-8.8 % ) and upper respiratory tract infection ( range 2.7%-5.5 % ) . Serious AEs ( SAEs ) and MACE were low ( ranges 6.8%-7.7 % and 0.5%-1.5 % , respectively ) . Significant improvements in bronchodilation and dyspnoea were maintained over 52 weeks versus placebo . Trends towards improvements in other symptoms and health status were observed versus placebo and monotherapies . AB/FF combinations increased the time to first exacerbation by approximately 30 % versus placebo ( p < 0.05 ) . CONCLUSION AB/FF 400/12 μg was well tolerated over 52 weeks with low incidences of AEs , SAEs and MACE that were comparable across treatment groups . Improvements in bronchodilation , symptoms and health status were maintained across 52 weeks Bronchodilator therapy is the backbone of the management of chronic obstructive pulmonary disease . In some patients , inhaled corticosteroids can be prescribed in combination with bronchodilators . Through a subgroup analysis of pooled data from two large phase III clinical trials of bronchodilator therapy according to concomitant inhaled corticosteroid use ( user vs. non-user ) , we sought to evaluate the clinical benefit of adding inhaled corticosteroids to dual bronchodilator therapy in chronic obstructive pulmonary disease . The primary focus of this analysis of pooled data from the phase III ACLIFORM and AUGMENT studies was to evaluate the efficacy of aclidinium/formoterol on lung function stratified by inhaled corticosteroid use . We found that lung-function end points were significantly improved regardless of concomitant inhaled corticosteroid use among patients treated with the dual bronchodilator aclidinium/formoterol 400/12 µg twice daily compared with placebo and both monotherapies . Together with the previously reported observations that aclidinium/formoterol 400/12 µg reduces exacerbations vs. placebo in inhaled corticosteroid users and improves dyspnoea compared to monotherapy in inhaled corticosteroid non-users , these data suggest that both groups achieve lung function improvements , which translates to different clinical benefits depending on whether or not a patient is receiving concomitant inhaled corticosteroids . Chronic lung disease : ‘ Triple ’ therapy could prove beneficialA dual bronchodilator therapy taken together with corticosteroid inhalers may benefit patients with severe chronic lung disease .  Bronchodilator drugs relax the lungs and widen airways in patients with chronic obstructive pulmonary disease ( COPD ) . While recent studies have shown that a dual bronchodilator therapy containing aclidinium and formoterol significantly improves lung function in COPD , little is known about combining the dual therapy with inhaled corticosteroids ( ICSs ) . Anthony D’Urzo at the University of Toronto , Canada , and co-workers analysed data from 3394 patients with COPD undergoing dual therapy trials . Of these , 1180 were already taking ICSs . The team compared symptoms in the ICS group with those not taking ICSs . The dual therapy improved lung function across both groups regardless of ICS use , though patients gained different clinical benefits depending on ICS use and disease severity The degree of acute improvement in spirometric indices after bronchodilator inhalation varies among chronic obstructive pulmonary disease ( COPD ) patients , and depends upon the type and dose of bronchodilator and the timing of administration . Acute bronchodilator responsiveness at baseline was examined in a large cohort of patients with moderate-to-very-severe COPD participating in the Underst and ing Potential Long-term Impacts on Function with Tiotropium ( UPLIFT ) trial , a 4-yr r and omised double-blind trial evaluating the efficacy of 18 μg tiotropium daily in reducing the rate of decline in lung function . After wash-out of respiratory medications , patients received 80 μg ipratropium followed by 400 μg salbutamol .  Spirometry was performed before and 90 min following ipratropium administration . The criteria used for forced expiratory volume in one second ( FEV1 ) responsiveness were : ≥12 % increase over baseline and ≥200 mL ; ≥15 % increase over baseline ; and ≥10 % absolute increase in the percentage predicted value . Of the patients , 5,756 had data meeting the criteria for analysis ( age 64.5 yrs ; 75 % male ; baseline FEV1 1.10 L ( 39.3 % predicted ) and forced vital capacity ( FVC ) 2.63 L ) . Compared with baseline , mean improvements were 229 mL in FEV1 and 407 mL in FVC . Of these patients , 53.9 % had ≥12 % and ≥200 mL improvement in FEV1 , 65.6 % had ≥15 % improvement in FEV1 , and 38.6 % had ≥10 % absolute increase in FEV1 % pred . The majority of patients with moderate-to-very-severe chronic obstructive pulmonary disease demonstrate meaningful increases in lung function following administration of inhaled anticholinergic plus sympathomimetic bronchodilators Background Combining two long-acting bronchodilators with complementary mechanisms of action may provide treatment benefits to patients with chronic obstructive pulmonary disease ( COPD ) that are greater than those derived from either treatment alone . The efficacy and safety of a fixed-dose combination ( FDC ) of aclidinium bromide , a long-acting muscarinic antagonist , and formoterol fumarate , a long-acting β2-agonist , in patients with moderate to severe COPD are presented . Methods In this 24-week double-blind study , 1692 patients with stable COPD were equally r and omized to twice-daily treatment with FDC aclidinium 400μg/formoterol 12μg ( ACL400/FOR12 FDC ) , FDC aclidinium 400μg/formoterol 6μg ( ACL400/FOR6 FDC ) , aclidinium 400μg , formoterol 12μg , or placebo administered by a multidose dry powder inhaler (Genuair ® /Pressair ® )*. Co 
    Output:
    
agent
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Background The combination of aclidinium bromide , a long-acting anticholinergic , and formoterol fumarate , a long-acting beta2-agonist ( 400/12 μg twice daily ) achieves improvements in lung function greater than either monotherapy in patients with chronic obstructive pulmonary disease ( COPD ) , and is approved in the European Union as a maintenance treatment . The effect of this combination on symptoms of COPD and exacerbations is less well established . We examined these outcomes in a pre-specified analysis of pooled data from two 24-week , double-blind , parallel-group , active- and placebo-controlled , multicentre , r and omised Phase III studies ( ACLIFORM and AUGMENT ) . Methods Patients ≥40 years with moderate to severe COPD ( post-bronchodilator forced expiratory volume in 1 s [FEV1]/forced vital capacity < 70 % and FEV1 ≥30 % but < 80 % predicted normal ) were r and omised ( ACLIFORM : 2:2:2:2:1 ; AUGMENT : 1:1:1:1:1 ) to twice-daily aclidinium/formoterol 400/12 μg or 400/6 μg , aclidinium 400 μg , formoterol 12 μg or placebo via Genuair ™ /Pressair ® . Dyspnoea ( Transition Dyspnoea Index ; TDI ) , daily symptoms ( EXAcerbations of Chronic pulmonary disease Tool [EXACT]-Respiratory Symptoms [ E-RS ] question naire ) , night-time and early-morning symptoms , exacerbations ( Healthcare Re source Utilisation [ HCRU ] and EXACT definitions ) and relief-medication use were assessed . Results The pooled intent-to-treat population included 3394 patients . Aclidinium/formoterol 400/12 μg significantly improved TDI focal score versus placebo and both monotherapies at Week 24 ( all p < 0.05 ) . Over 24 weeks , significant improvements in E-RS total score , overall night-time and early-morning symptom severity and limitation of early-morning activities were observed with aclidinium/formoterol 400/12 μg versus placebo and both monotherapies ( all p < 0.05 ) . The rate of moderate or severe HCRU exacerbations was significantly reduced with aclidinium/formoterol 400/12 μg compared with placebo ( p < 0.05 ) but not monotherapies ; the rate of EXACT-defined exacerbations was significantly reduced with aclidinium/formoterol 400/12 μg versus placebo ( p < 0.01 ) and aclidinium ( p < 0.05 ) . Time to first HCRU or EXACT exacerbation was longer with aclidinium/formoterol 400/12 μg compared with placebo ( all p < 0.05 ) but not the monotherapies . Relief-medication use was reduced with aclidinium/formoterol 400/12 μg versus placebo and aclidinium ( p < 0.01 ) . Conclusions Aclidinium/formoterol 400/12 μg significantly improves 24-hour symptom control compared with placebo , aclidinium and formoterol in patients with moderate to severe COPD . Furthermore , aclidinium/formoterol 400/12 μg reduces the frequency of exacerbations compared with placebo . Trial registration NCT01462942 and NCT01437397 ( Clinical Trials.gov The Phase IV , 8-week , r and omized , double-blind , placebo-controlled ACTIVATE study ( NCT02424344 ) evaluated the effect of aclidinium/formoterol ( AB/FF ) 400/12 μg twice daily on lung hyperinflation , exercise capacity , and physical activity in patients with moderate-to-severe COPD . Patients received AB/FF ( n=134 ) or placebo ( n=133 ) ( 1:1 ) via the Genuair ™ /Pressair ® dry powder inhaler for 8 weeks . From Weeks 5 to 8 , all patients participated in behavioral intervention ( BI ; daily messages providing step goals ) . The primary end point was trough functional residual capacity ( FRC ) at Week 4 . Exercise endurance time and physical activity were assessed at Week 4 ( pharmacotherapy only ) and at Week 8 ( 8 weeks of pharmacotherapy plus 4 weeks of BI ) . Other end points included post-dose FRC , residual volume , and inspiratory capacity ( IC ) at rest and during exercise . After 4 weeks , trough FRC improved with AB/FF versus placebo but did not reach significance ( 125 mL ; P=0.0690 ) . However , post-dose FRC , residual volume , and IC at rest improved significantly with AB/FF at Week 4 versus placebo ( all P<0.0001 ) . AB/FF significantly improved exercise endurance time and IC at isotime versus placebo at Week 4 ( P<0.01 and P<0.0001 , respectively ) and Week 8 ( P<0.05 and P<0.0001 , respectively ) . AB/FF achieved higher step counts ( P<0.01 ) with fewer inactive patients ( P<0.0001 ) at Week 4 versus placebo . Following BI , AB/FF maintained improvements in physical activity at Week 8 and nonsignificant improvements were observed with placebo . AB/FF 400/12 μg demonstrated improvements in lung hyperinflation , exercise capacity , and physical activity versus placebo that were maintained following the addition of BI . A 4-week period of BI might be too short to augment the improvements of physical activity observed with AB/FF INTRODUCTION Aclidinium bromide/formoterol fumarate ( AB/FF ) 400/12 μg efficacy and safety was demonstrated in two 6-month Phase III studies ( AUGMENT and ACLIFORM ) and a 12-month study in patients with moderate to severe chronic obstructive pulmonary disease ( COPD ) . This Phase III , double-blind , placebo-controlled , 6-month AUGMENT extension investigated the long-term safety and tolerability of AB/FF 400/12 μg ( NCT01572792 ) . METHODS Patients were r and omised in AUGMENT  ( 1:1:1:1:1 ) to twice-daily AB/FF 400/12 μg , AB/FF 400/6 μg , AB 400 μg , FF 12 μg or placebo . Patients completing AUGMENT were invited to continue the same treatment in the extension . Adverse events ( AEs ) , major adverse cardiovascular events ( MACE ) , laboratory tests , electrocardiograms and vital signs were recorded . Efficacy was assessed . RESULTS Of 1322 patients completing AUGMENT , 921 enrolled and 780 completed the extension .  AE incidence was low and comparable across treatment groups ; most common were nasopharyngitis ( range 4.8%-9.3 % ) , urinary tract infection ( range 4.1%-8.8 % ) and upper respiratory tract infection ( range 2.7%-5.5 % ) . Serious AEs ( SAEs ) and MACE were low ( ranges 6.8%-7.7 % and 0.5%-1.5 % , respectively ) . Significant improvements in bronchodilation and dyspnoea were maintained over 52 weeks versus placebo . Trends towards improvements in other symptoms and health status were observed versus placebo and monotherapies . AB/FF combinations increased the time to first exacerbation by approximately 30 % versus placebo ( p < 0.05 ) . CONCLUSION AB/FF 400/12 μg was well tolerated over 52 weeks with low incidences of AEs , SAEs and MACE that were comparable across treatment groups . Improvements in bronchodilation , symptoms and health status were maintained across 52 weeks Bronchodilator therapy is the backbone of the management of chronic obstructive pulmonary disease . In some patients , inhaled corticosteroids can be prescribed in combination with bronchodilators . Through a subgroup analysis of pooled data from two large phase III clinical trials of bronchodilator therapy according to concomitant inhaled corticosteroid use ( user vs. non-user ) , we sought to evaluate the clinical benefit of adding inhaled corticosteroids to dual bronchodilator therapy in chronic obstructive pulmonary disease . The primary focus of this analysis of pooled data from the phase III ACLIFORM and AUGMENT studies was to evaluate the efficacy of aclidinium/formoterol on lung function stratified by inhaled corticosteroid use . We found that lung-function end points were significantly improved regardless of concomitant inhaled corticosteroid use among patients treated with the dual bronchodilator aclidinium/formoterol 400/12 µg twice daily compared with placebo and both monotherapies . Together with the previously reported observations that aclidinium/formoterol 400/12 µg reduces exacerbations vs. placebo in inhaled corticosteroid users and improves dyspnoea compared to monotherapy in inhaled corticosteroid non-users , these data suggest that both groups achieve lung function improvements , which translates to different clinical benefits depending on whether or not a patient is receiving concomitant inhaled corticosteroids . Chronic lung disease : ‘ Triple ’ therapy could prove beneficialA dual bronchodilator therapy taken together with corticosteroid inhalers may benefit patients with severe chronic lung disease .  Bronchodilator drugs relax the lungs and widen airways in patients with chronic obstructive pulmonary disease ( COPD ) . While recent studies have shown that a dual bronchodilator therapy containing aclidinium and formoterol significantly improves lung function in COPD , little is known about combining the dual therapy with inhaled corticosteroids ( ICSs ) . Anthony D’Urzo at the University of Toronto , Canada , and co-workers analysed data from 3394 patients with COPD undergoing dual therapy trials . Of these , 1180 were already taking ICSs . The team compared symptoms in the ICS group with those not taking ICSs . The dual therapy improved lung function across both groups regardless of ICS use , though patients gained different clinical benefits depending on ICS use and disease severity The degree of acute improvement in spirometric indices after bronchodilator inhalation varies among chronic obstructive pulmonary disease ( COPD ) patients , and depends upon the type and dose of bronchodilator and the timing of administration . Acute bronchodilator responsiveness at baseline was examined in a large cohort of patients with moderate-to-very-severe COPD participating in the Underst and ing Potential Long-term Impacts on Function with Tiotropium ( UPLIFT ) trial , a 4-yr r and omised double-blind trial evaluating the efficacy of 18 μg tiotropium daily in reducing the rate of decline in lung function . After wash-out of respiratory medications , patients received 80 μg ipratropium followed by 400 μg salbutamol .  Spirometry was performed before and 90 min following ipratropium administration . The criteria used for forced expiratory volume in one second ( FEV1 ) responsiveness were : ≥12 % increase over baseline and ≥200 mL ; ≥15 % increase over baseline ; and ≥10 % absolute increase in the percentage predicted value . Of the patients , 5,756 had data meeting the criteria for analysis ( age 64.5 yrs ; 75 % male ; baseline FEV1 1.10 L ( 39.3 % predicted ) and forced vital capacity ( FVC ) 2.63 L ) . Compared with baseline , mean improvements were 229 mL in FEV1 and 407 mL in FVC . Of these patients , 53.9 % had ≥12 % and ≥200 mL improvement in FEV1 , 65.6 % had ≥15 % improvement in FEV1 , and 38.6 % had ≥10 % absolute increase in FEV1 % pred . The majority of patients with moderate-to-very-severe chronic obstructive pulmonary disease demonstrate meaningful increases in lung function following administration of inhaled anticholinergic plus sympathomimetic bronchodilators Background Combining two long-acting bronchodilators with complementary mechanisms of action may provide treatment benefits to patients with chronic obstructive pulmonary disease ( COPD ) that are greater than those derived from either treatment alone . The efficacy and safety of a fixed-dose combination ( FDC ) of aclidinium bromide , a long-acting muscarinic antagonist , and formoterol fumarate , a long-acting β2-agonist , in patients with moderate to severe COPD are presented . Methods In this 24-week double-blind study , 1692 patients with stable COPD were equally r and omized to twice-daily treatment with FDC aclidinium 400μg/formoterol 12μg ( ACL400/FOR12 FDC ) , FDC aclidinium 400μg/formoterol 6μg ( ACL400/FOR6 FDC ) , aclidinium 400μg , formoterol 12μg , or placebo administered by a multidose dry powder inhaler (Genuair ® /Pressair ® )*. Co 
    Output:
    