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.

Few studies have utilized 24-h serial spirometry to compare the effects of inhaled chronic obstructive pulmonary disease (COPD) therapies on lung function. The FULFIL study previously reported significant lung function improvements with once-daily single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus twice-daily single-inhaler budesonide/formoterol (BUD/FOR) in patients with symptomatic COPD at risk of exacerbations. This prespecified analysis evaluated 24-h serial spirometry data from a subgroup of 406 patients in FULFIL. BUD/FOR twice-daily dosing was maintained during 24-h spirometry. A post hoc analysis evaluated serial forced expiratory volume in 1 s (FEV1) at day 1 and week 24 by disease severity at screening (FEV1 < 50% predicted and no moderate or severe exacerbation in prior year, FEV1 < 50% predicted and ≥ 1 moderate or severe exacerbation in prior year, and FEV1 ≥ 50% and < 80% predicted and ≥ 2 moderate or ≥ 1 severe exacerbations in prior year). Odds of achieving a ≥ 100-mL increase from baseline in FEV1 within the first 6 h post dose on day 1 were significantly greater with FF/UMEC/VI than BUD/FOR [odds ratio 2.79 (95% confidence interval 1.56–4.98); p < 0.001]. FF/UMEC/VI led to greater improvements in weighted mean FEV1 over 0–6, 0–12, 0–24, and 12–24 h on day 1 and at week 24, with the greatest between-group differences at week 24 (range 196–210 mL; all p < 0.001). Significant between-treatment differences in FEV1 and forced vital capacity (FVC) in favor of FF/UMEC/VI versus BUD/FOR were seen at all time points at week 24 (FEV1 range 156–231 mL, all p < 0.001; FVC range 139–309 mL, all p ≤ 0.002). Serial FEV1 results were consistent irrespective of disease severity at screening. These findings further demonstrate sustained lung function benefits with once-daily FF/UMEC/VI single-inhaler triple therapy in patients with symptomatic COPD at risk of exacerbations across a range of disease severities.

Population pharmacokinetic methods were used to characterize the pharmacokinetics of fluticasone furoate (FF), umeclidinium (UMEC), and vilanterol (VI) in patients with chronic obstructive pulmonary disease (COPD) when administered as a fixed-dose combination via a single closed inhaler. Plasma concentration data from three studies were analyzed using non-linear mixed-effects modeling in NONMEM®. The pooled dataset consisted of 2948, 2589, and 3331 FF, UMEC, and VI observations from 714, 622, and 817 patients with COPD, respectively. There were 41%, 13%, and 21% of observations below the quantification limit for FF, UMEC, and VI, respectively. The pharmacokinetics of FF, UMEC, and VI were all adequately described by a two-compartment model with first-order absorption. The following covariates were statistically significant, but none were considered to be clinically relevant. For FF, Japanese heritage and FF/VI treatment on apparent inhaled clearance (CL/F) with FF CL/F 35% lower in patients of Japanese heritage across all treatments and FF CL/F 42% higher in patients with COPD following FF/VI administration. This is in line with the product label. For UMEC, weight, age, and smoking status on CL/F and weight on apparent volume of distribution (V2/F) with every 10% increase in age from 60 years of age leading to approximately a 6% decrease in UMEC CL/F and every 10% increase in weight from 70 kg leading to approximately a 6% increase in UMEC CL/F and approximately an 8% increase in UMEC V2/F. For a subject with COPD who smoked, UMEC CL/F was 28% higher. For VI, weight on CL/F and smoking status on V2/F with an approximately 4% increase in VI CL/F for every 10% increase in weight from 70 kg, and for a subject with COPD who smoked, VI V2/F was 46% higher. The majority of these covariates have been previously identified in historical analyses. None of these effects were clinically relevant in terms of systemic exposures and do not warrant dose adjustment. All FF, UMEC, and VI plasma concentrations were well interspersed with historical data and were all adequately described by a two-compartment model with first-order absorption. There were no clinically relevant differences in FF, UMEC, or VI systemic exposures when administered as FF/UMEC/VI, FF/VI + UMEC, or the dual combinations FF/VI and/or UMEC/VI.

Triple inhaled corticosteroid (ICS)/long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) therapy is recommended for symptomatic patients with chronic obstructive pulmonary disease (COPD) and at risk of exacerbations. However, the benefits versus side-effects of triple inhaled therapy for COPD, based on distinct patient clinical profiles, are unclear. FULFIL, a phase III, randomised, double-blind study, compared 24 weeks of once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 µg using the Ellipta inhaler with twice-daily budesonide/formoterol (BUD/FOR) 400/12 µg using the Turbuhaler. Subgroup analyses of forced expiratory volume in 1 s (FEV1), St George's Respiratory Questionnaire (SGRQ) Total score and exacerbation rates were carried out. Subgroups were defined by COPD medication at screening (ICS+LABA, BUD+FOR, ICS+LABA+LAMA, LAMA alone, tiotropium alone and LAMA+LABA), by disease severity (lung function and exacerbations) and by exacerbation history (exacerbation severity and frequency). In the intent-to-treat population (n=1810) at week 24, FF/UMEC/VI (n=911) versus BUD/FOR (n=899) improved FEV1 and SGRQ Total score and reduced mean annual exacerbation rates in all disease severity and exacerbation history subgroups. FF/UMEC/VI versus BUD/FOR improved FEV1 and SGRQ Total score in all medication subgroups and reduced mean annual exacerbation rates in all medication subgroups, except LAMA+LABA. Adverse events were similar across subgroups. These findings support the benefit of FF/UMEC/VI compared with dual ICS/LABA therapy in patients with symptomatic COPD regardless of disease severity or prior treatment and may help to inform clinical decision making.

Single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 μg has been shown to improve lung function and health status, and reduce exacerbations, versus budesonide/formoterol in patients with chronic obstructive pulmonary disease (COPD). We evaluated the non-inferiority of single-inhaler FF/UMEC/VI versus FF/VI + UMEC using two inhalers.

Clinically important deterioration (CID) is a novel composite end-point (lung function, health status, exacerbations) for assessing disease stability in patients with chronic obstructive pulmonary disease (COPD). We prospectively analysed CID in the FULFIL study. FULFIL (ClinicalTrials.gov NCT02345161; randomised, double-blind, double-dummy, multicentre study) compared 24 weeks of once daily, single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 µg with twice daily budesonide/formoterol (BUD/FOR) 400/12 μg in patients aged ≥40 years with symptomatic advanced COPD (Global Initiative for Chronic Obstructive Lung Disease group D). A subset of patients received study treatment for up to 52 weeks. Time to first CID event was assessed over 24 and 52 weeks using two approaches for the health status component: St George's Respiratory Questionnaire and COPD assessment test. FF/UMEC/VI significantly reduced the risk of a first CID event by 47–52% versus BUD/FOR in the 24- and 52-week populations using both CID definitions (p<0.001). The median time to first CID event was ≥169 days and ≤31 days with FF/UMEC/VI and BUD/FOR, respectively. Only stable patients with no CID at 24 weeks demonstrated sustained clinically important improvements in lung function and health status at 52 weeks versus those who had experienced CID. Once daily, single-inhaler FF/UMEC/VI significantly reduced the risk of CID versus twice daily BUD/FOR with a five-fold longer period without deterioration.

FULFIL was a 24 week phase III, randomized, double-blind, double-dummy trial comparing FF/UMEC/VI (od 100 µg/62.5 µg/25 µg) via a single ELLIPTA inhaler with BUD/FOR (bid 400 µg/12 µg) via TURBUHALER in symptomatic COPD patients at risk of exacerbations. This study demonstrated statistically significant improvements in lung function and SGRQ with FF/UMEC/VI versus BUD/FOR (Lipson, et al. AJRCCM 2017). Patient reported symptom severity was assessed using the Evaluating Respiratory Symptoms in COPD [E-RS:COPD] tool.

A population pharmacokinetic analysis was conducted from a subset of samples obtained from the Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy trial to characterize the pharmacokinetics of fluticasone furoate, umeclidinium, and vilanterol in patients with symptomatic COPD following treatment with fluticason furoate-umeclidinium-vilanterol combined in a single inhaler. This was a randomized, double-blind, double-dummy study comparing 24 weeks of once-daily triple therapy (fluticason furoate-umeclidinium-vilanterol, 100 mu g/62.5 mu g/25 mu g; Ellipta inhaler) with twice-daily dual therapy (budesonide/formoterol 400 mu g/12 mu g; Turbuhaler). The analyses were conducted in a subset of 74 patients who received fluticason furoate-umeclidinium-vilanterol and provided serial or sparse samples. Monte Carlo simulations and a model-based estimation approach both indicated that systemic drug concentrations of fluticasone furoate, umeclidinium, and vilanterol after administration of fluticason furoate-umeclidinium-vilanterol triple combination therapy from a single inhaler were within the ranges observed following administration of these drugs as monotherapy (fluticasone furoate, umeclidinium, and vilanterol) or as dual-combination therapy (fluticasone furoate/vilanterol or umeclidinium/vilanterol).

Directly recorded patient experience of symptoms and health-related quality of life (HRQoL) can complement lung function and exacerbation rate data in chronic obstructive pulmonary disease (COPD) clinical studies. The FULFIL study recorded daily symptoms and activity limitation together with additional patient-reported outcomes of dyspnea and HRQoL, as part of the prespecified analyses. FULFIL co-primary endpoint data have been previously reported.

Background: FULFIL reported statistically significant improvements in lung function and health status with once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100μg/62.5μg/25μg via the ELLIPTA® inhaler vs twice-daily budesonide/formoterol (BUD/FOR) 400μg/12μg via the Turbuhaler® in patients with advanced COPD (Lomas et al. ERJ 2016;48:PA4629). Given the clinical overlap of exacerbations and pneumonia, we analysed composites of these outcomes to assess the overall benefit/risk of FF/UMEC/VI compared with BUD/FOR. Methods: We performed post-hoc analyses in the ITT (24 weeks; FF/UMEC/VI, n=911; BUD/FOR, n=899) and extension (EXT; 52 weeks; FF/UMEC/VI, n=210; BUD/FOR, n=220) populations. There were two composite outcomes: time-to-first investigator-reported moderate (required antibiotics or oral/systemic corticosteroids)/severe (required hospitalisation) exacerbation or pneumonia event (investigator reported by a prespecified list of preferred terms); and time-to-first severe exacerbation/hospitalised pneumonia event. Analyses were based on a proportional hazards model. Results: For moderate/severe exacerbation or pneumonia, FF/UMEC/VI had a statistically significant reduction in risk vs BUD/FOR of 25% (ITT; 109 [12%] vs 130 [14%]; p=0.027) and 44% (EXT; 37 [18%] vs 63 [29%]; p=0.006). For severe exacerbation/hospitalised pneumonia, FF/UMEC/VI had a lower risk vs BUD/FOR of 17% (ITT; 22 [2%] vs 24 [3%]; p=0.541) and 65% (EXT; 8 [4%] vs 23 [10%]; p=0.010). Conclusion: The results of these exacerbation/pneumonia composite outcomes support a favourable benefit/risk profile of once-daily FF/UMEC/VI compared with BUD/FOR in patients with COPD. Funding: GSK (CTT116853)

Analysis of the FULFIL study by prior medication and disease severity is reported. FULFIL studied single inhaler, once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100μg/62.5μg/25μg vs twice-daily budesonide/formoterol (BUD/FOR) 400μg/12μg in advanced COPD (Lomas, et al ERJ 2016;48:PA4629). Subgroups were: by medication, ICS + LABA; BUD/FOR; ICS + LABA + LAMA; LAMA; TIO, and by disease severity, 1. FEV1 <50% predicted, no moderate/severe exacerbation; 2. FEV1 <50%, ≥1 moderate/severe exacerbation; 3. FEV1 ≥50–≤80%, ≥2 moderate or ≥1 severe exacerbations. Adjusted mean change from baseline in trough FEV1 and St George’s Respiratory Questionnaire (SGRQ) total score were calculated at week 24. In the intent-to-treat (ITT) population (N=1810) at week 24, FF/UMEC/VI improved FEV1 (Figure) and SGRQ (range: -1.1 to -3.5) vs BUD/FOR in all medication subgroups. FF/UMEC/VI improved FEV1 vs BUD/FOR in all disease subgroups (1. 115 vs -62 mL; 2. 108 vs -10 mL; 3. 204 vs -11 mL); treatment differences were significant (all groups p<0.001). FF/UMEC/VI improved SGRQ vs BUD/FOR in all disease subgroups (1. -4.8 vs -2.9; 2. -6.4 vs -3.9; 3. -8.5 vs -6.2); the improvement was significant (p<0.05) for groups 2 and 3. Improvements in FEV1 and SGRQ with once-daily FF/UMEC/VI vs twice-daily BUD/FOR were seen regardless of prior treatment or disease severity. Funding: GSK (NCT02345161;CTT116853)

Background: FULFIL compared once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100μg/62.5μg/25μg via the ELLIPTA ® inhaler with twice-daily budesonide/formoterol (BUD/FOR) 400μg/12μg via the Turbuhaler ® in patients (pts) with advanced COPD, showing statistically significant improvements in lung function and health-related quality of life with FF/UMEC/VI (Lomas et al. ERJ 2016;48:PA4629). We report healthcare resource utilisation and cost data from FULFIL. Methods: Pts recorded unscheduled healthcare contacts (all-cause and COPD-related), including home visits, physician visits, urgent care/outpatient visits, emergency room visits, number of hospitalisation days and contacts for COPD exacerbations. Healthcare costs were calculated from 2016 UK National Health Service Reference Costs ( post hoc ). Results: Over 24 weeks (ITT; FF/UMEC/VI, n=911; BUD/FOR, n=899), slightly fewer pts required overall healthcare contacts in the FF/UMEC/VI arm (19%) than BUD/FOR arm (20%). The proportion requiring contacts for exacerbations was lower for FF/UMEC/VI (8%) vs BUD/FOR (11%). Over 52 weeks (extension population [EXT]; FF/UMEC/VI, n=210; BUD/FOR, n=220), fewer pts in the FF/UMEC/VI arm vs the BUD/FOR arm required overall healthcare contacts or contacts for exacerbations (25% vs 33% and 12% vs 21%, respectively). Based on non-drug healthcare utilisation, non-drug costs per patient per year were lower for FF/UMEC/VI than BUD/FOR in the ITT (£653.80 vs £763.31) and EXT (£749.22 vs £988.03). Conclusion: FF/UMEC/VI resulted in reduced healthcare contacts for exacerbations and non-drug healthcare costs among pts with COPD compared with BUD/FOR. Funding GSK (CTT116853)

Chronic obstructive pulmonary disease is associated with a high healthcare resource and cost burden. Healthcare resource utilization was analyzed in patients with symptomatic chronic obstructive pulmonary disease at risk of exacerbations in the FULFIL study. Patients received either once-daily, single inhaler triple therapy (fluticasone furoate/umeclidinium/vilanterol) 100 µg/62.5 µg/25 µg or twice-daily dual inhaled corticosteroid/long-acting beta agonist therapy (budesonide/formoterol) 400 µg/12 µg.

Background: FULFIL showed statistically significant improvements in trough FEV 1 and health status with once-daily FF/UMEC/VI 100μg/62.5μg/25μg via the ELLIPTA ® inhaler (n=911) vs twice-daily budesonide/formoterol (BUD/FOR) 400μg/12μg via the Turbuhaler ® (n=899) in patients with advanced COPD (Lomas et al. ERJ 2016;48:PA4629). We report the population PK results for FF/UMEC/VI. Methods: PK blood samples (6mL) were taken from 74 patients in the FF/UMEC/VI arm: two samples (sparse; n=64) at weeks 12 (predose; 5–15min post-dose) and 24 (5–15min; 45–90min post-dose); seven samples (serial; n=10) at week 24 (predose; 5–15min, 45–90min, 2.5–4h, 6–8h, 10–12h, 23–24h post-dose). Derived parameters, including area under the curve (AUC) and maximum observed concentration (C max ), for FF (inhaled corticosteroid), UMEC (long-acting muscarinic antagonist) and VI (long-acting β 2 -agonist) from FULFIL were compared with historical data for FF, UMEC and VI mono-/dual therapy. Results: Steady state AUCs (geometric mean, pg*h/mL) from FULFIL were consistent with historical data for FF (188 vs 181 [FF]/182 [FF/VI]), UMEC (341 vs 312) and VI (666 vs 615). Steady state C max (geometric mean, pg/mL) for FF from FULFIL was also consistent with historical data (13.2 vs 11.5 [FF]/11.9 [FF/VI]). C max for UMEC and VI from FULFIL were lower than historical data (UMEC, 55.7 vs 69.3; VI, 101.4 vs 127.9); this was likely due to higher variability associated with smaller sample sizes and is not clinically relevant. Conclusion: Population PK results for FF/UMEC/VI triple therapy were consistent with data for FF, UMEC and VI mono-/dual therapy. Funding GSK (CTT116853)