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William W Busse,
Paul M O'Byrne,
Eugene R Bleecker,
Jan Lötvall, Ashley Woodcock,
Leslie Andersen,
Wesley Hicks,
Jodie Crawford,
Loretta Jacques,
Ludovic Apoux,
Eric D Bateman
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ABSTRACT: BACKGROUND: The inhaled corticosteroid fluticasone furoate (FF) in combination with the long-acting β(2) agonist vilanterol (VI) is in development for asthma and chronic obstructive pulmonary disease. OBJECTIVE: To assess the safety and tolerability of FF/VI over 52 weeks in patients with asthma. METHODS: Patients (aged ≥12 years; on inhaled corticosteroid) were randomised (2:2:1) to FF/VI 100/25 µg or FF/VI 200/25 µg once daily in the evening, or fluticasone propionate (FP) 500 µg twice daily. Safety evaluations included adverse events (AEs), non-fasting glucose, potassium, 24-h urinary cortisol excretion, ophthalmic assessments, heart rate and pulse rate. RESULTS: On-treatment AEs were similar across groups (FF/VI 66-69%; 73% FP). Oral candidiasis/oropharyngeal candidiasis was more common with FF/VI (6-7%) than FP (3%). Twelve serious AEs were reported; one (worsening hepatitis B on FP) was considered drug related. Statistically significant cortisol suppression was seen with FP compared with both FF/VI groups at Weeks 12 and 28 (ratios [95% CI] to FP ranged from 1.43 [1.11 to 1.84] to 1.67 [1.34 to 2.08]; p≤0.006), but not at Week 52 (ratios to FP were 1.05 [0.83 to 1.33] for FF/VI 100/25 µg and 1.09 [0.87 to 1.38] for FF/VI 200/25 µg). No clinically important changes in non-fasting glucose, potassium, QT interval corrected using Fridericia's formula (QTc[F]) or ophthalmic assessments were reported. Pulse rate (10 min post dose [T(max)], Week 52) was significantly increased with FF/VI versus FP (3.4 bpm, 95% CI 1.3 to 5.6; p=0.002 [FF/VI 100/25 µg]; 3.4 bpm, 95% CI 1.2 to 5.6; p=0.003 [FF/VI 200/25 µg]). Mean heart rate (24-h Holter monitoring) decreased from screening values in all groups (0.2-1.1 bpm FF/VI vs 5 bpm FP; Week 52). CONCLUSIONS: FF/VI (100/25 µg or 200/25 µg) administered once daily over 52 weeks was well tolerated by patients aged ≥12 years with asthma. The overall safety profile of FF/VI did not reveal any findings of significant clinical concern. CLINICALTRIALS.GOV: NCT01018186.
Thorax 02/2013; · 6.84 Impact Factor
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ABSTRACT: Fluticasone furoate (FF) is an inhaled corticosteroid (ICS) with 24-hour activity in development as a once-daily treatment for the long-term management of asthma.
To assess the efficacy and safety of 4 doses of once-daily FF administered using a dry powder inhaler in patients (≥12 years) with moderate asthma, uncontrolled on low-dose ICS (fluticasone propionate [FP] 200 μg/day or equivalent).
This double-blind, placebo-controlled, dose-ranging study randomized 622 patients to 1 of 6 treatments: FF (100, 200, 300, or 400 μg) once daily in the evening, FP 250 μg twice daily (active control), or placebo for 8 weeks. The primary endpoint was the change from baseline in predose evening forced expiratory colume in 1 second (FEV(1)) at week 8.
At week 8, relative to placebo, all doses of FF once daily and FP twice daily demonstrated significantly (P < .001) greater increases from baseline and greater than 200-mL increases in predose FEV(1). There was no evidence of a dose-response relationship between FF doses. Improvement with once-daily FF was similar to or greater than that for twice-daily FP. Secondary efficacy endpoint findings generally supported the efficacy of FF 100 to 400 μg once daily, although statistically significant improvements versus placebo in symptom-free 24-hour periods were only reported for FF 400 μg. There were few withdrawals due to lack of efficacy. Oral candidiasis was reported in 0 to 4% of patients; 24-hour urinary cortisol excretion ratios were similar across active treatment groups and not significantly different from placebo.
FF 100 to 400 μg once daily in the evening is effective and well tolerated in patients with asthma uncontrolled on low-dose ICS, with 100 μg and 200 μg, considered the most applicable doses in this asthma population.
clinicaltrials.gov Identifier: NCT00603278.
Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 11/2012; 109(5):353-358.e4. · 2.83 Impact Factor
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ABSTRACT: This randomized, double-blind, multicenter study was designed to evaluate the efficacy of inhaled once-daily fluticasone furoate (FF) administered in the evening in patients with persistent asthma not controlled by short-acting beta(2) agonists, and to determine the dose(s) suitable for further development.
Of 1459 patients screened, 598 received one of six treatments: placebo, FF (25 μg, 50 μg, 100 μg or 200 μg) once daily each evening, or fluticasone propionate (FP) 100 μg twice daily for 8 weeks. The primary endpoint was change from baseline in pre-dose evening forced expiratory volume in 1 s (FEV(1)).
A dose-response effect was observed for once-daily FF 25-200 μg including (p < 0.001) and excluding placebo (p = 0.03). FF 50-200 μg once daily significantly increased FEV(1) from baseline (p < 0.05 vs placebo), by >200 mL for FF 100 μg and 200 μg. Significant improvements were also achieved for peak expiratory flow, and percentage symptom-free and rescue-free 24 h periods. The magnitude of effect was at least as good as twice-daily FP. Overall, once-daily FF was well tolerated with no systemic corticosteroid effects.
FF 50-200 μg/day once daily in the evening demonstrated dose-related efficacy in asthma with 100-200 μg appearing to be the optimal doses for further evaluation. ClinicalTrials.gov: NCT00603382.
Respiratory medicine 02/2012; 106(5):642-50. · 2.33 Impact Factor
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ABSTRACT: Inhaled corticosteroids are the recommended first-line treatment for asthma but adherence to therapy is suboptimal. The objectives of this study were to compare the efficacy and safety of once-daily (OD) evening and twice-daily (BD) regimens of the novel inhaled corticosteroid fluticasone furoate (FF) in asthma patients.
Patients with moderate asthma (age ≥ 12 years; pre-bronchodilator forced expiratory volume in 1 second (FEV1) 40-85% predicted; FEV1 reversibility of ≥ 12% and ≥ 200 ml) were randomized to FF or fluticasone propionate (FP) regimens in a double-blind, crossover study. Patients were not permitted to have used any ICS for ≥ 8 weeks prior to enrolment and subsequently received doses of FF or FP 200 μg OD, FF or FP 100 μg BD and matching placebo by inhalation for 28 days each. Primary endpoint was Day 28 evening pre-dose (trough) FEV1; non-inferiority of FF 200 μg OD and FF 100 μg BD was assessed, as was superiority of all active treatment relative to placebo. Adverse events (AEs) and 24-hour urinary cortisol excretion were assessed.
The intent-to-treat population comprised 147 (FF) and 43 (FP) patients. On Day 28, pre-dose FEV1 showed FF 200 μg OD to be non-inferior (pre-defined limit -110 ml) to FF 100 μg BD (mean treatment difference 11 ml; 95% CI: -35 to +56 ml); all FF and FP regimens were significantly superior to placebo (p ≤ 0.02). AEs were similar to placebo; no serious AEs were reported. Urinary cortisol excretion at Day 28 for FF was lower than placebo (ratios: 200 μg OD, 0.75; 100 μg BD, 0.84; p ≤ 0.02).
FF 200 μg OD in the evening is an efficacious and well tolerated treatment for asthma patients and is not inferior to the same total BD dose.
Clinicaltrials.gov; NCT00766090.
Respiratory research 12/2011; 12:160. · 3.36 Impact Factor
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ABSTRACT: 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 (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.
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.
Thorax 08/2011; 67(1):35-41. · 6.84 Impact Factor
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ABSTRACT: 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.
Asthma patients maintained on ICS for ≥ 3 months with baseline morning forced expiratory volume in one second (FEV(1)) 50-80% of predicted normal value and FEV(1) reversibility of ≥ 12% and ≥ 200 ml were eligible. The primary endpoint was mean change from baseline FEV(1) at week 8 in pre-dose (morning or evening [depending on regimen], pre-rescue bronchodilator) FEV(1).
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 FEV(1) 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 FEV(1) 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 FEV(1) 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.
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.
NCT00398645.
Respiratory research 01/2011; 12:132. · 3.36 Impact Factor
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ABSTRACT: Abstract
Background
The combination of inhaled corticosteroids (ICS) and long-acting β2-agonists (LABA) is recommended by treatment guidelines for the treatment of persistent asthma. Two such combination products, salmeterol/fluticasone propionate (SFC, Seretide™ GSK, UK) and formoterol/budesonide (FBC, Symbicort™, AstraZeneca, UK) are commercially available.
Objectives
The purpose of these studies was to evaluate and compare the duration of bronchodilation of both combination products up to 24 hours after a single dose.
Methods
Two randomised, double blind, placebo-controlled, crossover studies were performed. Study A was conducted in 33 asthmatic adults receiving 400–1200 mcg of budesonide or equivalent. Serial forced expiratory volume in one second (FEV<sub>1</sub>) was measured over 24 hours to determine the duration of effect of both SFC (50/100 mcg) and FBC (4.5/160 mcg). Study B was conducted in 75 asthmatic adults receiving 800–1200 mcg of budesonide or equivalent and comprised a 4 week run-in of 400 mcg bd Becotide™ followed by 4 weeks treatment with either SFC 50/100 mcg bd or FBC 4.5/160 mcg bd taken in a cross-over manner. Serial 24-hour FEV<sub>1 </sub>was measured after the first dose and the last dose after each 4-weeks treatment period to determine the offset of action of each treatment.
Results
In study A, a single inhalation of SFC and FBC produced a sustained bronchodilation at 16 hours with an adjusted mean increase in FEV<sub>1 </sub>from pre-dose of 0.22 L (95% CI 0.19, 0.35 L) for SFC and 0.25 L (95% CI 0.21, 0.37 L) for FBC, which was significantly greater than placebo for both treatments (-0.05 L; p < 0.001). In study B, the slope of decline in FEV<sub>1 </sub>from 2–24 hours post dose was -16.0 ml/hr for SFC and -14.2 ml/hr for FBC. The weighted mean AUC over 24 hours was 0.21 Lxmin and 0.22 Lxmin and mean change from pre-dose FEV<sub>1 </sub>at 12 hours was 0.21 L for SFC and 0.20 L for FBC respectively
Conclusion
Both SFC and FBC produced a similar sustained bronchodilator effect which was prolonged beyond 12 hours post dose and was clearly measurable at 24 h.
Respiratory Research. 01/2006;
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ABSTRACT: The combination of inhaled corticosteroids (ICS) and long-acting beta2-agonists (LABA) is recommended by treatment guidelines for the treatment of persistent asthma. Two such combination products, salmeterol/fluticasone propionate (SFC, Seretide GSK, UK) and formoterol/budesonide (FBC, Symbicort, AstraZeneca, UK) are commercially available.
The purpose of these studies was to evaluate and compare the duration of bronchodilation of both combination products up to 24 hours after a single dose.
Two randomised, double blind, placebo-controlled, crossover studies were performed. Study A was conducted in 33 asthmatic adults receiving 400-1200 mcg of budesonide or equivalent. Serial forced expiratory volume in one second (FEV1) was measured over 24 hours to determine the duration of effect of both SFC (50/100 mcg) and FBC (4.5/160 mcg). Study B was conducted in 75 asthmatic adults receiving 800-1200 mcg of budesonide or equivalent and comprised a 4 week run-in of 400 mcg bd Becotide followed by 4 weeks treatment with either SFC 50/100 mcg bd or FBC 4.5/160 mcg bd taken in a cross-over manner. Serial 24-hour FEV1 was measured after the first dose and the last dose after each 4-weeks treatment period to determine the offset of action of each treatment.
In study A, a single inhalation of SFC and FBC produced a sustained bronchodilation at 16 hours with an adjusted mean increase in FEV1 from pre-dose of 0.22 L (95% CI 0.19, 0.35 L) for SFC and 0.25 L (95% CI 0.21, 0.37 L) for FBC, which was significantly greater than placebo for both treatments (-0.05 L; p < 0.001). In study B, the slope of decline in FEV1 from 2-24 hours post dose was -16.0 ml/hr for SFC and -14.2 ml/hr for FBC. The weighted mean AUC over 24 hours was 0.21 Lxmin and 0.22 Lxmin and mean change from pre-dose FEV1 at 12 hours was 0.21 L for SFC and 0.20 L for FBC respectively
Both SFC and FBC produced a similar sustained bronchodilator effect which was prolonged beyond 12 hours post dose and was clearly measurable at 24 h.
Respiratory research 01/2006; 7:110. · 3.36 Impact Factor
