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.     

Efficacy and safety of the combination fluticasone propionate plus salmeterol in asthmatic preschoolers: An observational study

Background: Inhaled Corticosteroids (ICS) are the cornerstone of asthma management in pediatric patients. However, in some cases, asthma is not adequately controlled on ICS alone. Long-acting beta₂-agonists (LABA) are one of the available additional therapies but their use has rarely been studied among children younger than 5 years. Objective: The aim of this observational study was to evaluate the efficacy and safety of the combination of fluticasone propionate and salmeterol (FP/SA) in asthmatic children younger than 5 years of age. Methods: A retrospective study of 796 children under the age of 5 years (2.87 ± 1.22 years, 64.2% males), who were treated with FP/SA was conducted. Hospitalization rates, frequency of wheezing, exercise induced asthma, nocturnal wheeze and drug-related side-effects were recorded through children's medical records. Results: The children had previously received short-acting β₂-agonists (73%), ICS (17%), montelukast (1%), and ICS with montelukast (2%). Mean duration of therapy with FP/SA was 12.45 ± 9.14 months. After adjusting for age, gender, and duration of treatment, a 89% reduction was recorded in annual hospitalization rates (from 27.13% before treatment to 3.01% after FP/SA therapy, p < 0.001), a 71% reduction in incidence of exercise-induced asthma (36.8% vs. after 10.6%, p < 0.001), a 81% reduction in nocturnal asthma (33.7% vs. after: 6.4%, p < 0.001), as well as in frequency of wheezing (p < 0.01),. No previous treatment carry-on effect was observed. No major drug-related side-effects occurred in the study group. Conclusions: Combination therapy (FP/SA) is well-tolerated and highly effective in asthmatic children under the age of 5 years.     

Effect of fluticasone propionate/salmeterol (250/50 microg) or salmeterol (50 microg) on COPD exacerbations

OBJECTIVES: COPD exacerbations are associated with significant morbidity and mortality. This randomized, double-blind, parallel-group, multicenter study evaluated the effect of fluticasone propionate/salmeterol 250/50 and salmeterol 50 microg twice daily on moderate to severe exacerbations. METHODS: Patients received standardized treatment with fluticasone propionate/salmeterol 250/50 during a 1-month run-in, followed by randomization to fluticasone propionate/salmeterol 250/50 or salmeterol for 12 months. Moderate to severe exacerbations were defined as worsening symptoms of COPD requiring treatment with oral corticosteroids, antibiotics, or hospitalization. RESULTS: In 782 patients with COPD (mean FEV(1)=0.94+/-0.36 L, 33% predicted normal), treatment with fluticasone propionate/salmeterol 250/50 significantly reduced (1) the annual rate of moderate to severe exacerbations by 30.5% compared with salmeterol (1.06 and 1.53 per subject per year, respectively, p<0.001), (2) the risk of time to first exacerbation by 25% (hazard ratio=0.750, p=0.003) and (3) the annual rate of exacerbations requiring oral corticosteroids by 40% (p<0.001). Clinical improvements observed during run-in treatment with fluticasone propionate/salmeterol 250/50 were better maintained over 12 months with fluticasone propionate/salmeterol 250/50 than salmeterol. Adverse events were reported for a similar percentage of subjects across groups. A higher reporting of pneumonia was observed with fluticasone propionate/salmeterol 250/50 than salmeterol (7% vs. 4%). CONCLUSIONS: We conclude that fluticasone propionate/salmeterol 250/50 is more effective than salmeterol at reducing the rate of moderate to severe exacerbations over 1 year. The benefits of this reduction relative to the risk of a higher incidence of reported pneumonia should be considered. This study supports the use of fluticasone propionate/salmeterol 250/50 for the reduction of COPD exacerbations in patients with COPD.     

The pharmacokinetics,safety, and tolerability of single,high-strength doses of fluticasone propionate and fluticasone propionate/salmeterol delivered via a novel multidose dry powder inhaler in adolescents and adults with persistent asthma

Objective: Characterize fluticasone propionate (Fp) and combination fluticasone propionate and salmeterol (FS) pharmacokinetic and safety profiles, delivered via a novel, inhalation-driven, multidose dry powder inhaler (MDPI). Methods: This multicenter, open-label, four-period crossover, single-dose study randomized patients aged ≥12 years with persistent asthma to Fp MDPI 200 mcg, FS MDPI 200/12.5 mcg, Fp dry powder inhaler (DPI) 500 mcg (250 mcg × 2 inhalations), or FS DPI 500/50 mcg. Blood samples for determination of Fp and salmeterol pharmacokinetic parameters including C_max, AUC_0–t, AUC_0–inf, t_max, and t_½ were collected predose through 36 h postdose (14 time points). Safety assessments comprised adverse events, vital signs, and physical examinations. The institutional review board approved the study protocol. Results: The pharmacokinetic analysis set and safety population each included 40 patients. Fp systemic exposure (C_max, AUC_0–t, and AUC_0–inf) was highest for Fp DPI 500 mcg and similar for Fp MDPI 200 mcg, FS MDPI 200/12.5 mcg, and FS DPI 500/50 mcg. Fp geometric mean t_½ values were similar across treatments. Salmeterol C_max was 20% lower and AUC_0–t and AUC_0–inf were approximately 50% lower with FS MDPI versus FS DPI. Median t_max and geometric mean t_½ were similar between FS MDPI and FS DPI. Adverse events were similar across treatments with no relevant changes in vital signs, physical examinations, or hematology test results. Conclusions: Fp MDPI and FS MDPI produced similar or lower systemic exposure to Fp and salmeterol, despite lower doses, versus conventional DPI devices, suggesting improved efficiency due to formulation and device differences.     

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。     

Comparison of the Clinical Efficacy of Salmeterol and Sustained-Release Tulobuterol (Patch) on Inadequately Controlled Asthma Patients on Inhaled Corticosteroids

Patients with inadequately controlled asthma on inhaled corticosteroid (400 to 1,600 μg/day chlorofluorocarbon beclomethasone equivalent) were treated with concomitant salmeterol (n = 18) or sustained-release tulobuterol (patch) (n = 18), or the inhaled corticosteroid dose was doubled (add-on) (n = 13) to compare clinical efficacy. () At 8 weeks, morning and evening peak expiratory flow rates were significantly improved in the salmeterol group only (p < 0.01). () Symptom and sleeplessness scores improved in the order, salmeterol (symptom score; p < 0.0001), inhaled corticosteroid add-on, and tulobuterol groups. () Only the salmeterol group showed significant improvement in the total Asthma Quality of Life Questionnaire score (p < 0.05). () No adverse reactions considered related to the study drugs were observed.     

Fluticasone furoate/vilanterol once daily improves night-time awakenings in asthma patients with night symptoms: Post hoc analyses of three randomized controlled trials

Objective: Symptoms, including night-time awakenings, affect the quality of life of people with asthma. Fluticasone furoate/vilanterol (FF/VI) reduces exacerbations, improves lung function, and rescue-free and symptom-free 24-hour periods in patients with asthma. These post hoc analyses compared daytime and night-time symptoms in patients with asthma who received FF/VI, versus FF, fluticasone propionate (FP) or placebo.

Methods: Daytime and night-time symptoms were collected via electronic daily diary cards in three Phase III randomized studies of once-daily FF/VI in patients with uncontrolled asthma on inhaled corticosteroids (ICSs) ± long-acting beta₂ agonists (n = 609/1039/586).

Endpoints included change from baseline in symptom-free days and nights (analyzed by Analysis of Covariance, covariates: baseline, region, sex, age, and treatment), time for patients to achieve seven consecutive symptom-free nights (analyzed by Cox proportional hazards' model, covariates as above), and proportion of patients experiencing 100% symptom-free nights per week (analyzed by logistic regression, covariates: percentage of symptom-free nights, sex, age, and treatment).

Results: Improvements in symptom-free days and nights were generally observed for all treatments. More patients who received FF/VI experienced 100% symptom-free nights in the last week of the treatment period than patients who received ICS alone or placebo. FF/VI also reduced time to achieve seven consecutive symptom-free nights. Patients with at least one night of symptoms at baseline experienced an additional 2.7 and 2.0 symptom-free nights per week with FF/VI 100/25 µg, versus 1.9 and 1.7 with FF alone; similar findings were seen with FF/VI 200/25 µg.

Conclusions: Benefits in terms of symptom-free days and nights were observed for patients receiving FF/VI versus comparators in these post hoc analyses.     

Comparison of high-dose salmeterol/fluticasone and moderate-dose salmeterol/fluticasone plus low-dose mometasone in patients with severe persistent asthma

Background and objective: The effects of adding a second inhaled corticosteroid with a different particle size, compared with using an increased dose of a single inhaled corticosteroid, were assessed in patients with persistent asthma. Methods: This was an open‐label study of Japanese asthma patients over 20 years of age. After a 1‐month run‐in period, 36 patients with inadequate control while using salmeterol/fluticasone propionate 50/250 µg (SFC50/250) bd, were randomized to receive SFC50/500 bd or SFC50/250 plus mometasone 100 µg bd (SFC50/250/MF100) for 2 months. Results: Both treatments resulted in improvements in morning and evening PEF. There were no significant changes in FEV₁, maximum mid‐expiratory flow, maximum expiratory flow rate at 50%, maximum expiratory flow rate at 25% or exhaled NO (FENO) in the SFC50/500 group. On the other hand, there were significant improvements in FEV₁% (+12.2%, P = 0.0142), %maximum mid‐expiratory flow (+28.9%, P = 0.0181), %MEF50 (+32.4%, P = 0.0206) and %MEF25 (+30.3%, P = 0.0113) in the SFC50/250/MF100 group. The changes in FENO (?23.2% (P = 0.0157) in the SFC50/250/MF100 group and ?14.5% (not significant) in the SFC50/500 group) did not differ significantly between the groups. Conclusions: In patients with severe persistent asthma, addition of low‐dose mometasone to SFC50/250 improved spirometric parameters, FENO and PEF, while an increase in dose from SFC50/250 to SFC50/ 500 only improved PEF.     

The severity of airways obstruction as a determinant of treatment response in COPD

Guidelines recommend that patients with COPD are stratified arbitrarily by baseline severity (FEV₁) to decide when to initiate combination treatment with a long-acting β₂-agonist and an inhaled corticosteroid. Assessment of baseline FEV₁ as a continuous variable may provide a more reliable prediction of treatment effects. Patients from a 1-year, parallel-group, randomized controlled trial comparing 50 μg salmeterol (Sal), 500 μg fluticasone propionate (FP), the combination (Sal/FP) and placebo, (bid), were categorized post hoc into FEV₁ <50% and FEV₁ ≥50% predicted subgroups (n=949/513 respectively). Treatment effects on clinical outcomes – lung function, exacerbations, health status, diary card symptoms, and adverse events – were investigated. Treatment responses based on a pre-specified analysis explored treatment differences by severity as a continuous variable. Lung function improved with active treatment irrespective of FEV₁; Sal/FP had greatest effect. This improvement appeared additive in milder disease; synergistic in severe disease. Active therapy significantly reduced exacerbation rate in patients with FEV₁ <50% predicted, not in milder disease. Health status and breathlessness improved with Sal/FP irrespective of baseline FEV₁; adverse events were similar across subgroups. The spirometric response to Sal/FP varied with baseline FEV₁, and clinical benefits were not restricted to patients with severe disease. These data have implications for COPD management decisions, suggesting that arbitrary stratifications of baseline severity are not necessarily indicative of treatment efficacy and that the benefits of assessing baseline severity as a continuous variable should be assessed in future trials.     

The impact of FDA regulatory activities on incident dispensing of LABA-containing medication: 2005–2011

Objective: Evidence of safety issues associated with long-acting beta₂-agonist (LABA) treatment has led to multiple regulatory activities by the U.S. Food and Drug Administration (FDA) on this class of medications. This study describes the impact of the regulatory activities on incident LABA-containing medication dispensing. Methods: A monthly rolling cohort of asthma patients who were eligible to initiate a LABA-containing product was created in the Mini-Sentinel Distributed Database between January 2005 and June 2011. Cohorts of individuals who initiated LABA were examined for the changes in the proportions of single-ingredient to fixed-dose inhaled corticosteroid (ICS)-LABA initiators, appropriate initiation of LABA-containing products, and use of controller medications. The impact of the 2005 and 2010 FDA regulatory activities associated with LABA-containing products was measured using interrupted time series with segmented regression. Results: LABA-containing product initiation was declining prior to the 2005 regulatory activities and continued to decline over the study period, accompanied by increased initiation of fixed dose ICS-LABA among LABA initiators. While the 2010 regulatory activities had no immediate impact on the proportion of LABA initiation in patients with prior controller medication dispensing and/or poor asthma control, there was an increasing positive trend toward LABA initiation in the appropriate patient population after the regulatory activities. Conclusion: The 2005 and 2010 FDA regulatory activities likely had an impact on communicating the safety concerns of LABA products. However, the impact cannot be viewed independent of scientific publications, guidelines for asthma treatment and other regulatory activities.     

A comparative study of inhaled ciclesonide 160 microg/day and fluticasone propionate 176 microg/day in children with asthma

Ciclesonide (CIC) is an inhaled corticosteroid (ICS) with high anti-inflammatory activity and low incidence of local and systemic adverse effects. The objective of this study was to compare the efficacy and safety of CIC with fluticasone propionate (FP) in children and adolescents with persistent asthma. This was a 12-week, randomized, double blind, parallel-group study. After a 2-to 4-week baseline period, a total of 556 children (ages 6-15 years) with asthma (forced expiratory volume in 1 sec [FEV(1)], 50% to 90% predicted) were treated twice daily with CIC 80 microg (ex-actuator, equivalent to 100 microg ex-valve) or FP 88 microg (ex-actuator, equivalent to 100 microg ex-valve) administered via a hydrofluoroalkane-propelled metered-dose inhaler. A statistically significant increase from baseline was observed in FEV(1) for both CIC (285 +/- 16 ml) and FP (285 +/- 15 ml) (P < 0.0001 for both) and in morning and evening peak expiratory flow (P < 0.0001 for both). Significant improvements were seen in asthma symptoms, use of rescue medication, and asthma symptom-free days in both treatment groups, without any differences between the treatment groups in changes from baseline. Two FP-treated patients experienced oral candidiasis and one patient experienced voice alteration. Creatinine-adjusted 24-hr urine cortisol levels increased from baseline levels by 10% in the CIC group (P < 0.05) and by 6% in the FP group (not significant). The efficacy and safety of CIC 160 microg/day were comparable to those of FP 176 microg/day in children with asthma.     

Combination Inhalers Containing Inhaled Corticosteroids and Long-Acting β2-Agonists: Improved Clinical Efficacy and Dosing Options in Patients with Asthma

Combination therapy with inhaled corticosteroids (ICS) and long-acting β₂-agonists (LABA) is a recognized treatment for adults with moderate to severe asthma. The introduction of inhalers containing both an ICS and a LABA simplifies treatment and improves asthma control. This review discusses clinical evidence that budesonide/formoterol and salmeterol/fluticasone are effective and well tolerated in asthma treatment. Moreover, the rapid onset of effect and long duration of action of budesonide and formoterol make once-daily dosing, adjustable maintenance dosing, and the novel treatment strategy of using budesonide/formoterol for maintenance and as needed for symptom relief, valuable treatment options for patients with asthma.     

Combination therapy with the single inhaler salmeterol/fluticasone propionate versus increased doses of inhaled corticosteroids in patients with asthma

BACKGROUND: Although results from a few meta-analyses were most uniformly supportive of the beneficial effect of combination therapy on lung function, there were inconsistent results on other endpoints such as asthma exacerbation. Single inhalers of salmeterol and fluticasone propionate have been available, and some studies compared the effect of combination products with increased doses of inhaled corticosteroids (ICSs) on several outcome variables. OBJECTIVES: We reviewed the studies systematically, providing a quantitative summary estimate on the efficacy and safety measures of the combination products. METHODS: We searched databases (Medline and Embase) from January 1997 to December 2005 using 'fluticasone and salmerterol' or 'Seretide' or 'Advair', in combination with 'randomized controlled trial'. The databases of GlaxoSmithKline Clinical Trial Register and Cochrane Controlled Trials Register, or relevant articles were searched for additional studies. RESULTS: Combination products had a comparatively low, but significant improvement in pulmonary function, with morning peak expiratory flow (PEF), evening PEF and FEV1 increasing by 17.86 liters/min, 15.57 liters/min and 0.09 liter, respectively, compared with increased doses of inhaled corticosteroid (ICSs) over 12 weeks' treatment. But there were no statistically significant differences in other endpoints such as asthma exacerbation, overall withdrawal and drug-related adverse events, with the exception of overall adverse events and symptom free 24 h, which favored combination products. CONCLUSIONS: Thecombination products provided a statistically significant improvement in lung function and in symptoms but provided no significantly increased protection against exacerbation. Unless high doses of ICSs are required, there is insufficient evidence at present to recommend the use of combination products rather than increased moderate doses of ICSs as a first-line treatment for patients uncontrolled on their current doses of ICSs.     

The effect of inhaled salmeterol, alone and in combination with fluticasone propionate, on management of COPD patients

Introduction: Airway inflammation is a known pathological feature of chronic obstructive pulmonary disease (COPD). We examined the effect of inhaled salmeterol, alone and in combination with fluticasone propionate, on the management of patients with COPD. Methods: Forty male COPD patients were randomly divided into two groups; group 1 (n = 20) were treated with long‐acting ß2‐agonist, and group 2 (n = 20) with long‐acting ß2‐agonist and inhaled glucocoticoid each day for 3 months. Pulmonary function tests (PFTs), including forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and peak expiratory flow (PEF), were measured at the beginning, 1 and 2 months after treatment and at the end of the study. The frequency of using inhaled salbutamol/day and the 6‐min walk distance were also measured at four different visits. The frequency of exacerbation was also recorded during the 90‐day treatment period in the two groups. Results: FEV₁, FVC and PEF were significantly higher after 30 days of treatment with fluticasone propionate (mean change from baseline in group 2: 155 mL, 200 mL and 70 L/s, respectively; P < 0.001). Six‐minute walk distance also increased significantly (mean change from baseline: 160 m; P < 0.001), and there was a 70%–80% reduction in the use of inhaled salbutamol (P < 0.001). All improvements were maintained over the remainder of the study period. Exacerbations over the 90‐day treatment period were significantly fewer than in the same 90‐day period in the previous year (2.8 ± 0.7 vs 0.8 ± 0.9; P < 0.001). In contrast, only PEF increased significantly with treatment in group 1 (salmeterol treatment alone). Conclusions: These results indicated that inhaled corticosteroids may be beneficial in some patients with COPD. Please cite this paper as: Mansori F, Nemat Khorasani A, Boskabady MH and Boskabady M. The effect of inhaled salmeterol, alone and in combination with fluticasone propionate, on management of COPD patients. Clin Respir J 2010; 4: 241–247.     

Effect of asthma compliance enhancement training on asthma control in patients on combination therapy with salmeterol/fluticasone propionate: a randomised controlled trial

Objective: We investigated if a higher proportion of adults with previously uncontrolled asthma can achieve total control when given salmeterol/fluticasone propionate (50/250 µg) bid and compliance enhancement training (CET) compared to those given medication alone. Methods: Open comparison of stable, but uncontrolled, adult asthmatics. After a 12‐week treatment period on salmeterol/fluticasone propionate (period 1), patients who failed to achieve control were randomised to continuing treatment with or without CET for 12 weeks (period 2). The primary end point was the proportion achieving total control of their asthma in 7 of the last 8 consecutive weeks of period 2. Results: A total of 361 subjects (50.4% males, mean age 40.0 ± 14.4 years) in 29 centres were included, of whom 75.9% were randomised into treatment period 2 (n = 140 in the intervention group). The proportion of subjects achieving total asthma control was 8.8% and 7.6%, respectively, in the intervention and control group [not significant (NS)]. Mean morning peak flow, forced expiratory volume in one second (FEV₁), asthma symptom score and quality of life improved significantly over the study period in both treatment groups. Furthermore, proportion of days with use of rescue medication declined from 59.7% ± 34.6% (55.7% ± 35.3%) during screening to 20.3% ± 29.2% (19.4% ± 30.9%) during treatment period 2 (NS). Conclusion: CET failed to increase the likelihood of achieving total control in asthmatics on salmeterol/fluticasone propionate compared to subjects receiving medication only. However, both groups had a significant improvement in asthma control. (Clinical Trials.gov number, NCT00351143) Please cite this paper as: Ulrik CS, Claudius BK, Tamm M, Harving H, Siersted HC, Backer V, Hellquist B, Dahl R, Høgholm A and Jøhnk IK. Effect of asthma compliance enhancement training on asthma control in patients on combination therapy with salmeterol/fluticasone propionate: a randomised controlled trial. The Clinical Respiratory Journal 2009; 3: 161–168.