Noushin Brealey

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 &bgr;2‐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 &mgr;g/62.5 &mgr;g/25 &mgr;g; ELLIPTA inhaler) with twice‐daily ICS/LABA therapy (budesonide/formoterol 400 &mgr;g/12 &mgr;g; 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 β2-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. Treatment choices between LABA/LAMA versus ICS/LABA versus ICS/LABA/LAMA in GOLD group D subjects with COPD http://ow.ly/bg7R300C2uo

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 β2‐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.)

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

Abstract 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 patients 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 ELLIPTA® 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.

Effects of Moderate Hepatic Impairment on the Pharmacokinetic Properties and Tolerability of Umeclidinium and Vilanterol in Inhalational Umeclidinium Monotherapy and Umeclidinium/Vilanterol Combination Therapy: An Open-Label, Nonrandomized Study

BACKGROUND The long-acting muscarinic antagonist umeclidinium (UMEC) is approved as a monotherapy, and in combination with the long-acting β2-agonist vilanterol (VI), as a once-daily inhaled maintenance bronchodilator therapy for chronic obstructive pulmonary disease in the US and EU; they are not indicated for the treatment of asthma. Preclinical and clinical data suggest that UMEC and VI are predominantly eliminated by the liver. OBJECTIVES The objectives of the study were to evaluate the effects of moderate hepatic impairment on the plasma and urinary pharmacokinetic properties of each drug, and on the tolerability of inhalational UMEC/VI 125/25 µg and UMEC 125 µg. METHODS This open-label, nonrandomized study was conducted in patients with moderate hepatic impairment (Child-Pugh score, 7-9) and in healthy volunteers (control). Patients and volunteers were administered a single dose of UMEC/VI 125/25 µg, and, after a 7- to 14-day washout period, repeat-dose UMEC 125 µg once daily for 7 days. Primary end points were the plasma pharmacokinetic properties of single- and repeat-dose UMEC and VI. Secondary end points were the urinary pharmacokinetic properties of UMEC, and the tolerability of each treatment. RESULTS All 18 enrolled patients and volunteers (12 men, 6 women; mean age, 53.6 years) completed the study. Mean systemic exposures of UMEC and VI were similar or numerically lower in patients with moderate hepatic impairment compared with those in healthy volunteers, but the differences were not clinically significant. UMEC accumulations with 7-day dosing of UMEC were similar between patients with moderate hepatic impairment and healthy volunteers. UMEC/VI 125/25 µg and UMEC 125 µg were well-tolerated, with no safety concerns identified. CONCLUSIONS The administration of UMEC/VI 125/25 µg or UMEC 125 µg in patients with moderate hepatic impairment did not result in clinically relevant increases in UMEC or VI exposures compared with those in healthy volunteers. Based on these findings, no dose adjustment for UMEC/VI or UMEC is warranted in patients with moderate hepatic impairment.

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.

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.

Reply to Morice and Hart: Increased Propensity for Pneumonia with Fluticasone in Chronic Obstructive Pulmonary Disease

1 GSK, King of Prussia, Pennsylvania; 2 Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; 3 GSK, Stockley Park West, Uxbridge, Middlesex, United Kingdom; 4 UCL Respiratory, University College London, London, United Kingdom; and 5 KLB Health Research, Lübeck, Germany * Employee of GSK at the time of study. Current affiliation is Roche, Basel, Switzerland. Page 1 of 3 AJRCCM Articles in Press. Published on 14-December-2017 as 10.1164/rccm.201711-2313LE

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).