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).

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.

Efficacy and safety of the p38 MAPK inhibitor losmapimod for patients with chronic obstructive pulmonary disease: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The p38 MAPK pathway seems to be involved in pathogenesis of chronic obstructive pulmonary disease (COPD). Losmapimod is a potent and selective inhibitor of p38 MAPK. We assessed the effect of losmapimod on exercise tolerance in patients with COPD. METHODS: We did this randomised, parallel-group, placebo-controlled trial at 46 secondary care centres in Argentina, Czech Republic, Estonia, Germany, Norway, South Korea, Ukraine, and USA between Nov 4, 2010, and Dec 22, 2011. We enrolled patients aged 40 years or older with moderate-to-severe COPD (6 min walking distance <350 m) who were current or previous smokers. Patients were randomly assigned (1:1:1:1) by a computer generated sequence to one of losmapimod 2·5 mg, 7·5 mg, or 15 mg, or placebo, twice daily for 24 weeks. Randomisation was stratified by country and exacerbation history (block size eight). Patients and investigators were masked to treatment assignment. The primary outcome was change in 6 min walking distance between baseline and week 24, assessed in the intention-to-treat population. This study is registered with ClinicalTrial.gov, number NCT01218126. FINDINGS: We screened 886 patients, of whom 602 were enrolled and received treatment. The difference between the placebo group and the losmapimod groups for mean change of 6 min walk distance was not significant: -6·7 m (95% CI -18·2 to 4·9) for losmapimod 2·5 mg, -4·7 m (-16·1 to 6·8) for losmapimod 7·5 mg, and -3·4 m (-15·1 to 8·2) for losmapimod 15 mg. The safety profile was much the same in each group, although drug-related adverse events were more common with losmapimod 7·5 mg (n=19, 13%) and losmapimod 15 mg (n=20, 13%) than with placebo (n=11, 7%) and losmapimod 2·5 mg (n=13, 9%). The most common serious adverse events were COPD exacerbation resulting in admission to hospital (eight patients [5%] taking placebo, six [4%] taking losmapimod 2·5 mg, two [1%] taking losmapimod 7·5 mg, and three [2%] taking losmapimod 15 mg) and pneumonia (four [3%] vs 0 [0%] vs 1 [1%] vs 4 [3%]). INTERPRETATION: Losmapimod did not cause an improvement in exercise tolerance or lung function, despite being well-tolerated in this COPD population. FUNDING: GlaxoSmithKline.

An oral inhibitor of p38 MAP kinase reduces plasma fibrinogen in patients with chronic obstructive pulmonary disease.

The aims were to determine the effect of an oral inhibitor of the signaling mediator p38 mitogen-activated protein kinase (GW856553, losmapimod) on sputum neutrophils, pulmonary function, and blood biomarkers of inflammation in chronic obstructive pulmonary disease (COPD). Three hundred and two individuals with GOLD stage II COPD were randomized to oral losmapimod 7.5 mg twice daily, inhaled salmeterol/fluticasone propionate 50 µg/500 µg combination (SFC), or placebo in a 12-week, randomized, double-blind, double-dummy study (MKI102428/NCT00642148). Neither losmapimod nor SFC had an effect on the primary end point of sputum neutrophils. Losmapimod was well tolerated and reduced plasma fibrinogen by 11% (-0.4 g/L, ratio of effect of losmapimod/placebo 0.89; 95% confidence interval, 0.83-0.96; P = .002) with nonsignificant reductions in interleukin-6, interleukin-8, and C-reactive protein. There was evidence of improvement in hyperinflation with losmapimod compared with placebo (overall P = .02). Inhaled SFC significantly improved lung function and reduced serum CC-16 (ratio of effect of SFC/placebo 0.87; 95% confidence interval, 0.82-0.93; P < .001). It was concluded that oral losmapimod significantly reduced plasma fibrinogen in patients with COPD.