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Background: This analysis from the 6-month AUSTRI study (GSK115359, n=11,679) explored the rate and heterogeneity of severe exacerbations with fluticasone propionate (FP) alone compared with FP plus salmeterol (FSC) in patients aged ≥12 years with persistent asthma and a 1-year history of exacerbations. Methods: Primary cause of severe exacerbation was grouped as: environmental, allergic, infective and other. Patient characteristics according to exacerbation (yes/no), primary cause, and period before and after events (Day -14 to +14) vs a corresponding 29-day period in non-exacerbating patients, were analysed post-hoc. Results: 1077 (9.2%) patients reported ≥1 severe exacerbation during study. Exacerbation cause was recorded as environmental for 14.3% of exacerbations, allergic for 8.4%, and infective for 45.3%. Rate of asthma exacerbations was significantly reduced by 21.8% (Ratio: 0.782; 95% CI: 0.691-0.886) for FSC vs FP patients. In patients with exacerbation, mean rescue use (puffs/day) increased from 1.5 (Day -14) to 3.2 (Day 1) and back to 1.5 (Day +14), compared with mean 0.8 puffs/day in non-exacerbating patients (Fig. 1). Conclusions: In patients with a history of severe asthma exacerbations, regular twice-daily dosing with FSC was associated with a lower rate of asthma exacerbations compared with FP. Rescue medication use was higher pre- and post-exacerbation than the average for non-exacerbating patients. Funding: GSK (ID 213505)

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.

Objective: To investigate whether once-daily (OD) fluticasone furoate (FF)/vilanterol (VI) provides greater long-term protection from postexercise fall in forced expiratory volume in 1 s (FEV1) than twice-daily (BD) fluticasone propionate (FP) in patients with asthma and exercise-induced bronchoconstriction. Methods: A randomized, double-blind, crossover study was conducted in patients (aged 12-50 years) on low-/mid-dose maintenance inhaled corticosteroid. Following a 4-week run-in period (FP 250 µg BD), patients with a ≥ 20% decrease in postexercise FEV1 received FF/VI 100/25 µg OD or FP 250 µg BD for 2 weeks. Exercise challenges were carried out 23 h after the first dose of study medication, and 12 and 23 h after evening clinic dose at the end of the 2-week treatment period. After a 2-week washout period (FP 250 µg), patients crossed over treatments, with procedures and tests repeated. The primary endpoint was mean maximal percentage decrease from pre-exercise FEV1 following exercise challenge 12-h postevening dose on Day 14. Results: The mean maximal percentage decrease from pre-exercise FEV1 after the 12-h exercise challenge (Day 14) was 15.02% with FF/VI, and 16.71% with FP (difference, -1.69; 95% confidence interval, -3.76 to 0.39; p = 0.109). After the 23-h exercise challenge (Day 14), respective mean maximal decreases were 11.90% and 14.05% (difference, -2.15; 95% confidence interval, -4.31 to 0.01). Conclusion: The study failed to show a difference between FF/VI and FP at providing long-term protection from exercise-induced bronchoconstriction.

Fluticasone furoate (FF; inhaled corticosteroid) combined with vilanterol (VI; long-acting beta(2) agonist) is a once-daily therapy for asthma and chronic obstructive pulmonary disease. This 12-week phase III study compared the efficacy and safety of once-daily (evening dosing) FF/VI 100/25 mcg versus FF 100 mcg (primary objective) and FF/VI 100/25 mcg versus FF/VI 200/25 mcg (descriptive comparison only) in patients (n = 1039) ≥12 years with moderate-to-severe persistent asthma.The primary end point was weighted mean (wm) 0-24-h serial forced expiratory volume in 1 s (FEV(1)) at week 12. Secondary end points (change from baseline) were trough FEV(1) and the proportion (%) of rescue-free 24-h periods (both powered), the proportion (%) of symptom-free 24-h periods, and morning and evening peak expiratory flow (PEF). Safety data (adverse events, AEs) were collected throughout.Compared with FF 100 mcg, FF/VI 100/25 mcg significantly improved wmFEV(1) (p 0.001), trough FEV(1) (p = 0.014), % rescue-free (p 0.001), % symptom-free (p = 0.002) 24-h periods, and morning and evening PEF (p 0.001). FF/VI 200/25 mcg produced small numerical improvements versus FF/VI 100/25 mcg for all end points. Incidence of AEs was similar across groups.FF/VI 100/25 mcg resulted in significant improvements in all primary and secondary end points versus FF 100 mcg. Numerical improvements occurred with FF/VI 200/25 mcg versus FF/VI 100/25 mcg. All treatments were well tolerated.

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.

Background Inhaled glucocorticosteroids (ICS) are the mainstay of treatment in asthma. Fluticasone furoate (FF) is a novel, once-daily ICS asthma therapy. This study investigated the efficacy and safety of FF 50 mcg in patients with mild-to-moderate persistent asthma. Methods A 24-week, multicenter, randomized, placebo-controlled and active-controlled, double-blind, double-dummy, parallel-group phase III study. Three hundred and fifty-one patients (aged ≥12 years; uncontrolled by non-ICS therapy) were randomized to treatment (1 : 1 : 1) with once-daily FF 50 mcg dosed in the evening, twice-daily fluticasone propionate (FP) 100 mcg or placebo. The primary endpoint was change from baseline in evening trough forced expiratory volume in 1 s (FEV1) at Week 24. Secondary endpoints were change from baseline in the percentage of rescue-free 24-h periods (powered endpoint), change from baseline in evening and morning peak expiratory flow, change from baseline in the percentage of symptom-free 24-h periods and number of withdrawals due to lack of efficacy. Results Evening trough FEV1 at Week 24 was not statistically significantly increased with FF 50 mcg once-daily (37 ml [95% CI: −55, 128]; P = 0.430), but was with FP 100 mcg twice daily (102 ml [10, 194]; P = 0.030), vs placebo. No consistent trends were observed across other endpoints, including the powered secondary endpoint. No safety concerns were raised for either active treatment. Conclusions FP 100 mcg twice daily improved evening trough FEV1 in patients with mild-to-moderate persistent asthma, but FF 50 mcg once daily did not demonstrate a significant effect. Secondary endpoints showed variable results. No safety concerns were identified for FF or FP.

SummaryInhaled corticosteroids (ICSs) improve asthma disease control; once-daily ICS administration may have advantages for patients. Our objective was to assess the efficacy and safety of the novel ICS fluticasone furoate (FF) over 24 weeks versus placebo.This was a 24-week double-blind, double-dummy, placebo- and active-controlled study (NCT01159912) of 343 asthma patients (≥12 years) not controlled by their current ICS. Patients were randomised (1:1:1) to FF100 μg, placebo (both administered once-daily [OD] via ELLIPTA™ dry powder inhaler in the evening) or fluticasone propionate (FP) 250 μg (administered twice-daily (BD) via DISKUS™/ACCUHALER™). Primary endpoint was change from baseline in pre-dose evening forced expiratory volume in 1s (FEV1) at Week 24; change from baseline in % rescue-free 24-h periods was a powered secondary endpoint. Adverse events (AEs) were assessed.FF100 μg OD and FP250 μg BD significantly improved pre-dose evening FEV1 compared with placebo at Week 24 (+146 ml [p = 0.009] and +145 ml [p = 0.011], respectively). Percentage of rescue-free 24-h periods was increased with FF100 μg OD (+14.8%) and FP250 μg BD (+17.9%) compared to placebo (both p

Fluticasone furoate (FF) is a novel inhaled corticosteroid with 24 h activity. FF is being developed as a once-daily treatment in combination with the long-acting β(2) agonist vilanterol trifenatate for asthma and chronic obstructive pulmonary disease.To determine the optimal dose(s) of FF for treating patients with asthma.An 8-week multicentre, randomised, double-blind study. 627 patients with persistent moderate-to-severe asthma, symptomatic on medium-dose inhaled corticosteroid therapy, were randomised to placebo, FF 200, 400, 600 or 800 μg (once daily in the evening using a novel dry powder inhaler), or fluticasone propionate 500 μg twice daily (via Diskus™/Accuhaler™). The primary efficacy measure was mean change from baseline in pre-dose evening forced expiratory volume in one second (FEV(1)). Other endpoints included morning and evening peak expiratory flow, and rescue/symptom-free 24 h periods.Each dose was significantly superior to placebo for the primary endpoint (p0.001) with efficacy at least similar to that reported with fluticasone propionate. There was no dose-response relationship across the FF doses studied. Peak expiratory flow improved in all groups (p0.001 vs placebo), and there were significant treatment effects on rescue/symptom-free 24 h periods with all active treatments. FF was generally well tolerated. The incidence of oral candidiasis was higher with FF 800 μg than placebo; pharmacokinetic and 24 h urinary cortisol analyses confirmed a higher systemic exposure of FF at this highest dose level.FF doses800 μg have a favourable therapeutic index. The absence of an efficacy dose response suggests that 200 μg is an appropriate dose in patients with moderate persistent asthma. CLINICALTRIALS.GOV IDENTIFIER: NCT00603746.

Rationale: The efficacy of FF and FF/VI have been studied in moderate/severe asthma. This analysis examined the effect of baseline eos level on response to different doses of FF and FF/VI. Methods: In post-hoc analyses of 2 studies (Woodcock A. et al. BMC Pulm Med 2014;14:113; Bernstein D.I. et al. Am J Respir Crit Care Med 2014:A6671; FFA114496: NCT01431950 & HZA116863: NCT01686633) that compared 2 doses of FF and FF/VI, patients were grouped by their baseline blood eos level (≤0.15GI/L or >0.15GI/L) and the effect on trough and weighted mean FEV1, and asthma control test (ACT) was analysed. Results: The table summarises the effects of FF and FF/VI on the endpoints in the 2 subgroups of patients at the end of the study. Conclusion: Across both studies, there was a trend towards greater lung function effects with the higher dose of FF or FF/VI in patients with a higher baseline eos level.

Introduction and objectives FF/VI, the first once daily inhaled corticosteroid/long-acting s2-agonist combination available for the treatment of asthma, has demonstrated a sustained 24 hour improvement in lung function and improvement in symptom-free 24 hour periods. Methods Post-hoc analyses of diary card data from three Phase III studies were performed to examine whether there was an improvement in night-time awakening during the studies for those patients treated with the addition of vilanterol to fluticasone furoate. The diary card scale used is described below. Changes in night-time awakenings over the duration of the studies were analysed for percentage of patients with ≥50% symptom-free nights, including the time taken for 50% of patients to achieve 7 nights without symptoms. Night-time Symptom Score: 0 = No symptoms during the night 1 = Symptoms causing me to wake once (or wake early) 2 = Symptoms causing me to wake twice or more (including waking early) 3 = Symptoms causing me to be awake for most of the night 4 = Symptoms so severe that I did not sleep at all To be counted as symptom-free during the night the patient needed to record a score of 0. Results The percentage of patients with ≥50% symptom-free nights was generally higher in patients treated with FF/VI compared to either FF or FP alone (Table below). The time (in days) for 50% of patients to achieve 7 nights without symptoms was achieved sooner with patients treated with FF/VI compared to FF alone (Table). Conclusions In general, night-time awakenings improved over time in asthma patients with FF/VI and improved faster with FF/VI compared with FF or placebo.

Background Fluticasone furoate (FF) is a novel, once-daily inhaled corticosteroid (ICS) that has been shown to improve lung function vs. placebo in asthma patients. This study evaluated the efficacy and safety of FF 50 mcg compared with placebo in asthma patients uncontrolled by non-ICS therapy. Methods This 12-week, multicentre, randomized, double-blind, placebo-controlled, parallel-group, phase III study randomized 248 patients (aged ≥12 years) to once-daily FF 50 mcg administered via the ELLIPTA™a dry powder inhaler or placebo. The primary endpoint was change from baseline in pre-dose evening trough forced expiratory volume in one second (FEV1). Secondary endpoints were change from baseline in percentage of rescue-free 24-h periods (powered), evening and morning peak expiratory flow, symptom-free 24-h periods and withdrawals due to lack of efficacy. Other endpoints included Asthma Control Test™, Asthma Quality of Life Questionnaire and ELLIPTA ease of use questions. Safety was assessed throughout the study. Results There was a significant difference in evening trough FEV1 between FF 50 mcg and placebo (treatment difference: 120 mL; p = 0.012). There was also a significant difference in rescue-free 24-h periods (11.6%; p = 0.004) vs. placebo. There were numerically greater improvements with FF vs. placebo for all remaining secondary endpoints. The incidence of adverse events was lower with FF (31%) than with placebo (38%); few were treatment-related (FF 50 mcg: n = 1

The inhaled corticosteroid fluticasone furoate (FF) and the long-acting β2 agonist vilanterol (VI) are in development as a combined once-daily therapy for asthma and chronic obstructive pulmonary disease. Our study objectives were to compare the efficacy and safety of once-daily FF/VI with FF alone and twice-daily fluticasone propionate (FP) in patients aged ≥12 years with moderate-to-severe persistent asthma. Patients (n=586) received FF/VI 200/25 μg or FF 200 μg once-daily (evening dosing), or FP 500 μg twice-daily for 24 weeks. Co-primary end-points were change from baseline in trough forced expiratory volume in 1 s (FEV1) weighted mean (wm) 0–24 h serial FEV1. Secondary end-points included change from baseline in percentage of rescue-free 24-h periods, percentage of symptom-free 24-h periods and total Asthma Quality of Life Questionnaire (AQLQ). Safety assessments included adverse events, 24-h urinary cortisol excretion, vital signs and ECG. FF/VI significantly improved trough FEV1 and wmFEV1 versus FF and FP. Significantly more rescue-free and symptom-free 24-h periods were reported with FF/VI versus FF. Treatment differences for AQLQ were not significant. Incidence of adverse events was similar across groups. No clinically significant differences were seen for 24-h urinary cortisol excretion, vital signs or ECG. FF/VI resulted in statistically greater improvements in lung function and symptomatic end-points versus FF, and was well tolerated in this asthma population., Fluticasone furoate (FF)/vilanterol improved lung function and symptomatic end-points compared with FF alone http://www.ow.ly/siK33

Background Fluticasone furoate (FF) is a novel long-acting inhaled corticosteroid (ICS). This double-blind, placebo-controlled randomized study evaluated the efficacy and safety of FF 200 mcg or 400 mcg once daily, either in the morning or in the evening, and FF 200 mcg twice daily (morning and evening), for 8 weeks in patients with persistent asthma. Methods Asthma patients maintained on ICS for ≥ 3 months with baseline morning forced expiratory volume in one second (FEV1) 50-80% of predicted normal value and FEV1 reversibility of ≥ 12% and ≥ 200 ml were eligible. The primary endpoint was mean change from baseline FEV1 at week 8 in pre-dose (morning or evening [depending on regimen], pre-rescue bronchodilator) FEV1. Results A total of 545 patients received one of five FF treatment groups and 101 patients received placebo (intent-to-treat population). Each of the five FF treatment groups produced a statistically significant improvement in pre-dose FEV1 compared with placebo (p < 0.05). FF 400 mcg once daily in the evening and FF 200 mcg twice daily produced similar placebo-adjusted improvements in evening pre-dose FEV1 at week 8 (240 ml vs. 235 ml). FF 400 mcg once daily in the morning, although effective, resulted in a smaller improvement in morning pre-dose FEV1 than FF 200 mcg twice daily at week 8 (315 ml vs. 202 ml). The incidence of oral candidiasis was low (0-4%) and UC excretion was comparable with placebo for all FF groups. Conclusions FF at total daily doses of 200 mcg or 400 mcg was significantly more effective than placebo. FF 400 mcg once daily in the evening had similar efficacy to FF 200 mcg twice daily and all FF regimens had a safety tolerability profile generally similar to placebo. This indicates that inhaled FF is an effective and well tolerated once-daily treatment for mild-to-moderate asthma. Trial registration NCT00398645

Introduction and objectives FF/VI is the first once daily inhaled corticosteroid/long-acting b 2 -agonist combination available for the treatment of asthma. Results from five phase III studies that have previously been presented demonstrated a sustained 24 h improvement in lung function and improvement in symptom-free 24 h periods. Methods Post-hoc analyses of diary card data from these studies were performed to examine whether there was any difference in the contribution of the day and night time symptom-free period to the 24 h symptom-free period. The diary card scale used is described below. Day-time Symptom Score: 0 = No symptoms during the day 1 = Symptoms for one short period during the day 2 = Symptoms for two or more short periods during the day 3 = Symptoms for most of the day which did not affect my normal daily activities 4 = Symptoms for most of the day which did affect my normal daily activities 5 = Symptoms so severe that I could not go to work or perform normal daily activities Night-time Symptom Score: 0 = No symptoms during the night 1 = Symptoms causing me to wake once (or wake early) 2 = Symptoms causing me to wake twice or more (including waking early) 3 = Symptoms causing me to be awake for most of the night 4 = Symptoms so severe that I did not sleep at all To be counted as symptom-free during the day or night the patient needed to record a score of 0. Results The post-hoc analyses demonstrated that the improvements in day and night time symptom –free periods were similar to the 24 h symptom free periods. See Figure 1 below. Conclusions In general benefits in symptom free days and symptom free nights contributed to the benefit of FF/VI over comparator groups in terms of 24 h symptom free periods.

Introduction and objectives FF/VI is the first once daily inhaled corticosteroid/long-acting b 2 -agonist combination available for the treatment of asthma. Data from five phase III studies that have previously been presented have generally demonstrated a sustained 24 h improvement in lung function and improvement in rescue-free 24 h periods compared with placebo (P), FF alone or fluticasone propionate (FP). Due to differences in study comparators, duration of study and primary endpoints, integration of the study results has not been possible therefore each study is considered separately. Methods Post-hoc analyses of diary card data from the 5 studies were performed to examine whether there was any difference in the contribution of the day and night time rescue medication use to the 24 h rescue-free period. Patients recorded in an electronic diary card the number of inhalations of rescue salbutamol/albuterol inhalation aerosol used during the day and night. To be counted as rescue-free during the day or night the patient needed to record a no use of rescue medication during that period. Results The post-hoc analyses demonstrated that the improvements in day and night time rescue –free periods were similar to the 24 h rescue free periods. See Figure 1 below. Conclusions In general the benefit of FF/VI on rescue free 24 h periods is reflected in the improvements seen in day and night time rescue use.

a Krefting Research Centre, University of Gothenburg, Box 424, SE 40530 Gothenburg, Sweden b Center for Genomics and Personalized Medicine, Wake Forest University School of Medicine, WinstonSalem, NC 27157, USA c Department of Medicine, University of Wisconsin, Madison, WI 53706, USA d Michael G DeGroote School of Medicine, Hamilton, Ontario L8S4L8, Canada e Institute of Inflammation and Repair, University of Manchester, University Hospital of South Manchester, Manchester M23 9LT, UK f Clinical Research Institute of Southern Oregon, Medford, OR 97504, USA g Respiratory Medicine Development Centre, GlaxoSmithKline, London UB11 1BT, UK h Quantitative Sciences Division, GlaxoSmithKline, Research Triangle Park, NC 27713, USA i Department of Medicine, University of Cape Town, Cape Town 7925, South Africa