Original articleInterventionsOnce-daily fluticasone furoate is efficacious in patients with symptomatic asthma on low-dose inhaled corticosteroids
Introduction
Inhaled corticosteroids (ICSs) are considered to be the most effective therapy for long-term control of mild persistent asthma1, 2, 3 as monotherapy or in combination with a long-acting beta2 agonist (LABA) for more severe disease. ICSs reduce symptoms, improve lung function, decrease bronchial hyperresponsiveness, may prevent airway remodeling, and are associated with prevention of asthma exacerbations and reduced asthma mortality.4, 5, 6, 7, 8 Despite this, asthma control remains suboptimal in a significant proportion of patients.9
Poor adherence is a frequent cause of inadequate asthma control,2, 10, 11 and it is known that adherence increases with less frequent dosing12 such that once-daily dosing is associated with higher adherence than twice-daily dosing.13, 14 Indications for once-daily ICS dosing in asthma are limited; therefore, there is a need for once-daily ICSs for all levels of asthma severity, which also offer potential combination with an LABA in a fixed-dose once-daily combination. Asthma symptoms can be worse at night, and this, in addition to circadian fluctuations in cortisol levels, appears to favor evening dosing.15, 16, 17 Indeed, clinical studies have shown that once-daily dosing of ICSs in the evening is at least as18 if not more19, 20 effective (in terms of improvements in lung function outputs) as once-daily dosing in the morning. Fluticasone furoate (FF) is a novel ICS with activity maintained for 24 hours post inhalation.21 It is under development for asthma as a monotherapy and as combination therapy with vilanterol for once-daily ICS/LABA therapy in asthma and chronic obstructive pulmonary disease (COPD). FF is distinct from fluticasone propionate (FP), with a 2-furoic acid ester replacing the simpler propionate ester at the 17α pocket.22 This results in greater occupancy and affinity for the glucocorticoid receptor and longer retention in respiratory tissues than FP.22, 23
The aim of this study was to assess the efficacy, safety, and tolerability of 4 doses of FF administered once daily in the evening in patients with moderate asthma uncontrolled on low-dose ICSs. Twice-daily FP (250 μg) was used as an appropriate active control. Some of the results of this study have been presented in abstract form.24
Section snippets
Design
An 8-week, phase IIb, multicenter, international, randomized, double-blind, double-dummy, parallel-group, placebo-controlled study (GlaxoSmithKline study number: FFA109685; clinicaltrials.gov: NCT00603278) conducted at 144 centers. This study was part of a large phase II program to help identify suitable doses of FF across a range of asthma severities for development as a monotherapy and as part of a fixed-dose ICS/LABA combination.
Patients
Patients were 12 years of age or older with moderate persistent
Patient characteristics
Of 1,406 screened patients, 622 patients were randomized to study treatment, and 615 received at least 1 dose of study medication (ITT population; Fig 1). Demographic characteristics were similar across study groups (Table 1).
Efficacy
A statistically significant (P < .001) linear trend test indicated the dose–response relationship slope across all once-daily FF treatment groups and placebo was not zero (Table 2). Two-sided tests of each dose versus placebo demonstrated superiority of all active
Discussion
The results from this study support the 24-hour duration of effect of a single daily dose of FF compared with twice-daily dosing of FP. All doses of once-daily FF significantly improved the predose evening FEV1 from baseline relative to placebo at week 8. The difference from placebo in predose FEV1 ranged from 207 mL (FF 100 μg) to 293 mL (FF 300 μg), with no evidence of a dose response. Efficacy was generally similar to twice-daily FP, but numerically better for all FF doses greater than 100
Acknowledgments
We acknowledge all patients who took part in the study and all of the investigators at the 144 centers. The authors wish to acknowledge the contribution of Susan Tomkins, GlaxoSmithKline, in the statistical analysis of the data, and also Ann Allen, GlaxoSmithKline, who was the study pharmacokineticist and had a significant role in developing the pharmacokinetic component of the study protocol. Editorial support in the form of development of draft outline, development of manuscript first draft,
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2019, Kendig's Disorders of the Respiratory Tract in ChildrenInhaled corticosteroids: Ocular safety and the hypothalamic-pituitary-adrenal axis
2016, Annals of Allergy, Asthma and ImmunologyCitation Excerpt :However, fluticasone furoate DPI does not appear to have any effect on cortisol suppression. In a randomized, double-blind, multinational study, 622 patients aged 12 to 75 years with moderate asthma received either 1 of 4 doses of fluticasone furoate, fluticasone propionate, or placebo for 8 weeks.23 Cortisol suppression was measured with 24-hour urinary cortisol excretion ratios.
Comparison of early effects of budesonide/formoterol maintenance and reliever therapy with fluticasone furoate/vilanterol for asthma patients requiring step-up from inhaled corticosteroid monotherapy
2016, Pulmonary Pharmacology and TherapeuticsCitation Excerpt :A new ICS/LABA combination containing fluticasone furoate (FF) and vilanterol (VI) is currently approved for asthma treatment. FF has been shown to have greater affinity for the glucocorticoid receptor, and longer retention in respiratory tissues than other glucocorticoids including FP and BUD [7]; it has also produced a significant improvement in lung function when administered in once daily evening doses [8]. VI has been shown to have a stronger affinity and selectivity profile for β2-adrenoceptor than FM, and a faster onset and longer duration of action than SM in human airways [9]; it also has an effective bronchodilation for 24 h in asthma patients treated with ICS [10].
Karen W. House, MS is deceased.
Disclosures: E. R. Bleecker has served as a consultant to and received lecture fees from GlaxoSmithKline and has performed clinical trials for GlaxoSmithKline, which have been administered by his employer Wake Forest University Health Sciences. E. D. Bateman has served as a consultant to and received lecture fees from GlaxoSmithKline, and his institution has received remuneration for participation in clinical trials sponsored by GlaxoSmithKline. W. W. Busse has served as a consultant to AstraZeneca, Boehringer Ingelheim, Novartis, and TEVA; served on advisory boards for Amgen, Centocor, GlaxoSmithKline, Johnson & Johnson, Merck Sharpe and Dohme, and Pfizer; received lecture fees from Merck Sharpe and Dohme; and received research funding from AstraZeneca, Ception, GlaxoSmithKline, MedImmune and Novartis. J. Lötvall has served as a consultant to and received lecture fees from AstraZeneca, GlaxoSmithKline, Merck Sharpe and Dohme, Novartis, and UCB Pharma; has been partly covered by some of these companies to attend previous scientific meetings, including the ERS and the AAAAI; and has participated in clinical research studies sponsored by AstraZeneca, GlaxoSmithKline, Merck Sharpe and Dohme, and Novartis. A. Woodcock has served as consultant to Almirall, AstraZeneca, Chiesi, GlaxoSmithKline, Merck Sharpe and Dohme, Novartis, and Schering Plough; and has received lecture fees and research grants from GlaxoSmithKline. L. Frith, L. Jacques, and A. M. Davis are employees of and hold stock in GlaxoSmithKline. B. Haumann was employed by GlaxoSmithKline at the time this study was conducted and continues to hold stock in GlaxoSmithKline. K. W. House was employed by and held stock in GlaxoSmithKline.
Funding Sources: Funded by GlaxoSmithKline (study number FFA109685; clinicaltrials.gov: NCT00603278).