Addition of salmeterol to fluticasone propionate treatment in moderate-to-severe asthma. Maintaining asthma control in persistent asthma: comparison of three strategies in a 6-month double-blind randomised study. Does measuring BHR add to guideline derived clinical measures in determining treatment for patients with persistent asthma? Fluticasone propionate and salmeterol administered via Diskus compared with salmeterol or fluticasone propionate alone in patients suboptimally controlled with short-acting beta2-agonists. Long-term treatment with fluticasone propionate/salmeterol via Diskus improves asthma control versus fluticasone propionate alone. Asthma exacerbations in African Americans treated for 1 year with combination fluticasone propionate and salmeterol or fluticasone propionate alone. Salmeterol/fluticasone propionate (50/500 microg) in combination in a Diskus inhaler (Seretide) is effective and safe in the treatment of steroid-dependent asthma. Clinical equivalence of salmeterol/fluticasone propionate in combination (50/100 microg twice daily) when administered via a chlorofluorocarbon-free metered dose inhaler or dry powder inhaler to patients with mild-to-moderate asthma. Adding salmeterol to an inhaled corticosteroid: long term effects on bronchial inflammation in asthma. The safety of twice-daily treatment with fluticasone propionate and salmeterol in pediatric patients with persistent asthma. Salmeterol and fluticasone propionate combined in a new powder inhalation device for the treatment of asthma: a randomized, double-blind, placebo-controlled trial. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Efficacy and safety of fluticasone propionate/salmeterol HFA 134A MDI in patients with mild-to-moderate persistent asthma. Initiation of maintenance therapy with salmeterol/fluticasone propionate combination therapy in moderate asthma: a comparison with fluticasone propionate. Efficacy and tolerability of fluticasone propionate/salmeterol administered twice daily via hydrofluoroalkane 134a metered-dose inhaler in adolescent and adult patients with persistent asthma: a randomized, double-blind, placebo-controlled, 12-week study. Efficacy and safety of fluticasone propionate 44 microg/salmeterol 21 microg administered in a hydrofluoroalkane metered-dose inhaler as an initial asthma maintenance treatment. Efficacy and safety of fluticasone propionate/salmeterol 250/50 mcg Diskus administered once daily.
This study was designed 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 practices 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 resulted 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. In patients controlled with SFC250 Diskus bd, this double-blind, randomised 6-month study compared continuing SFC250 to stepping down to either SFC100 bd or FP250 bd. Six hundred and three patients previously using 1,000 microg BDP (or equivalent) daily +LABA and controlled according to investigator's judgement were recruited. Patients received SFC250 bd during an 8-week open run-in period. Four hundred and seventy six patients (mean age=43 years, mean FEV(1)=2.9+/-1.0) who fulfilled the randomisation criterion ('Well-controlled' asthma according to the GOAL weekly definition for the last 2 weeks of the run-in period) entered a 24-week treatment period. The statistical hypothesis was based on a non-inferiority of SFC100 or FP250 compared to SFC250. The main criterion was the change from baseline in morning PEF over weeks 1-12 in the per-protocol population. The non-inferiority limit was -15 L/min. At inclusion, the three treatment groups were well balanced. Mean morning PEF was 476, 470 and 465 L/min in the SFC250, SFC100 and FP250 groups, respectively. The adjusted mean change in morning PEF over weeks 1-12 was +1.76+/-2.43 L/min for SFC250, -3.07+/-2.32 L/min for SFC100 and -16.51+/-2.46 L/min for FP250. SFC100 was at least as effective as SFC250 (treatment difference -4.83 [-12.39; 2.72], p=0.151) whereas FP250 was not (treatment difference -18.27 [-26.05; -10.49], p<0.001). Similar results were observed over weeks 13-24 in morning PEF (SFC100-SFC250=-4.54+/-3.84, p=0.238; FP250-SFC250=-20.11+/-3.92, p<0.0001). Secondary endpoints showed a similar pattern. Over weeks 1-12, SFC250 was significantly more effective than FP250 on evening PEF, daily symptoms and bronchodilator use. There was no difference between SFC100 and SFC250. The mean annual rate of moderate exacerbations was 0.16 in both SFC 250 and SFC 100 groups, and 0.21 in FP 250 group (ns, Poisson analysis). All treatments were well tolerated.
                In patients achieving asthma control with SFC250, stepping treatment down with SFC100 was at least as effective on lung function and symptoms as continuing SFC250, whereas FP250 was not. Little is known about the use of biomarkers in guiding treatment decisions in routine asthma management. The objective of this study was to determine whether adding a LABA to an ICS would control bronchial hyperresponsiveness (BHR) at an overall lower dose of ICS when titration of medication was based upon the assessment of routine clinical measures with or without the measurement of BHR.
                After a 2-week run-in period, subjects (> or = 12 years) were randomized to one of three treatment groups. Two groups followed a BHR treatment strategy (based on clinical parameters [lung function, asthma symptoms, and bronchodilator use] and BHR) and were treated with either fluticasone propionate/salmeterol (FSC(BHR) group) or fluticasone propionate (FP(BHR) group) (n=156 each). The third group followed a clinical treatment algorithm (based on clinical parameters alone) and were treated with fluticasone propionate (FP(REF) group; n=154). All treatments were administered via Diskus. Treatment doses were adjusted as needed every 8 weeks for 40 weeks according to the subject's derived severity class, which was based on clinical measures of asthma control with or without BHR.
                The mean total daily inhaled corticosteroids (ICS) dose during the double-blind treatment period was lower, although not statistically significant, in the FSC(BHR) group compared with the FP(BHR) group (a difference of -42.9 mcg; p=0.07). Compared with the FP(REF) group, the mean total daily ICS dose was higher in the FSC(BHR) group (a difference of 85.2 mcg) and was significantly higher in the FP(BHR) group (a difference of 131.2 mcg, p=0.037).
                This study demonstrated that for most subjects, control of BHR was maintained when treatment was directed toward control of clinical parameters. In addition, there was a trend towards control of BHR and clinical measures at a lower dose of ICS when used concurrently with salmeterol. Optimal therapy for many patients with persistent asthma requires control of both main components of this disease: inflammation and bronchoconstriction.
                To compare the efficacy and safety of initiating maintenance therapy with an inhaled, long-acting beta2-agonist and an inhaled corticosteroid administered from a single device with that of the individual agents alone.
                A 12-week, randomized, double-blind study was conducted in patients 12 years and older with persistent asthma who were symptomatic while taking as-needed, short-acting beta2-agonists alone. Treatments were administered twice daily via the Diskus device: salmeterol, 50 microg; fluticasone propionate, 100 microg; or fluticasone propionate, 100 microg, with salmeterol, 50 microg.
                Of 555 patients screened, 267 were randomly assigned to treatment. At end point, fluticasone propionate and salmeterol significantly increased predose forced expiratory volume in 1 second (FEV1) compared with salmeterol alone (0.51 +/- 0.05 L vs 0.38 +/- 0.04 L, P = .04). Fluticasone propionate and salmeterol significantly increased area under the serial FEV1 curve at treatment week 12 relative to predose FEV1 (baseline) on treatment day 1 (AUCb1, 8.4 +/- 0.6 L/h; P < or = .02) compared with salmeterol (6.2 +/- 0.5 L/h) and fluticasone propionate (7.0 +/- 0.6 L/h). Fluticasone propionate and salmeterol were significantly (P < or = .02) more effective than the individual agents used alone in improving morning and evening peak expiratory flow rate and asthma symptoms. In addition, fluticasone propionate and salmeterol effectively reduced rescue albuterol use (P < or = .04). All treatments were well tolerated.
                In patients symptomatic while taking short-acting beta2-agonists alone, initial maintenance treatment of the 2 main components of asthma, inflammation and smooth muscle dysfunction, with fluticasone propionate and salmeterol, 100 and 50 microg, administered via the Diskus results in greater improvements in overall asthma control compared with treatment of either component alone. This 52-week study was designed to assess the safety and efficacy of fluticasone propionate/salmeterol combination (FSC) 250/50 micrograms versus fluticasone propionate (FP) 250 micrograms in subjects with persistent asthma symptomatic on open-label FP 100 micrograms. The primary objective of this study was to show that FSC 250/50 micrograms was superior to FP 250 micrograms at increasing pulmonary function as measured by forced expiratory volume in 1 second over a 52-week treatment period. A secondary objective was to compare the rate of asthma attacks defined as (1) a sustained 2-day decrease in morning peak expiratory flow or increase in albuterol use for 2 consecutive days, (2) an asthma exacerbation requiring systemic corticosteroids, or (3) an unscheduled clinic or hospital visit for acute asthma symptoms. Three hundred six subjects received FSC 250/50 micrograms and 315 subjects received FP 250 micrograms. Both treatments were administered twice daily. Treatment with FSC 250/50 micrograms resulted in a significant improvement in lung function compared with FP 250 micrograms (p < 0.001). Additionally, treatment with FSC 250/50 micrograms resulted in a reduction in the rate of exacerbations of asthma (i.e., requiring systemic corticosteroids or unscheduled urgent care intervention) compared with FP 250 micrograms (0.170 versus 0.273, respectively; p = 0.017). There was no differentiation between treatments for less severe attacks of asthma. FSC 250/50 micrograms showed consistently greater improvement in lung function, symptom control, and decreased albuterol use. In addition, FSC 250/50 micrograms-treated subjects experienced fewer severe asthma exacerbations than subjects treated with FP 250 micrograms. This long-term prospective 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.
                This was a randomized, 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.
                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.
                In this large, prospective study among African Americans with asthma, the addition of salmeterol to FP resulted 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. This multicentre double-blind, double-dummy study compared the safety and efficacy of a new combination Diskus inhaler containing both salmeterol 50 microg and fluticasone propionate 500 microg (Seretide, GlaxoWellcome, France) with the same doses of the two drugs delivered via separate Diskus inhalers and with the same dose of fluticasone propionate alone. Patients were eligible for study entry if they had received an inhaled corticosteroid continuously for 12 weeks prior to run-in, and had received treatment with beclomethasone dipropionate or budesonide 1500-2000 microg day(-1) or fluticasone propionate 750-1000 microg day(-1) for at least 4 weeks prior to run-in. In total, 503 patients receiving inhaled corticosteroids were randomized to 28 weeks' treatment with either salmeterol/fluticasone propionate (50/500 microg) via a single Diskus inhaler (combination) and placebo, or salmeterol 50 microg and fluticasone propionate 500 microg administered via separate Diskus inhalers (concurrent), or fluticasone propionate 500 microg and placebo. All treatments were administered twice daily, mean morning peak expiratory flow rate (PEFR) and asthma symptoms were measured for the first 12 weeks and safety data were collected throughout the 28-week study. Over weeks 1 to 12, improvement in adjusted mean morning PEFR was 35 and 33 l min(-1), respectively, in the combination and concurrent therapy treatment groups (12 and 10% increase from baseline, respectively). The mean difference between treatments was -3 l min(-1) (90% confidence interval -10.4 l min(-1)) which was within the criteria for clinical equivalence. However, the combination therapy was statistically significantly superior to fluticasone propionate alone for mean morning PEFR (P<0.001) and other measures of lung function, whilst clinical equivalence of the combination and concurrent therapies was observed. All three treatments were well tolerated. In addition, there were no differences between the three treatments in either the c.hange in serum cortisol or urinary cortisol concentrations, which, for each treatment group, were no significantly different from baseline at the end of the treatment period. Thus, the combination of salmeterol and fluticasone propionate in a single inhaler is as well tolerated and effective in achieving asthma control in steroid-dependent patients as the separate administration of the two drugs, and both combination and concurrent therapy are superior to administration of the same dose of corticosteroid alone. This multi-centre, randomized, double-blind, double-dummy, parallel-group study was designed to investigate the hypothesis of equivalent efficacy and comparable safety of two inhaled presentations of salmeterol/fluticasone propionate combination product (SALM/FP) 50/100 microg administered twice daily to patients with mild-to-moderate asthma for 12 weeks. The delivery systems were a 25/50 microg strength hydrofluoroalkane (HFA) metered-dose inhaler (MDI) and a Diskus inhaler (50/100 microg strength). A third group received FP 100 microg twice daily via a chlorofluorocarbon MDI (50 microg strength). A total of 497 patients aged 11-79 years with reversible airways obstruction who were symptomatic on inhaled corticosteroid (ICS) therapy and had room for improvement in lung function were randomized to treatment in a double-blind, parallel-group design (SALM/FP MDI: n=165; SALM/FP Diskus: n=167; FP MDI: n=165) for 12 weeks. A total of 383 patients completed the study according to the protocol. According to the primary efficacy variable, increase in mean morning PEF over weeks 1-12, the two inhaled presentations of SALM/FP were clinically equivalent (adjusted mean increases 43 and 46 l min(-1); treatment difference 3 l min(-1); 95% confidence interval: -6 to 11 l min(-1)). Equivalence was also demonstrated by all secondary efficacy measures. The SALM/FP MDI was significantly superior to the FP MDI for increase in mean morning PEF (treatment difference 19 l min(-1); P<0.001) and for all secondary measures except FEV1 and symptom-free nights. There was no significant difference between the groups with respect to adverse events and serum cortisol levels. These results demonstrate that the SALM/FP 25/50 microg HFA MDI (two inhalations twice daily) is clinically equivalent to the SALM/FP 50/100 microg Diskus (one inhalation twice daily). Patients switching to SALM/FP from other MDI-based asthma treatments may now do so without a change of delivery device. Addition of the long acting beta2 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.
                After a 4 week fluticasone run-in period, 54 patients with allergic asthma were randomised to receive twice daily treatment with fluticasone 250 microg with or without salmeterol 50 microg for 1 year in a double blind, parallel group design (total daily dose of fluticasone 500 microg 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.
                Adding salmeterol to fluticasone resulted 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 alpha2-macroglobulin and albumin during the treatment period (p = 0.001).
                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 beta2 agonist is combined with inhaled corticosteroids. For children older than 5 years with asthma who remain symptomatic despite inhaled corticosteroid (ICS) therapy, the preferred treatment is to add an inhaled long-acting beta2-agonist vs increasing the ICS dose.
                To compare the safety of twice-daily treatment with inhaled fluticasone propionate plus the inhaled long-acting beta2-agonist salmeterol with that of fluticasone propionate used alone in children aged 4 to 11 years with persistent asthma.
                A randomized, multicenter, double-blind, active-controlled, parallel-group study in 203 children with persistent asthma who were symptomatic during ICS therapy. Patients received fluticasone propionate-salmeterol (100/50 microg) or fluticasone propionate (100 microg) alone twice daily for 12 weeks.
                The safety profile of fluticasone propionate-salmeterol was similar to that of fluticasone propionate alone. The overall incidence of adverse events was 59% for fluticasone propionate-salmeterol and 57% for fluticasone propionate. Both treatments were well tolerated. Two patients receiving fluticasone propionate-salmeterol and 5 receiving fluticasone propionate withdrew from the study because of worsening asthma. Changes in heart rate, blood pressure, and laboratory variables were infrequent and were similar between treatments. No patients had clinically significant abnormal electrocardiographic findings during treatment. Geometric mean 24-hour urinary cortisol excretion at baseline and after 12 weeks of treatment was comparable within and between groups; no patient in either group had abnormally low 24-hour urinary cortisol excretion after 12 weeks of treatment. The incidence of withdrawals due to asthma exacerbations was 2% in the fluticasone propionate-salmeterol group and 5% in the fluticasone propionate group.
                In pediatric patients with persistent asthma, fluticasone propionate-salmeterol twice daily was well tolerated, with a safety profile similar to that of fluticasone propionate used alone. Many patients with persistent asthma need both long-acting bronchodilators and inhaled corticosteroids for optimal asthma control.
                Our purpose was to compare the efficacy and safety of salmeterol 50 microg combined with fluticasone 100 microg (in a combination dry powder product) with that of placebo, fluticasone, or salmeterol alone.
                A 12-week randomized, double-blind, multicenter study was conducted in 356 patients aged 12 years or older with asthma. After a 14-day screening period, patients were randomized to treatment with salmeterol 50 microg combined with fluticasone 100 microg (combination product), salmeterol 50 microg, fluticasone 100 microg, or placebo administered in the Diskus dry powder inhaler (GlaxoWellcome, UK) twice daily.
                Mean change in FEV(1) at end point was significantly (P < or =.003) greater with the combination product (0.51 L) compared with placebo (0.01 L), salmeterol (0.11 L), and fluticasone (0.28 L). The combination product significantly increased (P < or =.013) area under the curve compared with placebo and fluticasone on day 1 and compared with placebo, salmeterol, and fluticasone at week 1 and week 12. Patients in the combination product group were less likely to withdraw from the study because of worsening asthma compared with those in the other groups (P < or =.020). The combination product significantly increased (P < or =.012) morning PEF (combination, 52.5 L/min; placebo, -23.7 L/min; salmeterol, -1.7 L/min; fluticasone, 17.3 L/min) and evening PEF at end point compared with the other groups. The combination product significantly (P < or =.025) reduced symptom scores and albuterol use compared with the other treatments and increased the percentage of nights with no awakenings and the percentage of days with no symptoms compared with placebo and salmeterol. All treatments were equally well tolerated.
                Salmeterol 50 microg and fluticasone 100 microg combined in the Diskus powder delivery device offers significant clinical advantages over salmeterol or fluticasone alone at the same doses. For most patients, asthma is not controlled as defined by guidelines; whether this is achievable has not been prospectively studied. A 1-year, randomized, 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. The objective of this study was to compare the efficacy and safety of fluticasone propionate (FP) (44 microg)/salmeterol (21 microg) delivered as two inhalations twice daily via a single hydrofluoroalkane (HFA 134a) metered dose inhaler (MDI) (FSC) with that of placebo HFA 134a (PLA), fluticasone propionate 44 microg chlorofluorocarbon (CFC) alone and salmeterol 21 microg CFC alone (S) in patients (n=360) with persistent asthma previously treated with beta2-agonists (short- or long-acting) or inhaled corticosteroids (ICS). After 12 weeks of treatment, patients treated with FSC had a significantly greater increase (p < or = 0.006) in mean FEV1 AUC(bl) compared with PLA, FP, or S. At end point, mean change from baseline in morning predose FEV1 for FSC (0.58 L) was significantly (p < or = 0.004) greater than PLA (0.14 L), FP (0.36 L), and S (0.25 L). Patients treated with FSC also had a significantly higher probability of remaining in the study without being withdrawn due to worsening asthma (2%) compared with those in the PLA (29%) and S (25%) groups (p < 0.001). Finally, treatment with FSC resulted in significantly (p < or = 0.007) greater improvements in morning and evening peak expiratory flow, need for rescue albuterol, and asthma symptom scores compared with FP, S, and PLA. The safety profile of FSC was also similar to FP or S alone. Initial maintenance treatment of the two main components of asthma, inflammation, and smooth muscle dysfunction (e.g., bronchoconstriction), with FSC results in greater overall improvements in asthma control compared with treatment of either individual component alone. The objective of this study was to investigate initial maintenance treatment with salmeterol/fluticasone propionate (Seretide) 50/250 microg twice daily (SFC) compared with fluticasone propionate (Flixotide) 250 microg twice daily (FP) (both via Diskus inhaler, GlaxoSmithKline, Greenford, UK) in patients with moderate persistent asthma currently only treated with inhaled short-acting beta2-agonists. A total of 362 adults and adolescents (12 to 80 years of age) were randomized to this 12-week double-blind parallel-group study. The primary endpoint was mean morning peak expiratory flow (PEF). Secondary efficacy endpoints included median percentages of symptom-free and rescue-free days and nights; the percentage of patients who achieved the pre-defined criteria for well-controlled asthma over weeks 5 to 12; and the incidence of asthma exacerbations. Safety was assessed by the incidence of adverse events. Superiority of SFC over FP alone was demonstrated for the primary and each secondary endpoint. The difference in adjusted mean change from baseline in morning PEF between SFC and FP was 21 L/min (95% CI: 11, 31; p<0.001). Significantly more patients achieved well-controlled asthma during treatment with SFC (46%) compared with FP (32%) (odds ratio 1.84; 95% CI: 1.17, 2.89; p=0.008). Both treatments were safe and well-tolerated. This study demonstrates that initial maintenance treatment with SFC 50/250 mug twice daily provides superior efficacy to FP 250 microg twice daily alone in patients with moderate persistent asthma. This study compared the efficacy and tolerability of the combination of fluticasone propionate (FP) and salmeterol (SAL) delivered via a single hydrofluoroalkane (HFA) 134a metered-dose inhaler (MDI) with those of its 2 components alone delivered via a chlorofluorocarbon (CFC) MDI and placebo (PLA) delivered via HFA MDI in adolescent and adult patients with persistent asthma that was not controlled by medium doses (equivalent to FP 440-660 microg/d) of inhaled corticosteroids (ICSs).
                This was a randomized, double-blind,placebo-controlled, parallel-group study consisting of a 2-week, single-blind, placebo run-in period followed by a 12-week, double-blind treatment period. Participants had to be > or =12 years of age and have a diagnosis of asthma requiring pharmacotherapy for at least 6 months before the study. Patients had to have used ICS therapy for > or =3 months before the study and at a consistent dose for the previous month. Lack of asthma control was defined as a forced expiratory volume in 1 second (FEV(1)) that was 40% to 85% of the predicted value. Patients could not enter the double-blind treatment period if they had 3 days when they required >12 puffs of rescue albuterol per day or >3 nighttime awakenings due to asthma that required treatment with albuterol during the 7 days before the randomization visit. Patients were randomized to receive one of the following treatments delivered via MDI twice daily for 12 weeks: FSC 220/42 microg HFA (2 inhalations of FSC 110/21 microg; 125 microg/21 microg ex-valve); FP 220 microg CFC (2 inhalations of FP 110 microg); SAL 42 microg CFC (2 inhalations of 21 microg); or 2 inhalations of PLA HFA. The primary efficacy end point for FSC versus FP was the mean area under the 12-hour serial FEV(1) curve relative to the prerandomization baseline (FEV(1) AUC(bl)). The primary efficacy end points for FSC versus SAL were the mean change from baseline in morning predose FEV(1) at end point and the probability of not being withdrawn from the study due to worsening asthma. Tolerability assessments included electrocardiograms, routine clinical laboratory tests, vital signs, oropharyngeal examinations, and physical examinations. Adverse events were assessed at each clinic visit.
                Thirty-two adolescent and 333 adult patients were randomly assigned to receive double-blind treatment. The treatment groups were comparable at baseline with respect to demographic characteristics (mean age, 38-41 years; white race, 78%-88%) and pulmonary function (mean percent predicted FEV(1), 68%-69%; mean asthma symptom score, 1.6 [scale 0-5]; and mean daily albuterol use, 3.1 puffs). After 12 weeks of treatment, the mean FEV(1) AUC(bl) was significantly greater in patients who received FSC compared with those who received FP, SAL, or PLA (7.0, 3.6, 5.3, and 1.4 L-h, respectively; all comparisons, P < or = 0.020). At end point, the mean change from baseline in morning predose FEV(1) for FSC was significantly greater than that for FP, SAL, and PLA (0.41, 0.19, 0.15, and -0.12 L; all comparisons, P < or = 0.001). During 12 weeks of treatment, 7% of patients receiving FSC were withdrawn due to worsening asthma, compared with 24% of patients receiving SAL and 54% of patients receiving PLA (P < 0.001); 11% of patients receiving FP were withdrawn due to worsening asthma. Treatment with FSC resulted in significant improvements in morning and evening peak expiratory flow compared with FP, SAL, and PLA (both, P < 0.001); need for rescue albuterol compared with FP and PLA (P < or =0.005); and asthma symptom scores compared with PLA (P < 0.001). The tolerability of FSC was similar to that of FP or SAL alone. The incidence of possibly drug-related adverse events was generally similar across treatment groups, and the most common (occurring in > or= 2% of patients) were headache (1%-4%), throat irritation (1%-2%), candidiasis of the mouth/throat (0%-2%), unspecified oropharyngeal plaques (0%-2%), and palpitations (0%-2%).
                In these adolescent and adult patients whose asthma was not controlled by medium doses of an ICS, FSC delivered via HFA 134a MDI (2 inhalations of 110/21-microg strength administered BID) was more effective in improving lung function than FP or SAL monotherapy or PLA. All treatments were well tolerated. We wanted to evaluate whether treatment with an inhaled corticosteroid and an inhaled long-acting beta2-agonist is more effective than an inhaled corticosteroid alone for patients using as-needed albuterol who are initiating maintenance treatment.
                To compare the efficacy and safety of twice-daily fluticasone propionate (FP) 88 microg and salmeterol 42 microg combined in a chlorofluorocarbon (CFC)-free (hydrofluoroalkane 134a) metered-dose inhaler (MDI) with the individual agents alone, each delivered through an MDI containing CFC propellants, in patient with persistent asthma previously uncontrolled with as-needed short-acting beta2-agonists alone.
                Patients with asthma (n = 283) were randomized to twice-daily treatment for 12 weeks with FP 88 microg combined with salmeterol 42 microg (FSC) in a CFC-free MDI or the individual components alone from CFC-containing MDIs.
                At endpoint, mean change from baseline in morning predose forced expiratory volume in 1 second was significantly (P < or = 0.016) greater with FSC (0.69 L) compared with FP (0.51 L) or salmeterol (0.47 L). Fewer patients treated with FSC withdrew due to worsening asthma (1%) compared with FP (3%) or salmeterol (8%; P = 0.024). FSC significantly increased (P < or = 0.002) morning and evening peak expiratory flow rate at endpoint (66.5 and 51.5 L/min, respectively) compared with FP (43.0 and 29.9 L/min, respectively) and salmeterol (29.2 and 21.6 L/min, respectively). In addition, asthma symptom scores were reduced, and percentages of days with no asthma symptoms increased in all treatment groups.
                Treatment with FSC in a CFC-free MDI is more effective than FP or salmeterol alone in asthma patients who are symptomatic taking short-acting beta2-agonists alone. The twice daily administration of an inhaled corticosteroid (ICS) and long-acting beta(2)-agonist (LABA) has been shown to be effective in achieving asthma control. The once daily administration of an ICS/LABA may be a treatment option for some patients.
                To assess the effectiveness of fluticasone propionate (FP)/salmeterol via a single inhaler (FSC) administered once daily compared with FP once daily, FSC twice daily, or placebo.
                A 12-week, randomized, double-blind multicenter study conducted in 844 patients > or = 12 years of age who were symptomatic while using a short-acting beta(2)-agonist alone. Blinded treatments included: FSC 250/50 mcg once daily in the evening (FSC 250/50 QD), FP 250 mcg once daily in the evening (FP 250 QD), FSC 100/50 mcg twice daily (FSC 100/50 mcg BID), or placebo. All treatments were delivered via the Diskus device.
                All treatments demonstrated greater improvements in efficacy measures compared with placebo. Overall, the greatest improvements were observed in the patients receiving FSC, either once or twice daily, compared with the FP 250 QD group. The two FSC treatments were similar except that QD dosing did not maintain improvements in lung function for 24h compared with twice daily dosing. All treatments were well tolerated. No suppression of HPA axis, as assessed by 24-h urinary cortisol excretion, was observed in any of the active treatment groups.
                In patients symptomatic on a short-acting beta(2)-agonist alone, FSC 100/50 mcg BID was shown to provide better efficacy than a higher strength (FSC 250/50 mcg) administered once daily. However, a once daily regimen was effective and may be a valuable treatment option for some patients. Registered at (http://ctr.gsk.co.uk/welcome.asp) (SAS30022).
We found no statistically significant differences in fatal or non-fatal serious adverse events in trials in which regular salmeterol was randomly allocated with ICS, in comparison to ICS alone at the same dose. Although 13,447 adults and 1862 children have now been included in trials, the frequency of adverse events is too low and the results are too imprecise to confidently rule out a relative increase in all cause mortality or non-fatal adverse events with salmeterol used in conjunction with ICS. However, the absolute difference between groups in the risk of serious adverse events was very small. We could not determine whether the increase in all cause non-fatal serious adverse events reported in the previous meta-analysis on regular salmeterol alone is abolished by the additional use of regular ICS. We await the results of large ongoing surveillance studies mandated by the FDA to provide more information. There were no asthma-related deaths and few asthma-related serious adverse events. Clinical decisions and information for patients regarding regular use of salmeterol have to take into account the balance between known symptomatic benefits of salmeterol and the degree of uncertainty and concern associated with its potential harmful effects.