A multicenter randomized, double-blind, placebo-controlled, parallel-group study to evaluate the effects of a 1-year regimen of orally inhaled fluticasone furoate 50 µg once daily on growth velocity in prepubertal, pediatric participants with well-controlled asthma.

INTRODUCTION: Growth impairment is a known adverse event (AE) of corticosteroids in children. This study aimed to assess the effect of once-daily (QD) inhaled fluticasone furoate (FF) versus placebo on growth velocity over 1 year in prepubertal children with well-controlled asthma. MATERIALS AND METHODS: This randomized, double-blind, parallel-group, placebo-controlled, multicenter study (NCT02889809) included prepubertal children, aged 5 to <9 years (boys), and 5 to <8 years (girls), with ≥6 months' asthma history. Children received inhaled placebo QD plus background open-label montelukast QD for a 16-week run-in period and were then randomized 1:1 to receive inhaled FF 50 µg QD or placebo QD (whilst continuing background open-label montelukast) for a 52-week treatment period. The primary endpoint was the difference in growth velocity (cm/year) over the treatment period. Other growth endpoints were measured, as were incidence of AEs and asthma exacerbation. Growth analyses included all intent-to-treat (ITT) participants with ≥3 post-randomization, on-treatment clinic visit height assessments (GROWTH population). RESULTS: Of 644 children in the run-in period, 477 (mean age 6.2 years, 63% male) entered the 52-week treatment period (ITT population: FF N = 238, placebo N = 239; GROWTH population: N = 457 [FF N = 231; placebo N = 226]). The least-squares mean difference in growth velocity for FF versus placebo was -0.160 cm/year (95% confidence interval: -0.462, 0.142). There were no new safety signals. CONCLUSIONS: Over 1 year, FF 50 µg QD had a minimal effect on growth velocity versus placebo, with no new safety signals.

Efficacy and safety of once-daily, single-inhaler fluticasone furoate/umeclidinium/vilanterol versus fluticasone furoate/vilanterol in Japanese patients with inadequately controlled asthma: the CAPTAIN study.

OBJECTIVE: In CAPTAIN, a double-blind, parallel-group, Phase IIIA study, fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) improved lung function, symptoms and asthma control versus FF/VI in patients with inadequately controlled asthma. Here, we report efficacy and safety from a Japanese cohort in CAPTAIN. METHODS: Adults with inadequately controlled asthma despite inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA) were randomized (1:1:1:1:1:1) to once-daily FF/VI (100/25 mcg or 200/25 mcg) or FF/UMEC/VI (100/31.25/25 mcg, 100/62.5/25 mcg, 200/31.25/25 mcg, or 200/62.5/25 mcg) for ≥24 weeks. Endpoints included change from baseline in clinic trough FEV1 (primary), annualized rate of moderate/severe asthma exacerbations (key secondary), clinic FEV1 3 h post-dose, and Asthma Control Questionnaire (ACQ)-7, St George's Respiratory Questionnaire (SGRQ) (all Week 24), Evaluating Respiratory Symptoms (E-RS): Asthma total scores (Weeks 21-24) (all secondary). Adverse events and adverse events of special interest were monitored. Clinical trials.gov registry no: NCT02924688. RESULTS: Overall, 229 of 2436 patients in the intention-to-treat (ITT) population were from Japan. In this cohort, change from baseline in trough FEV1 for FF/UMEC/VI 100/62.5/25 mcg versus FF/VI 100/25 mcg was 105 mL (95% confidence interval -5, 216) and 69 mL (-42, 179) for 200/62.5/25 mcg versus 200/25 mcg. These observations were supported by clinic FEV1 at 3 h post-dose. Moderate/severe exacerbation incidence was low and similar across pooled treatment groups (FF/VI, FF/UMEC 31.25 mcg/VI, FF/UMEC 62.5 mcg/VI). All pooled groups demonstrated clinically important improvements from baseline in ACQ-7, SGRQ and E-RS: Asthma total scores. Safety profiles were consistent with the overall ITT population, with no new safety concerns. CONCLUSION: FF/UMEC/VI is an effective option with a favorable risk-benefit profile in Japanese patients with uncontrolled moderate or severe asthma on ICS/LABA.

The impact of fluticasone furoate/vilanterol on healthcare resource utilisation in the Salford Lung Study in chronic obstructive pulmonary disease.

AIM: The Salford Lung Study (SLS) in chronic obstructive pulmonary disease (COPD) was a randomised controlled trial evaluating the effectiveness and safety of initiating fluticasone furoate/vilanterol (FF/VI) 100/25 µg versus continuing usual care (UC) in patients with COPD and a history of exacerbations. Here, we investigate the impact of initiating FF/VI on healthcare resource utilisation (HRU) in SLS COPD. METHODS: HRU and interventions were determined from patients' electronic health records. Annual rates of on-treatment all-cause and COPD-related secondary care contacts (SCCs) and primary care contacts (PCCs) for FF/VI versus UC were analysed using a general linear model. Costs were derived from national data sources. RESULTS: Least-squares (LS) mean annual rates of all-cause (9.81 versus 9.36) and COPD-related (1.57 versus 1.48) SCCs were similar for FF/VI and UC, as were rates of all-cause hospitalisations (0.87 versus 0.82). Mean duration of hospital stay/patient was 4.5 and 4.2 days, respectively. COPD-related SCC mean total cost/patient was £484 FF/VI and £475 UC. LS mean annual rates of all-cause PCCs were significantly higher for FF/VI (21.20 versus 18.88 UC; p < 0.001). LS mean annual rates of COPD-related PCCs were similar for FF/VI and UC (2.42 versus 2.46). All-cause PCC mean total cost/patient was £900 FF/VI versus £811 UC, but COPD-related PCC costs were similar (£116 versus £114). Direct COPD-related total medical costs/patient were significantly lower for FF/VI (LS geometric mean £806 versus £963 UC; p < 0.001). DISCUSSION: In patients with COPD and exacerbation history, FF/VI may represent a less costly alternative to current therapies.GlaxoSmithKline plc. study HZC115151; ClinicalTrials.gov NCT01551758.The reviews of this paper are available via the supplemental material section.

Benefit and safety of fluticasone furoate/vilanterol in the Salford Lung Study in chronic obstructive pulmonary disease (SLS COPD) according to baseline patient characteristics and treatment subgroups.

BACKGROUND: SLS COPD was the first open-label randomised controlled trial demonstrating a reduction in moderate/severe COPD exacerbations with once-daily inhaled fluticasone furoate/vilanterol (FF/VI) in everyday clinical practice. Here we report FF/VI effectiveness and safety in predefined patient subgroups. METHODS: Patients with COPD, exacerbation history, and receiving maintenance inhaler therapy, were randomised to initiate FF/VI 100/25 µg or continue usual care (UC) with 12 months' follow-up. Annual rates of moderate/severe exacerbations (primary outcome), selected secondary outcomes, and incidence of pneumonia serious adverse events of special interest (SAESI) were compared between randomisation groups across various patient subgroups/baseline treatment strata. SAESI rates by actual treatment were also assessed. RESULTS: Lower exacerbation rates were observed for FF/VI versus UC across all subgroups/strata, including ICS + LABA therapy subset (8.0% [0.1, 15.4]), except in patients without baseline airflow limitation (-0.5% [-29.8, 22.1]). Larger reductions compared to the overall analysis were observed for patients on ICS-containing regimens (excluding LAMA) before the study (15.6% [3.4, 26.3]), and with baseline CAT score <10 (25.3% [-0.4, 44.4]). Pneumonia SAESI rates were similar for FF/VI versus UC across all subgroups/strata, except the LABA, LAMA or LABA + LAMA stratum (incidence ratio 2.8 [0.9, 8.5]). SAESI rates were not increased for FF/VI versus other ICS + LABA. CONCLUSIONS: Initiating FF/VI versus continuing UC reduced exacerbation rates without increased pneumonia SAESI risk compared to other ICS-containing regimens and in various patient subgroups, consistent with primary study findings. FF/VI may be a therapeutic option for a broad population of COPD patients, including those with more severe disease.

Effectiveness versus efficacy trials in COPD: how study design influences outcomes and applicability.

Guidelines for chronic obstructive pulmonary disease (COPD) management are based largely on results from double-blind randomised controlled trials (RCTs) of efficacy. These trials have high internal validity and test whether a drug is efficacious, but they are conducted in highly selected populations that may differ significantly from patients with COPD seen in routine practice.We compared the baseline characteristics, healthcare use and outcomes between the Salford Lung Study (SLS), an open-label effectiveness RCT, with six recent large-scale efficacy RCTs. We also calculated the proportion of SLS patients who would have been eligible for inclusion in an efficacy RCT by applying the inclusion criteria used in efficacy trials of combination treatments.SLS patients were older, included more females and more current smokers, had more comorbidities (including asthma), and had more often experienced exacerbations prior to inclusion. In the SLS, rates of moderate or severe exacerbations, incidence of overall serious adverse events (SAEs), and SAEs of pneumonia were more frequent. A maximum of 30% of patients enrolled in the SLS would have been eligible for a phase IIIa regulatory exacerbation study.Patients in large COPD efficacy RCTs have limited representativeness compared with an effectiveness trial. This should be considered when interpreting efficacy RCT outcomes and their inclusion into guidelines.

Effectiveness of Fluticasone Furoate-Vilanterol for COPD in Clinical Practice.

BACKGROUND: Evidence for the management of chronic obstructive pulmonary disease (COPD) comes from closely monitored efficacy trials involving groups of patients who were selected on the basis of restricted entry criteria. There is a need for randomized trials to be conducted in conditions that are closer to usual clinical practice. METHODS: In a controlled effectiveness trial conducted in 75 general practices, we randomly assigned 2799 patients with COPD to a once-daily inhaled combination of fluticasone furoate at a dose of 100 µg and vilanterol at a dose of 25 µg (the fluticasone furoate-vilanterol group) or to usual care (the usual-care group). The primary outcome was the rate of moderate or severe exacerbations among patients who had had an exacerbation within 1 year before the trial. Secondary outcomes were the rates of primary care contact (contact with a general practitioner, nurse, or other health care professional) and secondary care contact (inpatient admission, outpatient visit with a specialist, or visit to the emergency department), modification of the initial trial treatment for COPD, and the rate of exacerbations among patients who had had an exacerbation within 3 years before the trial, as assessed in a time-to-event analysis. RESULTS: The rate of moderate or severe exacerbations was significantly lower, by 8.4% (95% confidence interval, 1.1 to 15.2), with fluticasone furoate-vilanterol therapy than with usual care (P=0.02). There was no significant difference in the annual rate of COPD-related contacts to primary or secondary care. There were no significant between-group differences in the rates of the first moderate or severe exacerbation and the first severe exacerbation in the time-to-event analyses. There were no excess serious adverse events of pneumonia in the fluticasone furoate-vilanterol group. The numbers of other serious adverse events were similar in the two groups. CONCLUSIONS: In patients with COPD and a history of exacerbations, a once-daily treatment regimen of combined fluticasone furoate and vilanterol was associated with a lower rate of exacerbations than usual care, without a greater risk of serious adverse events. (Funded by GlaxoSmithKline; Salford Lung Study ClinicalTrials.gov number, NCT01551758 .).

Efficacy and safety evaluation of once-daily fluticasone furoate/vilanterol in Asian patients with asthma uncontrolled on a low- to mid-strength inhaled corticosteroid or low-dose inhaled corticosteroid/long-acting beta2-agonist.

BACKGROUND: Response to inhaled corticosteroid (ICS)/long-acting beta2-agonist (LABA) combinations varies across ethnic groups. OBJECTIVE: To investigate the efficacy and safety of the ICS/LABA combination fluticasone furoate/vilanterol (FF/VI) 100/25 µg in Asian patients with asthma. METHODS: A randomized (1:1), 12-week, double-blind, placebo-controlled, parallel group, multicenter phase III study of once-daily FF/VI 100/25 µg versus placebo in patients of Asian ancestry ages ≥12 years with asthma, uncontrolled on a low- to mid-strength ICS or low-dose ICS/LABA. The primary end point was the mean change from baseline in the daily evening peak expiratory flow. Secondary end points were the mean change from baseline in percentage rescue-free 24-hour periods, daily morning peak expiratory flow, percentage symptom-free 24-hour periods, Asthma Quality of Life Questionnaire score, adverse events, and severe exacerbations. RESULTS: The intent-to-treat population was 307 patients. There were significant (p < 0.001) improvements from baseline for FF/VI 100/25 µg versus placebo in evening peak expiratory flow (51.0 L/min [95% confidence interval {CI}, 42.2-59.7 L/min]) and all secondary end points (percentage rescue-free 24-hour periods 21.8% [95% CI, 14.6-29.1%]; morning peak expiratory flow 52.9 L/min [95% CI, 44.2-61.6 L/min]; percentage symptom-free 24-hour periods 15.8% [95% CI, 9.4-22.3%]; Asthma Quality of Life Questionnaire score 0.52 [95% CI, 0.28, 0.75]). On-treatment adverse events were 35% with FF/VI (n = 2 [serious]), 31% with placebo; severe exacerbations were FF/VI (n = 1), placebo (n = 7). CONCLUSIONS: In patients of Asian ancestry, once-daily FF/VI 100/25 µg produced statistically and clinically significant improvements in efficacy end points versus placebo, with a generally similar safety profile. Results were consistent with a global phase III study of FF/VI 100/25 µg. Clinicaltrials.gov NCT01498679.

Fluticasone furoate/vilanterol 200/25 mcg in Asian asthma patients: a randomized trial.

BACKGROUND: This study investigated the efficacy and safety of the inhaled corticosteroid (ICS)/long-acting beta2-agonist (LABA) combination fluticasone furoate (FF)/vilanterol (VI) in Asian asthma patients. METHODS: A 12-week, double-blind, double-dummy, active-comparator, parallel-group, multicenter study. 309 Asian asthma patients (≥12 years, uncontrolled with high-strength ICS or mid-dose ICS/LABA) were randomized (1:1) and included in the intent-to-treat population; 155 received once-daily FF/VI 200/25 mcg and 154 received twice-daily fluticasone propionate (FP) 500 mcg. The primary endpoint was change from baseline in daily evening peak expiratory flow (PEF) averaged over 12 weeks. Secondary endpoints were mean change from baseline in % rescue-free 24-h periods, daily morning PEF, % symptom-free 24-h periods, and overall Asthma Quality of Life Questionnaire score. Safety assessments were performed. RESULTS: For change from baseline in daily evening PEF, the adjusted mean treatment difference for FF/VI versus FP of 28.5 L/min (95% confidence interval [CI]: 20.1, 36.9) was clinically and statistically significant (p < 0.001). For change from baseline in % rescue-free 24-h periods, the adjusted mean treatment difference (1.0%; 95% CI: -7.3, 9.2) was not statistically significant (p = 0.821). Statistical significance could not be inferred for the remaining endpoints due to the statistical hierarchy employed. Incidence of on-treatment adverse events was similar with FF/VI (26%; 3% treatment-related; n = 1 serious) and FP (27%; 3% treatment-related; n = 2 serious); none were fatal. No further safety concerns were identified. CONCLUSIONS: FF/VI improved evening PEF over 12 weeks versus FP in Asian patients, with a similar safety profile. The results are generally consistent with a global study comparing the same treatments.

Safety and tolerability of the novel inhaled corticosteroid fluticasone furoate in combination with the ß2 agonist vilanterol administered once daily for 52 weeks in patients >=12 years old with asthma: a randomised trial.

BACKGROUND: The inhaled corticosteroid fluticasone furoate (FF) in combination with the long-acting ß2 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 [Tmax], 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.