The effect of inhaled extrafine beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide on distal and central airway indices, assessed using Functional Respiratory Imaging in COPD (DARWiIN).

BACKGROUND: This study, in patients with symptomatic chronic obstructive pulmonary disease (COPD), explored switching therapy from non-extrafine high-dose inhaled corticosteroid/long-acting ß2-agonist (ICS/LABA; fluticasone propionate/salmeterol [FP/SLM]) to extrafine medium-dose beclometasone dipropionate/formoterol fumarate dihydrate/glycopyrronium (BDP/FF/G), both via dry-powder inhaler. Functional Respiratory Imaging, a quantitative computed tomography method with 3D reconstructions of pulmonary anatomy, was used to assess airway geometry and lung function. METHODS: Patients receiving a stable ICS/LABA regimen for ≥ 8 weeks were switched to FP/SLM 500/50 µg, one inhalation twice-daily (high-dose ICS) for 6 weeks. After baseline assessments (Visit 2 [V2]), therapy was switched to BDP/FF/G 100/6/10 µg, two inhalations twice-daily (medium-dose ICS) for 6 weeks, followed by V3. The primary endpoints were percentage changes in specific image-based airway volume (siVaw) and resistance (siRaw) from baseline to predose at V3 (i.e., chronic effects), assessed at total lung capacity (TLC) in central and distal lung regions. Secondary endpoints included siVaw and siRaw changes from pre-dose to post-dose at V2, and from pre-dose to post-dose at V3 at TLC (i.e., acute effects), and chronic and acute changes in siVaw and siRaw at functional residual capacity (FRC). Pre-dose forced expiratory volume in 1 s (FEV1) and COPD Assessment Test (CAT) were also assessed. RESULTS: There were no significant changes in pre-dose siVaw or siRaw at TLC from baseline to V3, although at FRC there was a significant decrease in mean siRaw in the distal airways (- 63.6%; p = 0.0261). In addition, in the distal airways there were significant acute effects at TLC on mean siVaw and siRaw (siVaw: 39.8% and 62.6%; siRaw: - 51.1% and - 57.2%, V2 and V3, respectively; all p < 0.001) and at FRC at V2 (siVaw: 77.9%; siRaw: - 67.0%; both p < 0.001). At V3, the mean change in pre-dose FEV1 was 62.2 mL (p = 0.0690), and in CAT total score was - 3.30 (p < 0.0001). CONCLUSIONS: In patients with symptomatic COPD receiving high-dose ICS/LABA, adding a long-acting muscarinic antagonist while decreasing the ICS dose by switching to medium-dose extrafine BDP/FF/G was associated with improved airway indices, especially in the distal airways, together with improvements in respiratory health status. Trial registration ClinicalTrials.gov (NCT04876677), first posted 6th May 2021.

Benefit of switching to mepolizumab from omalizumab in severe eosinophilic asthma based on patient characteristics.

BACKGROUND: The OSMO study assessed the efficacy of switching to mepolizumab in patients with severe eosinophilic asthma that was uncontrolled whilst receiving omalizumab. The objective of this analysis was to assess the proportion of patients achieving pre-defined improvements in up to four efficacy outcomes and the relationship between patient baseline characteristics and treatment response. METHODS: This was a post hoc analysis of OSMO study data (GSK ID:204471; ClinicalTrials.gov No. NCT02654145). Patients with severe eosinophilic asthma uncontrolled by high-dose inhaled corticosteroids, other controller(s) and omalizumab subcutaneously (≥ 4 months) were switched to mepolizumab 100 mg administered subcutaneously. Endpoints included the proportion of responders-i.e. patients achieving a pre-defined clinical improvement in ≥ 1 of the following outcomes: (1) Asthma Control Questionnaire (ACQ)-5 score (≥ 0.5-points), (2) St George's Respiratory Questionnaire (SGRQ) total score (≥ 4-points), (3) pre-bronchodilator forced expiratory volume in 1s (FEV1; ≥ 100 mL), all at Week 32, and (4) annualised rate of clinically significant exacerbations (≥ 50% reduction). RESULTS: Of the 145 patients included, 94%, 83%, 63% and 31% were responders for ≥ 1, ≥ 2, ≥ 3 and 4 outcomes, respectively; 75% and 78% were ACQ-5 and SGRQ score responders, and 50% and 69% were FEV1 and exacerbation responders. Subgroup analyses demonstrated improvements irrespective of baseline blood eosinophil count, prior omalizumab treatment regimen/duration, comorbidities, prior exacerbation history, maintenance oral corticosteroid use, ACQ-5 and SGRQ scores, and body weight/body mass index. CONCLUSIONS: After switching to mepolizumab, almost all patients with uncontrolled severe eosinophilic asthma on omalizumab achieved a beneficial response in ≥ 1 clinical outcome. Improvements were observed regardless of baseline characteristics. Trial registration This manuscript is a post hoc analysis of data from the OSMO study. ClinicalTrials.gov, NCT02654145. Registered January 13, 2016.

Clinical burden of illness among patients with severe eosinophilic COPD.

Background: There are currently limited real-world data on the clinical burden of illness in patients with COPD who continue to exacerbate despite receiving triple therapy. The aim of this study was to compare the burden of COPD in patients with and without a phenotype characterized by a high blood eosinophil count and high risk of exacerbations while receiving triple therapy. Methods: This retrospective cohort study (GSK ID: 207323/PRJ2647) used UK Clinical Practice Research Datalink records linked with Hospital Episode Statistics. Eligible patients had a COPD medical diagnosis code recorded between January 1, 2004 and December 31, 2014, and a blood eosinophil count recorded on/after that date. Patients were followed from index date (first qualifying blood eosinophil count) until December 31, 2015. The study phenotype was defined as ≥2 moderate/≥1 severe acute exacerbation of COPD (AECOPD) in the year prior to the index date, current use of multiple-inhaler triple therapy (MITT), and blood eosinophil count ≥150 cells/µL on the index date. Outcomes measured during follow-up included moderate/severe AECOPDs, severe AECOPDs, all-cause mortality, primary care (GP) clinical consultations, and non-AECOPD-related unscheduled hospitalizations. Results: Of 46,814 patients eligible for inclusion, 2512 (5.4%) met the definition of the study phenotype. Adjusted rate ratios (95% CI) of moderate/severe AECOPDs and all-cause mortality in patients with the study phenotype versus those without were 2.32 (2.22, 2.43) and 1.26 (1.16, 1.37), respectively. For GP visits and non-AECOPD-related unscheduled hospitalizations, adjusted rate ratios (95% CI), in patients with the study phenotype versus those without, were 1.09 (1.05, 1.12) and 1.31 (1.18, 1.46), respectively. Conclusion: Patients with COPD and raised blood eosinophil counts who continue to exacerbate despite MITT represent a distinct subgroup who experience substantial clinical burden and account for high healthcare expenditure. There is a need for more effective management and therapeutic options for these patients.

The clinical benefit of mepolizumab replacing omalizumab in uncontrolled severe eosinophilic asthma.

BACKGROUND: Mepolizumab and omalizumab are treatments for distinct but overlapping severe asthma phenotypes. OBJECTIVE: To assess if patients eligible for both biologics but not optimally controlled with omalizumab experience improved asthma control when switched directly to mepolizumab. METHODS: OSMO was a multicenter, open-label, single-arm, 32-week trial in patients with ≥2 asthma exacerbations in the year prior to enrollment, despite receiving high-dose inhaled corticosteroids and other controller(s), plus omalizumab (≥4 months). At baseline, patients with blood eosinophil counts ≥150 cells/µL (or ≥300 cells/µL in the prior year) and an Asthma Control Questionnaire (ACQ)-5 score ≥1.5 discontinued omalizumab and immediately commenced mepolizumab 100 mg subcutaneously every 4 weeks. Endpoints included change from baseline in ACQ-5 score (primary), St George's Respiratory Questionnaire (SGRQ) score and the proportions of ACQ-5 and SGRQ responders, all at Week 32, and the annualized exacerbation rate over the study period. RESULTS: At Week 32 (intent-to-treat population [n = 145]), the least squares (LS) mean changes (standard error [SE]) in ACQ-5 and SGRQ total scores were -1.45 (0.107) and -19.0 (1.64) points; with 77% and 79% of patients achieving the minimum clinically important differences (ACQ-5: ≥0.5 points; SGRQ: ≥4 points), respectively. The annualized rate of clinically significant exacerbations was 1.18 events/year, a 64% reduction from 3.26 events/year during the previous year. Safety and immunogenicity profiles were consistent with previous trials. CONCLUSION: After directly switching from omalizumab to mepolizumab, patients with uncontrolled severe eosinophilic asthma experienced clinically significant improvements in asthma control, health status, and exacerbation rate, with no tolerability issues reported.

Correct use and ease of use of a placebo dry powder inhaler in subjects with asthma and chronic obstructive pulmonary disease.

Correct use and ease of use of a placebo dry powder inhaler was evaluated in two single-arm, United States-multicenter, phase-IV studies in adults with asthma ( n = 259) or chronic obstructive pulmonary disease (COPD; n = 278) who were receiving maintenance inhaler therapy. Subjects demonstrating correct placebo inhaler use within three attempts at screening were instructed to take once-daily inhalations from the inhaler for 28 ± 2 days (continuing usual maintenance), followed by randomization to complete one of two versions of an ease-of-use questionnaire and reassessment for correct inhaler use. At study end, 96% asthma/93% COPD subjects rated the placebo inhaler as "easy" or "very easy" to use while demonstrating correct use. Furthermore, 99% asthma/99% COPD subjects indicated it was "easy" or "very easy" to determine number of doses remaining, and 81%/84%, respectively, indicated they would be "likely" or "very likely" to request their current medication in the inhaler, if available. Adverse event (AE) rates were 12% asthma/15% COPD, most frequently headache (3%/3%). Treatment-related AEs were reported in one subject with asthma (cough) and four subjects with COPD (cough, n = 3; back pain, n = 1). At study end, most subjects with asthma or COPD operated the placebo inhaler correctly and found it easy to use.

Predictors of pneumonia on routine chest radiographs in patients with COPD: a post hoc analysis of two 1-year randomized controlled trials.

Background: Patients with COPD are at risk for life-threatening pneumonia. Although anatomical abnormalities in the thorax may predispose to pneumonia, those abnormalities identified on routine chest X-rays (CXRs) in patients with COPD have not been studied to better understand pneumonia risk. Methods: We conducted a post hoc exploratory analysis of data from two replicate year-long clinical trials assessing the impact of fluticasone furoate-vilanterol versus vilanterol alone on COPD exacerbations (GSK studies: HZC102871/NCT01009463 and HZC102970/NCT01017952). Abnormalities on baseline CXRs from 179 patients who developed pneumonia and 50 randomly selected patients who did not were identified by blinded consensus readings conducted by two radiologists. Positive and negative likelihood ratios and diagnostic odds ratios (ORs) were calculated to evaluate the markers for subsequent pneumonia development during the 1-year study period. Results: Baseline characteristics distinguishing the pneumonia and non-pneumonia groups included a lower body mass index (24.9 vs 27.5 kg/m2, P=0.008), more severe airflow obstruction (mean post-bronchodilator forced expiratory volume in 1 second [FEV1]/forced vital capacity ratio: 42.3% vs 47.6%, P=0.003), and prior pneumonia (36% vs 20%, P=0.030). Baseline CXR findings with the highest diagnostic ORs were: elevated hemi-diaphragm (OR: 6.87; 95% CI: 0.90, 52.26), thick tracheal-esophageal stripe (OR: 4.39 [0.25, 78.22]), narrow cardiac silhouette (OR: 2.91 [0.85, 9.99]), calcified pleural plaque/mid-chest pleural thickening (OR: 2.82 [0.15, 53.76]), and large/prominent pulmonary artery shadow (OR: 1.94 [0.95, 3.97]). The presence of a narrow cardiac silhouette at baseline was associated with a statistically significant lower mean pre-bronchodilator FEV1 (P=0.040). There was also a trend for a lower mean pre-bronchodilator FEV1 in patients with a large/prominent pulmonary artery shadow at baseline (P=0.095). Conclusion: Findings on routine CXR that relate to pathophysiological mechanisms of pneumonia could help determine pneumonia risk in patients with COPD.

Umeclidinium/vilanterol as step-up therapy from tiotropium in patients with moderate COPD: a randomized, parallel-group, 12-week study.

INTRODUCTION: Patients with COPD who remain symptomatic on long-acting bronchodilator monotherapy may benefit from step-up therapy to a long-acting bronchodilator combination. This study evaluated the efficacy and safety of umeclidinium (UMEC)/vilanterol (VI) in patients with moderate COPD who remained symptomatic on tiotropium (TIO). METHODS: In this randomized, blinded, double-dummy, parallel-group study (NCT01899742), patients (N=494) who were prescribed TIO for ≥3 months at screening (forced expiratory volume in 1 s [FEV1]: 50%-70% of predicted; modified Medical Research Council [mMRC] score ≥1) and completed a 4-week run-in with TIO were randomized to UMEC/VI 62.5/25 µg or TIO 18 µg for 12 weeks. Efficacy assessments included trough FEV1 at Day 85 (primary end point), 0-3 h serial FEV1, rescue medication use, Transition Dyspnea Index (TDI), St George's Respiratory Questionnaire (SGRQ), and COPD Assessment Test (CAT). Safety evaluations included adverse events (AEs). RESULTS: Compared with TIO, UMEC/VI produced greater improvements in trough FEV1 (least squares [LS] mean difference: 88 mL at Day 85 [95% confidence interval {CI}: 45-131]; P<0.001) and FEV1 after 5 min on Day 1 (50 mL [95% CI: 27-72]; P<0.001). Reductions in rescue medication use over 12 weeks were greater with UMEC/VI versus TIO (LS mean change: -0.1 puffs/d [95% CI: -0.2-0.0]; P≤0.05). More patients achieved clinically meaningful improvements in TDI score (≥1 unit) with UMEC/VI (63%) versus TIO (49%; odds ratio at Day 84=1.78 [95% CI: 1.21-2.64]; P≤0.01). Improvements in SGRQ and CAT scores were similar between treatments. The incidence of AEs was similar with UMEC/VI (30%) and TIO (31%). CONCLUSION: UMEC/VI step-up therapy provides clinical benefit over TIO monotherapy in patients with moderate COPD who are symptomatic on TIO alone.

Dual Bronchodilator Therapy with Umeclidinium/Vilanterol Versus Tiotropium plus Indacaterol in Chronic Obstructive Pulmonary Disease: A Randomized Controlled Trial.

INTRODUCTION: The fixed-dose, long-acting bronchodilator combination of umeclidinium/vilanterol (UMEC/VI) has not previously been compared with a combination of a long-acting muscarinic antagonist and long-acting ß2-agonist in patients with chronic obstructive pulmonary disease (COPD). METHODS: This 12-week, randomized, blinded, triple-dummy, parallel-group, non-inferiority study compared once-daily UMEC/VI 62.5/25 mcg with once-daily tiotropium (TIO) 18 mcg + indacaterol (IND) 150 mcg in patients with moderate-to-very-severe COPD. The primary endpoint was the trough forced expiratory volume in 1 s (FEV1) on day 85 (predefined non-inferiority margin -50 mL), and the secondary endpoint was the 0- to 6-h weighted mean (WM) FEV1 on day 84. Other efficacy endpoints [including rescue medication use, the Transition Dyspnea Index (TDI) focal score, and the St. George's Respiratory Questionnaire (SGRQ) score] and safety endpoints [adverse events (AEs), vital signs, and COPD exacerbations] were also assessed. RESULTS: Trough FEV1 improvements were comparable between treatment groups [least squares (LS) mean changes from baseline to day 85: UMEC/VI 172 mL; TIO + IND 171 mL; treatment difference 1 mL; 95 % confidence interval (CI) -29 to 30 mL], demonstrating non-inferiority between UMEC/VI and TIO + IND. The treatments produced similar improvements in the trough FEV1 at other study visits and the 0- to 6-h WM FEV1 (LS mean changes at day 84: UMEC/VI 235 mL; TIO + IND 258 mL; treatment difference -23 mL; 95 % CI -54 to 8 mL). The results for patient-reported measures (rescue medication use, TDI focal score, and SGRQ score) were comparable; both treatments produced clinically meaningful improvements in TDI and SGRQ scores. The incidence of AEs and COPD exacerbations, and changes in vital signs were similar for the two treatments. CONCLUSION: UMEC/VI and TIO + IND, given once daily, provided similar improvements in lung function and patient-reported outcomes over 12 weeks in patients with COPD, with comparable tolerability and safety profiles. TRIAL NUMBERS: ClinicalTrials.gov study ID NCT02257385; GSK study no. 116961.

Chronic respiratory diseases and risk factors in 12 regions of the Russian Federation.

BACKGROUND: Estimation suggests that at least 4 million people die, annually, as a result of chronic respiratory disease (CRD). The Global Alliance against Chronic Respiratory Diseases (GARD) was formed following a mandate from the World Health Assembly to address this serious and growing health problem. OBJECTIVES: To investigate the prevalence of CRD in Russian symptomatic patients and to evaluate the frequency of major risk factors for CRD in Russia. METHODS: A cross-sectional, population-based epidemiological study using the GARD questionnaire on adults from 12 regions of the Russian Federation. Common respiratory symptoms and risk factors were recorded. Spirometry was performed in respondents with suspected CRD. Allergic rhinitis (AR) and chronic bronchitis (CB) were defined by the presence of related symptoms according to the Allergic Rhinitis and its Impact on Asthma and the Global Initiative for Obstructive Lung Disease guidelines; asthma was defined based on disease symptoms; chronic obstructive pulmonary disease (COPD) was defined as a post-bronchodilator forced expiratory volume per 1 second/forced vital capacity ratio <0.7 in symptomatic patients, following the Global Initiative for Obstructive Lung Disease guidelines. RESULTS: The number of questionnaires completed was 7,164 (mean age 43.4 years; 57.2% female). The prevalence of asthma symptoms was 25.7%, AR 18.2%, and CB 8.6%. Based on patient self-reported diagnosis, 6.9% had asthma, 6.5% AR, and 22.2% CB. The prevalence of COPD based on spirometry in patients with respiratory symptoms was estimated as 21.8%. CONCLUSION: The prevalence of respiratory diseases and risk factors was high in Russia when compared to available data. For bronchial asthma and AR, the prevalence for related symptoms was higher than self-reported previous diagnosis.

Risk of pneumonia with inhaled corticosteroid/long-acting ß2 agonist therapy in chronic obstructive pulmonary disease: a cluster analysis.

BACKGROUND: Pneumonia poses a significant risk in patients with moderate to severe chronic obstructive pulmonary disease but data are limited on the disease phenotypes most susceptible to pneumonia. METHODS: Cluster analysis using a data-driven recursive partitioning algorithm was employed using baseline data from two pooled one-year randomized exacerbation trials (n=3,255) of fluticasone furoate/vilanterol or vilanterol alone to identify distinct patient groups at greatest risk of pneumonia or serious (hospitalization or death) pneumonia. RESULTS: Five clusters were identified. Patients at greater risk of first pneumonia had more severe obstruction (forced expiratory volume in one second/forced vital capacity <46%) and either a body mass index <19 kg/m(2) (hazard ratio 7.8, 95% confidence interval 4.7-13.0; n=144) or a pneumonia history and greater comorbidities (hazard ratio 4.8, 95% confidence interval 3.0-7.7; n=374) relative to the cluster with the lowest pneumonia risk (reference; n=1310). Multiple comorbidities and use of psychoanaleptics also contributed to an increased risk of pneumonia in more obstructed patients. Independent of cluster, use of inhaled corticosteroids was associated with pneumonia (hazard ratio 1.89, 95% confidence interval 1.25-2.84) and serious pneumonia (hazard ratio 2.92, 95% confidence interval 1.40-6.01). CONCLUSION: Cluster analysis can identify patient populations at risk for serious safety outcomes and inform risk management strategies to optimize patient management. The greatest risk for pneumonia was in subjects with multiple pneumonia risk factors.