Long-term safety and asthma control measures with a budesonide/formoterol pressurized metered-dose inhaler in African American asthmatic patients: a randomized controlled trial. External validity of randomised controlled trials in asthma: to whom do the results of the trials apply? Regular inhaled salbutamol and asthma control: the TRUST randomised trial Montelukast and fluticasone compared with salmeterol and fluticasone in protecting against asthma exacerbation in adults: one year, double blind, randomised, comparative trial Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial Adding salmeterol to an inhaled corticosteroid: long term effects on bronchial inflammation in asthma Budesonide/formoterol maintenance and reliever therapy: an effective asthma treatment option? Budesonide/formoterol maintenance and reliever therapy: impact on airway inflammation in asthma Addition of montelukast or salmeterol to fluticasone for protection against asthma attacks: a randomized, double-blind, multicenter study. Leukotriene antagonists as first-line or add-on asthma-controller therapy. Budesonide/formoterol maintenance and reliever therapy via Turbuhaler versus fixed-dose budesonide/formoterol plus terbutaline in patients with asthma: phase III study results. Poor adherence with inhaled corticosteroids for asthma: can using a single inhaler containing budesonide and formoterol help? Effect of budesonide/formoterol maintenance and reliever therapy on asthma exacerbations Comparison of the effect of low-dose ciclesonide and fixed-dose fluticasone propionate and salmeterol combination on long-term asthma control. Combination of direct and indirect evidence in mixed treatment comparisons. Asthma control during long term treatment with regular inhaled salbutamol and salmeterol Safety and tolerability of the novel inhaled corticosteroid fluticasone furoate in combination with the β2 agonist vilanterol administered once daily for 52 weeks in patients ≥12 years old with asthma: a randomised trial The CONCEPT trial: a 1-year, multicenter, randomized,double-blind, double-dummy comparison of a stable dosing regimen of salmeterol/fluticasone propionate with an adjustable maintenance dosing regimen of formoterol/budesonide in adults with persistent asthma. Effect of long-term salmeterol therapy compared with as-needed albuterol use on airway hyperresponsiveness. Budesonide/formoterol for maintenance and relief in uncontrolled asthma vs. high-dose salmeterol/fluticasone. Budesonide/formoterol in a single inhaler for maintenance and relief in mild-to-moderate asthma: a randomized, double-blind trial. 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Omalizumab in Severe Allergic Asthma Inadequately Controlled With Standard Therapy Acute and chronic effects of a 5-lipoxygenase inhibitor in asthma: a 6-month randomized multicenter trial. Zileuton Study Group. A Comparison of Budesonide/Formoterol Maintenance and Reliever Therapy Versus Conventional Best Practice in Asthma Management in Spain Concurrent use of salmeterol with inhaled corticosteroids is more effective than inhaled corticosteroid dose increases. Sustained bronchoprotection, bronchodilatation, and symptom control during regular formoterol use in asthma of moderate or greater severity. The Canadian FO/OD1 Study Group. Comparison of addition of salmeterol to inhaled steroids with doubling of the dose of inhaled steroids. A six-month, placebo-controlled comparison of the safety and efficacy of salmeterol or beclomethasone for persistent asthma. Control of airway inflammation maintained at a lower steroid dose with 100/50 microg of fluticasone propionate/salmeterol. 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BACKGROUND Information surrounding the long-term safety of combination inhaled corticosteroid/long-acting β(2)-adrenergic agonist medications in African American asthmatic patients is limited . OBJECTIVE We sought to assess safety and asthma control with a budesonide/formoterol pressurized metered-dose inhaler ( pMDI ) versus budesonide over 1 year in African American patients . METHODS This 52-week , r and omized , double-blind , parallel-group , multicenter , phase 3B safety study ( NCT00419952 ) was conducted in 742 self-reported African American patients 12 years or older with moderate-to-severe asthma previously receiving medium- to high-dose inhaled corticosteroids . After 2 weeks using a 320 μg twice-daily budesonide pMDI , patients were r and omized 1:1 to 320/9 μg twice-daily budesonide/formoterol pMDI or 320 μg twice-daily budesonide pMDI . RESULTS Both treatments were well tolerated . Asthma exacerbation incidence and rate ( per patient-treatment year ) were lower with budesonide/formoterol versus budesonide ( incidence , 7.7 % vs 14.0 % [ P= .006 ] ; rate ratio , 0.615 [ P= .002 ] ) . Time to first asthma exacerbation was longer ( P= .018 ) with budesonide/formoterol versus budesonide . The most common adverse events , regardless of study drug relationship , were headache ( 9.5 % and 7.7 % ) , nasopharyngitis ( 6.9 % and 8.0 % ) , sinusitis ( 4.0 % and 6.3 % ) , and viral upper respiratory tract infection ( 5.8 % and 4.4 % ) for budesonide/formoterol and budesonide , respectively . Serious adverse events occurred in 12 and 15 patients , respectively ; none were considered drug related . No substantial or unexpected patterns of abnormalities were observed in laboratory , electrocardiographic , or Holter monitoring assessment s. Hospitalization caused by asthma exacerbation occurred in 0 and 4 patients in the budesonide/formoterol and budesonide groups , respectively . Pulmonary function and asthma control measures generally favored budesonide/formoterol . CONCLUSIONS In this population budesonide/formoterol pMDI was well tolerated over 12 months , with a safety profile similar to that of budesonide ; the asthma exacerbation rate was reduced by 38.5 % versus budesonide Background : Asthma is a heterogeneous disease with a wide range of clinical phenotypes , not all of which may be encompassed in the subjects included in r and omised controlled trials ( RCTs ) . This makes it difficult for clinicians to know to what extent the evidence derived from RCTs applies to a given patient . Aim : To calculate the proportion of  individuals with asthma who would have been eligible for the major asthma RCTs from the data of a r and om community survey of respiratory health . Methods : A postal survey was sent to 3500 r and omly selected individuals aged 25–75 years . Respondents were invited to complete a detailed respiratory question naire and pulmonary function testing . Participants with current asthma were assessed against the eligibility criteria of the 17 major asthma RCTs cited in the Global Initiative for Asthma ( GINA ) guidelines . Findings : A total of 749 participants completed the full survey , of whom 179 had current asthma . A median 4 % of participants with current asthma ( range 0–36 % ) met the eligibility criteria for the included RCTs . A median 6 % ( range 0–43 % ) of participants with current asthma on treatment met the eligibility criteria . Interpretation : This study shows that the major asthma RCTs on which the GINA guidelines are based may have limited external validity as they have been performed on highly selected patient population s. Most of the participants with current asthma on treatment in the community would not have been eligible for these RCTs BACKGROUND Previous work has suggested that the long-term regular use of inhaled beta2-agonist bronchodilators might lead to a deterioration in asthma control .  The aim of TRUST ( The Regular Use of Salbutamol Trial ) was to study the effects of regular use of inhaled salbutamol , the most widely prescribed bronchodilator in the UK , on the control of asthma . METHODS A r and omised , double-blind , placebo-controlled trial was undertaken in 983 patients with asthma being treated at least twice a week with short-acting beta2-agonist , alone or in combination with inhaled steroids ( 2 mg or less ) daily . Patients were aged 18 years and over and were recruited from 115 general practice s in the UK . 90 % ( 881 ) of the patients used inhaled corticosteroid therapy , and all patients continued to use their usual inhaled beta2-agonist for symptomatic relief . Patients were r and omised to receive 400 microg salbutamol or matched placebo via a Diskhaler four times per day for 12 months . The primary outcome measure was rate of exacerbations of asthma , with criteria based on data from diary cards completed daily by each patient , treatment with additional corticosteroids , or both . FINDINGS There were no differences in the annual rate , timing , or duration of exacerbations between the two groups . The mean morning peak expiratory flow was similar for the two groups . The mean evening peak expiratory flow ( p<0.001 ) and the diurnal variation ( p<0.001 ) were greater , and the use of rescue bronchodilator was less ( p<0.001 ) , in the group receiving regular salbutamol . INTERPRETATION There was no evidence that regular use of inhaled salbutamol 400 microg four times daily for a year increased the exacerbation rate of asthma in the population studied Abstract Objectives To assess the effect of montelukast versus salmeterol added to inhaled fluticasone propionate on asthma exacerbation in patients whose symptoms are inadequately controlled with fluticasone alone . Design and setting A 52 week , two period , double blind , multicentre trial during which patients whose symptoms remained uncontrolled by inhaled corticosteroids were r and omised to add montelukast or salmeterol .  Participants Patients ( 15 - 72 years ; n = 1490 ) had a clinical history of chronic asthma for ≥ 1 year , a baseline forced expiratory volume in one second ( FEV 1 ) value 50 - 90 % predicted , and a β agonist improvement of ≥ 12 % in FEV 1 . Main outcome measures The primary end point was the percentage of patients with at least one asthma exacerbation . Results 20.1 % of the patients in the group receiving montelukast and fluticasone  had an asthma exacerbation compared with 19.1 % in the group receiving salmeterol and fluticasone ; the difference was 1 % ( 95 % confidence interval -3.1 % to 5.0 % ) . With a risk ratio ( montelukast-fluticasone/salmeterol-fluticasone ) of 1.05 ( 0.86 to 1.29 ) , treatment with montelukast and fluticasone was shown to be non-inferior to treatment with salmeterol and fluticasone . Salmeterol and fluticasone  significantly increased FEV 1 before a β agonist was used and morning peak expiratory flow compared with montelukast and fluticasone ( P ≤ 0.001 ) , whereas FEV 1 after a β agonist was used and improvements in asthma specific quality of life and nocturnal awakenings were similar between the groups . Montelukast and fluticasone significantly ( P = 0.011 ) reduced peripheral blood eosinophil counts compared with salmeterol and fluticasone . Both treatments were generally well tolerated . Conclusion The addition of montelukast in patients whose symptoms remain uncontrolled by inhaled fluticasone could provide equivalent clinical control to salmeterol Background Patients with severe asthma are at increased risk of exacerbations and lower respiratory tract infections ( LRTI ) . Severe asthma is heterogeneous , encompassing eosinophilic and non-eosinophilic ( mainly neutrophilic ) phenotypes . Patients with neutropilic airway diseases may benefit from macrolides . Methods We performed a r and omised double-blind placebo-controlled trial in subjects with exacerbation-prone severe asthma . Subjects received low-dose azithromycin ( n=55 ) or placebo ( n=54 ) as add-on treatment to combination therapy of inhaled corticosteroids and long-acting β2 agonists for 6 months . The primary outcome was the rate of severe exacerbations and LRTI requiring treatment with antibiotics during the 26-week treatment phase . Secondary efficacy outcomes included lung function and scores on the Asthma Control Question naire ( ACQ ) and Asthma Quality of Life Question naire ( AQLQ ) . Results The rate of primary endpoints ( PEPs ) during 6 months was not significantly different between the two treatment groups : 0.75 PEPs ( 95 % CI 0.55 to 1.01 ) per subject in the azithromycin group versus 0.81 PEPs ( 95 % CI 0.61 to 1.09 ) in the placebo group ( p=0.682 ) . In a predefined subgroup analysis according to the inflammatory phenotype , azithromycin was associated with a significantly lower PEP rate  than placebo in subjects with non-eosinophilic severe asthma ( blood eosinophilia ≤200/µl ) : 0.44 PEPs ( 95 % CI 0.25 to 0.78 ) versus 1.03 PEPs ( 95 % CI 0.72 to 1.48 ) ( p=0.013 ) . Azithromycin  significantly improved the AQLQ score but there were no significant between-group differences in the ACQ score or lung function . Azithromycin was well tolerated , but was associated with increased oropharyngeal carriage of macrolide-resistant streptococci . Conclusions Azithromycin did not reduce the rate of severe exacerbations and LRTI in patients with severe asthma . However , the significant reduction in the PEP rate in azithromycin-treated patients with non-eosinophilic severe asthma warrants further study . Clinical Trials.gov number NCT00760838 Background : Addition of the long acting β2 agonist salmeterol to inhaled corticosteroids leads to better symptomatic asthma control than increasing the dose of inhaled corticosteroids . However , little is known about the long term effects of adding salmeterol on the asthmatic inflammatory process , control of which is considered important for the long term outcome of asthma . Methods : After a 4 week fluticasone run-in period , 54 patients with allergic asthma were r and omised to receive twice daily treatment with fluticasone 250 μg with or without salmeterol 50 μg for 1 year in a double blind , parallel group design ( total daily dose of fluticasone 500 μg in both treatment groups ) . Primary outcomes were sputum eosinophil numbers and eosinophil cationic protein concentrations . Secondary outcomes were neutrophil associated sputum parameters and a respiratory membrane permeability marker . The effects on allergen induced changes were determined before and at the end of the treatment period . Results : Adding salmeterol to fluticasone result ed in improved peak expiratory flow , symptom scores , rescue medication usage , and bronchial hyperresponsiveness ( p<0.05 for all ) . There was no sustained effect on sputum cell differential counts and cytokine concentrations during the treatment period or on changes induced by allergen challenge at the end of treatment ( p>0.05 ) . However , adding salmeterol significantly reduced sputum ratios of α2-macroglobulin and albumin during the treatment period ( p = 0.001 ) . Conclusions : The addition of salmeterol to fluticasone produces no sustained effect on allergen induced cellular bronchial inflammation but leads to a significant improvement in size selectivity of plasma protein permeation across the respiratory membrane . This may contribute to the improved clinical outcome seen in patients with allergic asthma when a long acting β2 agonist is combined with inhaled corticosteroids This 12-month dose-titration study assessed the effectiveness of budesonide/formoterol for maintenance plus relief with a control group using salmeterol/fluticasone for maintenance plus salbutamol for relief . Adolescents and adults ( n = 2,143 ; mean forced expiratory volume in one second ( FEV1 ) 73 % predicted ; mean inhaled corticosteroid ( ICS ) 884 µg·day−1 ) were r and omised  to budesonide/formoterol 160/4.5 µg two inhalations b.i.d . plus additional inhalations as needed , or salmeterol/fluticasone 50/250 µg b.i.d . plus salbutamol as needed . Treatment was prescribed open label ; after 4 weeks , physicians could titrate maintenance doses in accordance with normal clinical practice . Maintenance plus as-needed budesonide/formoterol prolonged the time to first severe exacerbation versus salmeterol/fluticasone ( 25 % risk reduction ) . The total number of severe exacerbations was significantly reduced in the budesonide/formoterol group ( 255 versus 329 ) . Both regimens provided sustained improvements in symptoms , as-needed use , quality of life and FEV1 , with differences in favour of the budesonide/formoterol group for as-needed use ( 0.58 versus 0.93 inhalations·day−1 ) and FEV1 ( post-β2-agonist values ) . Mean ICS dose during treatment was similar in both groups ( 653 µg budesonide·day−1 ( maintenance plus as-needed ) versus 583 µg fluticasone·day−1 ) . The simplified strategy using budesonide/formoterol for maintenance and reliever therapy is feasible , safe and at least as effective as salmeterol/fluticasone plus salbutamol The aim of the present study was to compare the effectiveness , safety and health economics of budesonide/formoterol maintenance and a novel reliever therapy with conventional best practice in patients with persistent asthma in Canada . After 2 weeks of usual therapy , 1,538 patients were r and omised for 6 months to open-label budesonide/formoterol maintenance and reliever therapy 160/4.5 μg twice daily and as needed , or to guideline -based conventional best practice  . Severe asthma exacerbations , reliever medication use and total inhaled corticosteroid dose were analysed in all patients and airway inflammation was assessed in a sub- study of 115 patients . No differences were seen in time to first severe exacerbation and severe asthma exacerbation rate . There were numerically fewer emergency room visits or hospitalisations with budesonide/formoterol maintenance and reliever therapy ( 4.4 versus 7.5 events per 100 patients · yr−1 , 41 % reduction ) ; however , this did not reach statistical significance . Mean total inhaled corticosteroid dose , reliever use , asthma medication costs and total annual costs per patient were all significantly lower with budesonide/formoterol maintenance and reliever therapy . Mean sputum eosinophil cell counts remained in the range for controlled inflammation in both groups . In conclusion , budesonide/formoterol maintenance and reliever therapy achieved similar or improved clinical control compared with conventional best practice , with significantly lower total inhaled corticosteroid dose and lower cost , while maintaining similar control of eosinophilic inflammation BACKGROUND For patients whose asthma is uncontrolled with low-dose inhaled corticosteroids , addition of alternative therapy instead of increasing the steroid dose is recommended by current treatment guidelines . OBJECTIVE To compare montelukast , a once-daily leukotriene receptor antagonist , and salmeterol , a twice-daily , long-acting beta-agonist , concomitantly administered with inhaled fluticasone , according to the percentage of patients without an asthma attack for 1 year . METHODS A r and omized , double-blind , double-dummy , multicenter study was conducted . Adult patients with moderate-to-severe persistent asthma ( ages 14 - 73 years ) receiving inhaled fluticasone ( 220 microg/d ) who remained symptomatic during a 4-week run-in period were r and omized to the addition of salmeterol ( 84 microg/d ) or montelukast ( 10 mg/d ) for 48 weeks . RESULTS Of the 1,473 r and omized patients , 743 were r and omized to montelukast and 730 to salmeterol ; 1,059 patients completed the study . Eighty percent of patients in the montelukast group and 83.3 % of patients in the salmeterol group remained attack free during the 48 weeks of treatment ( relative risk , 1.20 ; 95 % confidence interval , 0.96 - 1.49 ) . Montelukast significantly reduced blood eosinophil counts compared with salmeterol , whereas salmeterol significantly increased prealbuterol forced expiratory volume in 1 second , asthma-specific quality of life , morning peak expiratory flow rate , and decreased nocturnal awakenings compared with montelukast . Differences between treatments were small , and both treatments were generally well tolerated . CONCLUSIONS Addition of montelukast or salmeterol to an inhaled corticosteroid similarly protected most patients from experiencing an asthma attack during a 1-year period , but , based on noninferiority limits , the study was inconclusive with regard to a difference between treatment groups BACKGROUND Most r and omized trials of treatment for asthma study highly selected patients under idealized conditions . METHODS We conducted two parallel , multicenter , pragmatic trials to evaluate the real-world effectiveness of a leukotriene-receptor antagonist ( LTRA ) as compared with either an inhaled glucocorticoid for first-line asthma-controller therapy or a long-acting beta(2)-agonist ( LABA ) as add-on therapy in patients already receiving inhaled glucocorticoid therapy . Eligible primary care patients 12 to 80 years of age had impaired asthma-related quality of life ( Mini Asthma Quality of Life Question naire [ MiniAQLQ ] score ≤6 ) or inadequate asthma control ( Asthma Control Question naire [ ACQ ] score ≥1 ) . We r and omly assigned patients to 2 years of open-label therapy , under the care of their usual physician , with LTRA ( 148 patients ) or an inhaled glucocorticoid ( 158 patients ) in the first-line controller therapy trial and LTRA ( 170 patients ) or LABA ( 182 patients ) added to an inhaled glucocorticoid in the add-on therapy trial . RESULTS Mean MiniAQLQ scores increased by 0.8 to 1.0 point over a period of 2 years in both trials . At 2 months , differences in the MiniAQLQ scores between the two treatment groups met our definition of equivalence ( 95 % confidence interval [ CI ] for an adjusted mean difference , -0.3 to 0.3 ) . At 2 years , mean MiniAQLQ scores approached equivalence , with an adjusted mean difference between treatment groups of -0.11 ( 95 % CI , -0.35 to 0.13 ) in the first-line controller therapy trial and of -0.11 ( 95 % CI , -0.32 to 0.11 ) in the add-on therapy trial . Exacerbation rates and ACQ scores did not differ significantly between the two groups . CONCLUSIONS Study results at 2 months suggest that LTRA was equivalent to an inhaled glucocorticoid as first-line controller therapy and to LABA as add-on therapy for diverse primary care patients . Equivalence was not proved at 2 years . The interpretation of results of pragmatic research may be limited by the crossover between treatment groups and lack of a placebo group . ( Funded by the National Coordinating Centre for Health Technology Assessment U.K. and others ; Controlled Clinical Trials number , IS RCT N99132811 . ) BACKGROUND AND OBJECTIVE To evaluate the efficacy and tolerability of budesonide/formoterol as maintenance and reliever therapy versus budesonide/formoterol maintenance plus terbutaline in adults with persistent asthma not adequately controlled with inhaled corticosteroid ( ICS ) therapy alone . METHODS In this 12-month , r and omized , double-blind , parallel-group , phase III study ( NCT00839800 ) , patients ( age ≥ 16 years ; receiving maintenance ICS ; ≥ 1 severe exacerbation in the 12 months prior to study entry ) were r and omized to either budesonide/formoterol 160/4.5 μg 1 inhalation twice daily plus budesonide/formoterol 160/4.5 μg as-needed or budesonide/formoterol 160/4.5 μg 1 inhalation twice daily plus terbutaline 0.4 mg as-needed for 12 months . PRIMARY OUTCOME time to first severe asthma exacerbation ; secondary outcomes included : lung function , asthma symptom variables and tolerability . RESULTS Two thous and and ninety-one patients were r and omized : 170 ( 16 % ) receiving budesonide/formoterol maintenance and reliever therapy experienced 259 severe exacerbations versus 229 patients ( 22 % ) receiving budesonide/formoterol plus terbutaline who experienced 363 severe exacerbations  . Budesonide/formoterol maintenance and reliever therapy prolonged the time to first severe exacerbation  versus budesonide/formoterol plus terbutaline ( P = 0.0007 ) and reduced the instantaneous risk of an exacerbation by 30 % ( hazard ratio 0.70 , 95 % confidence interval 0.57 - 0.85 , P = 0.0003 ) . Times to first oral steroid use , first hospitalization and first emergency room treatment were all significantly prolonged in the budesonide/formoterol maintenance and reliever group versus budesonide/formoterol plus terbutaline . Both treatment groups were well tolerated . CONCLUSIONS Budesonide/formoterol maintenance and reliever therapy provided more effective asthma control , including a prolonged time to first severe asthma exacerbation , than budesonide/formoterol plus terbutaline and was well tolerated . Budesonide/formoterol maintenance and reliever therapy also improved lung function and asthma symptoms BACKGROUND Poor adherence with inhaled corticosteroids is an important problem in asthma management . Previous approaches to improving adherence have had limited success . AIM To determine whether treatment with a single inhaler containing a long-acting beta(2)-agonist and a corticosteroid for maintenance treatment and symptom relief can overcome the problem of poor adherence with inhaled corticosteroids . DESIGN OF STUDY R and omised , parallel group , open-label trial . SETTING Forty-four general practice s in Nottinghamshire . METHOD Participants who used less than 70 % of their prescribed dose of inhaled corticosteroid and had poorly controlled asthma were r and omised to budesonide 200 microg one puff twice daily plus their own short-acting beta(2)-agonist as required ( control group ) , or budesonide/formoterol 200/6 microg one puff once daily and as required ( active group ) for 6 months . The primary outcome was inhaled corticosteroid dose . RESULTS Seventy-one participants ( 35 control , 36 active group ) were r and omised . Adherence with budesonide in the control group was approximately 60 % of the prescribed dose . Participants in the active group used approximately 80 % more budesonide than participants in the control group ( 448 versus 252 microg/day , mean difference 196 mug , 95 % confidence interval 113 to 279 ; P<0.001 ) and were less likely to withdraw from the study ( 3 versus 13 ; P<0.01 ) . No safety issues were identified . CONCLUSION Using a single inhaler for both maintenance treatment and symptom relief approximately doubled the dose of inhaled corticosteroid taken , suggesting this could be a useful strategy to overcome the problems related to poor adherence with inhaled corticosteroids This r and omised , double-blind , 6-month study compared budesonide/formoterol for maintenance and relief with salmeterol/fluticasone and a fixed maintenance dose of budesonide/formoterol , both with terbutaline for relief . Following a 2-week run-in , 3335 symptomatic adults and adolescents ( mean FEV1 73 % predicted , mean inhaled corticosteroid dose 745 μg/day ) received budesonide/formoterol 160/4.5 μg one inhalation bid plus additional inhalations as needed , salmeterol/fluticasone 25/125 μg two inhalations bid plus as-needed terbutaline or budesonide/formoterol 320/9 μg one inhalation bid plus as-needed terbutaline . Budesonide/formoterol for maintenance and relief prolonged the time to first severe exacerbation requiring hospitalisation , emergency room treatment or oral steroids ( primary variable ) vs. fixed-dose salmeterol/fluticasone and budesonide/formoterol ( p = 0.0034 and p = 0.023 respectively ; log-rank test ) . Exacerbation rates were 19 , 16 and 12 events/100 patients /6 months for salmeterol/fluticasone , fixed-dose budesonide/formoterol and budesonide/formoterol for maintenance and relief , respectively , [ rate reduction vs. fixed-dose salmeterol/fluticasone ( 0.61 ; 95 % CI 0.49–0.76 , p < 0.001 ) and vs. fixed-dose budesonide/formoterol ( 0.72 ; 95 % CI 0.57–0.90 , p = 0.0048 ) ] . Budesonide/formoterol maintenance and relief patients used less inhaled corticosteroid vs. salmeterol/fluticasone and fixed-dose budesonide/formoterol patients . All treatments provided similar marked improvements in lung function , asthma control days and asthma-related quality of life  . Budesonide/formoterol for maintenance and relief reduces asthma exacerbations and maintains similar daily asthma control at a lower overall drug load compared with fixed-dose salmeterol/fluticasone and budesonide/formoterol BACKGROUND Patients with mild persistent asthma constitute about 70 % of the asthma population ; thus , it is important to know which first-line treatment is best for the management of mild asthma . We compared benefits of first-line treatment with ciclesonide and a combination of fluticasone and salmeterol in patients with mild asthma . METHODS Patients aged 12 to 75 years with mild persistent asthma were enrolled in a r and omized , double-blind , placebo-controlled study . After run-in , patients were r and omized to ciclesonide 160 μg once daily ( CIC160 ) , fluticasone propionate/salmeterol 100/50 μg bid ( FP200/S100 ) , or placebo for 52 weeks . The primary variable was time to first severe asthma exacerbation ; the co primary variable was the percentage of poorly controlled asthma days . Patients recorded asthma symptoms and salbutamol use in electronic diaries and completed a st and ardized version of the Asthma Quality of Life Question naire . RESULTS Compared with placebo , the time to first severe asthma exacerbation was prolonged , and lung function was improved with FP200/S100 treatment ( P = .0002 ) but not with CIC160 . Both CIC160 and FP200/S100 provided significantly fewer poorly controlled asthma days than placebo ( P ≤ .0016 for both active treatments ) . Moreover , both active treatments provided significantly more asthma symptom-free days ( P ≤ .0001 ) , rescue medication-free days ( P = .0005 , one-sided ) , and days with asthma control ( P ≤ .0033 ) . Overall Asthma Quality of Life Question naire scores were significantly higher in both active treatment groups than placebo ( P ≤ .0017 ) . CONCLUSIONS In mild asthma , FP200/S100 prolonged time to first severe asthma exacerbation , and CIC160 and FP200/S100 were clinical ly equieffective for most measures of asthma control . TRIAL REGISTRY Clinical Trials.gov ; No. : NCT00163358 ; URL : www . clinical trials.gov Mixed treatment comparison ( MTC ) meta- analysis is a generalization of st and ard pairwise meta- analysis for A vs B trials , to data structures that include , for example , A vs B , B vs C , and A vs C trials . There are two roles for MTC : one is to strengthen inference concerning the relative efficacy of two treatments , by including both ' direct ' and ' indirect ' comparisons . The other is to facilitate simultaneous inference regarding all treatments , in order for example to select the best treatment . In this paper , we present a range of Bayesian hierarchical models using the Markov chain Monte Carlo software WinBUGS . These are multivariate r and om effects models that allow for variation in true treatment effects across trials . We consider models where the between-trials variance is homogeneous across treatment comparisons as well as heterogeneous variance models . We also compare models with fixed ( unconstrained ) baseline study effects with models with r and om baselines drawn from a common distribution . These models are applied to an illustrative data set and posterior parameter distributions are compared . We discuss model critique and model selection , illustrating the role of Bayesian deviance analysis , and node-based model criticism . The assumptions underlying the MTC models and their parameterization are also discussed BACKGROUND The adverse effects of long term treatment of asthma with the short acting β agonist fenoterol have been established in both epidemiological and clinical studies . A study was undertaken to investigate the efficacy and safety of long term treatment with salbutamol and salmeterol in patients with mild to moderate bronchial asthma . METHODS In a two centre double dummy crossover study 165 patients were r and omly assigned to receive salbutamol 400 μg qid , salmeterol 50 μg bid , or placebo via a Diskhaler . All patients used salbutamol as required for symptom relief . The study comprised a four week run in and three treatment periods of 24 weeks , each of which was followed by a four week washout . Asthma control was assessed by measuring mean morning and evening peak expiratory flow rate ( PEFR ) , a composite daily asthma score , and minor and major exacerbation rates . Washout assessment s included methacholine challenge and bronchodilator dose response tests . Analysis was by intention to treat . RESULTS Data from 157 patients were analysed . Relative to placebo , the mean morning PEFR increased by 30 l/min ( 95 % CI 26 to 35 ) for salmeterol but did not change for salbutamol . Evening PEFR increased by 25 l/min ( 95 % CI 21 to 30 ) and 21 l/min ( 95 % CI 17 to 26 ) , respectively ( p<0.001 ) . Salmeterol improved the asthma score compared to placebo ( p<0.001 ) , but there was no overall difference with salbutamol . Only daytime symptoms were improved with salbutamol . The minor exacerbation rates were 0.29 , 0.88 , and 0.97 exacerbations/patient/year for salmeterol , salbutamol and placebo , respectively ( p<0.0001 for salmeterol ) . The corresponding major exacerbation rates were 0.22 , 0.51 and 0.40 , respectively ( p<0.03 for salmeterol ) . For salbutamol the asthma score deteriorated over time ( p<0.01 ) , and the time spent in major exacerbation was significantly longer compared with placebo ( 12.3 days ( 95 % CI 4.2 to 20.4 ) ) versus 8.4 days ( 95 % CI 5.2 to 11.6 ) , p = 0.02 ) . There was no evidence of rebound deterioration in asthma control , lung function , or bronchial hyperresponsiveness following cessation of either active treatment , and no evidence of tolerance to salbutamol or salmeterol . CONCLUSIONS Regular treatment with salmeterol is effective in controlling asthma symptoms and reduces minor more than major exacerbation rates .  Salbutamol was associated with improved daytime symptoms but subtle deterioration in asthma control occurred over time . Salbutamol should therefore be used only as required Background The inhaled corticosteroid fluticasone furoate ( FF ) in combination with the long-acting β2 agonist vilanterol ( VI ) is in development for asthma and chronic obstructive pulmonary disease . Objective To assess the safety and tolerability of FF/VI over 52 weeks in patients with asthma . Methods Patients ( aged ≥12 years ; on inhaled corticosteroid ) were r and omised ( 2:2:1 )  to FF/VI 100/25 µg or FF/VI 200/25 µg once daily in the evening , or fluticasone propionate ( FP ) 500 µg twice daily . Safety evaluations included adverse events ( AEs ) , non-fasting glucose , potassium , 24-h urinary cortisol excretion , ophthalmic assessment s , heart rate and pulse rate . Results On-treatment AEs were similar across groups ( FF/VI 66–69 % ; 73 % FP ) . Oral c and idiasis/oropharyngeal c and idiasis was more common with FF/VI ( 6–7 % ) than FP ( 3 % ) . Twelve serious AEs were reported ; one ( worsening hepatitis B on FP ) was considered drug related . Statistically significant cortisol suppression was seen with FP compared with both FF/VI groups at Weeks 12 and 28 ( ratios [ 95 % CI ] to FP ranged from 1.43 [ 1.11 to 1.84 ] to 1.67 [ 1.34 to 2.08 ] ; p≤0.006 ) , but not at Week 52 ( ratios to FP were 1.05 [ 0.83 to 1.33 ] for FF/VI 100/25 µg and 1.09 [ 0.87 to 1.38 ] for FF/VI 200/25 µg ) . No clinical ly important changes in non-fasting glucose , potassium , QT interval corrected using Fridericia 's formula ( QTc[F ] ) or ophthalmic assessment s were reported . Pulse rate ( 10 min post dose [ Tmax ] , Week 52 ) was significantly increased with FF/VI versus FP ( 3.4 bpm , 95 % CI 1.3 to 5.6 ; p=0.002 [ FF/VI 100/25 µg ] ; 3.4 bpm , 95 % CI 1.2 to 5.6 ; p=0.003 [ FF/VI 200/25 µg ] ) . Mean heart rate ( 24-h Holter monitoring ) decreased from screening values in all groups ( 0.2–1.1 bpm FF/VI vs 5 bpm FP ; Week 52 ) . Conclusions FF/VI ( 100/25 µg or 200/25 µg ) administered once daily over 52 weeks was well tolerated by patients aged ≥12 years with asthma .  The overall safety profile of FF/VI did not reveal any findings of significant clinical concern . Clinical Trials.gov BACKGROUND A patient-driven , adjustable maintenance dosing ( AMD ) approach to asthma therapy , in which the dose is adjusted by patients according to the severity of their symptoms , has recently been compared with fixed-dose therapy in open-label studies . OBJECTIVE This study used a double-blind , double-dummy design to compare the efficacy of 2 treatment approaches : stable dosing of salmeterol/fluticasone propionate ( SAL/FP ) and AMD of formoterol/budesonide ( FOR/BUD ) . METHODS This was a 1-year , multicenter , r and omized , double-blind , double-dummy study in adult patients with symptomatic asthma that was not controlled by therapy with 200 to 500 microg/d inhaled corticosteroid ( ICS ) plus a long-acting beta2 agonist , or with > 500 to 1000 microg/d ICS alone . Patients were r and omized to receive 1 inhalation of SAL/FP 50/250 microg BID or 2 inhalations of FOR/BUD 6/200 microg BID , both delivered via dry powder inhaler devices . After 4 weeks of stable dosing in both groups , eligible patients continued the study for an additional 48 weeks , receiving either a stable dose of SAL/FP or AMD of FOR/BUD . According to the AMD treatment plan , patients initially halved their dose and subsequently stepped up or down as indicated by the presence or absence of nocturnal awakenings due to asthma , frequency of rescue medication use , and changes in morning peak expiratory flow ( PEF ) . The primary end point was the percentage of symptom-free days . Other parameters included daily asthma symptom scores , morning PEF , percentage of days free of rescue medication use , daily rescue medication use , percentage of nighttime awakenings due to asthma , percentage of weeks with well-controlled asthma , and number of exacerbations requiring oral corticosteroids or emergency department ( ED ) visits/hospitalizations . Tolerability was assessed in terms of adverse events spontaneously reported or elicited at clinic visits . RESULTS The intent-to-treat population comprised 688 patients ( 344 per treatment arm ) with a mean age of 45 years and a mean baseline forced expiratory volume in 1 second 81 % of the predicted normal value . After 4 weeks ' stable dosing , 581 patients ( 295 SAL/FP , 286 FOR/BUD ) continued beyond visit 3 into the remaining 48-week treatment period . Over weeks 1 through 52 , patients receiving stable dosing of SAL/FP had a significantly greater percentage of symptom-free days compared with those receiving AMD of FOR/BUD ( median , 58.8 % vs 52.1 % , respectively ; P = 0.034 ) . The incidence of asthma exacerbations requiring oral steroids or an ED visit/hospitalization was 47 % lower with SAL/FP compared with FOR/BUD ( adjusted annual mean rate , 0.18 vs 0.33 ; P = 0.008 ) . During weeks 5 through 52 , patients in the FOR/BUD AMD group used a mean of 1.8 inhalations/d ( equivalent to BUD 360 microg/d ) , and 235 ( 82.2 % ) patients stepped down to 1 inhalation/d . Mean ( SD ) daily ICS exposure over 52 weeks was 463 ( 81 ) microg FP and 480 ( 238 ) microg BUD in the respective treatment arms . CONCLUSIONS In this adult population with persistent asthma , stable dosing of SAL/FP 50/250 microg BID result ed in significantly greater increases in symptom-free days , days free of rescue medication , and morning PEE , as well as almost halving the exacerbation rate , compared with AMD of FOR/BUD 6/200 microg . The results suggest that there is a minimum daily amount of maintenance therapy necessary to prevent exacerbations in adults with persistent asthma STUDY OBJECTIVES To determine the effect of long-term salmeterol aerosol therapy on  airway hyperresponsiveness  measured by methacholine challenge . DESIGN R and omized , double-blind , placebo-controlled , multicenter study . SETTING Thirty-one clinical centers in the United States . PATIENTS Four hundred eight asthmatic patients > or = 12 years of age with baseline FEV1 of > or = 70 % of predicted values . Patients were not using inhaled corticosteroids . INTERVENTIONS Twice-daily salmeterol aerosol , 42 microg , or placebo via metered-dose inhaler for 24 weeks . Backup albuterol was available . MEASUREMENTS AND RESULTS Pulmonary function tests were performed before , during , and after treatment . Subjects recorded asthma-related symptoms , morning and evening peak expiratory flow ( PEF ) levels , and use of supplemental albuterol daily on diary cards .  Methacholine challenges were performed 10 to 14 h postdose at weeks 4 , 12 , and 24 , and 3 and 7 days posttreatment . Over 24 weeks of treatment , salmeterol provided significant ( p < 0.001 ) protection against methacholine-induced bronchoconstriction of approximately one doubling dose of methacholine when compared to placebo with no evidence for a progressive decrease in protection . A rebound increase in airway hyperresponsiveness was not observed 3 and 7 days after cessation of salmeterol therapy . Salmeterol treatment result ed in sustained improvements of 0.21 to 0.26 L in morning premedication FEV1 and an improvement of 26.2 L/min in morning PEF when compared to placebo ( p < 0.001 ) . The use of salmeterol significantly reduced combined daytime asthma symptoms by 20 % when compared to placebo ( p = 0.005 ) . A total of 34 and 48 exacerbations , respectively , were reported in the Salmeterol and placebo groups , and no evidence was present for a difference in the severity of asthma exacerbations between groups . Adverse event profiles were similar for the salmeterol and placebo groups . CONCLUSIONS Regular long-term use of salmeterol aerosol result ed in sustained improvements in pulmonary function and asthma symptom control over the 24-week treatment period . There was no increase in bronchial hyperresponsiveness or loss of bronchoprotection at 24 weeks from that seen following 4 weeks of therapy . There was no evidence of rebound airway hyperresponsiveness after cessation of salmeterol treatment . Regular treatment with the long-acting beta-agonist salmeterol does not lead to clinical instability or vulnerability to unpredictable asthma attacks BACKGROUND Budesonide/formoterol maintenance and reliever therapy ( Symbicort SMART ) improves asthma control compared with fixed-dose inhaled corticosteroid/long-acting beta(2)-agonist ( ICS/LABA ) regimens , but its efficacy has not been assessed in comparison with sustained high-dose salmeterol/fluticasone ( Seretide ) plus a short-acting beta(2)-agonist ( SABA ) . METHODS Patients ( N=2309 ) with symptomatic asthma ( aged 12 years ; forced expiratory volume in 1s 50 % predicted ) , who had experienced an asthma exacerbation in the previous year , were r and omised to receive budesonide/formoterol 160/4.5 microg two inhalations twice daily and as needed , or one inhalation of salmeterol/fluticasone 50/500 microg twice daily plus terbutaline as needed , for 6 months . RESULTS Time to first severe exacerbation , the pre-specified primary outcome , was not significantly prolonged ( risk ratio 0.82 ; 95 % confidence interval 0.63 , 1.05 ) . Budesonide/formoterol maintenance and reliever therapy reduced total exacerbations from 31 to 25 events/100 patients /year ( P=0.039 ) , and exacerbations requiring hospitalisation/emergency room ( ER ) treatment from 13 to 9 events/100 patients /year ( P=0.046 ) . The treatments showed no difference in measures of lung function or asthma symptoms . The mean dose of ICS received was lower using budesonide/formoterol maintenance and reliever therapy ( 792 microg/day budesonide [ 1238 microg/day beclomethasone dipropionate ( BDP ) equivalent ] versus 1000 microg/day fluticasone [ 2000 microg/day BDP equivalent ] with salmeterol/fluticasone therapy ; P<0.0001 ) . Both treatments were well tolerated . CONCLUSION In the treatment of uncontrolled asthma , budesonide/formoterol maintenance and reliever therapy reduces the incidence of severe asthma exacerbations and hospitalisation/ER treatment with similar daily symptom control compared with sustained high-dose salmeterol/fluticasone plus SABA . This benefit is achieved with substantially less ICS exposure STUDY OBJECTIVE To compare a novel asthma management strategy --budesonide/formoterol in a single inhaler for both maintenance therapy and symptom relief -- with a higher dose of budesonide plus as-needed terbutaline . METHODS This was a 6-month , r and omized , double-blind , parallel-group study in patients with mild-to-moderate asthma ( n = 697 ; mean age , 38 years [ range , 11 to 79 years ] ; mean baseline FEV1 , 75 % of predicted ; mean inhaled corticosteroid [ ICS ] dosage , 348 microg/d ) . Following a 2-week run-in period , all patients received two blinded , dry powder inhalers , one containing maintenance medication and one containing medication to be used as needed for the relief of symptoms . Patients were r and omized to receive either budesonide/formoterol ( 80 microg/4.5 microg , two inhalations qd ) for maintenance plus additional inhalations as needed for symptom relief , or budesonide ( 160 microg , two inhalations qd ) for maintenance medication plus terbutaline ( 0.4 mg ) as needed . The primary efficacy variable was morning peak expiratory flow ( PEF ) . RESULTS Patients receiving budesonide/formoterol showed greater improvements in morning PEF than patients receiving budesonide ( increases of 34.5 L/min vs 9.5 L/min , respectively ; p < 0.001 ) . The risk of having a severe exacerbation ( hospitalization/emergency department [ ED ] treatment , oral steroids for asthma , or a > or = 30 % decrease from baseline in morning PEF on 2 consecutive days ) was 54 % lower with budesonide/formoterol vs budesonide ( p = 0.0011 ) . Budesonide/formoterol patients experienced 90 % fewer hospitalizations/ED treatments due to asthma than budesonide patients ( 1 vs 10 , respectively ; p = 0.026 ) . The increased efficacy with budesonide/formoterol was achieved with less ICS than was used in the budesonide group ( mean dose , 240 microg/d vs 320 microg/d , respectively ) and with 77 % fewer oral steroid treatment days vs budesonide ( 114 days vs 498 days , respectively ) . Both treatments were well tolerated . CONCLUSIONS Budesonide/formoterol for both maintenance and relief improves asthma control with a lower steroid load compared with a higher dose of budesonide plus terbutaline Guidelines on asthma management recommend that in patients who still have symptoms on treatment with low-dose inhaled corticosteroids the first step should be an increase in inhaled corticosteroid dose . The addition of long-acting inhaled beta 2-adrenoceptor agonists is another option . We have compared these two strategies in a r and omised , double-blind , parallel-group trial . We studied 429 adult asthmatic patients who still had symptoms despite maintenance treatment with 200 micrograms twice daily inhaled beclomethasone dipropionate ( BDP ) .  3 did not provide verifiable data . Of the others , 220 were assigned salmeterol xinafoate ( 50 micrograms twice daily ) plus BDP and 206 were assigned higher-dose BDP ( 500 micrograms twice daily ) for 6 months . The mean morning peak expiratory flow increased from baseline in both groups , but the increase was greater in the salmeterol/BDP group than in the higher-dose BDP group at all time points ( differences 16 - 21 L/min , p < 0.05 ) . Mean evening PEF also increased with salmeterol/BDP but not with higher-dose BDP . There were significant differences in favour of salmeterol/BDP in diurnal variation of PEF ( all time points ) and in use of rescue bronchodilator ( salbutamol ) and daytime and night-time symptoms ( some time points ) . There was no significant difference between the groups in adverse effects or exacerbations of asthma , indicating that in this group of patients regular beta 2-agonist therapy was not associated with any risk of deteriorating asthma control over 6 months . This study suggests a need for a flexible approach to asthma management Asthma control is improved by combining inhaled corticosteroids with long-acting beta2-agonists . However , fluctuating asthma control still occurs . We hypothesized that in patients receiving low maintenance dose budesonide/formoterol ( bud/form ) , replacing short-acting beta2-agonist ( SABA ) reliever with as-needed bud/form would provide rapid symptom relief and simultaneous adjustment in antiinflammatory therapy , thereby reducing exacerbations . In this double-blind , r and omized , parallel-group study , 2,760 patients with asthma aged 4 - 80 years ( FEV1 60 - 100 % predicted ) received either terbutaline 0.4 mg as SABA with bud/form 80/4.5 microg twice a day ( bud/form + SABA ) or bud 320 microg twice a day ( bud + SABA ) or bud/form 80/4.5 microg twice a day with 80/4.5 microg as-needed ( bud/form maintenance + relief ) . Children used a once-nocte maintenance dose . Bud/form maintenance + relief prolonged time to first severe exacerbation ( p < 0.001 ; primary endpoint ) , result ing in a 45 - 47 % lower exacerbation risk versus bud/form + SABA ( hazard ratio , 0.55 ; 95 % confidence interval , 0.44 , 0.67 ) or bud + SABA ( hazard ratio , 0.53 ; 95 % confidence interval 0.43 , 0.65 ) . Bud/form maintenance + relief also prolonged the time to the first , second , and third exacerbation requiring medical intervention ( p < 0.001 ) , reduced severe exacerbation rate , and improved symptoms , awakenings , and lung function compared with both fixed dosing regimens Safety concerns have been raised regarding the regular use of long-acting beta(2)-adrenergic agonists ( LABAs ) alone or with inhaled corticosteroids ( ICSs ) . The purpose of this study was to examine the long-term safety of budesonide/formoterol pressurized metered-dose inhaler ( pMDI ) . This 52-week , double-blind study ( SD-039 - 0728 ; n=708 ) included patients > or=12 years of age with moderate to severe persistent asthma previously receiving ICSs .  After 2 weeks on budesonide pMDI 320 microg twice daily ( b.i.d . ) , patients were r and omized 3:1:1 overall to budesonide/formoterol pMDI 640/18 microg b.i.d . , budesonide/formoterol pMDI 320/9 microg b.i.d . , or budesonide pMDI 640 microg b.i.d . The incidence of adverse events ( AEs ) was similar across the groups . Drug-related AEs ( > or=2 % overall ) were oral c and idiasis , tremor , and pharyngolaryngeal pain . No clinical ly meaningful differences in laboratory , electrocardiogram , or Holter monitor variables were observed . The percentage of patients with > or=1 asthma exacerbation was significantly lower ( p=0.006 ) with budesonide/formoterol 640/18 ( 12.2 % ) and numerically lower with budesonide/formoterol 320/9 ( 14.4 % ) versus budesonide ( 21.8 % ) . The number of asthma exacerbations per patient-treatment year was lower with budesonide/formoterol 640/18 ( 0.174 ; p=0.004 ) and budesonide/formoterol 320/9 ( 0.185 ; p=0.049 ) versus budesonide ( 0.315 ) . Improvements in forced expiratory volume in 1 second and diary variables were significantly greater ( p<0.001 ) with both budesonide/formoterol doses versus budesonide . Budesonide/formoterol 640/18 and 320/9 microg b.i.d . showed an acceptable safety profile relative to budesonide , with no significant or unexpected patterns of abnormalities observed by adding a LABA to budesonide for up to 1 year in this patient population . Improvements in asthma control were shown with both doses of budesonide/formoterol versus budesonide This study was design ed to determine whether the benefit of adding salmeterol was superior to doubling the dose of fluticasone propionate ( FP ) over 6 months , compared to a control group who remained on a lower dose of FP . The multi-centre , double-blind , parallel group study involved 496 symptomatic asthmatic patients with a history of exacerbations on 500 - 800 micrograms ( microg ) inhaled corticosteroids ( ICS ) twice daily ( b.d . ) in a broadly representative group of 100 hospitals and general practice s in six countries . Two doses of FP--250 microg b.d . ( FP250 ) or 500 microg b.d . (FP500)--were compared with the lower dose of FP plus a long-acting beta2-agonist , salmeterol 50 microg b.d . ( SM/FP250 ) . Patients symptomatic on the run-in dose of FP250 alone formed the control group in the treatment period . Over 6 months , SM/FP250 significantly improved mean morning peak expiratory flow rates ( amPEF ) by 42.1 l/min , more than twice the improvement achieved with either dose of FP alone . SM/FP250 also result ed in more symptom-free days and nights ( P < 0.002 ) and days and nights with no relief medication ( P < 0.001 ) . The number of severe exacerbations was low : 3 , 6 and 8 % in the SM/FP250 , low- and high-dose FP groups , respectively . This study confirms that adding salmeterol to low-dose inhaled FP offers greater improvements than either maintaining or doubling the dose of FP . Significant benefit was gained from adding salmeterol in a group of patients who appeared to have been at the top of their steroid dose-response curve receiving FP250 . There was no evidence of tolerance and a low incidence of exacerbations in all treatment groups ABSTRACT Objective : This long-term prospect i ve study was conducted in African Americans with persistent asthma to examine the safety and effectiveness of the combination of the inhaled corticosteroid , fluticasone propionate ( FP ) , and the long-acting beta-agonist , salmeterol , compared with FP alone . Research and design methods : This was a r and omized , double-blind , parallel group , multi-center trial in adolescent and adult subjects ≥12 years of age symptomatic on a low dose of an inhaled corticosteroid ( ICS ) .  The study consisted of a 2-week screening period on low dose ICS ; a 4-week open-label FP 250 mcg twice daily ( BID ) run-in ; a 52-week double-blind period ( FP/salmeterol [ FSC ] 100/50 mcg [ n = 239 ] or FP 100 mcg [ n = 236 ] BID ) , and a 4-week FP 250 mcg BID run-out period . Annualized exacerbation rate was the primary outcome for comparing the two treatments . Other measures of asthma control included peak expiratory flow , asthma symptoms , and albuterol use . Safety was assessed through adverse events . Results : Exacerbation rates were not significantly different in those treated with FSC 100/50 mcg ( 0.449 per year ) compared with FP 100 mcg ( 0.529 per year , p = 0.169 ) . When the per- protocol analysis was applied , the rates were 0.465 and 0.769 per year for FSC 100/50 mcg and FP 100 mcg , respectively . Treatment with FSC 100/50 mcg provided statistically greater improvements in lung function measures and nighttime awakenings ( p ≤ 0.050 ) and demonstrated numerically lower daily symptoms ( p = 0.216 ) and albuterol use ( p = 0.122 ) . Two subjects treated with FSC 100/50 mcg were hospitalized for an asthma exacerbation compared to three treated with FP 100 mcg . The overall incidence of adverse effects during double-blind treatment was similar between the FSC 100/50 mcg and FP 100 mcg treatment groups ( 61 % and 68 % , respectively ) . Frequent study visits were required of subjects during this long-term study , and it remains unknown whether this intervention may affect generalizability . Conclusion : In this large , prospect i ve study among African Americans with asthma , the addition of salmeterol to FP result ed in a similar low rate of exacerbations and improved other markers of asthma control . Both FSC 100/50 mcg and FP 100 mcg were well-tolerated , and the overall safety-profiles were similar over 1 year of treatment OBJECTIVE To study the effectiveness and safety of as-needed treatment of formoterol compared with the short-acting alternative terbutaline . METHODS Two double-blind , 12-month , parallel-group , non-inferiority trials comparing as-needed use of formoterol ( Oxis ) 4.5 microg and terbutaline ( Bricanyl ) 0.5 mg via dry-powder inhaler ( Turbuhaler ) , one in 675 patients with intermittent and one in 455 patients with mild persistent asthma , overall 6 - 87 years of age .  Peak expiratory flow ( PEF ) , symptoms , rescue medication use , exacerbations , airway responsiveness ( metacholine challenge ; subgroup of 127 patients ) , systemic effects ( high single-dose test ; subgroup of 87 patients ) , and safety ( adverse events ) were assessed . RESULTS Formoterol 4.5 microg was as effective as terbutaline 0.5 mg with regard to morning PEF ( non-inferiority ; lower 95 % confidence interval limit above -10 L/min ) . Metacholine sensitivity , exacerbation rates or use of rescue medication did not differ between treatments . Formoterol 54 microg was shown to give less systemic effects than terbutaline 6 mg . Both treatments were safe and well tolerated . CONCLUSIONS Formoterol 4.5 microg used as needed was at least as effective and safe as terbutaline 0.5 mg used as needed in intermittent and mild persistent asthma , and was associated with less systemic effects when administered as high single doses Adding inhaled long-acting beta(2)-agonists to a low dose of inhaled corticosteroids ( ICS ) , results in better clinical asthma control than increasing the dose of ICS . However , this approach may mask underlying airway inflammation . In a double-blind parallel-group study , we evaluated the effect of adding formoterol to a low dose of budesonide , compared with a higher dose of budesonide , on the composition of induced sputum . After a 4-wk run-in period of treatment with budesonide ( 800 microg , twice daily ) , 60 patients with moderate asthma were r and omly assigned to a 1-yr treatment with 400 microg of budesonide plus placebo , twice daily ( BUD800 ) , or 100 microg of budesonide plus 12 microg of formoterol , twice daily ( BUD200+F ) . All drugs were administered via Turbuhaler . Budesonide ( 800 microg , twice daily ) during run-in significantly reduced median sputum eosinophils from 4.5 to 0.68 % . No significant changes in the proportion of eosinophils , EG2(+ ) cells , other inflammatory cells , or ECP levels in sputum were observed over the ensuing 1-yr treatment with BUD200+F or BUD800 . Clinical asthma control was not significantly different between both groups . In conclusion , no significant differences in sputum markers of airway inflammation were observed during a 1-yr treatment with a low dose of inhaled budesonide plus formoterol compared with a higher dose of budesonide BACKGROUND Current treatment guidelines define inhaled corticosteroids such as fluticasone propionate ( FP ) as the cornerstone of anti-inflammatory therapy for asthma . OBJECTIVE The objective was to evaluate the efficacy and safety of adding salmeterol therapy to patients who remain symptomatic while receiving FP  as compared with increasing the dose of FP . METHODS In a multicenter , double-blind study conducted over 24-weeks , 437 patients aged 12 years and older and receiving FP 88 microg twice daily for 2 to 4 weeks were r and omly assigned to receive either salmeterol ( 42 microg twice daily ) or FP 220 microg twice daily . The primary efficacy endpoint was morning peak expiratory flow . Secondary measures included FEV1 , symptom scores , nighttime awakenings , and supplemental albuterol use . Safety was assessed by reported adverse events and asthma exacerbations . RESULTS The addition of salmeterol result ed in significantly greater improvements in lung function and symptom control as compared with increasing the dose of FP . Over weeks 1 to 24 , morning peak expiratory flow was increased by 47 L/min from baseline with salmeterol treatment as compared with 24 L/min with FP 220 microg twice daily ( P < .001 ) while the percent of symptom-free days increased from baseline by 26 % of days as compared with 10 % of days ( P < .001 ) . The adverse event profiles were similar between groups and fewer exacerbations were reported with salmeterol treatment . CONCLUSIONS The addition of salmeterol therapy to patients who remain symptomatic while using a low dose of FP was clinical ly and statistically superior to increasing the dose of FP BACKGROUND The role of combination ICS/LABA as initial controller therapy in mild , persistent asthma is uncertain . Therefore , the objective of this study was to compare the efficacy of initial controller therapy with fluticasone propionate ( FP ) 100 microg twice daily to the efficacy of fluticasone propionate/salmeterol xinafoate ( FSC ) 100/50 microg twice daily in patients with persistent asthma symptoms while using as-needed SABA alone . METHODS This r and omized , double-blind , parallel-group study was conducted at 45 general practice and 15 specialist centers . A total of 526 adult patients were r and omized to receive FP or FSC for 24 weeks . The primary efficacy endpoint was change in morning peak expiratory flow ( PEF ) from baseline . Secondary efficacy endpoints included symptom- and rescue-free days ; asthma exacerbation rate ; asthma-related health-care utilization ; and the onset of effect . Safety was assessed by monitoring adverse events . RESULTS Mean morning PEF was significantly greater in the FSC versus the FP group ( P<0.001 ) ; this greater effect was evident as early as the first week of treatment ( P<0.001 ) . The percentages of symptom-free days and rescue-free days in the FSC group were 7.7 % ( P=0.009 ) and 8.4 % ( P=0.001 ) higher than the FP group , respectively . Trends toward lower exacerbation-related health care-utilization for FSC versus FP were not statistically significant and exacerbation rates were not significantly different . The incidence of adverse events was low with both treatments . CONCLUSIONS : Treatment with FSC was a more effective initial controller therapy than FP monotherapy in ICS-naïve patients who had uncontrolled asthma while using as-needed SABA alone BACKGROUND Although inhaled glucocorticosteroids are recommended for persistent asthma , their long-term effect on recent onset , mild , persistent asthma has yet to be established . METHODS We did a r and omised , double-blind clinical trial in 7241 patients in 32 countries to assess the effects of budesonide  in patients who had had mild persistent asthma for less than 2 years and who had not had previous regular treatment with glucocorticosteroids . Patients aged 5 - 66 years received either budesonide or placebo once daily for 3 years in addition to their usual asthma medications . The daily budesonide dose was 400 microg , or 200 microg for children younger than 11 years . The primary outcome was time to first severe asthma-related event , and analysis was by intention to treat . FINDINGS 198 of 3568 patients on placebo and 117 of 3597 on budesonide had at least one severe asthma exacerbation ; hazard ratio 0.56 ( 95 % CI 0.45 - 0.71 , p<0.0001 ) . Patients on budesonide had fewer courses of systemic corticosteroids and more symptom-free days than did those on placebo . Compared with placebo , budesonide increased postbronchodilator forced expiratory volume in 1 s ( FEV1 ) from baseline by 1.48 % ( p<0.0001 ) after 1 year and by 0.88 % ( p=0.0005 ) after 3 years ( expressed as percent of the predicted value ) . The corresponding increase in prebronchodilator FEV1 was 2.24 % after 1 year and 1.71 % after 3 years ( p<0.0001 at both timepoints ) . The effect of treatment on all outcome variables was independent of the baseline lung function ( prebronchodilator or postbronchodilator ) or baseline medication . In children younger than 11 years , 3-year growth was reduced in the budesonide group by 1.34 cm . The reduction was greatest in the first year of treatment ( 0.58 cm ) than years 2 and 3 ( 0.43 cm and 0.33 cm , respectively ) . INTERPRETATION Long-term , once-daily treatment with low-dose budesonide decreases the risk of severe exacerbations and improves asthma control in patients with mild persistent asthma of recent onset SUMMARY Objectives : This study evaluated the efficacy and safety of a novel asthma management strategy – budesonide/formoterol for both maintenance and symptom relief ( Symbicort Single Inhaler Therapy * ) – compared with a higher maintenance dose of budesonide in patients with moderate to severe asthma . Methods : This was a 12-month , r and omised , double-blind , parallel-group study . Symptomatic patients with asthma ( n = 1890 ; mean age 43 years [ range 11 years–80 years ] , mean baseline forced expiratory volume in 1 s [ FEV1 ] 70 % of predicted , mean inhaled corticosteroid [ ICS ] dose 746 µg/day ) received either budesonide ( 160 µg , 2 inhalations twice daily ) plus terbutaline 0.4 mg as needed or a daily maintenance dose of budesonide/formoterol ( 160/4.5 µg , 2 inhalations once daily ) with additional inhalations of budesonide/formoterol 160/4.5 µg as needed . Time to first severe exacerbation ( hospitalisation/emergency room [ ER ] treatment or systemic steroids due to asthma worsening or a fall in morning peak expiratory flow [ PEF ] to ≤ 70 % of baseline on 2 consecutive days ) was the primary outcome variable . Results : A total of 1890 patients were r and omised , of whom 1563 ( 83 % ) had severe asthma .  The time to first severe exacerbation was prolonged by budesonide/formoterol single inhaler therapy ( p < 0.001 ) compared with a higher dose of budesonide . The risk of having a severe exacerbation was 39 % lower with budesonide/ formoterol single inhaler therapy compared with budesonide ( p < 0.001 ) . The number needed to treat to prevent one severe exacerbation per year  with budesonide/formoterol compared with budesonide was 5 . The budesonide/formoterol group had 45 % fewer severe exacerbations requiring medical intervention per patient compared with the budesonide group ( p < 0.001 ) . Budesonide/formoterol patients had fewer hospitalisations/ER treatments ( 15 vs 25 events , respectively [ descriptive statistics ] ) and fewer treatment days with systemic steroids ( 1776 days vs 3177 days , respectively [ descriptive statistics ] ) compared with budesonide patients . Budesonide/formoterol single inhaler therapy patients used less as-needed medication compared with budesonide patients ( 0.90 vs 1.42 inhalations/day ; p < 0.001 ) . The mean daily ICS dose was lower in the budesonide/formoterol group than in the budesonide group ( 466 µg/day vs 640 µg/day ) . Over the 12-month study period , the budesonide/formoterol group achieved asthma control sufficient to not require any additional as-needed medication on 60 % of days . Overall , budesonide/formoterol single inhaler therapy gave 31 more asthma control days ( a night and day with no asthma symptoms and no as-needed medication use ) per patient-year and 12 additional undisturbed nights per patient-year compared with a higher dose of budesonide . Both treatments were well tolerated . Conclusion : Budesonide/formoterol single inhaler therapy has the potential to provide a complete asthma management approach with one inhaler , demonstrating a high level of efficacy in patients with moderate to severe asthma BACKGROUND The Single combination budesonide-formoterol inhaler Maintenance And Reliever Therapy ( SMART ) regimen reduces severe asthma exacerbations in patients , but whether the high doses of corticosteroid and β agonist increase the risk of adverse effects with both short-term and cumulative exposure is not certain . Our aim was to investigate whether the SMART regimen would reduce the risk of overuse of β agonist , reduce the likelihood of patients to seek medical review when such episodes occurred , and if any reduction in severe asthma exacerbations would be at the cost of a higher burden of systemic corticosteroid . METHODS In this 24-week trial undertaken at four primary health-care practice s and one hospital in New Zeal and , patients ( aged 16 - 65 years ) with a recent asthma exacerbation were r and omly assigned in a 1:1 ratio to the SMART or st and ard fixed-dose regimen . Treatment in the SMART group consisted of two actuations of budesonide-formoterol ( 200 μg and 6 μg , respectively , per actuation ) twice daily , delivered through a combination metered dose inhaler ( MDI ) , with one extra actuation as needed for relief of symptoms ; treatment in the st and ard group consisted of two actuations of budesonide-formoterol ( 200 μg and 6 μg , respectively , per actuation ) twice daily through a combination MDI with one to two actuations of salbutamol ( 100 μg per actuation ) by MDI as needed for relief of symptoms . MDIs were monitored electronically to measure actual use of medication . The allocation sequence for r and omisation was computer generated , with a block size of eight per site . Participants , investigators , and the statistician were not masked to group assignment . The primary outcome was the proportion of participants with at least one high-use episode of β agonist ( more than eight actuations per day of budesonide-formoterol in addition to the four maintenance doses in the SMART group or more than 16 actuations per day of salbutamol in the st and ard group ) . Analysis was by intention to treat . This trial is registered with the Australian New Zeal and Clinical Trials Registry , number ACTRN12610000515099 . FINDINGS 303 patients were r and omly assigned to the SMART ( n=151 ) or st and ard group ( n=152 ) . No significant difference was noted between the SMART and st and ard groups in the proportion of participants with at least one high-use episode of β agonist ( 84 [ 56 % ] vs 68 [ 45 % ] , respectively , relative risk 1·24 [ 95 % CI 0·99 - 1·56 ] ; p=0·058 ) . There were fewer days of high use in the SMART group ( mean 5·1 days [ SD 14·3 ] vs 8·9 days [ 20·9 ] , relative rate 0·58 [ 0·39 - 0·88 ] ; p=0·01 ) . Of the patients who had at least one high-use episode , those in the SMART group had fewer days of high use without medical review ( 8·5 days [ 17·8 ] vs 18·3 days [ 24·8 ] , 0·49 [ 0·31 - 0·75 ] ; p=0·001 ) . The SMART regimen result ed in higher inhaled corticosteroid exposure ( 943·5 μg budesonide per day [ 1502·5 ] vs 684·3 μg budesonide per day [ 390·5 ] , respectively ; ratio of means 1·22 [ 1·06 - 1·41 ] ; p=0·006 ) , but reduced oral corticosteroid exposure ( 77·5 mg prednisone [ 240·5 ] vs 126·6 mg prednisone [ 382·1 ] , respectively ; p=0·011 ) , with no significant difference in composite systemic corticosteroid exposure ( 793·7 mg prednisone equivalent per year [ 893·1 ] vs 772·1 mg prednisone equivalent per year [ 1062·7 ] , respectively ; 1·03 [ 0·86 - 1·22 ] ; p=0·76 ) . Participants in the SMART group had fewer severe asthma exacerbations ( 35 [ weighted mean rate per year 0·53 ] vs 66 [ 0·97 ] ; relative rate 0·54 [ 0·36 - 0·82 ] ; p=0·004 ) . INTERPRETATION The SMART regimen has a favourable risk-to-benefit profile and can be recommended for use in adults at risk of severe asthma exacerbations . FUNDING Health Research Council of New Zeal and OBJECTIVE To determine whether initiation of maintenance treatment with the salmeterol (S)/fluticasone propionate ( FP ) combination ( Seretide/Viani/Advair ) is more effective than inhaled steroid alone in patients with asthma symptomatic on short-acting bronchodilator alone . DESIGN 150 asthma patients with symptoms and prn use of short-acting bronchodilator at least once a week were r and omised to 24 weeks ' treatment with either S/FP 50/100 microg bd ( n = 78 ) or FP 100 microg bd ( n = 72 ) . The primary endpoint was the percentage of symptom-free ' day + night 's . RESULTS The percentage of symptom-free ' day + night 's increased significantly more for S/FP ( 20 to 64 % ) compared to FP ( 24 to 51 % ) . The treatment difference was 15.3 % , P = 0.008 . In the sub-group of patients with mild asthma the treatment difference was also statistically significant in favour of S/FP ( P = 0.0245 , n = 74 ) . S/FP was also significantly superior to FP alone for : lung function , salbutamol use prn , day symptom score , symptom-free days , and episode-free ' day + night 's . Treatments were equally well tolerated . CONCLUSION Initial maintenance treatment with S/FP is significantly more effective than with inhaled steroid alone for patients symptomatic when treated with short-acting bronchodilator alone . This also apply to patients with mild persistent asthma Three hundred and fifty-three asthmatic patients who remained symptomatic despite treatment with budesonide 800 - 1200 microg day(-1 ) ( or equivalent ) were r and omized to a new combination therapy comprising salmeterol 50 microg and fluticasone propionate 250 microg ( Seretide , Advair , Viani 50/250 microg ) twice daily or budesonide 800 microg twice daily for 24 weeks . Patients kept daily records of their morning and evening peak expiratory flow ( PEF ) , daytime and night-time symptom scores and daytime and night-time use of rescue salbutamol . Mean morning PEF increased by 451 min(-1 ) ( baseline 361 l min(-1 ) ) in the salmeterol/fluticasone propionate combination ( SFC ) group and by 19 l min(-1 ) ( baseline 358 l min(-1 ) ) in the budesonide group over the 24 weeks . The adjusted mean morning PEF over weeks 1 to 24 was significantly greater in the SFC group , despite the > three-fold lower corticosteroid dose ( 406 vs. 380 l min(-1 ) ; P < 0.001 ) . A significantly greater improvement in evening PEF was also seen in the SFC group ( adjusted mean 416 vs. 398 l min(-1 ) ; P<0.001 ) . SFC also provided significantly better control of daytime symptoms and a significantly greater reduction in the requirement for rescue salbutamol compared with budesonide . These results demonstrate that SFC 50/250 microg twice daily is superior to budesonide 800 microg twice daily in the management of patients with moderate to severe asthma who are symptomatic on their existing dose of corticosteroid OBJECTIVE To evaluate direct asthma-related costs in Swedish primary care in a real-life setting . DESIGN 12-month open-label study . SETTING Swedish primary care in a real-life setting . PARTICIPANTS 1776 patients with persistent asthma . INTERVENTIONS Patients with persistent asthma were r and omised to one of three treatments : a free adjustable combination of budesonide ( 100 - 400 microg/inhalation ) and formoterol ( 4.5 or 9 microg/inhalation ) via separate inhalers plus terbutaline as needed ; budesonide/formoterol ( 160/4.5 microg or 80/4.5 microg , two inhalations twice daily ) plus terbutaline as needed ; budesonide/formoterol ( 160/4.5 microg or 80/4.5 microg , one inhalation twice daily or two inhalations once daily ) , for maintenance plus additional inhalations as needed . Doses depended on previous inhaled corticosteroid dose . Patients attended the clinic at 0 , 1.5 , and 12 months . Telephone interviews were conducted at 4 , 6 , 8 , and 10 months . MAIN OUTCOME MEASURES The primary endpoint was direct asthma-related healthcare costs . RESULTS Statistically significant reductions in annual direct costs per patient were observed with budesonide/formoterol maintenance and reliever therapy compared with the free adjustable combination of budesonide and formoterol ( -13 % , P<0.001 ) and fixed-dose budesonide/formoterol plus terbutaline ( -20 % , P<0.001 ) . Time to first severe exacerbation did not differ significantly across treatment groups , with a mean reduction of 28 % versus the free adjustable combination of budesonide and formoterol ( P=0.076 ) . Patients receiving budesonide/formoterol maintenance and reliever therapy used a significantly lower daily dose of budesonide  compared with the conventional ( P<0.001 ) . CONCLUSIONS This study reports direct cost savings with budesonide/formoterol maintenance and reliever therapy compared with conventional treatment regimens with at least equivalent efficacy ABSTRACT Objective : To evaluate efficacy and costeffectiveness of budesonide/formoterol ( Symbicort * ) maintenance ( one dose once or twice daily ) plus additional doses as needed ( Symbicort Maintenance And Reliever Therapy , SMART ) compared with a higher fixed dose of budesonide/ formoterol with formoterol as needed in patients with persistent asthma .  * Symbicort is a registered trade name of the AstraZeneca group of companies Study design and methods : 6‐month , open , r and omised study of 465 patients either not well controlled on an inhaled corticosteroid ( ICS ) , or well controlled on a combination of ICS and a long-acting β2‐agonist ( LABA ) . Treatments : budesonide/formoterol 160/4.5 µg , one inhalation , once or twice daily maintenance plus additional doses as-needed ( 1 × SMART or 2 × SMART ) , or budesonide/formoterol 160/4.5 µg two inhalations twice daily plus formoterol 4.5 µg as needed ( 2 × 2 FIX + F ) . Children 6–11 years old used an 80/4.5 µg dose strength . Primary variables of efficacy were the changes in the Asthma Control Question naire ( ACQ5 ) and morning peak expiratory flow ( PEF ) . Results : Mean age of patients 40 years ( range 6–82 years ) ; 53 % female . No differences between the groups were found in ACQ5 scores or asthma exacerbation rates . Morning PEF was higher in the 2 × 2 FIX + F group vs. the 1 × SMART and 2 × SMART groups ( differences 13 L/min and 9 L/min , respectively ; p < 0.002 ) . The 1 × SMART group showed a significant decrease in asthma controlled days compared with the two other groups . No difference was seen between the 2 × SMART group and the 2 × 2 FIX + F group . Treatment costs were significantly lower in the SMART groups compared with the 2 × 2 FIX + F group . Conclusion : Compared with the 2 × 2 FIX + F treatment the use of budesonide/formoterol was 30–40 % lower in the SMART groups while maintaining equal ACQ5 scores . Daily asthma control improved equally with 2 × SMART compared to 2 × 2 FIX + F with a reduction in asthma medication cost . The one dose once daily maintenance treatment ( 1 × SMART ) result ed in a low level of treatment failure ( exacerbations ) but led to more days with symptoms . Therefore , a daily dose of two inhalations seems to be the lowest appropriate dose in patients with moderate persistent asthma For most patients , asthma is not controlled as defined by guidelines ; whether this is achievable has not been prospect ively studied . A 1-year , r and omized , stratified , double-blind , parallel-group study of 3,421 patients with uncontrolled asthma compared fluticasone propionate and salmeterol/fluticasone in achieving two rigorous , composite , guideline -based measures of control : totally and well-controlled asthma . Treatment was stepped-up until total control was achieved ( or maximum 500 microg corticosteroid twice a day ) . Significantly more patients in each stratum ( previously corticosteroid-free , low- and moderate-dose corticosteroid users ) achieved control with salmeterol/fluticasone than fluticasone .  Total control was achieved across all strata : 520 ( 31 % ) versus 326 ( 19 % ) patients after dose escalation ( p < 0.001 ) and 690 ( 41 % ) versus 468 ( 28 % ) at 1 year for salmeterol/fluticasone and fluticasone , respectively . Asthma became well controlled in 1,071 ( 63 % ) versus 846 ( 50 % ) after dose escalation ( p < 0.001 ) and 1,204 ( 71 % ) versus 988 ( 59 % ) at 1 year . Control was achieved more rapidly and at a lower corticosteroid dose with salmeterol/fluticasone versus fluticasone . Across all strata , 68 % and 76 % of the patients receiving salmeterol/fluticasone and fluticasone , respectively , were on the highest dose at the end of treatment . Exacerbation rates ( 0.07 - 0.27 per patient per year ) and improvement in health status were significantly better with salmeterol/fluticasone . This study confirms that the goal of guideline -derived asthma control was achieved in a majority of the patients BACKGROUND The contributions of as-needed inhaled corticosteroids and long-acting beta2 agonists ( LABA ) to asthma control have not been fully established . We compared the efficacy and safety of three reliever strategies : a traditional short-acting beta2 agonist ; a rapid-onset LABA ( formoterol ) ; and a combination of LABA and an inhaled corticosteroid ( budesonide-formoterol ) in symptomatic patients receiving budesonide-formoterol maintenance therapy . METHODS We did a 12-month , double-blind , parallel-group study in 3394 patients ( aged 12 years or older ) , in 289 centres in 20 countries , who were using inhaled corticosteroids at study entry and symptomatic on budesonide-formoterol ( 160 microg and 4.5 microg , respectively ) , one inhalation twice daily , during a 2-week run-in . After run-in , patients were r and omly assigned budesonide-formoterol maintenance therapy plus one of three alternative as-needed medications-terbutaline ( 0.4 mg ) , formoterol ( 4.5 microg ) , or budesonide-formoterol ( 160 microg and 4.5 microg ) . The primary outcome was time to first severe exacerbation , defined as an event result ing in hospitalisation , emergency room treatment , or both , or the need for oral steroids for 3 days or more . FINDINGS Time to first severe exacerbation was longer with as-needed budesonide-formoterol versus formoterol ( p=0.0048 ; log-rank test ) and with as-needed formoterol versus terbutaline ( p=0.0051 ) . The rate of severe exacerbations was 37 , 29 , and 19 per 100 patients per year with as-needed terbutaline , formoterol , and budesonide-formoterol , respectively ( rate ratios budesonide-formoterol versus formoterol 0.67 [ 95 % CI 0.56 - 0.80 ; p<0.0001 ] ; budesonide-formoterol versus terbutaline 0.52 [ 0.44 - 0.62 ; p<0.0001 ] ; formoterol versus terbutaline 0.78 [ 0.67 - 0.91 ; p=0.0012 ] ) . Asthma control days increased to a similar extent in all treatment groups . As-needed formoterol did not significantly improve symptoms compared with as-needed terbutaline . All treatments were well tolerated . INTERPRETATION Both monocomponents of budesonide-formoterol given as needed contribute to enhanced protection from severe exacerbations in patients receiving combination therapy for maintenance BACKGROUND Asthma treatment guidelines recommend addition of controller medications for patients with poorly controlled asthma . We compared the effectiveness of once-daily oral controller therapy with either an antileukotriene receptor antagonist ( montelukast ) or low-dose theophylline added to existing medications in patients with poorly controlled asthma . METHODS We conducted a r and omized , double-masked , placebo-controlled trial in 489 participants with poorly controlled asthma r and omly assigned to  placebo , theophylline ( 300 mg/d ) , or montelukast ( 10 mg/d ) . Participants were monitored for 24 wk to measure the rate of episodes of poor asthma control ( EPACs ) defined by decreased peak flow , increased beta-agonist use , increased oral corticosteroid use , or unscheduled health care visits . OBSERVATIONS There was no significant difference in EPAC rates ( events/person/yr ) compared with placebo : low-dose theophylline , 4.9 ( 95 % confidence interval [ CI ] , 3.6 - 6.7 ; not significant ) ; montelukast , 4.0 ( 95 % CI , 3.0 - 5.4 ; not significant ) ; and placebo , 4.9 ( 95 % CI , 3.8 - 6.4 ) . Both montelukast and theophylline caused small improvements in prebronchodilator FEV(1 ) of borderline significance . Nausea was more common with theophylline only during the first 4 wk of treatment . Neither treatment improved asthma symptoms or quality of life . However , in patients not receiving inhaled corticosteroids , addition of low-dose theophylline significantly ( p < 0.002 ) improved asthma control and symptoms as well as lung function . CONCLUSIONS Neither montelukast nor low-dose theophylline lowered the EPAC rate of poor asthma control in patients with poorly controlled asthma despite improved lung function . For patients not using inhaled corticosteroids , low-dose theophylline improved asthma symptom control more than montelukast or placebo , and provides a safe and low-cost alternative asthma treatment OBJECTIVE The aim of this study was to assess asthma control using salmeterol plus fluticasone propionate ( FP ) in combination ( SFC ) versus salmeterol or FP as monotherapy in patients with mild to moderate asthma . METHODS In this r and omised , double-blind , parallel-group study , 322 symptomatic patients were recruited , of which 282 were r and omised to receive either salmeterol ( 50 microg ) , FP ( 250 microg ) , or SFC ( 50 microg/250 microg ) , via a single Diskus inhaler twice daily for 12 months . Outcome variables included the number of patients requiring an increase in study medication and the number experiencing 2 exacerbations during the 12-month treatment period . Airway hyper-responsiveness ( AHR ) and lung function tests were performed at clinic visits . Peak expiratory flow , rescue medication use , symptom scores and adverse events were recorded in diary cards . RESULTS Fewer patients required an increase in study medication with SFC ( 10.5 % ) than with either FP ( 34.8 % ) or salmeterol ( 61.1 % ) ( P<0.001 ) . Significantly fewer patients experienced 2 exacerbations with SFC ( 4.2 % ) , compared with FP ( 17.4 % ; P<0.01 ) or salmeterol ( 40 % ; P<0.001 ) . SFC improved AHR to a significantly greater extent than FP ( methacholine PC20=1.8 mg/ml vs. 1.1 mg/ml ; P<0.05 ) or salmeterol ( methacholine PC20=1.8 mg/ml vs. 0.7 mg/ml ; P<0.001 ) . CONCLUSIONS The protection against exacerbations may be attributed to better control of inflammation , AHR and lung function parameters achieved with salmeterol and FP in combination , compared with either treatment alone The optimal treatment for mild asthma is uncertain . We assessed the effects of adding a long-acting inhaled beta-agonist , formoterol , to low doses of an inhaled corticosteroid , budesonide , for 1 yr in subjects with mild asthma , receiving no or only a small dose of inhaled corticosteroid . The 698 corticosteroid free patients ( Group A ) were assigned to twice daily treatment with 100 microg budesonide , 100 microg budesonide plus 4.5 microg formoterol , or placebo .  The 1,272 corticosteroid-treated patients ( Group B ) were assigned to twice daily treatment with 100 microg budesonide , 100 microg budesonide plus 4.5 microg formoterol , 200 microg budesonide , or 200 microg budesonide plus 4.5 microg formoterol . The main outcome variables were time to the first severe asthma exacerbation and poorly controlled asthma days . In Group A , budesonide alone reduced the risk for severe exacerbations by 60 % and poorly controlled days by 48 % ; adding formoterol increased lung function with no change in other end points . By contrast , in Group B , adding formoterol reduced the risk for the first severe exacerbation and for poorly controlled days by 43 and 30 % , respectively . Thus , in corticosteroid-free patients , low dose inhaled budesonide alone reduced severe exacerbations and improved asthma control , and in patients already receiving inhaled corticosteroid , adding formoterol was more effective than doubling the corticosteroid dose BACKGROUND The long acting beta 2 agonist formoterol has proved to be an effective bronchodilator with a prolonged action of 12 - 14 hours . However , the precise role of formoterol in the maintenance treatment of asthma is still under debate . A study was performed to investigate the efficacy and safety of treatment with formoterol for six months in subjects with asthma . METHODS In a multicentre double blind , placebo controlled , parallel group study 239 subjects with mild to moderate asthma were r and omly assigned to treatment with either inhaled formoterol 24 micrograms twice daily ( n = 125 ) or placebo ( n = 114 ) during eight months . The study consisted of a four week run in period , a 24 week treatment period , and a four week washout period . All subjects were using regular inhaled corticosteroids ( 100 - 3200 micrograms daily ) but were still needing at least five inhalations of short acting beta 2 agonist per week for symptom relief . The study was performed in 10 outpatient clinics in Canada , and five outpatient clinics and one coordinating centre for 44 Dutch general practitioners in The Netherl and s. Twice daily self-reported peak expiratory flow ( PEF ) measurements , symptom scores , and rescue beta 2 agonist use during the last 28 treatment days compared with baseline values were used as main outcome measures . Spirometric values were measured at entry , at the start of treatment , after four , 12 and 24 weeks of treatment , and after four weeks washout . RESULTS One hundred and twenty five subjects received formoterol 24 micrograms twice daily via Turbohaler and 114 received placebo .  Baseline FEV1 was 67.1 % predicted and mean bronchodilator reversibility was 26 % . The mean total asthma symptom score was 3.6 ( maximum possible 21 ) . A significant decrease in symptoms in favour of formoterol ( difference from placebo -0.64 , 95 % CI -0.04 to -1.23 , p = 0.04 ) was observed . Compared with placebo , morning PEF increased ( difference from placebo 28 l/min , 95 % CI 18.3 to 37.7 , p = 0.0001 ) and the use of short acting beta 1 agonists decreased ( daytime difference from placebo -1.1 inhalation , 95 % CI -1.4 to -0.7 , p = 0.0001 ) in the formoterol group . PEF returned to baseline following discontinuation of formoterol , as did asthma symptom scores . Thirty three patients treated with formoterol and 32 treated with placebo required treatment with prednisolone during the study ( 58 and 55 courses , respectively ) . CONCLUSIONS Adding formoterol 24 micrograms twice daily by Turbohaler to inhaled corticosteroids was effective in improving symptom scores and morning PEF , and decreasing the use of rescue beta 2 agonists . There was no apparent loss of asthma control during 24 weeks of treatment with formoterol Background : Previous studies have indicated the benefits of adding long acting β2 agonists to inhaled corticosteroids in the maintenance treatment of moderate to severe asthma . The effects of adding eformoterol to corticosteroids on asthma control and exacerbations in patients with mild to moderate asthma were studied . Methods : After a run in period of 7–14 days on existing medication , 663 symptomatic patients were r and omised to receive budesonide Turbohaler 400 μg twice daily together with either eformoterol Turbohaler 9 μg ( delivered dose ) or placebo twice daily . After 4 weeks patients whose asthma was well controlled ( n=505 ) were re-r and omised to receive budesonide 400 μg daily and either eformoterol 9 μg or placebo twice daily for a further 6 months . Results : Patients receiving eformoterol  achieved asthma control 10 days sooner than those receiving budesonide alone , and improvements in lung function , symptoms , quality of life , and relief β2 agonist use were significantly greater with eformoterol . During the 6 month follow up the frequency of mild exacerbations was significantly lower in the eformoterol group than in those receiving budesonide alone ( 7.2 versus 10.5 per patient , 95 % confidence interval for ratio 0.49 to 0.96 , p=0.03 ) . The time to first day of poorly controlled asthma was 97 days in the eformoterol group compared with 42 days in the placebo group ( p=0.003 ) . Conclusions : Adding eformoterol to a low or moderate dose of budesonide in mild asthma result ed in faster and more effective control than treatment with budesonide alone . Eformoterol allowed the corticosteroid dose to be reduced while also decreasing the rate of mild exacerbations compared with budesonide alone . These data suggest a therapeutic advantage of adding eformoterol to inhaled corticosteroids in patients with mild to moderate asthma OBJECTIVE To compare the efficacy of theophylline plus salmeterol/fluticasone propionate combination product ( SFC ) with SFC plus placebo in asthmatic patients . METHODS In this r and omized , stratified , parallel-group study , 325 patients were r and omized to receive either 200 mg theophylline plus 50/250 μg SFC or placebo tablet plus 50/250 μg SFC twice daily for 24 weeks . Outcome variables included the level of asthma control ( assessed by the Asthma Control Test ) and the number of patients experiencing ≥1 exacerbations during the 24-week treatment period . Testing of lung function as well as measurement of the levels of inflammatory markers in induced sputum was performed . RESULTS There were significantly fewer patients with ≥1 asthma exacerbation in the theophylline plus SFC group ( 29.6 % ) when compared with the SFC plus placebo group ( 46.9 % ) ( p = 0.004 ) . Theophylline plus SFC improved the FEF(25 - 75 % ) value , which indicates enhanced small airway function , to a greater extent than SFC plus placebo ( 66.9 ± 18.8 % and 57.4 ± 17.6 % , respectively ; p < 0.001 ) . A significant decrease in eosinophil count and concentration of eosinophil cationic protein in induced sputum was also seen in the theophylline plus SFC group when compared with the SFC plus placebo group ( 4.1 ± 2.2 % and 6.3 ± 2.7 % , 63.6 ± 39.5 μg/L and 89.4 ± 45.6 μg/L , respectively ; all p < 0.01 ) . CONCLUSION The combination of theophylline plus SFC may provide greater protection against asthma exacerbations , and its administration is accompanied by significant improvements in small airway function and airway inflammation BACKGROUND The role of long-acting , inhaled beta2-agonists in treating asthma is uncertain . In a double-blind study , we evaluated the effects of adding inhaled formoterol to both lower and higher doses of the inhaled glucocorticoid budesonide . METHODS After a four-week run-in period of treatment with budesonide ( 800 microg twice daily ) , 852 patients being treated with glucocorticoids  were r and omly assigned to one of four treatments given twice daily by means of a dry-powder inhaler ( Turbuhaler ) : 100 microg of budesonide plus placebo , 100 microg of budesonide plus 12 microg of formoterol , 400 microg of budesonide plus placebo , or 400 microg of budesonide plus 12 microg of formoterol . Terbutaline was permitted as needed . Treatment continued for one year ; we compared the frequency of exacerbations of asthma , symptoms , and lung function in the four groups . A severe exacerbation was defined by the need for oral glucocorticoids or a decrease in the peak flow to more than 30 percent below the base-line value on two consecutive days . RESULTS The rates of severe and mild exacerbations were reduced by 26 percent and 40 percent , respectively , when formoterol was added to the lower dose of budesonide . The higher dose of budesonide alone reduced the rates of severe and mild exacerbations by 49 percent and 37 percent , respectively . Patients treated with formoterol and the higher dose of budesonide had the greatest reductions -- 63 percent and 62 percent , respectively . Symptoms of asthma and lung function improved with both formoterol and the higher dose of budesonide , but the improvements with formoterol were greater . CONCLUSIONS In patients who have persistent symptoms of asthma despite treatment with inhaled glucocorticoids , the addition of formoterol to budesonide therapy or the use of a higher dose of budesonide may be beneficial . The addition of formoterol to budesonide therapy improves symptoms and lung function without lessening the control of asthma BACKGROUND Budesonide/formoterol maintenance and reliever therapy maintains asthma control and reduces exacerbation frequency compared with higher fixed-dose combination regimens . Its effects on eosinophilic airway inflammation and structure are unknown . OBJECTIVE We sought to compare the effects of budesonide/formoterol 200/6 microg twice daily plus as-needed with budesonide/formoterol 800/12 microg twice daily on airway eosinophils and remodeling . METHODS This 52-week , parallel-group , r and omized , double-blind study of 127 asthma patients who were symptomatic despite therapy compared ( 1 ) the change between induced sputum percent eosinophils at baseline and the geometric mean of 4 on-treatment values and ( 2 ) the change in endobronchial biopsy eosinophil counts pre- and post-treatment . RESULTS Mean daily doses of budesonide/formoterol were 604/18 microg in the maintenance and reliever therapy group and 1,600/24 microg in the high fixed-dose group . In the former , the geometric mean percent sputum eosinophils remained unchanged ( 1.6 % to 1.9 % ) , whereas biopsy specimen subepithelial eosinophils increased ( 6.2 to 12.3 cells/mm(2 ) ) . Sputum and biopsy eosinophil counts decreased with high fixed-dose treatment ( 2.2 % to 1.2 % and 7.7 to 4.8 cells/mm(2 ) , respectively ) , result ing in significant treatment differences of 0.7 % ( ratio , 1.8 ; 95 % CI , 1.2 - 2.8 ; P = .0038 ) and 7.5 cells/mm(2 ) ( ratio , 2.9 ; 95 % CI , 1.6 - 5.3 ; P < .001 ) , respectively . There were no between-treatment differences in reticular basement membrane thickness , exhaled nitric oxide , exacerbation frequency , or FEV(1 ) . CONCLUSION Compared with fixed-dose combination treatment containing a 4-fold higher maintenance dose of budesonide , budesonide/formoterol maintenance and reliever therapy is associated with higher eosinophil counts , but these remain within the range associated with stable clinical control BACKGROUND The management of asthma has changed since the introduction of budesonide/formoterol ( Symbicort ® ) as both maintenance and reliever therapy ( SMART ) . SMART and its effects on bronchial hyperresponsiveness ( BHR ) have not been studied in primary care . AIMS To compare the effects of SMART and guideline -driven usual care ( UC ) on BHR and clinical asthma severity in primary care practice . METHODS Patients with mild-to-moderate stable asthma were r and omised to receive SMART treatment ( n=54 ) ( budesonide/formoterol 80/4.5 μg Turbuhaler ® , two puffs once daily and extra inhalations as needed ) or UC treatment ( n=48 ) for 12 months . Diary data , Asthma Control Question naire scores , forced expiratory volume in 1 second ( FEV1 ) , and peak expiratory flow ( PEF ) measurements were collected during run-in and after 1 , 3 , 6 , and 12 months of treatment . BHR , measured as the dose of histamine provoking a fall in FEV1 of 20 % ( PD20-histamine ) , was determined at r and omisation and after 12 months . RESULTS One hundred and two patients with asthma participated in the study .  The change in PD20-histamine during the study was not significantly different between the SMART and UC groups ( p=0.26 ) . The mean inhaled corticosteroid ( ICS ) dose was 326 μg beclomethasone dipropionate ( BDP ) equivalents/day ( 95 % CI 254 to 399 ) with SMART , which was significantly lower ( p<0.0001 ) than the mean ICS dose with UC treatment ( 798 μg BDP equivalents/day ( 95 % CI 721 to 875 ) . Morning and evening PEF values increased significantly with SMART treatment compared with UC ; FEV1 , symptoms and asthma control did not differ . CONCLUSIONS Despite a 59 % lower dose of ICS , BHR and other clinical outcomes remained stable during SMART treatment while PEF values improved This r and omized , double-blind , double-dummy , parallel group clinical trial compared the efficacy and safety of adding salmeterol xinafoate to concurrent inhaled beclomethasone dipropionate therapy with doubling the dose of beclomethasone dipropionate in patients experiencing symptoms on low-dose beclomethasone .  Salmeterol added to low-dose beclomethasone was superior ( p < or = 0.05 ) to doubling the dose of beclomethasone in improving peak expiratory flow ( PEF ) and forced expiratory volume in 1 sec ( FEV1 ) , and in reducing symptoms of asthma , sleep loss , nighttime awakenings , and use of albuterol . Both treatment regimens had comparable safety profiles . In asthma patients inadequately controlled despite the use of low-dose inhaled corticosteroids ( i.e. , less than 400 microg per day ) , the addition of salmeterol may be a more effective treatment option than doubling the dose of inhaled corticosteroids BACKGROUND Both inhaled corticosteroids and leukotriene modifiers are used in the maintenance treatment of persistent asthma . OBJECTIVE The goal was to compare the efficacy and safety of low-dose fluticasone propionate ( FP ) and montelukast as first-line maintenance therapy in symptomatic patients by using short-acting beta2-agonists alone to treat persistent asthma . METHODS In this multicenter , r and omized , double-blind , double-dummy , parallel-group study , 533 patients ( > 15 years old ) with persistent asthma who remained symptomatic while taking short-acting beta2-agonists alone were treated with FP ( 88 microg [ 2 puffs of 44 microg ] twice daily ) or montelukast ( 10 mg once daily ) for 24 weeks . RESULTS Compared with treatment with montelukast , treatment with FP result ed in significantly greater improvements at endpoint in morning predose FEV(1 ) ( 22.9 % vs 14.5 % , P < .001 ) , forced midexpiratory flow ( 0.66 vs 0.41 L/sec , P < .001 ) , forced vital capacity ( 0.42 vs 0.29 L , P = .002 ) , morning peak expiratory flow ( PEF ) ( 68.5 vs 34.1 L/min , P < .001 ) , and evening PEF ( 53.9 vs 28.7 L/min , P < .001 ) . Similar improvements in PEF were observed in patients with milder asthma ( > 70%-80 % predicted FEV(1 ) ) . At endpoint , FP was more effective than montelukast at decreasing rescue albuterol use ( 3.1 puffs/day vs 2.3 puffs/day , P < .001 ) , asthma symptom scores ( -0.85 [ 48.6 % decrease ] vs -0.60 [ 30.5 % ] , P < .001 ) , and nighttime awakenings due to asthma ( -0.64 awakenings/night [ 62 % decrease ] vs -0.48 awakenings/night [ 47.5 % ] , P = .023 ) , and FP increased the percentage of symptom-free days ( 32.0 % vs 18.4 % of days , P < .001 ) compared with montelukast . The adverse event and asthma exacerbation profiles for FP and montelukast were similar . CONCLUSIONS Low-dose FP is more effective than montelukast as first-line maintenance therapy for patients with persistent asthma who are undertreated and remain symptomatic while taking short-acting beta2-agonists alone BACKGROUND Inhaled corticosteroids ( ICS ) and long-acting β(2)-agonists ( LABAs ) are recommended in patients with asthma that is not well-controlled ; however , many patients continue to have inadequately controlled asthma despite this therapy . OBJECTIVE To evaluate the efficacy and safety of omalizumab in patients with inadequately controlled severe asthma who are receiving high-dose ICS and LABAs , with or without additional controller therapy . DESIGN Prospect i ve , multicenter , r and omized , parallel-group , double-blind , placebo-controlled trial . ( Clinical Trials.gov registration number : NCT00314575 ) . SETTING 193 investigational sites in the United States and 4 sites in Canada . PATIENTS 850 patients aged 12 to 75 years who had inadequately controlled asthma despite treatment with high-dose ICS plus LABAs , with or without other controllers . INTERVENTION Omalizumab ( n = 427 ) or placebo ( n = 423 ) was added to existing medication regimens for 48 weeks . MEASUREMENTS The primary end point was the rate of protocol -defined exacerbations over the study period . Secondary efficacy end points included the change from baseline to week 48 in mean daily number of puffs of albuterol , mean total asthma symptom score , and mean overall score on the st and ardized version of the Asthma Quality of Life Question naire ( AQLQ[S ] ) . Safety end points included the frequency and severity of treatment-emergent adverse events . RESULTS During 48 weeks , the rate of protocol -defined asthma exacerbations was significantly reduced for omalizumab compared with placebo ( 0.66 vs. 0.88 per patient ; P = 0.006 ) , representing a 25 % relative reduction ( incidence rate ratio , 0.75 [ 95 % CI , 0.61 to 0.92 ] ) . Omalizumab improved mean AQLQ(S ) scores ( 0.29 point [ CI , 0.15 to 0.43 ] ) , reduced mean daily albuterol puffs ( -0.27 puff/d [ CI , -0.49 to -0.04 puff/d ] ) , and decreased mean asthma symptom score ( -0.26 [ CI , -0.42 to -0.10 ] ) compared with placebo during the 48-week study period . The incidence of adverse events ( 80.4 % vs. 79.5 % ) and serious adverse events ( 9.3 % vs. 10.5 % ) were similar in the omalizumab and placebo groups , respectively . LIMITATIONS The results are limited by early patient discontinuation ( 20.8 % ) . The study was not powered to detect rare safety events or the treatment effect in the oral corticosteroid subgroup . CONCLUSION In this study , omalizumab provided additional clinical benefit for patients with severe allergic asthma that is inadequately controlled with high-dose ICS and LABA therapy . PRIMARY FUNDING SOURCE Genentech and Novartis Pharmaceuticals BACKGROUND Leukotrienes produced by the 5-lipoxygenase pathway of arachidonic acid metabolism may mediate bronchoconstriction and inflammatory changes important in the pathophysiology of asthma . Leukotriene inhibition may be effective in asthma management . OBJECTIVE This clinical trial was performed to assess the long-term efficacy and safety of zileuton , an inhibitor of 5-lipoxygenase . METHODS In this multicenter , double-blind , parallel-group , placebo-controlled trial , 600 mg of zileuton , 400 mg of zileuton , or placebo was given orally , each four times daily for 6 months . Patients with mild to moderate asthma ( n = 373 ) , 18 to 62 years of age , being managed with regularly inhaled beta-agonist alone , were r and omized to the zileuton or placebo groups ( n = 122 to 126 ) . Outcome measures included serial spirometry , daily peak expiratory flow rates , daytime and nocturnal symptoms , frequency of beta-agonist use , and number of asthma exacerbations treated with systemic corticosteroids . RESULTS An acute bronchodilatory effect was observed 2 to 5 hours after the initial dose of medication in both 400 mg zileuton and 600 mg zileuton groups compared to the placebo group . Both zileuton groups had significantly greater improvements in FEV1 than did the placebo group by day 8 . On day 36 , FEV1 improved 16 % and 12 % from baseline for patients treated with 600 mg zileuton and 400 mg zileuton , respectively , compared with an improvement of 6 % for the placebo-treated group ( p < 0.01 , zileuton 600 mg vs placebo ) . Blood eosinophil levels were significantly reduced in both zileuton-treated groups compared with the placebo group . In the group receiving 600 mg zileuton , morning peak expiratory flow rate improved by 7 % to 10 % ; daytime and nocturnal symptoms decreased by 37 % and 31 % , respectively ; beta-agonist use decreased by 31 % ; and the proportion of patients requiring steroid rescue medication during the study was reduced by 62 % ( p < 0.05 for all comparisons of zileuton , 600 mg , vs placebo ) . Improvements were sustained over 6 months . Adverse events were similar in the three groups with no apparent , dose-related side effects . CONCLUSION Zileuton produces objective and subjective improvements in patients with mild to moderate asthma and is well tolerated Objective . To study the effectiveness and safety in a real-life setting of budesonide/formoterol ( Symbicort ) Maintenance And Reliever Therapy ® ( Symbicort SMART ® ) , a simplified management approach with one inhaler , compared with conventional best practice ( CBP ) with multiple inhalers in patients with persistent asthma . Design . Open-label r and omized controlled parallel-group trial , 6-month treatment . Participants . A total of 654 adult patients , with persistent asthma receiving treatment with inhaled corticosteroids ( ICS ) , either alone or in conjunction with long-acting β2-agonist .  Main outcome measures . Time to first severe asthma exacerbation and number of severe asthma exacerbations . Results . No difference between groups was seen in time to first severe exacerbation ( p = .2974 ) . Exacerbation rates were low in both groups . A total of 22 patients in the Symbicort SMART group experienced a total of 24 severe asthma exacerbations , and 31 patients in the CBP group experienced a total of 34 severe asthma exacerbations ( annual rate 0.16 vs. 0.22 , p = .2869 ) . The mean daily dose of ICS expressed in beclomethasone dipropionate equivalent was significantly lower in the Symbicort SMART group ( including as-needed use ) versus the CBP group ( 799 μg vs.1184 μg ; p < .001 ) . Mean scores in Asthma Control Question naire , five- question version , improved significantly in the SMART group compared with the CBP group ( p =  .0292  ) . Symbicort SMART and CBP were equally well tolerated . The mean drug cost per patient per 6 months was lower for the patients in the SMART group compared with patients receiving CBP ( € 295.32 vs. € 387.98 , p < .0001 ) . Conclusions . A simplified regimen using budesonide/formoterol maintenance and reliever therapy ( Symbicort SMART ) was at least as effective at improving clinical control compared with CBP with a significantly lower ICS dose and lower drug costs This r and omized , double-blind , parallel , multi-center study was design ed to determine whether the addition of salmeterol to existing inhaled corticosteroid therapy provides greater therapeutic benefit than doubling the dose of inhaled corticosteroids in symptomatic patients with asthma . A total of 514 adults were r and omized to either beclomethasone 168 micrograms plus salmeterol 42 micrograms twice daily or beclomethasone 336 micrograms twice daily for 24 weeks . Both treatments result ed in significantly improved symptom control and increased pulmonary function . However , beclomethasone plus salmeterol provided greater improvements than doubling the dose of beclomethasone ( p < or = 0.05 ) in FEV1 and in daily-recorded measurements of morning ( 38 L/minute versus 20 L/minute after treatment with higher dose beclomethasone ) and evening peak expiratory flow , asthma symptom scores , symptom-free days , supplemental albuterol use , and days and nights not requiring albuterol . There were no significant differences between treatment groups in the number of patients with abnormal response to corticotropin stimulation at Treatment Week 24 . No treatment differences in asthma exacerbation and adverse event frequency rates were seen . Beclomethasone 168 micrograms plus salmeterol 42 micrograms administered twice daily was superior to beclomethasone 336 micrograms taken twice daily in patients symptomatic on beclomethasone 168 micrograms , with no added safety risks BACKGROUND Recent studies have raised concern that regular inhalation of beta2 -agonists may cause a worsening of asthma control compared with on-dem and dosing regimens . OBJECTIVE The objective of this study was to compare the effect of twice daily formoterol ( Foradil ) , 4 times daily albuterol , and on-dem and albuterol on bronchial hyperresponsiveness ( BHR ) , lung function measurements , symptoms , and other indicators of disease control over 6 months in patients with asthma of moderate or greater severity receiving concomitant inhaled corticosteroids . We also looked for occurrence of rebound BHR on discontinuation of treatment . METHODS This was a multicenter , parallel-group , double-blind , clinical trial . Methacholine PC20 was the primary outcome variable . Other outcome variables included symptom scores , use of rescue medication , morning peak expiratory flow ( PEF ) , serial FEV1 measurements , and asthma exacerbations . RESULTS Of the 271 r and omized patients , 217 completed the study .  Formoterol was significantly superior to on-dem and albuterol with regard to methacholine PC20 , FEV1 , PEF , symptom scores , and use of rescue medication at each measured time point/interval . Regular albuterol was superior to on-dem and albuterol with regard to PC20 and FEV1 , but not PEF or various clinical scores . After a small drop in the magnitude of bronchoprotection and bronchodilatation occurring shortly after r and omization , there was no evidence of progressive tolerance to either regular treatment for any of the measured variables or of rebound increase in BHR 2 days after the end of treatment . The formoterol group had the lowest number of exacerbation days , as defined by high intake of rescue bronchodilator and /or symptom scores , whereas the number of exacerbations requiring increased corticosteroid coverage was similar in the 3 groups . CONCLUSION In patients with asthma of moderate or greater severity receiving inhaled corticosteroids , formoterol taken twice daily result ed in superior bronchoprotection , bronchodilatation , and clinical control compared with on-dem and albuterol over 6 months . Four times daily albuterol was superior to on-dem and albuterol for only some of the end points . Progressive tolerance and a rebound increase in BHR on discontinuation of beta-agonists were not A study was done to compare the efficacy and safety of the coprescription of salmeterol 50 microgram twice daily or 100 microgram twice daily with beclomethasone dipropionate ( BDP ) 500 micrograms twice daily ( SALM 50 and SALM 100 ) with BDP 1,000 microgram twice daily ( BDP 1,000 ) in patients with asthma not controlled by BDP 500 microgram twice daily ( or the equivalent ) . Following a run-in period , 738 patients at 72 centers were r and omized to treatment for 24 wk in a double-blind , parallel-group study during which they maintained a daily record of peak expiratory flow rates ( PEFRs ) and symptom scores . At about 40 of the centers , bronchial hyperresponsiveness ( BHR ) to histamine was measured during and at 3 and 14 d after stopping treatment . Both groups taking salmeterol showed an improvement of more than 45 L/min in their morning PEFR and 30 L/min in their evening PEFR , compared with respective improvements of 16 L/min and 6 L/min in the group taking BDP 1,000 . Both the SALM 50 and SALM 100 groups had a significantly increased percentage of symptom-free and rescue-free days and nights compared with the BDP 1,000 group , and there was no difference between the two salmeterol groups . None of the treatments altered BHR . Exacerbation rates did not differ among the three groups . We conclude that in this selected group of symptomatic patients taking BDP 500 micrograms twice daily , the addition of salmeterol provides better improvement in lung function and symptom control , without altering BHR or increasing exacerbation rates , than does doubling the dose of BDP BACKGROUND There is a paucity of data comparing the long-term safety and efficacy of long-acting inhaled beta2-agonists versus low-dose inhaled corticosteroids in the treatment of asthma . OBJECTIVE To compare the safety and efficacy of salmeterol xinafoate , beclomethasone dipropionate ( BDP ) , and placebo over a 6-month treatment period in patients with persistent asthma . METHODS Salmeterol ( 42 microg twice daily ) , BDP ( 84 microg four times daily ) , or placebo was administered via metered-dose inhaler to 386 adolescent and adult inhaled corticosteroid-naive patients in a r and omized , double-blind , double-dummy , parallel-group study . Eligible patients demonstrated a forced expiratory volume in 1 second ( FEV1 ) from 65 % to 90 % of predicted values .  Pulmonary function , symptom control , frequency of asthma exacerbations , bronchial hyperresponsiveness ( BHR ) to methacholine challenge , and adverse events were assessed . RESULTS There were few statistically significant differences between the two active treatments over 6 months of therapy . Asthma symptoms and lung function were significantly improved with both salmeterol and BDP compared with placebo ( changes from baseline in FEV1 of 0.28 L ( SE = 0.04 ) and 0.23 L ( SE = 0.04 ) , respectively , compared with 0.08 L ( SE = 0.04 ) ; P < or = .014 ) . There were no significant differences among the treatment groups with respect to the distribution of asthma exacerbations over time . Both salmeterol and BDP significantly reduced BHR compared with placebo ( P < or = .033 ; changes from baseline of 1.29 ( SE = 0.26 ) and 1.42 ( SE = 0.24 ) doubling doses at 6 months , respectively , compared with 0.24 ( SE = 0.29 ) doubling dose for placebo ) . No rebound effect in BHR was seen upon cessation of any of the three treatment regimens . There were no clinical ly important differences in the safety profiles among the three treatments . CONCLUSIONS Both salmeterol and BDP are effective and well-tolerated when administered for 6 months to inhaled corticosteroid-naive patients with persistent asthma BACKGROUND Inhaled corticosteroids ( ICSs ) have been shown to reverse epithelial damage and decrease lamina reticularis thickness in patients with asthma . OBJECTIVE This study investigated whether clinical asthma control and airway inflammation could be maintained after switching therapy from medium-dose fluticasone propionate ( FP ) to low-dose FP administered with the long-acting beta2-agonist ( LABA ) salmeterol . METHODS Eighty-eight subjects ( age , > or = 18 years ) who , during open-label screening , demonstrated improved asthma control after an increase from 100 microg of FP  twice daily to 250 microg of FP  twice daily were r and omized to receive 100/50 microg of FP/salmeterol through a Diskus inhaler ( GlaxoSmithKline , Research Triangle Park , NC ) twice daily or continue 250 microg of FP twice daily through a Diskus inhaler for 24 weeks . Clinical outcomes were monitored , and bronchial biopsy specimens and bronchoalveolar lavage fluid were obtained before and after 24 weeks of treatment . RESULTS There were no significant differences between treatments with respect to eosinophils in the bronchial mucosa and bronchoalveolar lavage fluid ; mucosal mast cells , neutrophils , or CD3 + , CD4 + , CD8 + , or CD25 + T lymphocytes ; or concentration of mediators ( GM-CSF , IL-8 , and eosinophil cationic protein ) . The 2 treatments were not different with respect to lamina reticularis thickness . Consistent with the airway inflammatory measures , clinical and physiologic measures of asthma control were also similar . CONCLUSION This study demonstrates that control of asthma and airway inflammation is maintained over the 24-week treatment period when patients requiring a medium-dose ICS are switched to a lower-dose ICS with a LABA . CLINICAL IMPLICATION S A lower-dose ICS with a LABA is effective in controlling inflammation and providing clinical asthma control , confirming current guideline recommendations SUMMARY Background : Current asthma guidelines recommend that patients are educated to adjust their medication according to their asthma severity using physician-guided self-management plans . However , many patients take a fixed dose of their controller medication and adjust their reliever medication according to asthma symptoms . Objectives : This study examined whether asthma control improved if patients adjusted the maintenance dose of budesonide/formoterol ( Symbicort Turbuhaler * 160/4.5 |ig ) according to asthma severity compared with traditional fixed dosing ( FD ) regimens . * Symbicort and Turbuhaler are registered trademarks owned by the AstraZeneca group , t Seretide and Diskus are trademarks of GlaxoSmithKline . Methods : Symptomatic patients with asthma ( n = 658 , mean symptom score 1.5 , mean inhaled corticosteroids 735|ig/day , mean forced expiratory volume in 1 second [ FEV1 ] 84 % predicted ) were r and omised after 2 weeks ' run-in to either : budesonide/formoterol adjustable maintenance dosing ( AMD ) , budesonide/formoterol FD or salmeterol/fluticasone ( Seretide Diskust 50/250 |ig ) FD . In a 4-week double-blind period , both budesonide/formoterol AMD and FD groups received two inhalations twice daily ( bid ) and salmeterol/fluticasone FD patients received one inhalation bid . In the following 6-month open extension , both FD groups continued with the same treatment . Patients in the AMD group with well-controlled asthma stepped down to one inhalation bid ; others continued with two inhalations bid . All AMD patients could increase to four inhalations bid for 7 - 14 days if symptoms worsened . All patients used terbutaline or salbutamol for symptom relief throughout . The primary variable was the odds of achieving a well-controlled asthma week ( WCAW ) . Results : The odds ratio for achieving a WCAW did not differ between the FD regimens ; however , during the open period , budesonide/formoterol AMD increased the odds of achieving a WCAW vs. budesonide/formoterol FD ( odds ratio 1.335 ; 95 % CI : 1.001,1.783 ; p = 0.049 ) despite a 15 % reduction in average study drug use . Budesonide/formoterol AMD patients had a lower exacerbation rate over the study : 40 % lower vs. salmeterol/fluticasone FD ( p = 0.018 ) ; 32 % lower vs. budesonide/formoterol FD ( NS ) . During the double-blind period , there were no clinical ly relevant differences between the budesonide/formoterol FD and salmeterol/fluticasone FD groups . Budesonide/formoterol AMD patients used less reliever medication in the open extension : 0.58 vs. 0.92 occasions/day for budesonide/formoterol FD ( p = 0.001 ) and 0.80 occasions/day for salmeterol/fluticasone FD ( p = 0.011 ) . Conclusions : Adjustable maintenance dosing with budesonide/formoterol provides more effective asthma control by reducing exacerbations and reliever medication usage compared with fixed-dose salmeterol/fluticasone STUDY OBJECTIVES To evaluate the effectiveness and safety of inhaled salmeterol in patients managed in nonspecialist practice setting s. DESIGN A r and omized , double-blind , 6-month , parallel-group study involving 253 centers . SETTING Primarily nonspecialist practice s ( n = 232 ) . PATIENTS A total of 911 subjects ( 417 men ; 494 women ) who met American Thoracic Society asthma criteria were enrolled and r and omized to treatment with either twice-daily salmeterol aerosol ( 50 microg ; n = 455 ) or matching placebo twice daily ( n = 456 ) . Both groups were allowed to take salbutamol as needed . All subjects were previously treated with anti-inflammatory maintenance therapy that was continued throughout the study . MEASUREMENTS AND RESULTS The primary outcome variable was the proportion of subjects with serious asthma exacerbations defined as an exacerbation requiring hospitalization , emergency department visit , or use of prednisone during the treatment period . A total of 712 subjects competed the study . There was no significant difference in the proportion of subjects experiencing serious exacerbations between the salmeterol and placebo groups ( 20.8 % vs 20.9 % , respectively ; p = 0.935 ; power > 88 % ) . Peak expiratory flow was significantly higher in the salmeterol group ( 398 L/min vs 386 L/min for placebo ; p < 0.01 ) . Median daily use of salbutamol was two inhalations for the salmeterol group and three inhalations for placebo ( p < 0.001 ) . The proportion of subjects sleeping through the night was significantly higher in the salmeterol group ( 74 % ) as compared to placebo ( 68 % ; p = 0.028 ) . CONCLUSIONS Salmeterol treatment is effective in subjects typically cared for in the primary -care setting and does not increase the frequency of severe exacerbations A guided , adjustable-dosing regimen with budesonide/formoterol was investigated in asthma patients . In a r and omised , open , multicentre study , 1034 patients received budesonide/ formoterol ( Symbicort , Turbuhaler , ) 80/4.5 microg or 160/4.5 microg ( depending on pre- study inhaled corticosteroid dose ) two inhalations twice daily for four weeks , followed by adjustable or fixed maintenance dosing for six months . Patients receiving adjustable dosing stepped down to one inhalation twice daily if symptoms were controlled and could , if symptoms worsened , step up to four inhalations twice daily for one or two weeks according to a self-guided management plan . The primary efficacy variable was occurrence of exacerbations . Compared with fixed dosing , adjustable dosing was associated with fewer patients experiencing exacerbations ( 6.2 % vs 9.5 % , NNT 30 , p<0.05 ) , fewer daily inhalations of budesonide/formoterol ( 2.35 vs 3.95 , p<0.001 ) , lower costs ( six-month saving Euros 98 , p<0.001 ) and was similarly well tolerated . Adjustable maintenance dosing with budesonide/formoterol provides more effective asthma control than fixed dosing , and reduces costs OBJECTIVE To compare the long-term effects of an inhaled corticosteroid with those of a leukotriene modifier on measures of clinical efficacy , subject preference , and safety in patients with persistent asthma . PATIENTS AND METHODS Between November 17 , 1998 , and May 26 , 2000 , we conducted a multicenter , r and omized , double-blind , double-dummy , parallel-group study of patients aged 15 years or older with persistent asthma . The patients were symptomatic while taking short-acting beta2-agonists alone  and were treated with fluticasone propionate ( 88 microg [ 2 puffs of 44 microg ] twice daily ) or montelukast ( 10 mg/d ) for 24 weeks . Measures of pulmonary function , asthma symptoms , albuterol use , nighttime awakenings , physician assessment s of efficacy , patient satisfaction , asthma-related quality of life , and safety were evaluated . RESULTS A total of 522 patients were r and omized to receive fluticasone or montelukast , and 395 patients completed the study . At end point , treatment with fluticasone significantly improved pulmonary function , asthma symptom scores , the percentage of symptom-free days , rescue albuterol use , and the number of nighttime awakenings due to asthma when compared with montelukast ( P < or = .002 , each comparison ) . Significantly more patients were satisfied with fluticasone therapy ( 83 % ) compared with montelukast therapy ( 66 % ) ( P<.001 ) , and fluticasone therapy was rated as effective by a significantly greater portion of physicians ( 67 % ) than was montelukast therapy ( 54 % ) ( P<.001 ) . Treatment with fluticasone significantly improved asthma-related quality -of-life measures compared with montelukast ( P < or = .01 ) . The incidence of asthma exacerbations was similar in the fluticasone ( 19 patients , 7 % ) and montelukast ( 21 patients , 8 % ) treatment groups , although slightly more patients in the montelukast group were withdrawn from the study because of asthma exacerbations ( 6 % vs 4 % , respectively ) . CONCLUSION Long-term treatment with a low dose of inhaled fluticasone is more effective than oral montelukast as first-line maintenance therapy for the treatment of persistent asthma Background and objective : The efficacy and safety of twice-daily inhaled salmeterol/fluticasone propionate combination ( SFC ) therapy have been well established in the treatment of adults and adolescents with asthma . Once-daily administration of SFC could also be appropriate in patients with mild persistent asthma . This study aim ed to investigate whether once-daily SFC 50 μg/100 μg was at least as effective as fluticasone propionate ( FP ) 100 μg twice daily , and more effective than twice-daily placebo , over 52 weeks as initial maintenance therapy in patients with mild persistent asthma . Methods : This was a r and omized , double-blind , double-dummy , placebo-controlled , multicentre , parallel-group study carried out in primary and secondary care . Patients aged between 12 and 79 years with a documented clinical history of asthma for ≥6 months who were currently receiving inhaled short-acting β2-adrenoceptor agonists only were enrolled . Patients were r and omized to receive either once-daily inhaled SFC 50 μg/100 μg , twice-daily inhaled FP 100 μg ( i.e. twice the dose of FP compared with SFC ) or placebo for 52 weeks . The primary efficacy endpoints were mean morning peak expiratory flow ( PEF ) , as recorded by patients prior to the use of bronchodilator or study medication , and the rate of investigator-recorded asthma exacerbations . Results : Patients receiving twice-daily FP and once-daily SFC showed greater improvements in mean morning PEF compared with those receiving placebo ( FP , difference in means 20.1 L/min ; 95 % CI 14.7 , 25.5 ; p < 0.001 ; SFC , difference in means 14.8 L/min ; 95 % CI 9.4 , 20.2 ; p < 0.001 ) . The difference in adjusted mean PEF between once-daily SFC and twice-daily FP was —5.3 L/min ( 95 % CI −9.1,−1.6 ) . PEF results showed that once-daily SFC was non-inferior to twice-daily FP . Over 52 weeks , there was a 35 % reduction in exacerbation rates with once-daily SFC , which in this respect demonstrated superiority over placebo ( p < 0.001 ) . Non-inferiority between once-daily SFC and twice-daily FP with respect to exacerbation rates was not shown . Once-daily SFC significantly improved clinic forced expiratory flow between 25 % and 75 % of forced vital capacity ( difference in means 0.129 L/s ; p < 0.001 ) and clinic PEF ( difference in means 10.8 L/min ; p < 0.001 ) compared with twice-daily FP . Both treatments were well tolerated and the safety profile of each was similar to that seen with placebo . Conclusion : In patients with mild persistent asthma not previously receiving maintenance therapy , once-daily SFC 50 μg/100 μg is an effective treatment compared with placebo , and was non-inferior to twice-daily FP 100 μg with respect to mean morning PEF . However , in this study , once-daily SFC was not as efficacious as twice-daily FP in reducing asthma exacerbation rates . This study confirms the benefits of regular maintenance treatment in patients with mild persistent asthma BACKGROUND Treatment guidelines recommend the regular use of inhaled corticosteroids for patients with mild persistent asthma . We investigated whether the symptom-driven use of a combination of beclomethasone dipropionate and albuterol ( also known as salbutamol ) in a single inhaler would be as effective as the regular use of inhaled beclomethasone and superior to the as-needed use of inhaled albuterol . METHODS We conducted a 6-month , double-blind , double-dummy , r and omized , parallel-group trial . After a 4-week run-in , patients with mild asthma were r and omly assigned to receive one of four inhaled treatments : placebo twice daily plus 250 microg of beclomethasone and 100 microg of albuterol in a single inhaler as needed ( as-needed combination therapy ) ; placebo twice daily plus 100 microg of albuterol as needed ( as-needed albuterol therapy ) ; 250 microg of beclomethasone twice daily and 100 microg of albuterol as needed ( regular beclomethasone therapy ) ; or 250 microg of beclomethasone and 100 microg of albuterol in a single inhaler twice daily plus 100 microg of albuterol as needed ( regular combination therapy ) . The primary outcome was the morning peak expiratory flow rate . RESULTS In 455 patients with mild asthma who had a forced expiratory volume in 1 second of 2.96 liters ( 88.36 % of the predicted value ) , the morning peak expiratory flow rate during the last 2 weeks of the 6-month treatment was higher ( P=0.04 ) and the number of exacerbations during the 6-month treatment was lower ( P=0.002 ) in the as-needed combination therapy group than in the as-needed albuterol therapy group , but the values in the as-needed combination therapy group were not significantly different from those in the groups receiving regular beclomethasone therapy or regular combination therapy . The cumulative dose of inhaled beclomethasone  was lower in the as-needed combination therapy group than in the groups receiving regular beclomethasone therapy or regular combination therapy ( P<0.001 for both comparisons ) . CONCLUSIONS In patients with mild asthma , the symptom-driven use of inhaled beclomethasone ( 250 microg ) and albuterol ( 100 microg ) in a single inhaler is as effective as regular use of inhaled beclomethasone ( 250 microg twice daily ) and is associated with a lower 6-month cumulative dose of the inhaled corticosteroid . ( Clinical Trials.gov number , NCT00382889 [ Clinical Trials.gov ] . ) AIM To compare the effects of fluticasone and placebo on asthma control in patients with mild asthma . METHOD Adults with FEV1 > 80 % predicted and reliever use < or=2 times/week were r and omised to receive fluticasone 250 mcg/day or placebo double-blind for 11 months . Exacerbations were treated with four weeks ' fluticasone 500 mcg/day . Primary outcomes were electronically-recorded morning PEF and FEV1 , analysed by mixed model regression . RESULTS 44 subjects were r and omised ( 23-fluticasone , 21-placebo ) . Fluticasone led to significantly better morning FEV1 ( mean difference 5.4 % predicted , p<0.0001 ) , morning PEF , clinic spirometry , exhaled nitric oxide levels , and airway hyperresponsiveness , but there were no differences in reliever use , symptoms or quality of life . Fewer patients had mild exacerbations on fluticasone ( 22 % vs 62 % , p=0.02 ) . CONCLUSION The goals of asthma treatment include not only control of symptoms , but also prevention of future adverse outcomes such as exacerbations - which can occur even in mild asthma . This study showed that treatment with low dose inhaled corticosteroids led to significant improvements in lung function , exacerbations , and in pathophysiological predictors of future risk , even though symptoms were minimal at entry . For patients with mild asthma , discussion about treatment needs to consider not only short-term benefit , side effects and cost , but also long-term reduction of risk . This study was completed prior to m and atory registration for clinical trials BACKGROUND Lung deposition is crucial for asthma treatment . However , there is no study comparing the potential role of lung co-deposition of combination therapy ( inhaled corticosteroid and long-acting beta2 agonist ) in the same inhaler . In moderate to severe asthmatics , an extra-fine hydrofluoroalkane combination of beclomethasone dipropionate and formoterol given via a single pressurised metered-dose inhaler ( pMDI ) was compared with beclomethasone dipropionate chlorofluorocarbon ( CFC ) pMDI and formoterol dry powder inhaler ( DPI ) given via separate inhalers . METHODS In a double-blind , double-dummy , 24-week r and omised clinical trial , 645 patients with moderate to severe asthma uncontrolled by regular treatment with inhaled corticosteroids received regular treatment with extra-fine fixed combination beclomethasone dipropionate 200 microg/formoterol 12 microg bid , or beclomethasone dipropionate ( 500 microg bid ) via CFC pMDI and formoterol ( 12 microg bid ) via DPI , or beclomethasone dipropionate ( 500 microg bid ) via CFC pMDI . The primary outcome was morning peak expiratory flow ( PEF ) . Secondary outcomes included lung function measured at clinic , asthma symptoms and control , exacerbations . RESULTS Beclomethasone dipropionate/formoterol combination via single inhaler or via separate inhalers improved morning PEF . However , the combination via single inhaler was more effective than given via separate inhalers for asthma control . Both combination treatments were superior to beclomethasone dipropionate alone in improving lung function and asthma control . All treatments were well tolerated . INTERPRETATION In patients with moderate to severe asthma , beclomethasone dipropionate/formoterol in a single inhaler was as effective as beclomethasone dipropionate plus formoterol and superior to beclomethasone dipropionate alone in improving lung function . For the first time with a single inhaler , beclomethasone dipropionate/formoterol was significantly superior to separate components for asthma control
OBJECTIVE To determine the comparative effectiveness and safety of current maintenance strategies in preventing  exacerbations  of asthma .