Paul Dorinsky

Purpose: Blood eosinophil (EOS) count can guide treatment decisions for chronic obstructive pulmonary disease (COPD). In the 52-week ETHOS study (NCT02465567), budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) triple therapy at two inhaled corticosteroid doses reduced moderate/severe exacerbation rates and improved lung function, symptoms, and disease-related quality of life (QoL) versus dual therapy with glycopyrronium/formoterol fumarate dihydrate (GFF) or budesonide/formoterol fumarate dihydrate (BFF) in patients with moderate-to-very severe COPD. This subgroup analysis evaluated treatment benefits in ETHOS by baseline EOS count. Methods: Patients (40− 80 years) with a COPD history were randomly assigned 1:1:1:1 to receive BGF 320/14.4/10 μg, BGF 160/14.4/10 μg, GFF 14.4/10 μg, or BFF 320/10 μg via a metered-dose inhaler. This post-hoc analysis assessed endpoints by baseline EOS count using Global Initiative for Obstructive Lung Disease thresholds (< 100, ≥ 100, ≥ 100−< 300, ≥ 300 cells/mm³), and investigated continuous relationships between treatment effects and EOS count on exacerbations, symptoms, disease-related QoL, lung function, and safety. Results: In the modified intention-to-treat population (n=8509), 82.6% had EOS counts ≥ 100 cells/mm³. BGF 320 reduced moderate/severe exacerbation rates versus GFF in the ≥ 100, ≥ 100−< 300, and ≥ 300 subgroups; treatment differences increased with EOS count. BGF 320 improved rescue medication use and lung-function outcomes across all subgroups, and St George’s Respiratory Questionnaire total score, Transition Dyspnea Index focal score, and Exacerbations of Chronic Pulmonary Disease Tool total score in all except the < 100 subgroup versus GFF. Benefits of BGF 320 versus BFF were generally consistent across subgroups. Safety data were comparable across subgroups. Conclusion: Benefits of BGF versus GFF were observed across EOS counts, particularly at ≥ 100 cells/mm³; versus BFF, benefits were largely independent of EOS. These findings confirm that benefits of ICS-containing triple therapy are not restricted to EOS counts ≥ 300 cells/mm³, supporting recommendations to consider triple therapy in patients with an exacerbation history and EOS counts ≥ 100 cells/mm³. Graphical Abstract:

Background: Chronic obstructive pulmonary disease (COPD) are managed predominantly in primary care. However, key opportunities to optimize treatment are often not realized due to unrecognized disease and delayed implementation of appropriate interventions for both diagnosed and undiagnosed individuals. The COllaboratioN on QUality improvement initiative for achieving Excellence in STandards of COPD care (CONQUEST) is the first-of-its-kind, collaborative, interventional COPD registry. It comprises an integrated quality improvement program focusing on patients (diagnosed and undiagnosed) at a modifiable and higher risk of COPD exacerbations. The first step in CONQUEST was the development of quality standards (QS). The QS will be imbedded in routine primary and secondary care, and are designed to drive patient-centered, targeted, risk-based assessment and management optimization. Our aim is to provide an overview of the CONQUEST QS, including how they were developed, as well as the rationale for, and evidence to support, their inclusion in healthcare systems. Methods: The QS were developed (between November 2019 and December 2020) by the CONQUEST Global Steering Committee, including 11 internationally recognized experts with a specialty and research focus in COPD. The process included an extensive literature review, generation of QS draft wording, three iterative rounds of review, and consensus. Results: Four QS were developed: 1) identification of COPD target population, 2) assessment of disease and quantification of future risk, 3) non-pharmacological and pharmacological intervention, and 4) appropriate follow-up. Each QS is followed by a rationale statement and a summary of current guidelines and research evidence relating to the standard and its components. Conclusion: The CONQUEST QS represent an important step in our aim to improve care for patients with COPD in primary and secondary care. They will help to transform the patient journey, by encouraging early intervention to identify, assess, optimally manage and followup COPD patients with modifiable high risk of future exacerbations.

Background: In the Phase III, 52-week ETHOS study (NCT02465567), budesonide/glycopyrronium/formoterol metered dose inhaler (BGF MDI) fixed-dose combination significantly reduced exacerbations vs. dual therapies. However, use of inhaled corticosteroids (ICS) may also increase pneumonia risk. Objective: To quantify exacerbation benefits relative to pneumonia risk (expressed as numbers needed to treat [NNT] and numbers needed to harm [NNH], respectively) in ETHOS. Methods: Patients with moderate-to-very severe COPD and ≥ 1 moderate/severe exacerbation in the prior year received BGF MDI 320/14.4/10 µg or 160/14.4/10 µg, glycopyrronium/formoterol (GFF) MDI 14.4/10 µg or budesonide/formoterol (BFF) MDI 320/10 µg twice-daily via a single Aerosphere inhaler. Exacerbation and pneumonia rates were used to calculate NNT and NNH. Results: BGF MDI 320 µg reduced exacerbation rates vs. GFF MDI (NNT = 3 [95% CI 3, 5]) and vs. BFF MDI (NNT = 7 [95% CI 4, 18]), (mITT, n = 8509). Pneumonia rates across treatments were 0.02 – 0.05 per patient year, and were lower for BGF MDI than BFF MDI; for BGF MDI 320 µg vs. GFF MDI, NNH = 58 (95% CI 29, 152) ([Table 1]). Conclusions: In patients with moderate/very severe COPD, BGF MDI 320 µg reduced exacerbation risk vs. both dual therapies. For the ICS component, the NNH (BGF MDI 320 µg vs. GFF MDI) suggests a low pneumonia risk for BGF MDI relative to its benefits on exacerbations. Article published online: 30 April 2021 © 2021. Thieme. All rights reserved. Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart, Germany

Purpose: In the Phase III, 24-week KRONOS study (NCT02497001), triple therapy with budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) reduced exacerbation rates versus glycopyrrolate/formoterol fumarate (GFF) MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) and no requirement for a history of exacerbations. We report a post hoc analysis investigating whether the benefits observed were driven by patients with ≥ 1 exacerbation in the 12 months prior to the study. Patients and Methods: Patients received BGF MDI 320/18/9.6 μg, GFF MDI 18/9.6 μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12 μg twice-daily. Post hoc analyses were conducted on exacerbation and lung function results from patients with and without a documented exacerbation in the 12 months prior to the study. Results: Overall, 74% (1411/1896) of the modified-intent-to-treat (mITT) population had no moderate/severe exacerbations in the 12 months prior to the study. BGF MDI reduced exacerbation rates versus GFF MDI in the prior (58%; unadjusted p=0.0003) and no prior (48%; unadjusted p=0.0001) exacerbations subgroups. The magnitude of reduction in exacerbation rates was generally similar within subgroups for BGF MDI versus BFF MDI and BUD/FORM DPI. In the prior exacerbations subgroup, risk during treatment for time to first exacerbation was lower with BGF MDI versus GFF MDI (p=0.0022) and BFF MDI (p=0.0110); excluding the first 30 days of data yielded similar results. The magnitude of reduction in exacerbation rates for BGF MDI compared with GFF MDI increased with eosinophil count. Conclusion: In patients with or without a history of exacerbations in the 12 months prior to the study, BGF MDI reduced exacerbation rates versus GFF MDI, suggesting results observed in the overall population were not driven by the small subgroup with a prior history of exacerbations.

Background: In the Phase III, 52-week ETHOS study (NCT02465567), BGF MDI triple fixed-dose combination, reduced moderate/severe COPD exacerbation rate vs dual therapies; however, rates are known to vary by season. Objective: To assess exacerbation rates by season in ETHOS. Methods: Patients with moderate-to-very severe COPD and ≥1 moderate/severe exacerbation in the prior year received BGF MDI 320/14.4/10 μg or 160/14.4/10 μg, glycopyrronium/formoterol (GFF) MDI 14.4/10 μg or budesonide/formoterol (BFF) MDI 320/10 μg twice-daily via a single Aerosphere inhaler. Annualised exacerbation rates were assessed using negative binomial regression. Results: In the mITT population (n=8509), 56.5% of patients had ≥2 exacerbations in the previous year. BGF MDI 320/14.4/10 µg and 160/14.4/10 µg reduced exacerbation rate vs GFF MDI and BFF MDI (Figure); rate ratios vs GFF MDI for winter, spring, summer and fall were 0.83, 0.77, 0.71, 0.77 and 0.82, 0.82, 0.81, 0.66, respectively (all p<0.02 [unadjusted]); and vs BFF MDI were 0.88, 0.95, 0.80, 0.89 and 0.87, 1.01, 0.92, 0.77, respectively. Conclusions: In patients with moderate-to-very severe COPD and an exacerbation history, seasonal variation in exacerbation rate occurred in each treatment group. A reduction in exacerbation rate was generally observed across all seasons for BGF MDI (both dose levels) vs LAMA/LABA and ICS/LABA.