Long-Term Once-Daily Tiotropium Respimat® Is Well Tolerated and Maintains Efficacy over 52 Weeks in Patients with Symptomatic Asthma in Japan: A Randomised, Placebo-Controlled Study The effect of fluticasone furoate/umeclidinium in adult patients with asthma: a randomized, dose-ranging study. A randomised controlled trial of tiotropium in adolescents with severe symptomatic asthma The Effect of Tiotropium in Symptomatic Asthma Despite Low- to Medium-Dose Inhaled Corticosteroids: A Randomized Controlled Trial. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials Validation of the AQLQ12+ among adolescents and adults with persistent asthma Assessment of second-line treatments for patients with uncontrolled moderate asthma. Modification of the asthma quality of life questionnaire (standardised) for patients 12 years and older What are minimal important changes for asthma measures in a clinical trial? Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma. Measurement properties and interpretation of three shortened versions of the asthma control questionnaire. Pulmonary function assessment in mild to moderate persistent asthma patients receiving montelukast, doxofylline, and tiotropium with budesonide: a randomized controlled study. Tiotropium in asthma poorly controlled with standard combination therapy. Tiotropium add-on therapy in adolescents with moderate asthma: A 1-year randomized controlled trial. Anticholinergic vs Long-Acting β-Agonist in Combination With Inhaled Corticosteroids in Black Adults With Asthma: The BELT Randomized Clinical Trial. Tiotropium or salmeterol as add-on therapy to inhaled corticosteroids for patients with moderate symptomatic asthma: two replicate, double-blind, placebo-controlled, parallel-group, active-comparator, randomised trials.
Background This study assessed the long-term safety and efficacy of tiotropium Respimat , a long-acting inhaled anticholinergic bronchodilator , in asthma , added on to inhaled corticosteroids ( ICS ) with or without long-acting β2-agonist ( LABA ) . Methods 285 patients with symptomatic asthma , despite treatment with ICS±LABA  , were r and omised 2:2:1 to once-daily tiotropium 5 μg , tiotropium 2.5 μg or placebo for 52 weeks ( via the Respimat SoftMist inhaler ) added on to ICS±LABA , in a double-blind , placebo-controlled , parallel-group study ( NCT01340209 ) . Primary objective : to describe the long-term safety profile  of tiotropium . Secondary end points included : trough forced expiratory volume in 1 second ( FEV1 ) response ; peak expiratory flow rate ( PEFR ) response ; seven- question Asthma Control Question naire ( ACQ-7 ) score . Results At Week 52 , adverse-event ( AE ) rates  with tiotropium 5 μg , 2.5 μg and placebo were 88.6 % , 86.8 % and 89.5 % , respectively . Commonly reported AEs with tiotropium 5 μg , 2.5 μg and placebo were nasopharyngitis ( 48.2 % , 44.7 % , 42.1 % ) , asthma ( 28.9 % , 29.8 % , 38.6 % ) , decreased PEFR ( 15.8 % , 7.9 % , 21.1 % ) , bronchitis ( 9.6 % , 13.2 % , 7.0 % ) , pharyngitis ( 7.9 % , 13.2 % , 3.5 % ) and gastroenteritis ( 10.5 % , 3.5 % , 5.3 % ) . In the tiotropium 5 μg , 2.5 μg and placebo groups , 8.8 % , 5.3 % and 5.3 % of patients reported drug-related AEs ; 3.5 % , 3.5 % and 15.8 % reported serious AEs . Asthma worsening was the only serious AE reported in more than one patient . At Week 52 , adjusted mean trough FEV1 and trough PEFR responses were significantly higher with tiotropium 5 μg ( but not 2.5 μg ) versus placebo . ACQ-7 responder rates were higher with tiotropium 5 μg and 2.5 μg versus placebo at Week 24 . Conclusions The long-term tiotropium Respimat  safety profile was comparable with that of placebo Respimat , and associated with mild to moderate , non-serious AEs in patients with symptomatic asthma despite ICS±LABA therapy . Compared with placebo , tiotropium 5 μg , but not 2.5 μg , significantly improved lung function and symptoms , supporting the long-term efficacy of the 5 μg dose . Trial Registration Clinical Trials.gov BACKGROUND We evaluated the dose-response of umeclidinium ( UMEC ; a long-acting muscarinic antagonist ) combined with fluticasone furoate ( FF ; an inhaled corticosteroid [ ICS ] ) in patients with asthma . METHODS In a double-blind , three-period crossover study , 421 subjects ( symptomatic on ICS ) , were r and omized to a sequence of three of seven treatments : FF 100 mcg alone , FF 100 mcg combined with UMEC ( 15.6 , 31.25 , 62.5 , 125 , or 250 mcg ) , or vilanterol 25 mcg ( a long-acting β-agonist ) , inhaled once-daily for 14 days ( 12 - 14-day washout ) . Trough forced expiratory volume in one second ( FEV1 ) , peak expiratory flow ( PEF ) , and safety were assessed . RESULTS Period baseline was a significant covariate , indicating a potential carryover effect between treatment periods . Across all treatment periods , trough FEV1 improved with FF/UMEC 125 and 250 versus FF ( treatment difference 0.055 L [ both doses ] ; p = 0.018 ) . FF/UMEC increased morning ( 15.9 - 22.9 L/min ) and evening ( 16.2 - 28.8 L/min ) PEF versus FF . As intended assessment s were confounded , post hoc Period 1 data analyses were performed , demonstrating significant increases in trough FEV1 with FF/UMEC 31.25 , 62.5 , and 250 versus FF . Trough FEV1 improvements with FF/UMEC were greater in subjects with fixed ( 0.095 - 0.304 L ) versus non-fixed ( -0.084 to 0.041 L ) obstruction . The incidence of on-treatment adverse events was 13 - 25 % across groups . No treatment-related effects on laboratory parameters were reported . CONCLUSION FF/UMEC may be a viable treatment for patients with asthma symptomatic on ICS ; benefit may be most prominent in those with fixed obstruction . The carryover effect suggests future UMEC studies should use an alternative design . Clinical Trials.gov : NCT01573624 We present results from the first phase III trial of once-daily tiotropium add-on to inhaled corticosteroids ( ICS ) plus one or more controller therapies in adolescents with severe symptomatic asthma . In this double-blind , parallel-group trial ( NCT01277523 ) , 392 patients aged 12–17 years were r and omised to receive once-daily tiotropium 5 µg or 2.5 µg , or placebo , as an add-on to ICS plus other controller therapies over 12 weeks . The primary and key secondary end-points were change from baseline ( response ) in peak forced expiratory volume in 1 s ( FEV1 ) within 3 h post-dosing ( FEV1(0–3h ) ) and trough FEV1 , respectively , after 12 weeks of treatment  . Tiotropium 5 µg provided numerical improvements in peak FEV1(0–3h ) response , compared with placebo ( 90 mL ; p=0.104 ) , and significant improvements were observed with tiotropium 2.5 µg ( 111 mL ; p=0.046 ) . Numerical improvements in trough FEV1 response and asthma control were observed with both tiotropium doses , compared  with placebo . The safety and tolerability  of tiotropium were comparable with those of  placebo . Once-daily tiotropium Respimat add-on to ICS plus one or more controller therapies in adolescents with severe symptomatic asthma  was well tolerated . The primary end-point of efficacy was not met , although positive trends for improvements in lung function and asthma control were observed  . Tiotropium add-on therapy provided numerical improvements in outcomes in adolescents with asthma BACKGROUND Tiotropium , a once-daily long-acting anticholinergic bronchodilator , has demonstrated efficacy in patients with asthma who were symptomatic despite treatment with medium- to high-dose inhaled corticosteroids ( ICS ) . OBJECTIVE The objective of this study was to evaluate the efficacy and safety of once-daily tiotropium Respimat ( 5 μg or 2.5 μg ) , compared with placebo Respimat , as add-on therapy to low- to medium-dose ICS for adults with symptomatic asthma . METHODS A phase III , double-blind , placebo-controlled trial was conducted ( NCT01316380 ) . Adults with symptomatic asthma receiving low- to medium-dose ICS ( 200 - 400 μg budesonide or equivalent dose ) and a pre-bronchodilator forced expiratory volume in 1 second ( FEV1 ) ≥60 % and ≤90 % of predicted normal were r and omized to 12 weeks of treatment with once-daily tiotropium Respimat 5 μg or 2.5 μg , or placebo Respimat , as add-on therapy to ICS . The primary endpoint was peak FEV1(0 - 3h ) response . RESULTS In total , 464 patients were r and omized ( 61 % female ; mean age 43 years ; mean baseline FEV1 78 % of predicted normal ) . After 12 weeks , both tiotropium Respimat doses were superior to placebo ( adjusted mean difference from placebo : 5 μg , 128 mL ; 2.5 μg , 159 mL ; both P < .001 ) . Both doses of tiotropium Respimat were also superior to placebo with regard to the secondary endpoints of adjusted mean trough FEV1 and FEV1 area under the curve(0 - 3h ) responses , and the other endpoints of morning and evening peak expiratory flow . Adverse events were comparable across the treatment groups . CONCLUSIONS Once-daily tiotropium Respimat add-on therapy to low- to medium-dose ICS in adults with symptomatic asthma is an efficacious bronchodilator , and its safety and tolerability are comparable with those of placebo Respimat Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more Background To date , there is limited psychometric evidence on the Asthma Quality of Life Question naire ( AQLQ12 + ) among population s that include adolescents and adults . Objective To provide evidence of the psychometric properties of the AQLQ12 + as a measure of asthma-specific quality of life ( QOL ) in patients with persistent asthma treated with a combination of inhaled glucocorticoid and long-acting beta2-agonist  , as well as explore the predictors of at least a minimally important AQLQ12 + improvement . Methods The psychometric properties of the AQLQ12 + were assessed through post hoc analysis of two large ( n = 740 and 778 ) Phase III , r and omized , double-blinded , placebo-controlled efficacy studies of mometasone furoate/formoterol fumarate ( MF/F ) combination compared with monotherapy in subjects with persistent asthma previously treated with either low-dose or medium-dose inhaled glucocorticoids .  Results With 15 % and 8 % participation from 12- to 17-year olds , blinded trial data demonstrated excellent reproducibility ( ICC range : 0.76–0.85 ) and moderate-to-strong construct validity with other measures of asthma health at baseline and over time for the AQLQ12 + . A greater percentage of the MF/F treatment group ( 44 % ) achieved an important change at 26 weeks on the AQLQ12 +  compared with formoterol fumarate ( F , 23 % ) and placebo ( 18 % ) treatment groups in the low-dose study ( P < 0.001 ) and the medium-dose study ( 50 % ( MF/F ) versus 34 % ( F ) and 23 % ( placebo ) ; P < 0.001 ) . Pre-r and omization nighttime awakenings and rescue medications use were significant predictors of AQLQ12 + improvement . Conclusions These findings provide strong support for the measurement properties of the AQLQ12 + among patients with persistent asthma and confidence in the AQLQ12 + improvements demonstrated by the MF/F treatment group AIM To evaluate the best second-line treatments for patients with uncontrolled moderate asthma . METHODS A single-center , r and om study was conducted in adult patients with uncontrolled moderate asthma to evaluate the effects of add-on treatments . After add-on treatments for 4 and 12 weeks , the concentration of exhaled nitric oxide ( FeNO ) , average daily durnal peak expiratory flow ( PEF ) variability and asthma control test ( ACT ) score were measured . RESULTS 94 patients have been divided into three groups to take different add-on treatments , in tiotropium bromide group , montelukast sodium group and double-dose inhaled corticosteroid ( ICS ) group . After four weeks , most patients improved their symptoms and ACT scores , with lower concentration of FeNO and small PEF variability . In double-dose ICS group , almost all patients took the complete controls of asthma , compared to those in other two groups . After additional 12 weeks ' therapy , patients in all three groups nearly achieved complete controls of asthma . There were two patients with pneumonia in double-dose ICS group . Patients in double-dose ICS group had higher ACT scores , lower concentrations of FeNO and smaller PEF variabilities , but a higher risk of pneumonia , compared to those in other two groups . The differences of PEF variabilities and ACT scores between tiotropium group and double-dose ICS group were not significant . CONCLUSION Tiotropium in combination with ICS plus LABA showed the similar effects with double-dose ICS plus LABA , without adverse effects , which might be the best option for optimal control of asthma Background The age limit for some adult asthma clinical trials has recently been lowered to 12 years . In this study we have made minor modifications to the st and ardised version of the adult Asthma Quality of Life Question naire ( AQLQ(S ) ) to make it valid for patients 12 years and older ( AQLQ12 + ) . Methods We have used two clinical trial data bases , in which the AQLQ12 + was used , to compare the measurement properties of the question naire in patients 12–17 years and patients 18 years and older . A total of 2433 patients ( 12–75 years ) , with current asthma and with data that could be evaluated both at r and omisation and end of treatment , were included . Results The analysis showed that internal consistency , responsiveness and correlations with other clinical indices were very similar in patients 12–17 years and patients 18 years and older . Conclusion The measurement properties of the  AQLQ12 +  are similar in adolescents and adults and therefore the instrument is valid for use in adult studies which include children 12 years and older In this study , the perceptions of asthmatics to change in their disease was associated with observed changes in clinical asthma measures , in order to identify the threshold where changes in clinical asthma measures are perceivable by patients . The study included 281 asthmatic patients , aged 18 - 63 yrs , in a r and omized , placebo-controlled clinical trial of a leukotriene antagonist .  Changes were related in : 1 ) asthma symptom scores ; 2 ) inhaled beta-agonist use ; 3 ) forced expiratory volume in one second ( FEV1 ) ; and 4 ) peak expiratory flow ( PEF ) to a global question that queried overall change in asthma since starting the study drug . Additional analyses examined differences in the group reporting minimal improvement by treatment ( active treatment versus placebo ) , sex and age groups . The average minimal patient perceivable improvement for each measure was : 1 ) -0.31 points for the symptom score on a scale of 0 - 6 ; 2 ) -0.81 puffs x day(-1 ) for inhaled beta-agonist use ; 3 ) 0.23 L for FEV1 ; and 4 ) 18.79 L x min(-1 ) for PEF . In general placebo-treated patients and older patients , who reported minimal improvement , experienced less mean improvement from baseline than active-treated patients and younger patients , who reported minimal improvement . Determining the minimal patient perceivable improvement value for a measure may be helpful to interpret changes . However , interpretation should be carried out cautiously when reporting a single value as a clinical ly important change BACKGROUND The efficacy and safety of inhaled long-acting β(2)-adrenergic agonists in asthmatic patients with the B16-Arg/Arg genotype has been question ed , and the use of antimuscarinics has been proposed as an alternative in patients whose symptoms are not controlled by inhaled corticosteroids ( ICSs ) . OBJECTIVE We compared the efficacy and safety of the long-acting anticholinergic tiotropium with salmeterol and placebo added to an ICS in B16-Arg/Arg patients with asthma that was not controlled by ICSs alone . METHODS In a double-blind , double-dummy , placebo-controlled trial , after a 4-week run-in period with 50 μg of twice-daily salmeterol administered through a metered-dose inhaler , 388 asthmatic patients were r and omized 1:1:1 to 16 weeks of treatment with 5 μg of Respimat tiotropium administered daily in the evening , 50 μg of salmeterol administered twice daily through a metered-dose inhaler , or placebo . Patients aged 18 to 67 years demonstrated reversibility to bronchodilators , and their symptoms were uncontrolled by regular ICSs ( 400 - 1000 μg of budesonide/equivalent ) . ICS regimens were maintained throughout the trial . The mean weekly morning peak expiratory flow ( PEF ) before r and omization was 358 ± 115.7 L/min ( range , 80.3 - 733.0 L/min ) . RESULTS Changes in weekly PEF from the last week of the run-in period to the last week of treatment ( primary end point : change in PEF ) were -3.9 ± 4.87 L/min ( n = 128 ) for tiotropium and -3.2 ± 4.64 L/min ( n = 134 ) for salmeterol , and these were superior to placebo ( -24.6 ± 4.84 L/min , n = 125 , P < .05 ) . Tiotropium was noninferior to salmeterol ( estimated difference , -0.78 L/min [ 95 % CI , -13.096 to 11.53 ] ; P = .002 ; α = .025 , 1-sided ; noninferiority , 20 L/min ) . Tiotropium and salmeterol were numerically superior  to  placebo in some patient-reported secondary outcomes . Adverse events were comparable across treatments . CONCLUSION Tiotropium was more effective than placebo and as effective as salmeterol in maintaining improved lung function in B16-Arg/Arg patients with moderate persistent asthma .  Safety profiles were comparable The Asthma Control Question naire ( ACQ ) measures the adequacy of asthma treatment as identified by international guidelines . It consists of seven items ( 5 x symptoms , rescue bronchodilator use and FEV1 % of predicted normal ) . A validation study suggested that in clinical studies measurement of FEV1 and bronchodilator use may not be needed but this has never formally been tested in a clinical trial . The aims of this analysis were ( 1 ) to examine the measurement properties of three shortened versions of the ACQ ( symptoms alone , symptoms plus FEV1 and symptoms plus short-acting beta2-agonist )  and ( 2 ) to determine whether using the shortened versions would alter the results of a clinical trial . In the r and omised trial , 552 adults completed the ACQ at baseline and after 13 and 26 weeks of treatment . The analysis showed that the measurement properties of all four versions of the ACQ are very similar . Agreement between the original ACQ and the reduced versions was high ( intraclass correlation coefficients : 0.94 - 0.99 ) . Mean differences between the ACQ and the shortened versions were less than 0.04 ( on the 7-point scale ) . Clinical trial results using the four versions were almost identical with the mean treatment difference ranging from -0.09 ( P=0.17 ) , to -0.13 ( P=0.07 ) . For interpretability , the minimal important difference for all four versions was close to 0.5 . In conclusion , these three shortened versions of the ACQ can be used in large clinical trials without loss of validity or change in interpretation BACKGROUND There is no comparative study among asthma patients receiving first-line versus various second-line treatment regimens for mild to moderate persistent asthma . OBJECTIVE We assessed the pulmonary function  in asthma patients receiving montelukast , doxofylline , and tiotropium with budesonide  in a pilot group . METHODS Patients were recruited as per the study criteria and r and omly allocated to 4 groups to receive budesonide ( 400 µg ) with formoterol ( 12 µg ) , doxofylline ( 400 mg ) , montelukast ( 10 mg ) , or tiotropium ( 18 µg ) for a period of 3 months . Outcomes included forced expiratory volume in 1 second ( FEV1 ) and rescue medication use . RESULTS A total of 167 patients were recruited ; among them , 123 patients completed the study . At baseline , no significant difference ( P > 0.05 ) was observed in any of the outcome measures . Significant within-group improvement in FEV1 was observed in all the groups . At day 90 , between-group difference revealed that improvement in FEV1 was significantly ( P < 0.05 ) high for budesonide plus formoterol followed by budesonide plus doxofylline , budesonide plus montelukast , and , lastly , budesonide plus tiotropium . Similarly , within-group comparison revealed a significant ( P < 0.05 ) reduction in rescue medication use in all the groups . The intensity in decrease was more in budesonide plus formoterol group followed by budesonide plus doxofylline , budesonide plus montelukast , and budesonide plus tiotropium groups . CONCLUSION On the basis of our findings , among the second-line treatment regimens , budesonide plus doxofylline and budesonide plus montelukast was found to be better than budesonide plus tiotropium in patients with mild to moderate persistent asthma . Further studies with a larger sample size are likely to be useful BACKGROUND Some patients with asthma have frequent exacerbations and persistent airflow obstruction despite treatment with inhaled glucocorticoids and long-acting beta-agonists ( LABAs ) . METHODS In two replicate , r and omized , controlled trials involving 912 patients with asthma who were receiving inhaled glucocorticoids and LABAs  , we compared the effect on lung function and exacerbations of adding tiotropium ( a total dose of 5 μg ) or placebo , both delivered by a soft-mist inhaler once daily for 48 weeks . All the patients were symptomatic , had a post-bronchodilator forced expiratory volume in 1 second ( FEV(1 ) ) of 80 % or less of the predicted value , and had a history of at least one severe exacerbation in the previous year . RESULTS The patients had a mean baseline FEV(1 ) of 62 % of the predicted value ; the mean age was 53 years . At 24 weeks , the mean ( ±SE ) change in the peak FEV(1 ) from baseline was greater with tiotropium than with placebo in the two trials : a difference of 86±34 ml in trial 1 ( P=0.01 ) and 154±32 ml in trial 2 ( P<0.001 ) . The predose ( trough ) FEV(1 ) also improved in trials 1 and 2 with tiotropium , as compared with placebo : a difference of 88±31 ml ( P=0.01 ) and 111±30 ml ( P<0.001 ) , respectively . The addition of tiotropium  increased the time to the first severe exacerbation ( 282 days vs. 226 days ) , with an overall reduction of 21 % in the risk of a severe exacerbation ( hazard ratio , 0.79 ; P=0.03 ) . No deaths occurred ; adverse events were similar in the two groups . CONCLUSIONS In patients with poorly controlled asthma despite the use of inhaled glucocorticoids and LABAs , the addition of tiotropium significantly increased the time to the first severe exacerbation and provided modest sustained bronchodilation . ( Funded by Boehringer Ingelheim and Pfizer ; Clinical Trials.gov numbers , NCT00772538 and NCT00776984 . ) BACKGROUND Results from phase III clinical trials in adults and phase II clinical trials in children and adolescents demonstrate that tiotropium is an effective treatment when added to inhaled corticosteroid ( ICS ) maintenance therapy . OBJECTIVE We sought to assess the efficacy and safety of once-daily tiotropium Respimat added to ICSs with or without a leukotriene receptor antagonist in a phase III trial in adolescent patients with moderate symptomatic asthma . METHODS In this 48-week , double-blind , placebo-controlled , parallel-group study , 398 patients aged 12 to 17 years were r and omized to receive 5 μg ( 2 puffs of 2.5 μg ) or 2.5 μg ( 2 puffs of 1.25 μg ) of once-daily tiotropium or placebo ( 2 puffs ) administered through the Respimat device every evening , each as add-on treatment to ICS background therapy , with or without a leukotriene receptor antagonist ; long-acting β2-agonist therapy was not permitted during the study . RESULTS Improvement in peak FEV1 within 3 hours after dosing at 24 weeks ( primary end point ) was statistically significant with both tiotropium doses compared with placebo : 5 μg of tiotropium , 174 mL ( 95 % CI , 76 - 272 mL ) ; 2.5 μg of tiotropium , 134 mL ( 95 % CI , 34 - 234 mL ) . Significant improvements in trough FEV1 at week 24 ( a secondary end point ) were observed with the 5-μg dose only . Trends for improvement in asthma control and health-related quality of life over the 48-week treatment period were observed . CONCLUSIONS Once-daily tiotropium  significantly improved lung function and was safe and well tolerated when added to at least ICS maintenance therapy in adolescent patients with moderate symptomatic asthma . Larger responses were observed with the 5-μg tiotropium dose IMPORTANCE The efficacy and safety of long-acting β-agonists ( LABAs ) have been question ed . Black population s may be disproportionately affected by LABA risks . OBJECTIVE To compare the effectiveness and safety of tiotropium vs LABAs , when used with inhaled corticosteroids ( ICS ) in black adults with asthma and to determine whether allelic variation at the Arg16Gly locus of the β2-adrenergic receptor ( ADRB2 ) geneis associated with treatment response . DESIGN , SETTING , AND PARTICIPANTS A multisite ( n = 20 ) , open-label , parallel-group , pragmatic r and omized clinical trial conducted from March 2011 through July 2013 , enrolling black adults with moderate to severe asthma in the United States . INTERVENTIONS Patients eligible for , or receiving , step 3 or step 4 combination therapy per National Heart , Lung , and Blood Institute guidelines , received ICS plus either once-daily tiotropium ( n = 532 ) or twice-daily LABAs ( n = 538 , ) and were followed up for up to 18 months . Patients underwent genotyping , attended study visits at baseline , 1 , 6 , 12 , and 18 months , and completed monthly question naires . MAIN OUTCOMES AND MEASURES The primary outcome was time to asthma exacerbation , defined as a worsening asthma event requiring oral or parenteral corticosteroids . Secondary outcomes included patient-reported outcomes ( Asthma Quality of Life Question naire , Asthma Control Question naire [ ACQ ] , Asthma Symptom Utility Index , and Asthma Symptom-Free Days question naire ) , spirometry ( FEV1 ) , rescue medication use , asthma deteriorations , and adverse events . RESULTS There was no difference between LABA + ICS vs tiotropium + ICS in time to first exacerbation ( mean No. of exacerbations/person-year , 0.42 vs 0.37 ( rate ratio , 0.90 [ 95 % CI , 0.73 to 1.11 ] , log-rank P = .31 ) . There was no difference in change in FEV1 at 12 months ( 0.003 L for LABA + ICS vs -0.018 L for tiotropium + ICS ; between-group difference , 0.020 [ 95 % CI , -0.021 to 0.061 ] , P = .33 ) and at 18 months ( -0.053 L vs -0.078 L ; between-group difference , 0.025 [ 95 % CI , -0.045 to 0.095 ] , P = .49 ) . There were no differences in ACQ score at 18 months ( change in score from baseline , -0.68 for LABA + ICS vs -0.72 for tiotropium + ICS ; between-group difference , 0.04 [ 95 % CI , -0.18 to 0.27 ] , P = .70 ) . There were no differences in other patient-reported outcomes . Arg16Gly ADRB2 alleles were not associated with differences in the effects of tiotropium + ICS vs LABA + ICS ( hazard ratio for time to first exacerbation , 0.84 [ 95 % CI , 0.47 to 1.51 ] for Arg/Arg vs 0.85 [ 95 % CI , 0.63 to 1.15 ] for Arg/Gly or Gly/Gly , P = .97 ) . CONCLUSIONS / RELEVANCE Among black adults with asthma treated with ICS , adding a LABA did not improve time to asthma exacerbation compared with adding tiotropium . These findings were not affected by polymorphisms at the Arg16Gly locus of ADRB2 . These findings do not support the superiority of LABA + ICS compared with tiotropium + ICS for black patients with asthma . TRIAL REGISTRATION Clinical Trials.gov identifier : NCT01290874 BACKGROUND In patients with severe asthma , tiotropium improves lung function and exacerbation risk when added to high-dose inhaled corticosteroids plus long-acting β2 agonists . We aim ed to assess the safety and efficacy of tiotropium in patients with moderate asthma who were symptomatic despite treatment with medium-dose inhaled corticosteroids . METHODS We did two 24-week , replicate , r and omised , double-blind , placebo-controlled , parallel-group , active-comparator trials at 233 sites in 14 countries . Eligible patients were aged 18 - 75 years with symptomatic asthma and a pre-bronchodilator forced expiratory volume in 1 s ( FEV1 ) of 60 - 90 % predicted despite use of medium-dose inhaled corticosteroids , and had never smoked or were ex-smokers for 1 year or more with 10 pack-years or less . Patients were r and omly assigned ( 1:1:1:1 ) , with computer-generated pseudor and om numbers , to receive once-daily tiotropium 5 μg or 2·5 μg , twice-daily salmeterol 50 μg , or placebo , while maintaining inhaled corticosteroids . Patients and study investigators were masked to treatment allocation . Prespecified co- primary endpoints , assessed at week 24 in the full analysis set , were peak FEV1 response , measured within the first 3 h after evening dosing ; trough FEV1 response ; and responder rate assessed according to the seven- question Asthma Control Question naire ( ACQ-7 ) . These studies are registered with Clinical Trials.gov , numbers NCT01172808 and NCT01172821 . FINDINGS Between Aug 24 , 2010 , and Nov 13 , 2012 , we r and omly assigned 2103 patients  to the tiotropium 5 μg group ( n=519 ) , the tiotropium 2·5 μg group ( n=520  )  , the salmeterol  group ( n=541 ) , or the placebo group ( n=523 ) ; 1972 ( 94 % ) patients completed the study . Peak and trough FEV1 responses were significantly greater with tiotropium and salmeterol than with placebo and were similar in both studies . With pooled data , difference versus  placebo in peak FEV1 was 185 mL ( 95 % CI 146 - 223 ) in the tiotropium 5 μg group , 223 mL ( 185 - 262 ) in the tiotropium 2·5 μg group , and 196 mL ( 158 - 234 ) in the salmeterol group ( all p<0·0001 ) ; difference in trough FEV1 was 146 mL ( 95 % CI 105 - 188 ) , 180 mL ( 138 - 221 ) , and 114 mL ( 73 - 155 ; all p<0·0001 ) , respectively . There were more ACQ-7 responders in the tiotropium 5 μg ( OR 1·32 , 95 % CI 1·02 - 1·71 ; p=0·035 ) and 2·5 μg ( 1·33 , 1·03 - 1·72 ; p=0·031 ) groups , and the salmeterol group ( 1·46 , 1·13 - 1·89 ; p=0·0039 ) , than in the placebo group . 48 ( 2 % ) of 2100 patients had serious adverse events ( tiotropium 5 μg n=11 , tiotropium 2·5 μg n=12 , salmeterol n=11 , placebo n=14 ) . INTERPRETATION Once-daily tiotropium add-on to medium-dose inhaled corticosteroids reduces airflow obstruction and improves asthma control in patients with moderate symptomatic asthma . Patterns of response with both tiotropium doses were similar to those of salmeterol , and all active compounds had good safety and tolerability . Tiotropium is a safe and effective bronchodilator , and an alternative to salmeterol in this patient population . FUNDING Boehringer Ingelheim
Importance Long-acting muscarinic antagonists ( LAMAs ) are a potential adjunct therapy to inhaled corticosteroids in the management of persistent asthma .
Objective To conduct a systematic review and meta- analysis of the effects associated with LAMA vs placebo or vs other controllers as an add-on therapy to inhaled corticosteroids and the use of a LAMA as add-on therapy to inhaled corticosteroids and long-acting & bgr;-agonists ( LABAs ; hereafter referred to as triple therapy ) vs inhaled corticosteroids and LABA in patients with uncontrolled , persistent asthma .