Richard Forth

Fluticasone furoate demonstrates efficacy in patients with asthma symptomatic on medium doses of inhaled corticosteroid therapy: an 8-week, randomised, placebo-controlled trial

Background 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 β2 agonist vilanterol trifenatate for asthma and chronic obstructive pulmonary disease. Objectives To determine the optimal dose(s) of FF for treating patients with asthma. Methods 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 (FEV1). Other endpoints included morning and evening peak expiratory flow, and rescue/symptom-free 24 h periods. Results Each dose was significantly superior to placebo for the primary endpoint (p<0.001) 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 (p<0.001 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. Conclusions FF doses <800 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.

Once-daily fluticasone furoate alone or combined with vilanterol in persistent asthma

The inhaled corticosteroid fluticasone furoate (FF) and the long-acting &bgr;2 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 &mgr;g or FF 200 &mgr;g once-daily (evening dosing), or FP 500 &mgr;g 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

Efficacy in asthma of once-daily treatment with fluticasone furoate: a randomized, placebo-controlled trial

BackgroundFluticasone 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.MethodsAsthma 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.ResultsA 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.ConclusionsFF 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 registrationNCT00398645

Fluticasone Furoate–Vilanterol 100-25 mcg Compared with Fluticasone Furoate 100 mcg in Asthma: A Randomized Trial

BACKGROUND The inhaled corticosteroid fluticasone furoate (FF) in combination with the long-acting β2-agonist vilanterol (VI) is under development for the treatment of asthma and chronic obstructive pulmonary disease. OBJECTIVE To compare the efficacy and safety of FF-VI and FF in patients (≥ 12 years old) with persistent asthma. METHODS In a randomized, double-blind, parallel-group study, patients (n = 609) (intent-to-treat population) received FF-VI 100-25 mcg, FF 100 mcg, or placebo once daily (evening) by using a dry powder inhaler for 12 weeks. Coprimary end points were change from baseline in trough FEV1 and serial (0-24 hours) weighted mean FEV1 (wmFEV(1)). Rescue-free 24-hour periods and safety also were assessed. RESULTS Placebo increased trough FEV1 (196 mL) and wmFEV(1) (212 mL) versus baseline. Compared with placebo, FF-VI and FF significantly improved trough FEV1 (172 mL [P < .001] and 136 mL [P = .002]), respectively, and serial wmFEV(1) (302 mL [P < .001] and 186 mL [P = .003]), respectively. Treatment differences between FF-VI and FF approached significance for serial wmFEV(1) (116 mL; P = .060) but not for trough FEV1 (36 mL; P = .405). The percentage of rescue-free 24-hour periods with FF-VI was 10.6% greater than FF and 19.3% greater than placebo. Statistically significant (P = .032) urinary cortisol suppression was observed with FF-VI (ratio, 0.82) relative to placebo, but not with FF. Adverse event and safety profiles were similar across treatment groups. CONCLUSIONS Significant improvement in lung function was observed with FF-VI and FF versus placebo in patients with persistent asthma. Improvement of FEV1 when VI was added to FF was not significant. The high placebo response in evening trough FEV1 may have influenced the assessment of efficacy.

Once-daily fluticasone furoate 50 mcg in mild-to-moderate asthma: a 24-week placebo-controlled randomized trial.

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.

Fluticasone furoate (FF)/vilanterol (100/25 mcg or 200/25 mcg) or FF (100 mcg) in persistent asthma

Abstract Objectives: Fluticasone furoate (FF; inhaled corticosteroid) combined with vilanterol (VI; long-acting beta2 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. Methods: The primary end point was weighted mean (wm) 0–24-h serial forced expiratory volume in 1 s (FEV1) at week 12. Secondary end points (change from baseline) were trough FEV1 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. Results: Compared with FF 100 mcg, FF/VI 100/25 mcg significantly improved wmFEV1 (p < 0.001), trough FEV1 (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. Conclusions: 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.

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

ABSTRACT 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.

P158 Fluticasone furoate(FF)/vilanterol (VI) once daily improves night-time awakenings in asthma

Introduction and objectives FF/VI, the first once daily inhaled corticosteroid/long-acting ß2-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. Abstract P158 Table 1 Treatment comparisons for % patients with ≥50% symptom free nights over the study duration HZA106827 (Weeks 1–12) REF Placebo (n = 203) FF 100 (n = 204) FF/VI 100 (n = 201) % of patients 35% 46% 59% Odds Ratio (95% CI) FF vs PbO:2.29(1.41, 3.73) FF/VI vs PbO:4.66(2.84, 7.66) Odds Ratio (95% CI) FF/VI vsFF 100:2.04(1.29, 3.22) Time (days) when 50% of patients achieved 7 nights without symptoms Did not occur during study 70 44 HZA106863 (Weeks 1–12) REF FF 100 (n = 346) FF/VI 100 (n = 345) FF/VI 200 (n = 345) % of patients 42% 43% 48% Odds Ratio (95% CI) FF/VI 100 vsFF 100:1.33(0.93, 1.91) FF/VI 200 vsFF/VI 100:1.23(0.87, 1.74) Time (days) when 50% of patients achieved 7 nights without symptoms 86 64 48 HZA106829 (Weeks 1–24) REF FF 200 (n = 193) FF/VI 200 (n = 197) FP 500 (n = 195) % of patients 41% 51% 46% Odds Ratio (95% CI) FF/VI 200 vsFF 200:1.59(0.99, 2.55) Odds Ratio (95% CI) FF/VI 200 vsFP 500:1.09(0.69, 1.74) Time (days) when 50% of patients achieved 7 nights without symptoms 111 72 84

P155 Fluticasone furoate (FF)/Vilanterol (VI) once daily reduces rescue medication use both day and night

Introduction and objectives FF/VI is the first once daily inhaled corticosteroid/long-acting b2-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.Abstract P155 Figure 1 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.