Amanda Oliver

The efficacy of once-daily fluticasone furoate/vilanterol in asthma is comparable with morning or evening dosing

AIM To investigate the effect of time of day of dosing (morning or evening) on lung function following administration of fluticasone furoate (FF)/vilanterol (VI) 100/25 mcg. METHODS Double-blind, placebo-controlled, randomised, three-way crossover study. Subjects with persistent asthma (N = 26) received FF/VI (morning or evening) or matching placebo once-daily for 14 (± 2 days) via dry powder inhaler (DPI). Weighted mean (0-24h) and pre-treatment FEV1 (morning and evening) were determined after the Day 14 evening dose, together with mean pre-treatment (morning and evening) peak expiratory flow (PEF) on Days 2-12. RESULTS FF/VI 100/25 administered morning or evening produced clinically significant increases in weighted mean FEV1: the differences [95% confidence interval (CI)] from placebo were 377 mL [293, 462] and 422 mL [337, 507], respectively; the difference between morning and evening dosing was -44 mL [-125, 36]. Day 14 pre-treatment morning FEV1 differences [95% CI] from placebo were 403 mL [272, 533] and 496 mL [369, 624] after morning and evening dosing, respectively; the morning:evening treatment difference was -94 mL [-221, 34]. Pre-treatment evening FEV1 differences [95% CI] from placebo were 275 mL [169, 380] and 309 mL [205, 413] after morning and evening dosing, respectively; the morning:evening treatment difference was -34 mL [-138, 70]. FF/VI (morning or evening) produced rapid increases in PEF with the full effect apparent after the first dose and maintained throughout the 14-day treatment period. CONCLUSION FF/VI 100/25 produces comparable improvements in lung function whether dosed in the morning or evening in subjects with persistent asthma.

Modulation of allergen-induced bronchoconstriction by fluticasone furoate and vilanterol alone or in combination

This placebo‐controlled study assessed the effects of the once‐daily inhaled corticosteroid (ICS) fluticasone furoate (FF) and long‐acting beta2‐agonist (LABA) vilanterol (VI) on early and late asthmatic responses (EAR/LAR) and airway hyper‐responsiveness (AHR).

Combined fluticasone furoate/vilanterol reduces decline in lung function following inhaled allergen 23 h after dosing in adult asthma: a randomised, controlled trial

BackgroundThere is a need for preventative asthma maintenance therapy that provides lasting bronchoprotection against allergen provocation. Fluticasone furoate (FF) is a novel inhaled once-daily corticosteroid, being investigated as monotherapy for asthma and in combination with vilanterol (VI), a novel inhaled once-daily long-acting beta-agonist, for asthma and chronic obstructive pulmonary disease.MethodsIn a crossover study of 52 subjects with mild asthma, FF/VI 100/25mcg and FF 100 dosed once-daily in the evening for 28 days were compared with placebo to evaluate their capacity to provide bronchoprotection against the early asthmatic response (EAR) stimulated by an inhaled allergen challenge. Bronchoprotection was assessed by change from post-saline baseline in weighted mean (wm) forced expiratory volume in 1 s (FEV1) for the first 2 h post-allergen challenge, which was on Day 29 (22–23 h post final dose on Day 28). The EAR was also assessed using maximum percent decrease from post-saline baseline and minimum absolute FEV1; the incidence of adverse events was a secondary endpoint.ResultsFF/VI 100/25 and FF 100 both provided significant bronchoprotection against the EAR for all endpoints assessed. For wmFEV1 over the first 2 h post-allergen challenge, a 162 mL (95% CI, 87 to 237 mL) difference was observed between placebo and FF 100, while a 145 mL (95% CI, 69 to 222 mL) difference was observed between placebo and FF/VI 100/25 treatment. No difference between active treatments was observed (−17 mL; 95% CI, –91 to 57 mL). Both treatments were well tolerated.ConclusionsFF 100 alone and in combination with VI 25 provides significant bronchoprotection against the EAR in subjects with mild asthma. That this protection is provided at the trough of dosing, i.e. 23 h post last dose, supports the utility of FF 100 and FF/VI 100/25 as viable once-daily therapies.Trial registrationClinicaltrials.gov identifier: NCT01128569, GSK Study number: HZA113090

Tolerability of Fluticasone Furoate/Vilanterol Combination Therapy in Children Aged 5 to 11 Years With Persistent Asthma

BACKGROUND Asthma is a chronic disease afflicting millions of children worldwide. Short-acting β2-agonist reliever medications and inhaled corticosteroid (ICS) maintenance therapies are effective treatments; however, many children remain uncontrolled with short-acting β2-agonist and ICS treatment, in which case guidelines recommend adding a long-acting β2-agonist. OBJECTIVE We sought to investigate the safety profile, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) properties of the long-acting β2-agonist vilanterol (VI) combined with the ICS fluticasone furoate (FF) administered via the ELLIPTA dry powder inhaler (GlaxoSmithKline, London, United Kingdom) in children aged 5 to 11 years with persistent asthma. METHODS In this randomized, double-blind, repeated-dose, 2-way crossover study, data from 8- to 11-year-old children with asthma were reviewed before those from 5- to 7-year-old children with asthma. Patients received once-daily FF/VI, 100/25 µg, or FF, 100 µg, in the morning for 14 days, followed by a ≥7-day washout period before switching to the other treatment for 14 days; the study duration was ≤11 weeks. Primary end points were adverse events (AEs), clinical laboratory measurements, peak expiratory flow, maximum heart rate, blood pressure, and electrocardiographic parameters. Secondary end points comprised PK (AUC0-4, Cmax) and PD (serum potassium [0-4 hours], serum cortisol [0-12 hours], and glucose [0-4 hours]) parameters on day 14. RESULTS Twenty-six children were randomized (58% boys; mean age, 8.1 years). No clinically significant changes in the primary end points were observed. Five patients reported 4 and 2 AEs with FF/VI and FF therapy, respectively. After FF/VI or FF treatment, the geometric mean ratios (90% CIs) for FF AUC0-4 (1.02 [0.86-1.22]) and FF Cmax (0.98 [0.65-1.48]) were similar. For serum glucose (0-4 hours) concentration, a difference of 0.50 mM (95% CI, 0.19-0.82 mM) was observed for FF/VI versus FF; no differences were observed for other PD parameters. No AEs were judged to be serious or treatment related. The PK profile of FF did not seem to be altered by VI and was not affected by age or sex. The significance of an increased serum glucose level is difficult to judge as measurements were taken from nonfasted patients. Results can be compared only with active treatment, and the ability to generalize is limited by the small number of patients in this single-center study. CONCLUSIONS Once-daily repeated dosing of FF/VI, 100/25 µg, using the ELLIPTA dry powder inhaler was as well tolerated as FF, 100 µg, in this small, selected population of 5- to 11-year-old, mostly white/caucasian children with persistent asthma.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Vilanterol, a Novel Inhaled Long-Acting β-Agonist, in Children Aged 5–11 Years with Persistent Asthma: A Randomized Trial

This multi‐center, randomized, double‐blind, placebo‐controlled, two‐way crossover study was designed to characterize the safety, tolerability, pharmacokinetic, and pharmacodynamic profile of single and once‐daily repeat doses of vilanterol 25 µg in children aged 5–11 years. Twenty‐eight children with persistent asthma received a single inhaled dose of vilanterol 25 µg or placebo via the ELLIPTA™ dry powder inhaler (DPI) on Day 1, followed 7 days later by once‐daily treatment for 7 days. Nine (33%) subjects reported adverse events (AEs) with vilanterol 25 µg and 6 (23%) with placebo. No serious or drug‐related AEs were reported; 3 subjects experienced upper respiratory tract infection (URTI) with vilanterol 25 µg versus none with placebo. Similar pharmacokinetic profiles of vilanterol 25 µg were observed irrespective of age or gender. No clinically relevant changes in heart rate, Fridericias correction (QTcF), maximum glucose or minimum potassium parameters were observed during treatment with vilanterol 25 µg compared with placebo treatment. Vilanterol was well‐tolerated and no long‐acting ß2‐agonist (LABA)‐mediated AEs were observed. The pharmacokinetic profile of vilanterol 25 µg suggests exposure is similar regardless of age or gender in a pediatric population aged 5–11 years.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Fluticasone Furoate, a Novel Inhaled Corticosteroid, in Children Aged 5-11 Years With Persistent Asthma: A Randomized Trial

This multi‐center, randomized, double‐blind, placebo‐controlled, two‐way crossover study characterized the safety, tolerability, pharmacokinetics, and pharmacodynamics of fluticasone furoate (FF) in children (5–11 years) with persistent asthma. Twenty‐seven children received inhaled FF 100 µg or placebo via the ELLIPTA™ dry powder inhaler once daily for 14 days, with a ≥7 day washout period. Adverse events (AEs) were reported by eight (31%) and four (16%) subjects during FF 100 µg and placebo treatment, respectively. Headache was reported by three subjects during FF 100 µg treatment and by no subjects during placebo treatment, all other AEs were reported by only one subject on either treatment; there were no serious AEs. Following repeat dosing, the arithmetic mean (SD) FF Cmax was 26.71 pg/mL (9.16) at 31 minutes post‐dose. Arithmetic mean (SD) FF AUC(0–t) was 121.44 pg h/mL (83.04). Arithmetic mean values for weighted mean (SD) serum cortisol (0–12 hours) on day 14 were 56.49 (16.51) and 67.57 (20.66) ng/mL for FF 100 µg and placebo, respectively. No clinically significant effect of FF on serum cortisol levels was observed. FF was well tolerated. Pharmacokinetic profiles were well defined and did not differ between age groups in the study population, and no clinically significant suppression of serum cortisol was observed.

Randomized Trial of Once-Daily Fluticasone Furoate in Children with Inadequately Controlled Asthma

OBJECTIVE To evaluate the dose-response, efficacy, and safety of fluticasone furoate (FF; 25 µg, 50 µg, and 100 µg), administered once daily in the evening during a 12-week treatment period to children with inadequately controlled asthma. STUDY DESIGN This was a Phase IIb, multicenter, stratified, randomized, double-blind, double-dummy, parallel-group, placebo- and active-controlled study in children aged 5-11 years with inadequately controlled asthma. The study comprised a 4-week run-in period, 12-week treatment period, and 1-week follow-up period. Children were randomized to receive either placebo once daily, fluticasone propionate (FP) 100 µg twice daily, FF 25 µg, FF 50 µg, or FF 100 µg each once daily in the evening. Primary endpoint was the mean change from baseline in daily morning peak expiratory flow (PEF) averaged over weeks 1-12. Adverse events (AEs) also were investigated. RESULTS In total, 593 children were included in the intent-to-treat population. The difference vs placebo in change from baseline daily morning PEF averaged over weeks 1-12 was statistically significant for the FF 25, FF 50, FF 100, and FP 100 groups (18.6 L/min, 19.5 L/min, 12.5 L/min, and 14.0 L/min, respectively; P < .001 for all). The incidence of AEs was greater in the FF groups (32%-36%) than in the placebo group (29%); the most frequent AE was cough. CONCLUSION FF and FP resulted in significant improvements in morning PEF compared with placebo, suggesting that they are effective treatments for children with inadequately controlled asthma. All treatments were well tolerated; no new safety concerns were identified. TRIAL REGISTRATION ClinicalTrials.gov:NCT01563029.