Efficacy and safety of once-daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI in patients with inadequately controlled asthma (CAPTAIN): a double-blind, randomised, phase 3A trial.

BACKGROUND: Despite inhaled corticosteroid plus long-acting ß2-agonist (ICS/LABA) therapy, 30-50% of patients with moderate or severe asthma remain inadequately controlled. We investigated the safety and efficacy of single-inhaler fluticasone furoate plus umeclidinium plus vilanterol (FF/UMEC/VI) compared with FF/VI. METHODS: In this double-blind, randomised, parallel-group, phase 3A study (Clinical Study in Asthma Patients Receiving Triple Therapy in a Single Inhaler [CAPTAIN]), participants were recruited from 416 hospitals and primary care centres across 15 countries. Participants were eligible if they were aged 18 years or older, with inadequately controlled asthma (Asthma Control Questionnaire [ACQ]-6 score of ≥1·5) despite ICS/LABA, a documented health-care contact or a documented temporary change in asthma therapy for treatment of acute asthma symptoms in the year before screening, pre-bronchodilator FEV1 between 30% and less than 85% of predicted normal value, and reversibility (defined as an increase in FEV1 of ≥12% and ≥200 mL in the 20-60 min after four inhalations of albuterol or salbutamol) at screening. Participants were randomly assigned (1:1:1:1:1:1), via central based randomisation stratified by pre-study ICS dose at study entry, to once-daily FF/VI (100/25 µg or 200/25 µg) or FF/UMEC/VI (100/31·25/25 µg, 100/62·5/25 µg, 200/31·25/25 µg, or 200/62·5/25 µg) administered via Ellipta dry powder inhaler (Glaxo Operations UK, Hertfordshire, UK). Patients, investigators, and the funder were masked to treatment allocation. Endpoints assessed in the intention-to-treat population were change from baseline in clinic trough FEV1 at week 24 (primary) and annualised moderate and/or severe asthma exacerbation rate (key secondary). Other secondary endpoints were change from baseline in clinic FEV1 at 3 h post-dose, St George's Respiratory Questionnaire (SGRQ) total score, and ACQ-7 total score, all at week 24. Change from baseline in Evaluating Respiratory Symptoms in Asthma total score at weeks 21-24 was also a secondary endpoint but is not reported here. Exploratory analyses of biomarkers of type 2 airway inflammation on treatment response were also done. This study is registered with ClinicalTrials.gov, NCT02924688, and is now complete. FINDINGS: Between Dec 16, 2016, and Aug 31, 2018, 5185 patients were screened and 2439 were recruited and randomly assigned to FF/VI (100/25 µg n=407; 200/25 µg n=406) or FF/UMEC/VI (100/31·25/25 µg n=405; 100/62·5/25 µg n=406; 200/31·25/25 µg n=404; 200/62·5/25 µg n=408), with three patients randomly assigned in error and not included in analyses. In the intention-to-treat population, 922 (38%) patients were men, the mean age was 53·2 years (SD 13·1) and body-mass index was 29·4 (6·6). Baseline demographics were generally similar across all treatment groups. The least squares mean improvement in FEV1 change from baseline for FF/UMEC/VI 100/62·5/25 µg versus FF/VI 100/25 µg was 110 mL (95% CI 66-153; p<0·0001) and for 200/62·5/25 µg versus 200/25 µg was 92 mL (49-135; p<0·0001). Adding UMEC 31·25 µg to FF/VI produced similar improvements (FF/UMEC/VI 100/31·25/25 µg vs FF/VI 100/25 µg: 96 mL [52-139; p<0·0001]; and 200/31·25/25 µg vs 200/25 µg: 82 mL [39-125; p=0·0002]). These results were supported by the analysis of clinic FEV1 at 3 h post-dose. Non-significant reductions in moderate and/or severe exacerbation rates were observed for FF/UMEC 62·5 µg/VI versus FF/VI (pooled analysis), with rates lower in FF 200 µg-containing versus FF 100 µg-containing treatment groups. All pooled treatment groups demonstrated mean improvements (decreases) in SGRQ total score at week 24 compared with baseline in excess of the minimal clinically important difference of 4 points; however, there were no differences between treatment groups. For mean change from baseline to week 24 in asthma control questionnaire-7 score, improvements (decreases) exceeding the minimal clinically important difference of 0·5 points were observed in all pooled treatment groups. Adding UMEC to FF/VI resulted in small, dose-related improvements compared with FF/VI (pooled analysis: FF/UMEC 31·25 µg/VI versus FF/VI, -0·06 (95% CI -0·12 to 0·01; p=0·094) FF/UMEC 62·5 µg/VI versus FF/VI, -0·09 (-0·16 to -0·02, p=0·0084). By contrast with adding UMEC, the effects of higher dose FF on clinic trough FEV1 and annualised moderate and/or severe exacerbation rate were increased in patients with higher baseline blood eosinophil count and exhaled nitric oxide. Occurrence of adverse events was similar across treatment groups (patients with at least one event ranged from 210 [52%] to 258 [63%]), with the most commonly reported adverse events being nasopharyngitis (51 [13%]-63 [15%]), headache (19 [5%]-36 [9%]), and upper respiratory tract infection (13 [3%]-24 [6%]). The incidence of serious adverse events was similar across all groups (range 18 [4%]-25 [6%)). Three deaths occurred, of which one was considered to be related to study drug (pulmonary embolism in a patient in the FF/UMEC/VI 100/31·25/25 µg group). INTERPRETATION: In patients with uncontrolled moderate or severe asthma on ICS/LABA, adding UMEC improved lung function but did not lead to a significant reduction in moderate and/or severe exacerbations. For such patients, single-inhaler FF/UMEC/VI is an effective treatment option with a favourable risk-benefit profile. Higher dose FF primarily reduced the rate of exacerbations, particularly in patients with raised biomarkers of type 2 airway inflammation. Further confirmatory studies into the differentiating effect of type 2 inflammatory biomarkers on treatment outcomes in asthma are required to build on these exploratory findings and further guide clinical practice. FUNDING: GSK.

Single-Inhaler Triple Therapy and Health-Related Quality of Life in COPD: The IMPACT Study.

INTRODUCTION: The phase 3 InforMing the PAthway of COPD (chronic obstructive pulmonary disease) Treatment (IMPACT) trial, single-inhaler therapy with fluticasone furoate (FF) 100 µg, umeclidinium (UMEC) 62.5 µg, and vilanterol (VI) 25 µg demonstrated a reduction in the rate of moderate or severe exacerbations compared with FF/VI or UMEC/VI in patients with symptomatic COPD at risk of exacerbations. This article reports additional evidence of improvements in symptoms and health-related quality of life (HRQoL) with FF/UMEC/VI compared with either FF/VI or UMEC/VI from the IMPACT study. METHODS: Patient-reported HRQoL assessments and symptom measures included as pre-specified IMPACT end points were the St George's Respiratory Questionnaire (SGRQ), COPD Assessment Test (CAT), and Baseline Dyspnea Index (BDI) as the anchor for the Transitional Dyspnea Index (TDI) focal score (BDI/TDI) in a subset of patients enrolled at study sites in North America and Europe. Change from baseline was assessed at weeks 4, 28, and 52. RESULTS: The intent-to-treat population included 10,355 patients (TDI population: 5058 patients). Clinically meaningful improvements in SGRQ total score between baseline and week 52 favored FF/UMEC/VI over FF/VI (- 1.8 units, p < 0.001) and UMEC/VI (- 1.8 units, p < 0.001). Similar improvements in the CAT and TDI focal score were also observed with FF/UMEC/VI versus FF/VI or UMEC/VI. CONCLUSIONS: This study demonstrates that in patients with symptomatic COPD at risk of exacerbations, once-daily FF/UMEC/VI, compared with FF/VI or UMEC/VI, improves patient-perceived HRQoL and symptoms. TRIAL REGISTRATION NUMBER: NCT02164513.

A phase IIb, randomised, parallel-group study: the efficacy, safety and tolerability of once-daily umeclidinium in patients with asthma receiving inhaled corticosteroids.

BACKGROUND: Patients with asthma uncontrolled on inhaled corticosteroids may benefit from umeclidinium (UMEC), a long-acting muscarinic antagonist. METHODS: This Phase IIb, double-blind study included patients with reversible, uncontrolled/partially-controlled asthma for ≥6 months, receiving ≥100 mcg/day fluticasone propionate (or equivalent) for ≥12 weeks. Following a 2-week run-in on open-label fluticasone furoate (FF) 100 mcg, patients were randomised (1:1:1) to receive UMEC 31.25 mcg, UMEC 62.5 mcg or placebo on top of FF 100 mcg once-daily for 24 weeks. As-needed salbutamol was provided. Primary and secondary endpoints were change from baseline in clinic trough forced expiratory volume in 1 s (FEV1) and clinic FEV1 3 h post-dose, respectively, at Week 24. Other endpoints included change from baseline in home daily spirometry (trough FEV1, evening FEV1, morning [pre-dose] and evening peak expiratory flow) over 24 weeks. Safety was assessed throughout the study. RESULTS: The intent-to-treat population comprised 421 patients (UMEC 31.25 mcg: n =139, UMEC 62.5 mcg: n =139, placebo: n =143). UMEC 31.25 mcg and 62.5 mcg demonstrated significantly greater improvements from baseline in clinic trough FEV1 at Week 24 (difference [95% CI]: 0.176 L [0.092, 0.260; p<0.001] and 0.184 L [0.101, 0.268; p<0.001], respectively), clinic FEV1 3 h post-dose at Week 24 (0.190 L [0.100, 0.279; p<0.001] and 0.198 L [0.109, 0.287; p<0.001], respectively) and mean change from baseline in daily home spirometry over 24 weeks versus placebo. No new safety signals were identified. CONCLUSIONS: UMEC is a highly effective bronchodilator that leads to improved lung function when administered as a single bronchodilator on top of FF in subjects with fully reversible, uncontrolled/partially-controlled moderate asthma. These data support a favourable benefit/risk profile for UMEC (31.25 mcg and 62.5 mcg). TRIAL REGISTRATION: GSK study ID: 205832; Clinicaltrials.gov ID: NCT03012061.

Reduction in All-Cause Mortality with Fluticasone Furoate/Umeclidinium/Vilanterol in Patients with Chronic Obstructive Pulmonary Disease.

Rationale: The IMPACT (Informing the Pathway of Chronic Obstructive Pulmonary Disease Treatment) trial demonstrated a significant reduction in all-cause mortality (ACM) risk with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) versus UMEC/VI in patients with chronic obstructive pulmonary disease (COPD) at risk of future exacerbations. Five hundred seventy-four patients were censored in the original analysis owing to incomplete vital status information.Objectives: Report ACM and impact of stepping down therapy, following collection of additional vital status data.Methods: Patients were randomized 2:2:1 to FF/UMEC/VI 100/62.5/25 µg, FF/VI 100/25 µg, or UMEC/VI 62.5/25 µg following a run-in on their COPD therapies. Time to ACM was prespecified. Additional vital status data collection and subsequent analyses were performed post hoc.Measurements and Main Results: We report vital status data for 99.6% of the intention-to-treat population (n = 10,355), documenting 98 (2.36%) deaths on FF/UMEC/VI, 109 (2.64%) on FF/VI, and 66 (3.19%) on UMEC/VI. For FF/UMEC/VI, the hazard ratio for death was 0.72 (95% confidence interval, 0.53-0.99; P = 0.042) versus UMEC/VI and 0.89 (95% confidence interval, 0.67-1.16; P = 0.387) versus FF/VI. Independent adjudication confirmed lower rates of cardiovascular and respiratory death and death associated with the patient's COPD.Conclusions: In this secondary analysis of an efficacy outcome from the IMPACT trial, once-daily single-inhaler FF/UMEC/VI triple therapy reduced the risk of ACM versus UMEC/VI in patients with symptomatic COPD and a history of exacerbations.

Anaemia and iron dysregulation: untapped therapeutic targets in chronic lung disease?

Hypoxia is common in many chronic lung diseases. Beyond pulmonary considerations, delivery of oxygen (O2) to the tissues and subsequent O2 utilisation is also determined by other factors including red blood cell mass and iron status; consequently, disruption to these mechanisms provides further physiological strains on an already stressed system. O2 availability influences ventilation, regulates pulmonary blood flow and impacts gene expression throughout the body. Deleterious effects of poor tissue oxygenation include decreased exercise tolerance, increased cardiac strain and pulmonary hypertension in addition to pathophysiological involvement of multiple other organs resulting in progressive frailty. Increasing inspired O2 is expensive, disliked by patients and does not normalise tissue oxygenation; thus, other strategies that improve O2 delivery and utilisation may provide novel therapeutic opportunities in patients with lung disease. In this review, we focus on the rationale and possibilities for doing this by increasing haemoglobin availability or improving iron regulation.

Circulating neutrophils levels are a predictor of pneumonia risk in chronic obstructive pulmonary disease.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have excess risk of developing pneumonia; however, no definitive biomarkers of risk have been established. We hypothesized that blood neutrophils would help predict pneumonia risk in COPD. METHODS: A meta-analysis of randomized, double-blind clinical trials of COPD patients meeting the following criteria were selected from the GlaxoSmithKline trial registry: ≥1 inhaled corticosteroid-containing (ICS) arm (fluticasone propionate/salmeterol or fluticasone furoate/vilanterol), a control arm (non-ICS), pre-randomization blood neutrophil counts, ≥24-week duration. The number of patients with pneumonia events and time to first event (Kaplan-Meier analysis) were evaluated (post-hoc), stratified by baseline blood neutrophil count and ICS use. A Cox proportional hazards model was used to calculate hazard ratios (HR), split by median baseline blood neutrophils. RESULTS: Ten studies (1998 to 2011) with 11,131 patients were identified. The ICS (n = 6735) and non-ICS (n = 4396) cohorts were well matched in neutrophil distributions and demographics. Increasing neutrophil count was associated with an increased proportion of patients with pneumonia events; patients below the median neutrophil count were at less risk of a pneumonia event (HR, 0.75 [95% confidence interval 0.61-0.92]), and had longer time to a first event, compared with those at/above the median. The increase in pneumonia risk by neutrophil count was similar between the two cohorts. CONCLUSIONS: Increased blood neutrophils in COPD were associated with increased pneumonia risk, independent of ICS use. These data suggest blood neutrophils may be a useful marker in defining treatment pathways in COPD.

Blood eosinophils and treatment response with triple and dual combination therapy in chronic obstructive pulmonary disease: analysis of the IMPACT trial.

BACKGROUND: Previous studies have highlighted a relationship between reduction in rate of exacerbations with therapies containing inhaled corticosteroids (ICS) and baseline blood eosinophil count in patients with chronic obstructive pulmonary disease (COPD). The IMPACT trial showed that once-daily single-inhaler triple therapy significantly reduced exacerbations versus dual therapies. Blood eosinophil counts and smoking status could be important modifiers of treatment response to ICS. We aimed to model these relationships and their interactions, including outcomes other than exacerbations. METHODS: IMPACT was a phase 3, randomised, double-blind, parallel-group, 52-week global study comparing once-daily single-inhaler triple therapy (fluticasone furoate-umeclidinium-vilanterol) with dual inhaled therapy (fluticasone furoate-vilanterol or umeclidinium-vilanterol). Eligible patients had moderate-to-very-severe COPD and at least one moderate or severe exacerbation in the previous year. We used fractional polynomials to model continuous blood eosinophil counts. We used negative binomial regression for numbers of moderate and severe exacerbations, severe exacerbations, and pneumonia. We modelled differences at week 52 in trough FEV1, St George's Respiratory Questionnaire (SGRQ) total score, and Transition Dyspnoea Index using repeated measurements mixed effect models. IMPACT was registered with ClinicalTrials.gov, number NCT02164513. FINDINGS: The magnitude of benefit of regimens containing ICS (fluticasone furoate-umeclidinium-vilanterol n=4151 and fluticasone furoate-vilanterol n=4134) in reducing rates of moderate and severe exacerbations increased in proportion with blood eosinophil count, compared with a non-ICS dual long-acting bronchodilator (umeclidinium-vilanterol n=2070). The moderate and severe exacerbation rate ratio for triple therapy versus umeclidinium-vilanterol was 0·88 (95% CI 0·74 to 1·04) at blood eosinophil count less than 90 cells per µL and 0·56 (0·47 to 0·66) at counts of 310 cells per µL or more; the corresponding rate ratio for fluticasone furoate-vilanterol versus umeclidinium-vilanterol was 1·09 (0·91 to 1·29) and 0·56 (0·47 to 0·66), respectively. Similar results were observed for FEV1, Transition Dyspnoea Index, and SGRQ total score; however, the relationship with FEV1 was less marked. At blood eosinophil counts less than 90 cells per µL and at counts of 310 cells per µL or more, the triple therapy versus umeclidinium-vilanterol treatment difference was 40 mL (95% CI 10 to 70) and 60 mL (20 to 100) for trough FEV1, -0·01 (-0·68 to 0·66) and 0·30 (-0·37 to 0·97) for Transition Dyspnoea Index score, and -0·01 (-1·81 to 1·78) and -2·78 (-4·64 to -0·92) for SGRQ total score, respectively. Smoking status modified the relationship between observed efficacy and blood eosinophil count for moderate or severe exacerbations, Transition Dyspnoea Index, and FEV1, with former smokers being more corticosteroid responsive at any eosinophil count than current smokers. INTERPRETATION: This analysis of the IMPACT trial shows that assessment of blood eosinophil count and smoking status has the potential to optimise ICS use in clinical practice in patients with COPD and a history of exacerbations. FUNDING: GlaxoSmithKline.

Reliability, validity and responsiveness of E-RS:COPD in patients with spirometric asthma-COPD overlap.

BACKGROUND: The Evaluating Respiratory Symptoms in Chronic Obstructive Pulmonary Disease (E-RS:COPD) is a patient-reported diary that assesses respiratory symptoms in stable COPD. METHODS: This post hoc analysis of a randomized, double-blind, parallel-arm trial (GSK ID: 200699; NCT02164539) assessed the structure, reliability, validity and responsiveness of the E-RS, and a separate wheeze item, for use in patients with a primary diagnosis of asthma or COPD, but with spirometric characteristics of both (fixed airflow obstruction and reversibility to salbutamol; a subset of patients referred to as spirometric asthma-COPD overlap [ACO]; N = 338). RESULTS: Factor analysis demonstrated that E-RS included Cough and Sputum, Chest Symptoms, and Breathlessness domains, with a Total score suitable for quantifying overall respiratory symptoms (comparative fit index: 0.9), consistent with the structure shown in COPD. The wheeze item did not fit the model. Total and domain scores were internally consistent (Cronbach's alpha: 0.7-0.9) and reproducible (intra-class correlations > 0.7). Moderate correlations between RS-Total and RS-Breathlessness scores were observed with St George's Respiratory Questionnaire (SGRQ) Total and Activity domain scores at baseline (r = 0.43 and r = 0.48, respectively). E-RS scores were sensitive to change when a patient global impression of change and SGRQ change scores were used to define responders, with changes of ≥ - 1.4 in RS-Total score interpreted as clinically meaningful. CONCLUSIONS: E-RS:COPD scores were reliable, valid and responsive in this sample, suggesting the measure may be suitable for evaluating the severity of respiratory symptoms and the effects of treatment in patients with asthma and COPD that exhibit spirometric characteristics of both fixed airflow obstruction and reversibility. Further study of this instrument and wheeze in new samples of patients with ACO is warranted.

Seasonal variation in asthma exacerbations in the AUSTRI and VESTRI studies.

Seasonal variation in the benefit of LABA/ICS versus ICS on asthma exacerbation rate is observed in children. http://ow.ly/pcZF30o8hHk.

Blood eosinophils: a biomarker of COPD exacerbation reduction with inhaled corticosteroids.

BACKGROUND: Growing evidence suggests that blood eosinophil count is associated with patient responsiveness to inhaled corticosteroids (ICS). We performed post hoc predictive modeling on data from the FORWARD study and two replicate studies by Dransfield, to evaluate the relationships between baseline eosinophil count and the effect of ICS on exacerbations and lung function in patients with COPD. METHODS: The studies assessed ICS/long-acting ß2 agonist (LABA) combinations vs LABA alone. Using data from each study, we modeled COPD exacerbation rates, predose FEV1, and St George's Respiratory Questionnaire score ([FORWARD only]) over a continuous range of eosinophils (0-1,000 eosinophils/µL in FORWARD, 0-993 eosinophils/µL in Dransfield). RESULTS: In all studies, ICS/LABA reduced exacerbations versus LABA alone across all eosinophil levels, with progressively greater reductions at increasing baseline blood eosinophil counts. In FORWARD, annual exacerbation rates ranged from 0.78 to 0.83 per year between 0 and 1,000 eosinophils/µL in the ICS/LABA arm, and from 0.81 to 1.54 per year in the LABA-only arm. In the Dransfield studies, exacerbation rates ranged from 0.54 to 1.02 per year in the ICS/LABA arm between 0 and 993 eosinophils/µL, and from 0.56 to 1.75 per year in the LABA-only arm. Change in FEV1 was not associated with eosinophil count in ICS-treated patients in FORWARD, whereas an increased treatment benefit in terms of FEV1 was observed at higher eosinophil levels in the Dransfield studies. ICS/LABA led to greater improvements in St George's Respiratory Questionnaire total scores compared to LABA alone in patients in FORWARD with ≥67 eosinophils/µL. CONCLUSION: Higher blood eosinophil count in patients with COPD is associated with an increased beneficial effect from ICS in terms of exacerbation reduction. Further prospective data are required to assess the role of blood eosinophils as a biomarker for therapeutic recommendations.

Blood eosinophil levels as a biomarker in COPD.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder and patients respond differently to treatment. Blood eosinophils are a potential biomarker to stratify patient subsets for COPD therapy. We reviewed the value of blood eosinophils in predicting exacerbation risk and response to corticosteroid treatment in the available literature (PubMed articles in English; keywords: "COPD" and "eosinophil"; published prior to May 2017). Overall, clinical data suggest that in patients with a history of COPD exacerbations, a higher blood eosinophil count predicts an increased risk of future exacerbations and is associated with improved response to treatment with inhaled corticosteroids (in combination with long-acting bronchodilator[s]). Blood eosinophils are therefore a promising biomarker for phenotyping patients with COPD, although prospective studies are needed to assess blood eosinophils as a biomarker of corticosteroid response for this.

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 .).

Use of clinical characteristics to predict spirometric classification of obstructive lung disease.

Background: There is no consensus on how to define patients with symptoms of asthma and chronic obstructive pulmonary disease (COPD). A diagnosis of asthma-COPD overlap (ACO) syndrome has been proposed, but its value is debated. This study (GSK Study 201703 [NCT02302417]) investigated the ability of statistical modeling approaches to define distinct disease groups in patients with obstructive lung disease (OLD) using medical history and spirometric data. Methods: Patients aged ≥18 years with diagnoses of asthma and/or COPD were categorized into three groups: 1) asthma (nonobstructive; reversible), 2) ACO (obstructive; reversible), and 3) COPD (obstructive; nonreversible). Obstruction was defined as a post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity <0.7, and reversibility as a post-albuterol increase in FEV1 ≥200 mL and ≥12%. A primary model (PM), based on patients' responses to a health care practitioner-administered questionnaire, was developed using multinomial logistic regression modeling. Other multivariate statistical analysis models for identifying asthma and COPD as distinct entities were developed and assessed using receiver operating characteristic (ROC) analysis. Partial least squares discriminant analysis (PLS-DA) assessed the degree of overlap between groups. Results: The PM predicted spirometric classifications with modest sensitivity. Other analysis models performed with high discrimination (area under the ROC curve: asthma model, 0.94; COPD model, 0.87). PLS-DA identified distinct phenotypic groups corresponding to asthma and COPD. Conclusion: Within the OLD spectrum, patients with asthma or COPD can be identified as two distinct groups with a high degree of precision. Patients outside these classifications do not constitute a homogeneous group.

Biological effects of p38 MAPK inhibitor losmapimod does not translate to clinical benefits in COPD.

RATIONALE: p38 mitogen-activated protein kinase (MAPK) expression is increased in chronic inflammatory disease. Losmapimod, a p38 MAPK inhibitor, has been developed as a potential anti-inflammatory therapy in COPD. OBJECTIVES: To evaluate the effect of losmapimod in reducing exacerbations in subjects with moderate-to-severe COPD. METHODS: In this double-blind, parallel-group study, subjects at risk of COPD exacerbations and ?2% blood eosinophils at screening, were randomized 1:1 to losmapimod 15 mg or placebo (variable treatment duration: 26-52 weeks). The primary endpoint was the annualized rate of moderate/severe exacerbations. Using a Bayesian framework, treatment success was defined as >90% posterior probability that the true ratio of the losmapimod/placebo exacerbation rate was <1. Lung function and health status (St George's Respiratory Questionnaire (SGRQ)) were also assessed. RESULTS: A planned interim analysis resulted in early study termination due to the low probability of a successful study outcome; a total of 94 subjects were randomized to placebo and 90 to losmapimod 15 mg, and 14 and 10 subjects respectively completed the study. Losmapimod treatment was not associated with an improvement in the adjusted posterior median annualized exacerbation rate (losmapimod/placebo ratio: 1.04 (95% Cr I: 0.63, 1.73)). The posterior probability for the losmapimod/placebo annualized rate ratio being <1 was 0.44 (success criterion: >0.90). A statistically significant improvement in post-bronchodilator forced expiratory volume in 1 s was seen at Week 26, at the 5% significance level, with losmapimod treatment versus placebo (p = 0.007). Changes from baseline in SGRQ total score were similar in both groups. No new risks or safety signals were identified with losmapimod treatment. CONCLUSIONS: Losmapimod treatment did not reduce the rate of exacerbations in, subjects with COPD at high risk of exacerbation and ?2% blood eosinophils. These data do not support its use as a therapy in COPD in addition to standard of care.