Once-daily fluticasone furoate/vilanterol versus twice-daily fluticasone propionate/salmeterol in patients with asthma well controlled on ICS/LABA

Objective: We aimed to demonstrate non-inferiority of once-daily fluticasone furoate/vilanterol 100/25 µg (FF/VI) to twice-daily fluticasone propionate/salmeterol 250/50 µg (FP/SAL) in adults/adolescents with asthma well controlled on inhaled corticosteroid/long-acting β₂ agonist (ICS/LABA). Methods: This was a randomized, double-blind, double-dummy, parallel-group, 24-week study (NCT02301975/GSK study 201378). Patients whose asthma met study-defined criteria for control were randomized 1:1:1 to receive FF/VI, FP/SAL or twice-daily FP 250 µg for 24 weeks. Primary endpoint was change from baseline in evening trough forced expiratory volume in 1 second (FEV₁). Secondary endpoints included rescue-/symptom-free 24-hour periods. Safety was also assessed. Results: The intent-to-treat (ITT) population included 1504 randomized and treated patients (504 FF/VI; 501 FP/SAL; 499 FP); mean age 43.5 years, 64% female. FF/VI demonstrated non-inferiority (using a margin of ?100 mL) to FP/SAL for evening trough FEV₁ at Week 24 (ITT: 19 mL [95% confidence interval (CI) ?11 to 49]; per protocol population [N = 1336]: 6 mL [95% CI ?27 to 40]). Improvement in evening trough FEV₁ at Week 24 for both FF/VI (123 mL; p < 0.001) and FP/SAL (104 mL; p < 0.001) was greater than FP. FF/VI increased rescue-/symptom-free 24-hour periods by 1.2%/1.2% compared with FP/SAL. All treatments were well tolerated. On-treatment adverse event (AE) rates were 43% to 45% across arms; there were no drug-related serious AEs. Conclusions: FF/VI was non-inferior to FP/SAL for evening trough FEV₁ at 24 weeks. These data suggest that patients well controlled on FP/SAL could step across to FF/VI without loss of control.     

Adrenal suppression with dry powder formulations of fluticasone propionate and mometasone furoate

Mometasone furoate (MF) and fluticasone propionate (FP) are high potency inhaled corticosteroids. The systemic bioavailability of MF is claimed to be negligible, leading to a minimal potential for systemic adverse effects. We assessed the overnight urinary cortisol/creatinine as the primary outcome of adrenal suppression in 21 patients with persistent asthma (mean FEV1 = 91%). Patients were randomized in a crossover fashion to receive 2 weekly consecutive doubling incremental doses of either FP Accuhaler (500, 1,000, and 2,000 microg/day) or MF Twisthaler (400, 800, and 1,600 microg/day). For the 21 per protocol completed patients, there was significant suppression of overnight urinary cortisol/creatinine with high and medium doses of both drugs-as geometric mean fold suppression (95% confidence interval) from baseline: FP 2,000 microg, 1.85 (1.21-2.82, p = 0.002); FP 1,000 microg, 1.45 (1.07-1.96, p = 0.02); MF 1,600 microg, 1.92 (1.26-2.93, p = 0.001); and MF 800 microg, 1.39 (1.04-1.88, p = 0.02). For secondary outcomes of 8:00 A.M. plasma cortisol, serum osteocalcin, and early morning urinary cortisol/creatinine, there was significant suppression with MF and FP at the highest dose. Our data refute the assertion that MF has negligible systemic bioavailability and a lower potential for systemic adverse effects compared with FP.     

Mometasone furoate is a less specific glucocorticoid than fluticasone propionate.

Fluticasone propionate (FP) and mometasone furoate (MF) are potent synthetic corticosteroids that are widely used as anti-inflammatory agents to treat respiratory diseases. As part of the assessment of the potential for side-effects associated with their use, their activities, not only at the glucocorticoid receptor (GR) but also at the other members of the steroid nuclear receptor family, have been compared. Cell-based functional systems were established to measure different aspects of GR function, as well as the activity at all the other steroid nuclear receptors. The effects of MF and FP on the GR were potent and indistinguishable. Neither corticosteroid showed any activity at the oestrogen receptor, while both were weak antagonists of the androgen receptor. FP was a relatively weak agonist of the progesterone receptor but MF was a very potent agonist of the progesterone receptor, giving activity at similar concentrations to those that stimulate the GR (concentration generating 50% maximal effect (EC50)=50 pM). Moreover, while FP was a weak antagonist of the mineralocorticoid receptor (concentration generating 50% maximal inhibitory effect=80 nM), MF displayed potent partial agonist activity (EC50=3 nM, 30%). Mometasone furoate is considerably less specific for the glucocorticoid receptor than fluticasone propionate, showing significant activity at other nuclear steroid receptors.     

Salmeterol/fluticasone propionate in a Single Inhaler Device versus theophylline+fluticasone propionate in patients with COPD

STUDY OBJECTIVES: The aim of this study was to compare the relative efficacy in terms of improvement in symptoms and lung function of salmeterol/fluticasone propionate (SLM/FP) combination administered through the Diskus inhaler versus theophylline (THEO) added to FP Diskus in patients with stable chronic obstructive pulmonary disease (COPD). METHODS AND MEASUREMENTS: Eighty patients were randomized to receive 4 months of treatment in one of two treatment groups: (1) fixed combination of SLM 50 microg and FP 500 microg Diskus, 1 inhalation twice daily; or (2) FP Diskus 500 microg, 1 inhalation twice daily, plus oral titrated THEO twice daily. Patients attended the clinic before and after 4, 8, 12 and 16 weeks of treatment for evaluations of pulmonary function, and dyspnea, which was assessed using an analogic visual scale. Also the supplemental salbutamol use was measured. RESULTS:. Sixty-six patients completed the 4-month treatment period: 37 patients receiving SLM/FP and 29 patients receiving THEO+FP. Patients were withdrawn for various reasons, the most common of which were poor compliance with the protocol, exacerbation and GI events. A gradual increase in FEV(1) was observed with each treatment. Maximum significant increases in FEV(1) over baseline values that were observed after 4 months of treatment were as follows: SLM/FP 0.172 l (95% CI: 0.084-0.260) and THEO+FP 0.155 l (95% CI: 0.054-0.256). SLM/FP experienced significantly (p<0.05) greater improvements in dyspnea, and required significantly fewer supplemental salbutamol treatments than the THEO+FP group. CONCLUSIONS: Our results suggest that SLM/FP combination may provide substantial benefits in both physiologic and clinical outcomes in symptomatic patients with COPD. It also causes a more effective control than THEO+FP.     

Initiation of maintenance therapy with salmeterol/fluticasone propionate combination therapy in moderate asthma: a comparison with fluticasone propionate.

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.     

Fluticasone propionate/formoterol: A fixed-combination therapy with flexible dosage

International guidelines describe asthma control as the main outcome of asthma management. Prevention of symptoms, improved quality of life, and reduction of exacerbations are the main components, consequently decreasing health care costs. However, many of these objectives remain unmet in real life: several surveys show that a large proportion of asthmatic patients are not well controlled despite the efficacy of current available treatment.Several randomized controlled clinical trials indicate that combining inhaled corticosteroids and long-acting β₂-agonists, by means of a single inhaler, greatly improves the management of the disease. The results of 9 multicenter phase III clinical studies demonstrate that the fixed combination of fluticasone propionate/formoterol in a single inhaler is effective in terms of lung function and symptom control. These studies highlight the dose flexibility, safety and tolerability of this new inhaled combination. These characteristics meet the recommendations of international guidelines, and the preferences of respiratory physicians who identified these aspects as critical components of a successful asthma therapy. Combination of fluticasone propionate/formoterol in a single inhaler provides potent anti-inflammatory activity of fluticasone propionate and rapid onset of action of the β₂-agonist formoterol making this association a viable treatment option both in terms of effectiveness and compliance.     

Improvement in asthma endpoints when aiming for total control: salmeterol/fluticasone propionate versus fluticasone propionate alone.

AIMS: To investigate the magnitude of change in morning peak expiratory flow (PEF), asthma symptoms, and rescue beta2-agonist use, when the aim of treatment is to achieve guideline-defined control. METHODS: This was a protocol-defined analysis of data from the previously-reported one-year, stratified, randomised, double-blind, parallel-group GOAL study comparing the use of salmeterol/fluticasone propionate with fluticasone propionate alone in achieving guideline-defined control; this analysis assessed the magnitude of change in single specific endpoints which were amalgamated into the composite measure of control used in the primary GOAL analysis. RESULTS: Across all strata, improvements were seen for each outcome at 52 weeks as compared to baseline: mean morning PEF, 58.2 l/min (salmeterol/fluticasone propionate) versus 33.9 l/min (fluticasone propionate alone); symptom scores, -1.0 versus -0.8; symptom-free days, 72.5% versus 54.5%; mean of zero night awakenings, 31% versus 22%; rescue-free days, 87.3 versus 74.7; annualised rate of severe exacerbations, 0.02 versus 0.03; p<0.001 for all treatment differences. CONCLUSIONS: Aiming for guideline-defined control resulted in sustained, clinically relevant improvements in a range of individual asthma outcomes. Improvements were greatest with salmeterol/fluticasone propionate versus fluticasone propionate alone.     

单用丙酸氟替卡松和并用沙美特罗对哮喘气道炎症的作用比较

目的比较单用吸入激素(ICS)和并用长效β2激动剂(LABA)对哮喘患者气道炎症的作用;观察哮喘控制水平是否与患者气道炎症控制水平一致。方法研究设计为随机、双盲的对照研究,共入组27例哮喘患者,其中单用丙酸氟替卡松(FP)治疗(FP组)14例,并用沙美特罗治疗(联合治疗组)13例,并在治疗前、治疗12周和治疗24周通过瑞氏染色和ELISA法分别对诱导痰炎性细胞计数、IL-4和IL-5进行检测。结果 (1)同基线相比,第一阶段治疗后,两组患者诱导痰中炎性细胞计数、IL-4和IL-5表达无明显变化(P0.05);第二阶段治疗后,两组患者诱导痰中嗜酸性细胞数(EOS)、IL-4和IL-5表达显著降低(P0.05),两组间比较无显著差别(P0.05);(2)第二阶段治疗结束后,获得良好控制和完全控制患者诱导痰中IL-5、IL-4水平较基线均得到显著降低(P0.05),而未获得哮喘控制患者上述细胞因子水平较基线无显著变化(P0.05)。结论联合应用ICS和LABA能提高哮喘的控制水平,这种控制水平的提高得益于LABA的支气管扩张作用而不是增强的抗炎活性。     

Inhaled salmeterol/fluticasone propionate combination in chronic obstructive pulmonary disease

Salmeterol/fluticasone propionate is a fixed-dose combination of the long-acting beta2-adrenoceptor agonist salmeterol and the corticosteroid fluticasone propionate and is inhaled via the Diskus powder inhaler. In three randomized, double-blind, 24-week or 52-week studies in >2850 patients with chronic obstructive pulmonary disease (COPD), administration of salmeterol/fluticasone propionate 50/250 microg twice daily (in one study) and salmeterol/fluticasone propionate 50/500 microg twice daily (in the other studies) provided greater improvement in lung function than placebo or either component alone at the same nominal dosage. Both strengths of the combination product administered twice daily resulted in clinically meaningful increases in scores in health-related quality-of-life questionnaires that were specific for respiratory disease. Improvements in this and almost all other secondary measures of efficacy, including symptomatic outcomes, were significantly greater with the combination product than with placebo. Administration of salmeterol/fluticasone propionate as a combination product did not result in any untoward interactions that affected the pharmacodynamic, pharmacokinetic or tolerability profiles of the individual components. Candidiasis, hoarseness/dysphonia, throat irritation and headache occurred more frequently with salmeterol/fluticasone propionate than with placebo in patients with COPD.     

Initiation of maintenance treatment with salmeterol/fluticasone propionate 50/100 microg bd versus fluticasone propionate 100 microg bd alone in patients with persistent asthma: integrated analysis of four randomised trials

OBJECTIVES: To identify the asthma patients, on short-acting beta2-agonists alone, who would benefit from initial maintenance therapy (IMT) with salmeterol/fluticasone (SFC) propionate 50/100 microg bd compared with fluticasone propionate (FP) 100 microg bd alone. The results of an integrated analysis of data from four previous trials are presented. METHODS: The four original trials were randomised, double-blind, parallel group studies and included patients who had received IMT with SFC 50/100 microg bd or FP 100 microg bd. Patients were >or=12 years with a 6 month history of asthma and >or=15% reversibility in FEV1. Patients had either not received inhaled corticosteroids in the preceding month or were steroid na?ve. Patients were assessed to determine whether any GINA-defined asthma characteristics or combination of asthma characteristics could predict those individuals who would achieve well controlled asthma status with IMT with SFC rather than with inhaled steroid alone. Patients with persistent asthma were assessed based on GINA-defined baseline asthma characteristics and well controlled asthma status in response to each treatment was investigated according to combinations of these baseline features. Subsequently, a further range of endpoints, including asthma symptoms, rescue medication use and asthma control, were analysed over weeks 1-12 for the combinations of features where the treatment difference in well controlled asthma status was greatest. RESULTS: The results of the initial analyses demonstrated that patients exhibiting two or three features of uncontrolled asthma at baseline were more likely to achieve well controlled asthma when treated with SFC than with FP alone, the most significant difference being observed in patients with three baseline features (odds ratio 2.60, 95% CI: 1.87, 3.62, p<0.001). Patients with one baseline feature showed no difference between the FP and SFC groups. Further analyses on data from patients with two or three baseline asthma features, showed that treatment with SFC resulted in significantly greater improvements in mean morning PEF, percentage symptom-free days, nights with no awakenings and rescue-free days compared with FP. In addition, asthma control was achieved earlier in patients in the SFC group. SFC and FP were well tolerated as shown previously in the four individual trials. CONCLUSIONS: Patients on short-acting beta2-agonists alone with two or three features of uncontrolled asthma (moderate to severe airflow limitation/daily symptoms/daily rescue medication use) are most likely to achieve better control, earlier, with SFC 50/100 microg bd initial maintenance treatment compared with FP 100 microg bd alone.     

Oropharyngeal candidiasis with dry-powdered fluticasone propionate: 500 microg/day versus 200 microg/day

We aimed to determine the frequency of oropharyngeal candidiasis and its clinical correlates in the asthmatic patients who use fluticasone propionate (FP) as a dry powdered inhaler. We selected four groups of patients: 62 asthmatic patients who were taking 200 microg/d FP, 122 asthmatics who were taking 500 microg/d FP, 50 asthmatic patients who had not been on inhaled corticosteroid (ICS) treatment and 40 normal non-asthmatic subjects. The frequency of positive swabs for Candida colonization was higher in 500 microg/d FP group than asthmatics without ICS use (chi2 = 6.8, p < 0.05) and normal controls (chi2 = 4.9, p < 0.05), whereas it wasn't different in the 200 microg/day FP group when compared to controls. When we considered patients who used ICS, the most effective variables affecting the occurrence of Candida colonization were washing of the throat by the patients (OR = 9.4, 95 % Confidence Interval [CI] = 3.9-22.7, p < 0.0001) and duration of ICS use more than 12 months (OR = 2.5, 95 % CI = 1.1-2.6, p < 0.05). The present study showed that in the patients who use ICS, the most important determinants on colonization were not washing the throat regularly and duration of ICS use for more than 12 months.     

Antiinflammatory effects of salmeterol/fluticasone propionate in chronic obstructive lung disease

RATIONALE: No currently available treatment is reported to reduce the exaggerated airway wall inflammation of chronic obstructive pulmonary disease. OBJECTIVES: We tested the hypothesis that inhaled combined long-acting beta2-agonist (salmeterol) and corticosteroid (fluticasone propionate) will reduce inflammation. METHODS: Bronchial biopsies and induced sputum were taken from 140 current and former smokers (mean age, 64 yr) with moderate to severe disease, randomized in a 13-wk double-blind study to placebo (n = 73) or salmeterol/fluticasone propionate 50/500 microg (n = 67) twice daily. Biopsies were repeated at 12 wk and sputa at 8 and 13 wk. After adjustment for multiplicity, comparisons between active and placebo were made for median change from baseline in the numbers of biopsy CD8+ and CD68+ cells/mm2 and sputum neutrophils. MEASUREMENTS AND MAIN RESULTS: Combination therapy was associated with a reduction in biopsy CD8+ cells of -118 cells/mm2 (95% confidence interval [CI], -209 to -42; p = 0.02), a reduction of 36% over placebo (p = 0.001). CD68+ cells were unaffected by combination treatment. Sputum differential (but not total) neutrophils reduced progressively and, at Week 13, significantly with combination treatment (median treatment difference, 8.5%; 95% CI, 1.75%-15.25%; p = 0.04). The combination also significantly reduced biopsy CD45+ and CD4+ cells and cells expressing genes for tumor necrosis factor-alpha and IFN-gamma and sputum total eosinophils (all p < or = 0.03). These antiinflammatory effects were accompanied by a 173-ml (95% CI, 104-242; p < 0.001) improvement in prebronchodilator FEV1. CONCLUSIONS: The combination of salmeterol and fluticasone propionate has a broad spectrum of antiinflammatory effects in both current and former smokers with chronic obstructive pulmonary disease, which may contribute to clinical efficacy.