Steven Pascoe

Blood eosinophils and inhaled corticosteroid/long-acting β-2 agonist efficacy in COPD

Objective We performed a review of studies of fluticasone propionate (FP)/salmeterol (SAL) (combination inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA)) in patients with COPD, which measured baseline (pretreatment) blood eosinophil levels, to test whether blood eosinophil levels ≥2% were associated with a greater reduction in exacerbation rates with ICS therapy. Methods Three studies of ≥1-year duration met the inclusion criteria. Moderate and severe exacerbation rates were analysed according to baseline blood eosinophil levels (<2% vs ≥2%). At baseline, 57–75% of patients had ≥2% blood eosinophils. Changes in FEV1 and St Georges Respiratory Questionnaire (SGRQ) scores were compared by eosinophil level. Results For patients with ≥2% eosinophils, FP/SAL was associated with significant reductions in exacerbation rates versus tiotropium (INSPIRE: n=719, rate ratio (RR)=0.75, 95% CI 0.60 to 0.92, p=0.006) and versus placebo (TRISTAN: n=1049, RR=0.63, 95% CI 0.50 to 0.79, p<0.001). No significant difference was seen in the <2% eosinophil subgroup in either study (INSPIRE: n=550, RR=1.18, 95% CI 0.92 to 1.51, p=0.186; TRISTAN: n=354, RR=0.99, 95% CI 0.67 to 1.47, p=0.957, respectively). In SCO30002 (n=373), no significant effects were observed (FP or FP/SAL vs placebo). No relationship was observed in any study between eosinophil subgroup and treatment effect on FEV1 and SGRQ. Discussion Baseline blood eosinophil levels may represent an informative marker for exacerbation reduction with ICS/LABA in patients with COPD and a history of moderate/severe exacerbations.

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).

Understanding asthma-chronic obstructive pulmonary disease overlap syndrome.

Asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS) is a loosely-defined clinical entity referring to patients who exhibit characteristics of both asthma and chronic obstructive pulmonary disease (COPD). Clinical definitions and classifications for ACOS vary widely, which impacts our understanding of prevalence, diagnosis and treatment of the condition. This literature review was therefore conducted to characterize the prevalence of ACOS and the effect of different disease definitions on these estimates, as this has not previously been explored. From an analysis of English language literature published from 2000 to 2014, the estimated prevalence of ACOS ranges from 12.1% to 55.2% among patients with COPD and 13.3%-61.0% among patients with asthma alone. This variability is linked to differences in COPD and asthma diagnostic criteria, disease ascertainment methods (spirometry-based versus clinical or symptom-based diagnoses and claims data), and population characteristics including age, gender and smoking. Understanding the reasons for differences in prevalence estimates of ACOS across the literature may help guide decision making on the most appropriate criteria for defining ACOS and aid investigators in designing future ACOS clinical studies aimed at effective treatment.

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.)

A post-hoc subgroup analysis of data from a six month clinical trial comparing the efficacy and safety of losmapimod in moderate-severe COPD patients with ≤2% and >2% blood eosinophils.

BACKGROUND A six month study of the p38 MAPK inhibitor, losmapimod, suggested a trend in reducing COPD exacerbations with the 15 mg twice daily dose. OBJECTIVE AND METHODS Using data from this study which evaluated the efficacy of twice daily losmapimod, 2.5 mg, 7.5 mg, and 15 mg, versus placebo in patients with moderate-to-severe COPD, we analysed the effect of losmapimod in reducing the rate of moderate/severe exacerbations in patient subgroups with ≤2% and >2% blood eosinophils at baseline. Lung function, fibrinogen and hsCRP were also evaluated. RESULTS In the ≤2% eosinophil subgroup, there was an exposure-related reduction in the rate of moderate/severe exacerbations with losmapimod relative to placebo (losmapimod 15 mg: 55% reduction; losmapimod 7.5 mg: 29%; losmapimod 2.5 mg: 10%); with the 15 mg dose reaching statistical significance (15 mg/placebo mean rate ratio [95% CI]: 0.45 [0.22; 0.90]). There was also an improvement in lung function with 15 mg losmapimod over Weeks 1-12. No improvement in the rate of moderate/severe exacerbations or post-bronchodilator FEV1 was observed for subjects treated with Losmapimod compared to placebo in the patient subgroup with blood eosinophils >2% at baseline. Transient reductions in fibrinogen and hsCRP were observed with losmapimod 7.5 mg and 15 mg in both eosinophil subgroups. CONCLUSIONS These findings indicate eosinophil-related heterogeneity within COPD and suggest that losmapimod could be a potential therapy to reduce exacerbations in COPD patients with eosinophil levels ≤2%. This needs to be explored further in a prospectively designed study with pre-specified criteria for blood eosinophil subgroups in COPD patients.

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