Inhaled glucocorticoid-induced metabolome changes in asthma.

Objective: The aim of this study was toidentify dose-related systemic effects of inhaled glucocorticoids (GCs) on the global metabolome. Design and methods: Metabolomics/lipidomic analysis from plasma was obtained from 54 subjects receiving weekly escalating doses (µg/day) of fluticasone furoate (FF; 25, 100, 200, 400 and 800), fluticasone propionate (FP; 50, 200, 500, 1000 and 2000), budesonide (BUD; 100, 400, 800, 1600 and 3200) or placebo. Samples (pre- and post-dose) were analysed using ultrahigh-performance liquid chromatography-tandem mass spectroscopy and liquid chromatography-mass spectrometry. Ions were matched to library standards for identification and quantification. Statistical analysis involved repeated measures ANOVA, cross-over model, random forest and principal component analysis using log-transformed data. Results: Quantifiable metabolites (1971) had few significant changes (% increases/decreases; P < 0.05) vs placebo: FF 1.34 (0.42/0.92), FP 1.95 (0.41/1.54) and BUD 2.05 (0.60/1.45). Therapeutic doses had fewer changes: FF 0.96 (0.36/0.61), FP 1.66 (0.44/1.22) and BUD 1.45 (0.56/0.90). At highest/supratherapeutic doses, changes were qualitatively similar: reduced adrenal steroids, particularly glucuronide metabolites of cortisol and cortisone and pregnenolone metabolite DHEA-S; increased amino acids and glycolytic intermediates; decreased fatty acid ß-oxidation and branched-chain amino acids. Notable qualitative differences were lowered dopamine metabolites (BUD) and secondary bile acid profiles (BUD/FF), suggesting CNS and gut microbiome effects. Conclusions: Dose-dependent metabolomic changes occurred with inhaled GCs but were seen predominately at highest/supratherapeutic doses, supporting the safety of low and mid therapeutic doses. At comparable therapeutic doses (FF 100, FP 500 and BUD 800 µg/day), FF had the least effect on the most sensitive markers (adrenal steroids) vs BUD and FP.

Therapeutic index of inhaled corticosteroids in asthma: A dose-response comparison on airway hyperresponsiveness and adrenal axis suppression.

AIMS: To compare the airway potency, systemic activity and therapeutic index of three inhaled corticosteroids that differ in glucocorticoid receptor binding affinity, physicochemical and pharmacokinetic properties. METHODS: This escalating-dose, placebo-controlled, cross-over study randomised adults with asthma to 1 or 2 treatment periods with ≥25 days washout in-between. Each treatment period comprised five 7-day dose escalations (µg/d): fluticasone furoate (FF; 25 → 100 → 200 → 400 → 800), fluticasone propionate (FP; 50 → 200 → 500 → 1000 → 2000), budesonide (BUD; 100 → 400 → 800 → 1600 → 3200) or placebo. Airway hyperresponsiveness to adenosine-5'-monophosphate (AMP PC20 ) was assessed on day 8. Plasma cortisol was assessed on day 1 (predose baseline) and from pre-PM dose on day 6 to pre-PM dose day 7 (24-h weighted mean). RESULTS: Fifty-four subjects were randomised. FF showed greater airway potency than FP and BUD (AMP PC20 dose at which 50% of the maximum effect is achieved [ED50 ] values: 48.52, 1081.27 and 1467.36 µg/d, respectively). Systemic activity (cortisol suppression) ED50 values were 899.99, 1986.05 and 1927.42 µg/d, respectively. The therapeutic index (ED50 cortisol suppression/ED50 AMP PC20 ) was wider for FF (18.55) than FP (1.84) and BUD (1.31). FF 100 µg/d and 200 µg/d were both comparable in terms of airway potency with high doses of FP (≥1000 µg twice daily [BID]) and BUD (≥1500 µg/BID). The systemic activity of FF 100 µg/d and 200 µg/d (cortisol suppression: 7.41% and 14.28%, respectively) was comparable with low doses of FP (100 µg/BID and 250 µg/BID) and BUD (100 µg/BID and 200 µg/BID). CONCLUSION: This study provides evidence that FF can provide more protection against airway hyperresponsiveness, with less systemic activity, than FP or BUD. This suggests that all inhaled corticosteroids are not therapeutically similar and may differ in their therapeutic index. (203162; NCT02991859).

24-Hour Serial Spirometric Assessment of Once-Daily Fluticasone Furoate/Umeclidinium/Vilanterol Versus Twice-Daily Budesonide/Formoterol in Patients with COPD: Analysis of the FULFIL Study.

INTRODUCTION: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Preventing clinically important deterioration with single-inhaler triple therapy in COPD.

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.

Hair analysis to monitor adherence to prescribed chronic inhaler drug therapy in patients with asthma or COPD.

BACKGROUND: Poor adherence to inhaled drug therapy in individuals with asthma and/or chronic obstructive pulmonary disease (COPD) may be associated with suboptimal therapeutic outcomes. Measurement of drug residues in hair samples has been employed to assess oral medication use over time. Here, we test the feasibility of analyzing hair samples from patients with asthma and/or COPD for assessing adherence to prescribed inhaled medication. METHODS: In total, 200 male and female subjects, ≥ 18 years of age, with stable asthma and/or COPD who were receiving an acceptable standard of care daily inhaled product consistently, were recruited. Head hair samples were taken during a single visit to the clinical site and grouped by hair color according to the Fischer-Saller scale. Drug residues were extracted from milled hair samples using solid-phase extraction and analyzed using liquid chromatography-tandem mass spectrometry. RESULTS: Inhaled drugs were detected in hair for 72% of subjects from whom it was possible to analyze hair samples (n = 157/200). Most hair samples obtained from subjects receiving formoterol or vilanterol had amounts of drug present that allowed determination of a quantifiable concentration, and demonstrated a dose response. Drugs were detected in all hair colors, with higher concentrations of formoterol observed in dark-haired versus light-haired individuals. CONCLUSIONS: This is the first study to demonstrate that inhaled medication can be measured in hair samples from subjects with asthma and/or COPD. The results show that hair drug concentration data could potentially provide a record of historical adherence to inhaled therapeutics.

Population Pharmacokinetic Analysis of Fluticasone Furoate/Umeclidinium/Vilanterol via a Single Inhaler in Patients with COPD.

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 µg/62.5 µg/25 µg; Ellipta inhaler) with twice-daily dual therapy (budesonide/formoterol 400 µg/12 µg; 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).

Single-inhaler triple therapy in symptomatic COPD patients: FULFIL subgroup analyses.

Triple inhaled corticosteroid (ICS)/long-acting muscarinic antagonist (LAMA)/long-acting ß2-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.

Once-Daily Single-Inhaler Triple versus Dual Therapy in Patients with COPD.

BACKGROUND: The benefits of triple therapy for chronic obstructive pulmonary disease (COPD) with an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting ß2-agonist (LABA), as compared with dual therapy (either inhaled glucocorticoid-LABA or LAMA-LABA), are uncertain. METHODS: In this randomized trial involving 10,355 patients with COPD, we compared 52 weeks of a once-daily combination of fluticasone furoate (an inhaled glucocorticoid) at a dose of 100 µg, umeclidinium (a LAMA) at a dose of 62.5 µg, and vilanterol (a LABA) at a dose of 25 µg (triple therapy) with fluticasone furoate-vilanterol (at doses of 100 µg and 25 µg, respectively) and umeclidinium-vilanterol (at doses of 62.5 µg and 25 µg, respectively). Each regimen was administered in a single Ellipta inhaler. The primary outcome was the annual rate of moderate or severe COPD exacerbations during treatment. RESULTS: The rate of moderate or severe exacerbations in the triple-therapy group was 0.91 per year, as compared with 1.07 per year in the fluticasone furoate-vilanterol group (rate ratio with triple therapy, 0.85; 95% confidence interval [CI], 0.80 to 0.90; 15% difference; P<0.001) and 1.21 per year in the umeclidinium-vilanterol group (rate ratio with triple therapy, 0.75; 95% CI, 0.70 to 0.81; 25% difference; P<0.001). The annual rate of severe exacerbations resulting in hospitalization in the triple-therapy group was 0.13, as compared with 0.19 in the umeclidinium-vilanterol group (rate ratio, 0.66; 95% CI, 0.56 to 0.78; 34% difference; P<0.001). There was a higher incidence of pneumonia in the inhaled-glucocorticoid groups than in the umeclidinium-vilanterol group, and the risk of clinician-diagnosed pneumonia was significantly higher with triple therapy than with umeclidinium-vilanterol, as assessed in a time-to-first-event analysis (hazard ratio, 1.53; 95% CI, 1.22 to 1.92; P<0.001). CONCLUSIONS: Triple therapy with fluticasone furoate, umeclidinium, and vilanterol resulted in a lower rate of moderate or severe COPD exacerbations than fluticasone furoate-vilanterol or umeclidinium-vilanterol in this population. Triple therapy also resulted in a lower rate of hospitalization due to COPD than umeclidinium-vilanterol. (Funded by GlaxoSmithKline; IMPACT ClinicalTrials.gov number, NCT02164513 .).

Once-Daily Triple Therapy in Patients with COPD: Patient-Reported Symptoms and Quality of Life.

INTRODUCTION: 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. METHODS: FULFIL was a phase III, 24-week, randomized, double-blind, double-dummy, multicenter study comparing once-daily single inhaler triple therapy [fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI)] 100 µg/62.5 µg/25 µg with twice-daily inhaled corticosteroid/long-acting ß2-agonist therapy [budesonide/formoterol (BUD/FOR)] 400 µg/12 µg in patients with symptomatic COPD at risk of exacerbations. A subset participated for 52 weeks. Patient-reported assessments were: Evaluating Respiratory Symptoms in COPD™ (E-RS: COPD), St George's Respiratory Questionnaire (SGRQ) for COPD, COPD Assessment Test (CAT), baseline and transitional dyspnea indices (TDI) and daily and global anchor questions for activity limitation. RESULTS: FF/UMEC/VI showed greater reductions from baseline in 4-weekly mean E-RS: COPD total and all subscale scores compared with BUD/FOR; differences were statistically significant (P < 0.05) at each time period. FF/UMEC/VI also demonstrated greater improvements from baseline at weeks 4 and 24 in SGRQ domain scores and TDI focal score compared with BUD/FOR. At weeks 4 and 24, improvements greater than the minimal clinically important difference from baseline were observed in CAT score with FF/UMEC/VI, but not BUD/FOR; differences were statistically significant (P ≤ 0.003). CONCLUSION: These findings demonstrate sustained daily symptom and HRQoL benefits of FF/UMEC/VI versus BUD/FOR. The inclusion of the CAT may provide data that are readily generalizable to everyday clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT02345161. FUNDING: GSK.

Single-inhaler fluticasone furoate/umeclidinium/vilanterol versus fluticasone furoate/vilanterol plus umeclidinium using two inhalers for chronic obstructive pulmonary disease: a randomized non-inferiority study.

BACKGROUND: 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. METHODS: Eligible patients with COPD (aged ≥40 years; ≥1 moderate/severe exacerbation in the 12 months before screening) were randomized (1:1; stratified by the number of long-acting bronchodilators [0, 1 or 2] per day during run-in) to receive 24-week FF/UMEC/VI 100/62.5/25 µg and placebo or FF/VI 100/25 µg + UMEC 62.5 µg; all treatments/placebo were delivered using the ELLIPTA inhaler once-daily in the morning. Primary endpoint: change from baseline in trough forced expiratory volume in 1 s (FEV1) at Week 24. The non-inferiority margin for the lower 95% confidence limit was set at - 50 mL. RESULTS: A total of 1055 patients (844 [80%] of whom were enrolled on combination maintenance therapy) were randomized to receive FF/UMEC/VI (n = 527) or FF/VI + UMEC (n = 528). Mean change from baseline in trough FEV1 at Week 24 was 113 mL (95% CI 91, 135) for FF/UMEC/VI and 95 mL (95% CI 72, 117) for FF/VI + UMEC; the between-treatment difference of 18 mL (95% CI -13, 50) confirmed FF/UMEC/VI's was considered non-inferior to FF/VI + UMEC. At Week 24, the proportion of responders based on St George's Respiratory Questionnaire Total score was 50% (FF/UMEC/VI) and 51% (FF/VI + UMEC); the proportion of responders based on the Transitional Dyspnea Index focal score was similar (56% both groups). A similar proportion of patients experienced a moderate/severe exacerbation in the FF/UMEC/VI (24%) and FF/VI + UMEC (27%) groups; the hazard ratio for time to first moderate/severe exacerbation with FF/UMEC/VI versus FF/VI + UMEC was 0.87 (95% CI 0.68, 1.12). The incidence of adverse events was comparable in both groups (48%); the incidence of serious adverse events was 10% (FF/UMEC/VI) and 11% (FF/VI + UMEC). CONCLUSIONS: Single-inhaler triple therapy (FF/UMEC/VI) is non-inferior to two inhalers (FF/VI + UMEC) on trough FEV1 change from baseline at 24 weeks. Results were similar on all other measures of efficacy, health-related quality of life, and safety. TRIAL REGISTRATION: GSK study CTT200812; ClinicalTrials.gov NCT02729051 (submitted 31 March 2016).

Once-Daily Triple Therapy in Patients with Advanced COPD: Healthcare Resource Utilization Data and Associated Costs from the FULFIL Trial.

INTRODUCTION: 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. METHODS: FULFIL was a phase III, randomized, double-blind, double-dummy, multicenter study. Unscheduled contacts with healthcare providers were recorded by patients in a daily electronic diary; the costs of healthcare resource utilization were calculated post hoc using UK reference costs. RESULTS: Over 24 weeks, slightly fewer patients who received fluticasone furoate/umeclidinium/vilanterol (169/911; 18.6%) required contacts with healthcare providers compared with budesonide/formoterol (180/899; 20.0%). Over 52 weeks in an extension population, fewer patients who received fluticasone furoate/umeclidinium/vilanterol required unscheduled contacts with healthcare providers compared with budesonide/formoterol (25.2% vs. 32.7%). Non-drug costs per treated patient per year were lower in the fluticasone furoate/umeclidinium/vilanterol group than the budesonide/formoterol group over 24 and 52 weeks (£653.80 vs. £763.32 and £749.22 vs. £988.03, respectively), with the total annualized cost over 24 weeks being slightly greater for fluticasone furoate/umeclidinium/vilanterol than budesonide/formoterol (£1,289.35 vs. £1,267.45). CONCLUSIONS: This healthcare resource utilization evidence suggests that, in a clinical trial setting over a 24- or 52-week timeframe, non-drug costs associated with management of a single inhaler fluticasone furoate/umeclidinium/vilanterol are lower compared with twice-daily budesonide/formoterol. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT02345161. FUNDING: GSK.

FULFIL Trial: Once-Daily Triple Therapy for Patients with Chronic Obstructive Pulmonary Disease.

RATIONALE: Randomized data comparing triple therapy with dual inhaled corticosteroid (ICS)/long-acting ß2-agonist (LABA) therapy in patients with chronic obstructive pulmonary disease (COPD) are limited. OBJECTIVES: We compared the effects of once-daily triple therapy on lung function and health-related quality of life with twice-daily ICS/LABA therapy in patients with COPD. METHODS: The FULFIL (Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy) trial was a randomized, double-blind, double-dummy study comparing 24 weeks of once-daily triple therapy (fluticasone furoate/umeclidinium/vilanterol 100 µg/62.5 µg/25 µg; ELLIPTA inhaler) with twice-daily ICS/LABA therapy (budesonide/formoterol 400 µg/12 µg; Turbuhaler). A patient subgroup remained on blinded treatment for up to 52 weeks. Co-primary endpoints were change from baseline in trough FEV1 and in St. George's Respiratory Questionnaire (SGRQ) total score at Week 24. MEASUREMENTS AND MAIN RESULTS: In the intent-to-treat population (n = 1,810) at Week 24 for triple therapy (n = 911) and ICS/LABA therapy (n = 899), mean changes from baseline in FEV1 were 142 ml (95% confidence interval [CI], 126 to 158) and -29 ml (95% CI, -46 to -13), respectively, and mean changes from baseline in SGRQ scores were -6.6 units (95% CI, -7.4 to -5.7) and -4.3 units (95% CI, -5.2 to -3.4), respectively. For both endpoints, the between-group differences were statistically significant (P < 0.001). There was a statistically significant reduction in moderate/severe exacerbation rate with triple therapy versus dual ICS/LABA therapy (35% reduction; 95% CI, 14-51; P = 0.002). The safety profile of triple therapy reflected the known profiles of the components. CONCLUSIONS: These results support the benefits of single-inhaler triple therapy compared with ICS/LABA therapy in patients with advanced COPD. Clinical trial registered with www.clinicaltrials.gov (NCT02345161).

A phase III randomised controlled trial of single-dose triple therapy in COPD: the IMPACT protocol.

Patients with symptomatic advanced chronic obstructive pulmonary disease (COPD) who experience recurrent exacerbations are particularly at risk of poor outcomes and present a significant burden on healthcare systems. The relative merits of treating with different inhaled combination therapies e.g. inhaled corticosteroids (ICS)/long-acting ß2-agonist (LABA), LABA/long-acting muscarinic antagonists (LAMA), ICS/LABA/LAMA, in this patient group are poorly understood, as is reflected in current guidelines. The InforMing the PAthway of COPD Treatment (IMPACT) study will evaluate the efficacy and safety of fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) versus FF/VI or UMEC/VI over a 52-week treatment period. The study has been designed with a focus on understanding the comparative merits of each treatment modality in different phenotypes/endotypes.This is a phase III, randomised, double-blind, three-arm, parallel-group, global multicentre study comparing the rate of moderate and severe exacerbations between FF/UMEC/VI and FF/VI or UMEC/VI over a 52-week treatment period. The study aims to recruit 10 000 patients from approximately 1070 centres. Eligible patients are aged ≥40 years, with symptomatic advanced COPD (Global initiative for chronic Obstructive Lung Disease (GOLD) group D) and an exacerbation in the previous 12 months.The first patients were recruited to the IMPACT study (ClinicalTrials.gov: NCT02164513) in June 2014 and the anticipated completion date is July 2017.

Systemic Exposures of Fluticasone Propionate and Salmeterol Following Inhalation via Metered Dose Inhaler with the Mini Spacer Compared with the Aerochamber Plus Spacer.

BACKGROUND: The Mini Spacer has been developed for use with Ventolin(®) metered dose inhalers (MDIs) to improve accessibility to affordable spacers in developing countries. To ensure patient safety is not compromised if the Mini Spacer is used off-label with fluticasone propionate (FP) or salmeterol/FP combination (SFC) MDIs (currently not recommended), this study compared the systemic exposure of FP and salmeterol following delivery of FP and SFC MDIs with the Mini Spacer and the Aerochamber Plus(®) spacer (Aerochamber). METHODS: This was an open-label, randomized, single dose, crossover study in healthy subjects that evaluated four treatments: i) FP 250 µg MDI with Mini Spacer; ii) FP 250 µg MDI with Aerochamber; iii) SFC 25/250 µg with Mini Spacer; iv) SFC 25/250 µg with Aerochamber. There was a minimum 7 day washout between treatments. Pharmacokinetic samples were collected over 24 hours post-dose. The co-primary endpoints were FP area under the concentration-time curve from time zero to 24 h [FP AUC(0-24)] and salmeterol maximum plasma concentration [Cmax]. RESULTS: FP systemic exposure in terms of AUC(0-24) was lower following inhalation with the Mini Spacer compared with the Aerochamber for both FP 250 µg (Mini Spacer/Aerochamber Ratio 0.76 [90% CI: 0.57-1.01]) and SFC 25/250 µg (Ratio 0.74 [90% CI: 0.56-0.99]). Salmeterol systemic exposure was also lower following SFC 25/250 µg with Mini Spacer compared with Aerochamber (Cmax Ratio 0.90 [90% CI 0.48-1.66]). The incidence of adverse events was low and similar with each treatment. CONCLUSIONS: In the event of use of the Mini Spacer with FP and SFC MDIs, which is not recommended, FP and salmeterol systemic exposure is unlikely to be higher than if MDIs were to be used with the Aerochamber. However, these data do not indicate that the Mini Spacer and Aerochamber are interchangeable.

Effect of Disease Severity in Asthma and Chronic Obstructive Pulmonary Disease on Inhaler-Specific Inhalation Profiles Through the ELLIPTA® Dry Powder Inhaler.

BACKGROUND: Two studies were undertaken to characterize the maximal effort inhalation profiles of healthy subjects and patients with asthma or chronic obstructive pulmonary disease (COPD) through a moderate-resistance dry powder inhaler (DPI). Correlations between inhaler-specific inhalation characteristics and inhaler-independent lung function parameters were investigated. METHODS: Healthy subjects (n = 15), patients with mild, moderate, or severe asthma (n = 45), and patients with mild, moderate, severe, or very-severe COPD (n = 60) were included in the studies. Inhalation pressure drop versus time profiles were recorded using an instrumented ELLIPTA® DPI or bespoke resistor component with equivalent resistivity. Inhaler-independent lung function assessments included pharyngometry, spirometry, plethysmography, and diffusion. RESULTS: For the inhaler-specific inhalation profiles, the mean maximal effort peak inspiratory flow rates (PIFRs) varied across the subgroups from 65.8-110.6 L/min (range: 41.6-142.9). Peak pressure drop, PIFR, inhaled volume, and average inhalation flow rate (primary endpoints) did not differ markedly between healthy subjects and patients with asthma or mild COPD. Moderate, severe, and very-severe COPD patients demonstrated lower mean peak pressure drops, PIFRs and inhaled volumes, which tended to decrease with increasing COPD severity. Severe and very-severe COPD patients demonstrated shorter mean inhalation times compared with all other participants. Inhaler-independent lung function parameters were consistent with disease severity, and statistically significant (p < 0.05) strong correlations (R > 0.7) with components of the inhaler-specific inhalation profiles were observed in the COPD cohort; correlations in the asthma cohort tended to be weaker. CONCLUSIONS: All participants achieved a maximal effort PIFR ≥ 41.6 L/min through the moderate resistance of the ELLIPTA inhaler. Patients with asthma achieved similar inhalation profiles to healthy subjects, but increasing COPD severity tended to reduce a patient's inhalation capability. Correlation analyses suggest that some lung function parameters may be a useful indicator of ability to inhale efficiently through a moderate-resistance DPI, such as the ELLIPTA inhaler.

Pharmacokinetics of fluticasone furoate, umeclidinium, and vilanterol as a triple therapy in healthy volunteers.

OBJECTIVE: Two single-center, four-way, single-dose, crossover studies assessed the systemic exposure, systemic pharmacodynamics (PD), and safety profile of the closed triple fluticasone furoate/ umeclidinium/vilanterol (FF/UMEC/VI) therapy compared with dual therapies. These are the first studies where pharmacokinetic (PK) profile assessment was possible for this inhaled triple fixed-dose combination product. METHODS: Healthy volunteers were randomized to receive 4 consecutive inhalations (each administered as a single dose) via a single ELLIPT® dry powder inhaler: in study 1 (CTT116415/NCT01691547), FF/UMEC/VI at total doses of 400/500/100 µg, FF/UMEC 400/500 µg, UMEC/VI 500/100 µg, or FF/VI 400/100 µg; in study 2 (200587/NCT01894386), FF/UMEC/VI at total doses of 400/500/100 µg or 400/250/100 µg, FF/VI 400/100 µg, or UMEC/VI 250/100 µg. PK and PD parameters and safety were assessed. RESULTS: Of 88 subjects, 95% completed both studies and received all planned treatments. Total systemic exposure was similar for FF, UMEC, and VI when administered as a triple therapy compared with FF/VI and UMEC/VI. No clinically significant systemic PD findings were detected. The incidence of adverse events was low and similar across treatment arms. CONCLUSIONS: Systemic exposure to all three components of the closed triple therapy, following single-dose delivery, was similar to that seen with the dual therapies FF/VI and UMEC/VI. The delivered lung dose and safety profile of all three agents, delivered via a single inhaler, are expected to be similar to those of the dual therapies.

Effect of severe renal impairment on umeclidinium and umeclidinium/vilanterol pharmacokinetics and safety: a single-blind, nonrandomized study.

BACKGROUND: Umeclidinium and vilanterol, long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease, are primarily eliminated via the hepatic route; however, severe renal impairment may adversely affect some elimination pathways other than the kidney. OBJECTIVES: To evaluate the effect of severe renal impairment on the pharmacokinetics of umeclidinium and umeclidinium/vilanterol. METHODS: Nine patients with severe renal impairment (creatinine clearance <30 mL/min) and nine matched healthy volunteers received a single dose of umeclidinium 125 µg; and after a 7- to 14-day washout, a single dose of umeclidinium/vilanterol 125/25 µg. RESULTS: No clinically relevant increases in plasma umeclidinium or vilanterol systemic exposure (area under the curve or maximum observed plasma concentration) were observed following umeclidinium 125 µg or umeclidinium/vilanterol 125/25 µg administration. On average, the amount of umeclidinium excreted in 24 hours in urine (90% confidence interval) was 88% (81%-93%) and 89% (81%-93%) lower in patients with severe renal impairment compared with healthy volunteers following umeclidinium 125 µg and umeclidinium/vilanterol 125/25 µg administration, respectively. Treatments were well tolerated in both populations. CONCLUSION: Umeclidinium 125 µg or umeclidinium/vilanterol 125/25 µg administration to patients with severe renal impairment did not demonstrate clinically relevant increases in systemic exposure compared with healthy volunteers. No dose adjustment for umeclidinium and umeclidinium/vilanterol is warranted in patients with severe renal impairment.