RATIONALE While cigarette smoking is the leading cause of COPD, not all smokers at risk experience rapid decline in lung function. Repeated testing of lung function over at least 2 years is needed to reliably determine rapid lung function decline, limiting its utility for early detection of subjects likely to develop chronic airflow obstruction (CAO) in at-risk populations. We hypothesized that combining circulatory protein markers with clinical variables at baseline could be integrated into a predictive model to identify ever-smokers who will likely be rapid lung function decliners (RD) or non-decliners (ND). This hypothesis was tested in 100 subjects from the Lovelace Smokers’ Cohort (LSC), a longitudinal study examining CAO risk factors and lung function trajectories and validated in 462 smokers with similar characteristics, drawn from the COPDGene cohort. METHODS The LSC included 100 cigarette smokers aged 40-60 years with ≥15 pack-years of smoking, enrolled between 2001 and 2015. Plasma samples were collected at baseline and after a median of 17 years of follow-up. Participants were categorized as ND (n=49) or RD (n=51) based on FEV₁ trajectories (threshold of 40 ml/year decline in FEV1). Proteomic analysis was performed using LC-MS/MS (Thermo Fisher Orbitrap Astral mass spectrometer), and data were processed via DIANN 1.8.1 and MSStats 4.2.0. Machine learning (ML) methods including Convolutional Neural Networks (CNN) and ensemble classifiers were applied for feature selection. RESULTS Proteomic analysis identified 765 proteins, with 39 differentially expressed between RD vs. ND at baseline (p < 0.05). However, only three proteins, including IGFBP4, remained significant after FDR correction (q ≤ 0.05). These differences were not observed after 17-years. Logistic regression of 11 protein features identified by ML analysis of the LSC demonstrated good prediction of RD risk in the COPDGene cohort (AUC ROC = 0.76). Pathway analysis revealed proteins associated with natural resilience to CAO, including cardiometabolic (e.g., CFH, IGFBP4) and pulmonary-specific (e.g., Contactin-1) pathways. Models incorporating these protein markers with clinical variables (e.g., FEV₁, smoking history and hypertension) outperformed clinical variables-only models, correctly identifying nearly 10% more RD, while also slightly improving the negative classification rate. CONCLUSIONS In middle-aged ever-smokers, a predictive model integrating circulatory protein markers with clinical variables effectively identifies individuals at risk of having rapid decline in lung function, offering potential insights into early detection of subjects likely to develop CAO and resilience factors that may be amenable to novel therapies.

Dans l’étude ETHOS de phase III de 52 semaines (NCT02465567), la trithérapie budésonide/glycopyrrolate/formotérol (BGF) a réduit les taux d’exacerbation modérée/sévère par rapport aux bithérapies chez les patients atteints de BPCO modérée à très sévère. Le recours à un traitement de secours béta-2 agonistes à courte durée d’action (SABA) tend à augmenter avec l’intensification du fardeau des symptômes. Cette analyse post-hoc a évalué la consommation de SABA à l’approche d’une exacerbation de BPCO et son intérêt pour révéler une exacerbation imminente. ETHOS est une étude multinationale, randomisée, en double aveugle et en groupes parallèles. Les patients atteints de BPCO modérée à très sévère ayant subi au moins 1 exacerbation modérée/sévère au cours de l’année précédente ont été randomisés pour recevoir BGF 320/18/9,6 μg, BGF 160/18/9,6 μg, glycopyrrolate/formotérol 18/9,6 μg ou budésonide/formotérol 320/9,6 μg. Tous les traitements ont été administrés 2 fois par jour par l’aérosol doseur Aerosphere. Le SABA a été fourni comme traitement de secours à la demande tout au long de l’étude. Dans cette analyse post-hoc, la consommation de SABA comme traitement de secours a été évaluée de 30 jours avant, le jour même et jusqu’à 30 jours après la première exacerbation modérée/sévère. La date de début de l’exacerbation a été définie comme la date de début du traitement (corticoïde systémique et/ou ATB systémique), la date de début de l’hospitalisation ou la date du décès. Comme cette analyse a utilisé des données postérieures à la randomisation, il existe certains facteurs confondants liés au traitement. Par conséquent, l’analyse s’est focalisée sur les résultats globaux des groupes de traitement, plutôt que sur la comparaison entre ces groupes. Dans tous les groupes de traitement, la consommation de SABA a augmenté dans les 30 jours précédant la première exacerbation modérée/sévère et a diminué dans les 30 jours suivant celle-ci. La consommation moyenne de SABA a augmenté progressivement de J-30 (variation entre les traitements allant de 3,5 à 3,9 bouffées/jour) à J-7 (variation entre les traitements allant de 3,9 à 4,4 bouffées/jour) avant la première exacerbation modérée/sévère (Fig. 1). Une augmentation plus abrupte a été observée à partir de J-7. Bien que la comparaison des groupes de traitement n’ait pas été l’objectif de l’analyse, la consommation moyenne de SABA était numériquement inférieure avec le BGF 320 par rapport aux bithérapies, à la fois avant et après une exacerbation. Bien que des études prospectives soient nécessaires, la mise en évidence d’une augmentation de recours aux SABA à l’approche d’une exacerbation de BPCO pourrait faciliter une détection plus précoce de ces exacerbations par les patients, permettant ainsi une intervention plus rapide des professionnels de santé pour prévenir et réduire la gravité de ces exacerbations.

Background: In the Phase III ETHOS study (NCT02465567), budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) triple therapy at two inhaled corticosteroid (ICS) doses reduced moderate/severe exacerbation rates and improved symptoms, health-related quality of life (HRQoL), and lung function versus glycopyrronium/formoterol fumarate dihydrate (GFF) or budesonide/formoterol fumarate dihydrate (BFF) dual therapy in patients with moderate-to-very-severe chronic obstructive pulmonary disease (COPD). Here, we assessed whether the benefit for BGF versus GFF was driven by patients who received ICS before randomization to GFF. Methods: ETHOS was a 52-week, randomized, double-blind, multicenter, parallel-group study in symptomatic patients with COPD and >= 1 moderate/severe exacerbation in the previous year. Patients received BGF 320/14.4/10 mu g, BGF 160/14.4/10 mu g, GFF 14.4/10 mu g, or BFF 320/10 mu g twice daily via a single metered dose Aerosphere (TM) inhaler. In these subgroup analyses, efficacy and safety were assessed in patients with or without prior ICS use in the 30 days before screening. Results: The modified intent-to-treat population comprised 8509 patients (prior ICS use, n = 6810 [80%]; no prior ICS use, n = 1699 [20%]). Moderate/severe exacerbation rates were reduced by 24% and 23% in patients with and without prior ICS use, respectively, with BGF 320 versus GFF. Benefits of BGF 320 versus GFF were also similar in patients with and without prior ICS use across other endpoints relating to exacerbations, symptoms, HRQoL, lung function, and safety. Trends were similar for BGF 160 versus GFF. Conclusion: Benefits on exacerbations, symptoms, HRQoL, and lung function with BGF versus GFF were observed, irrespective of prior ICS use in the 30 days before screening.

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 mu g, BGF 160/14.4/10 mu g, GFF 14.4/10 mu g, or BFF 320/10 mu g 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.

Background Triple therapy with budesonide/glycopyrronium/formoterol (BGF) 320/14.4/10µg reduced all-cause mortality (ACM) risk vs dual therapies, with a significant reduction (HR 0.51; unadjusted p=0.0035) vs glycopyrronium/formoterol (GFF) in the 52-week ETHOS trial of COPD (NCT02465567).

Chronic obstructive pulmonary disease (COPD) is the end result of a series of dynamic and cumulative gene-environment interactions over a lifetime. The evolving understanding of COPD biology provides novel opportunities for prevention, early diagnosis, and intervention. To advance these concepts, we propose therapeutic trials in two major groups of subjects: "young" individuals with COPD and those with pre-COPD. Given that lungs grow to about 20 years of age and begin to age at approximately 50 years, we consider "young" patients with COPD those patients in the age range of 20-50 years. Pre-COPD relates to individuals of any age who have respiratory symptoms with or without structural and/or functional abnormalities, in the absence of airflow limitation, and who may develop persistent airflow limitation over time. We exclude from the current discussion infants and adolescents because of their unique physiological context and COPD in older adults given their representation in prior randomized controlled trials (RCTs). We highlight the need of RCTs focused on COPD in young patients or pre-COPD to reduce disease progression, providing innovative approaches to identifying and engaging potential study subjects. We detail approaches to RCT design, including potential outcomes such as lung function, patient-reported outcomes, exacerbations, lung imaging, mortality, and composite endpoints. We critically review study design components such as statistical powering and analysis, duration of study treatment, and formats to trial structure, including platform, basket, and umbrella trials. We provide a call to action for treatment RCTs in 1) young adults with COPD and 2) those with pre-COPD at any age.

BACKGROUND:Demographic and disease characteristics have been associated with the risk of chronic obstructive pulmonary disease (COPD) exacerbations. Using previously collected multinational clinical trial data, we developed models that use baseline risk factors to predict an individual's rate of moderate/severe exacerbations in the next year on various pharmacological treatments for COPD. METHODS:Exacerbation data from 20,054 patients in the ETHOS, KRONOS, TELOS, SOPHOS, and PINNACLE-1, PINNACLE-2, and PINNACLE-4 studies were pooled. Machine learning was used to identify predictors of moderate/severe exacerbation rates. Important factors were selected for generalized linear modeling, further informed by backward variable selection. An independent test set was held back for validation. RESULTS:Prior exacerbations, eosinophil count, forced expiratory volume in 1 s percent predicted, prior maintenance treatments, reliever medication use, sex, COPD Assessment Test score, smoking status, and region were significant predictors of exacerbation risk, with response to inhaled corticosteroids (ICSs) increasing with higher eosinophil counts, more prior exacerbations, or additional prior treatments. Model fit was similar in the training and test set. Prediction metrics were ~10% better in the full model than in a simplified model based only on eosinophil count, prior exacerbations, and ICS use. CONCLUSION:These models predicting rates of moderate/severe exacerbations can be applied to a broad range of patients with COPD in terms of airway obstruction, eosinophil counts, exacerbation history, symptoms, and treatment history. Understanding the relative and absolute risks related to these factors may be useful for clinicians in evaluating the benefit: risk ratio of various treatment decisions for individual patients.Clinical trials registered with www.clinicaltrials.gov (NCT02465567, NCT02497001, NCT02766608, NCT02727660, NCT01854645, NCT01854658, NCT02343458, NCT03262012, NCT02536508, and NCT01970878).

Hintergrund Die 52-wöchige Studie ETHOS (NCT02465567) untersuchte die Wirksamkeit und Sicherheit einer Triple-Therapie mit Budesonid/Glycopyrronium/Formoterol (BUD/GLY/FORM) in zwei Dosierungen im Vergleich zu entsprechenden dualen Therapien bei Patienten mit mittelschwerer bis sehr schwerer COPD.

Background In the Phase III KRONOS study, triple therapy with budesonide/glycopyrronium/formoterol fumarate metered dose inhaler (BGF MDI) was shown to reduce exacerbations and improve lung function versus glycopyrronium/formoterol fumarate dihydrate (GFF) MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD). However, whether the benefits related to the ICS component of BGF are driven by patients with high blood eosinophil counts (EOS) and/or airway reversibility has not been previously studied. Methods KRONOS was a Phase III, double-blind, parallel-group, multicenter, randomized, controlled study of patients with moderate-to-very-severe COPD. Patients were randomized 2:2:1:1 to receive BGF 320/14.4/10 μg, GFF 14.4/10 μg, budesonide/formoterol fumarate dihydrate (BFF) MDI 320/10 μg via a single Aerosphere inhaler, or open-label budesonide/formoterol fumarate dihydrate dry powder inhaler 400/12 μg (BUD/FORM DPI; Symbicort Turbuhaler) twice-daily for 24 weeks. Efficacy outcomes included in this post-hoc analysis were change from baseline in morning pre-dose trough FEV 1 over weeks 12–24 and the rate of moderate-to-severe and severe COPD exacerbations. Adverse events in the non-reversible subgroup are also reported. Results Of 1896 patients analyzed, 948 (50%) were non-reversible and had EOS < 300 cells/mm 3 . In this group, BGF significantly improved morning pre-dose trough FEV 1 versus BFF and BUD/FORM (least squares mean treatment difference, 95% confidence interval [CI] 69 mL [39, 99], unadjusted p < 0.0001 and 51 mL [20, 81], unadjusted p = 0.0011, respectively) and was comparable to GFF. BGF also significantly reduced annual moderate-to-severe exacerbation rates versus GFF (rate ratio [95% CI] 0.53 [0.37, 0.76], unadjusted p = 0.0005), with numerical reductions observed versus BFF and BUD/FORM. These results were similar for the overall study population. Safety findings were generally similar between non-reversible patients with EOS < 300 cells/mm 3 and the overall population. Conclusions In patients with moderate-to-very-severe COPD without airway reversibility and EOS < 300 cells/mm 3 , BGF significantly improved morning pre-dose trough FEV 1 versus BFF and BUD/FORM and significantly reduced the rate of moderate-to-severe exacerbations versus GFF. These findings demonstrate that BGF can provide benefits for a broad range of patients with COPD, and that the overall findings of the KRONOS primary analysis were not driven by patients with reversible airflow obstruction or high eosinophil counts. Trial registration ClinicalTrials.gov, NCT02497001. Registered 14 July 2015, https://clinicaltrials.gov/ct2/show/NCT02497001

Background: For patients who experience COPD exacerbations on LAMA/LABA, GOLD recommends step-up to ICS/LAMA/LABA triple therapy for those with blood eosinophil counts (EOS) ≥ 100 cells/mm3. In the 52-week ETHOS trial (NCT02465567), triple therapy with BGF MDI at two ICS dose levels reduced the rate of moderate/severe COPD exacerbations vs. dual therapies.

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.

Chronic Obstructive Pulmonary Disease is the end-result of a series of dynamic and cumulative gene-environment interactions over a lifetime. The evolving understanding of COPD biology provides novel opportunities for prevention, early diagnosis, and intervention. To advance these concepts we propose therapeutic trials in two major groups of subjects: those individuals with COPD and those with pre-COPD. Given that lungs grow to about 20 years of age and begin to age at approximately 50 years, we consider COPD those patients in the age range of 20-50 years. Pre-COPD relates to individuals of any age who have respiratory symptoms with or without structural and/or functional abnormalities, in the absence of airflow limitation, and who may develop persistent airflow limitation over time. We exclude from the current discussion infants and adolescents because of their unique physiological context and COPD in older adults given their representation in prior randomized clinical trials (RCTs). We highlight the need of RCTs focused on young COPD or Pre-COPD patients to reduce disease progression, providing innovative approaches to identifying and engaging potential study subjects. We detail approaches to RCTs design including potential outcomes such as lung function, patient reported outcomes, exacerbations, lung imaging, mortality, and composite endpoints. We critically review study design components such as statistical powering and analysis, duration of study treatment, and formats to trial structure including platform, basket, and umbrella trials. We provide a call to action for treatment RCTs in (1) young adults with COPD and (2) those with pre-COPD at any age.

Abstract Background For patients with chronic obstructive pulmonary disease (COPD), greater improvements in lung function have been demonstrated for triple versus dual inhaled therapies in traditional spirometry studies. This study was the first to use functional respiratory imaging (FRI), known for increased sensitivity to airway changes versus spirometry, to assess the effect of the inhaled corticosteroid (ICS) component (budesonide) on lung function in patients with moderate-to-severe COPD and a blood eosinophil count > 150 cells/mm3. Methods Patients in this Phase IIIb (NCT03836677), randomized, double-blind, crossover study received twice-daily budesonide/glycopyrrolate/formoterol fumarate (BGF) 320/18/9.6 μg fixed-dose triple therapy and glycopyrrolate/formoterol fumarate (GFF) 18/9.6 μg fixed-dose dual therapy over 4 weeks, each delivered via a single metered dose Aerosphere inhaler. Primary endpoints were the improvements from baseline for each treatment in specific (i.e. corrected for lobar volume) image-based airway volume (siVaw) and resistance (siRaw) measured via FRI taken at total lung capacity (Day 29). Secondary outcomes included spirometry and body plethysmography. Adverse events were monitored throughout the study. Results A total of 23 patients were randomized and included in the intent-to-treat analysis (mean age 64.9 years, 78.3% males, 43.5% current smokers, mean predicted post-bronchodilator forced expiratory volume in 1 s [FEV1] 63.6%). BGF and GFF both statistically significantly increased siVaw from baseline at Day 29 (geometric mean ratio [GM], 95% confidence interval [CI]: 1.72 [1.38, 2.13] and 1.53 [1.28, 1.83], respectively, both p < 0.0001), with a greater increase observed for BGF versus GFF (GM, 95% CI 1.09 [1.03, 1.16], p = 0.0061). Statistically significant reductions in siRaw were also observed with both BGF and GFF (GM, 95% CI 0.50 [0.39, 0.63] and 0.52 [0.40, 0.67], respectively, both p < 0.0001). Additionally, significant improvements from baseline in post-dose FEV1 were observed with BGF and GFF (mean 346 mL, p = 0.0003 and 273 mL, p = 0.0004, respectively). Safety findings were consistent with the known profiles of BGF and GFF. Conclusions As observed using FRI, triple therapy with BGF resulted in greater increases in airway volume, and reductions in airway resistance versus long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) dual therapy with GFF, reflecting the ICS component’s contribution in patients with moderate-to-severe COPD. Trial registration: ClinicalTrials.gov, NCT03836677. Registered 11 February 2019, https://clinicaltrials.gov/ct2/show/NCT03836677

Pour les patients atteints de BPCO et qui présentent des exacerbations sous LAMA/LABA, les recommandations GOLD proposent une escalade thérapeutique avec l’utilisation de la trithérapie CSI/LAMA/LABA pour ceux dont le nombre taux d’éosinophiles sanguins (EOS) est ≥ 100 cellules/mm3. Dans l’étude ETHOS de 52 semaines (NCT02465567), la trithérapie avec ID-BGF à deux niveaux de dose de corticostéroïdes inhalés (CSI) a réduit le taux d’exacerbations modérées/sévères de BPCO comparé aux bithérapies glycopyrronium/formotérol (GFF) et budésonide/formotérol (BFF). L’objectif est d’évaluer les taux d’exacerbations chez les patients avec un taux d’EOS < 100 et ≥ 100 cellules/mm3 dans l’étude ETHOS. Les patients atteints de BPCO modérée à très sévère ayant ≥ 1 exacerbation modérée/sévère au cours de l’année précédente ont été randomisés pour recevoir ID-BGF 320/14,4/10 μg ou 160/14,4/10 μg, ID-GFF 14,4/10 μg ou ID-BFF 320/10 μg (tous les traitements ont été administrés deux fois par jour dans un inhalateur unique Aerosphere). Dans la population ITT modifiée (n = 8509), 82,6 % des patients avaient un taux d’EOS ≥ 100 cellules/mm3. Chez ces patients, les deux doses de ID-BGF ont réduit les exacerbations modérées/sévères par rapport au ID-GFF (de 28–29 %, les deux p < 0,0001) et au ID-BFF (de 11 à 12 %, les deux p < 0,03 ; Tableau 1). Chez les patients avec un taux d’EOS < 100 cellules/mm3, les deux doses de ID-BGF ont réduit les exacerbations par rapport à ID-BFF (p < 0,04) mais non par rapport à ID-GFF. ID-BGF a réduit les exacerbations vs ID-GFF et ID-BFF chez les patients avec un taux d’EOS ≥ 100 cellules/mm3 mais seulement vs ID-BFF chez ceux ayant un taux d’EOS < 100 cellules/mm3, ce qui suggère que ce seuil peut être un guide utile pour l’escalade de la bithérapie LAMA/LABA à la trithérapie par ID-BGF.

Background Triple therapy with inhaled corticosteroids/long-acting muscarinic antagonists/long-acting β 2 -agonists (ICS/LAMA/LABA) is recommended for patients with chronic obstructive pulmonary disease (COPD) with continued symptoms or exacerbations, despite treatment with LAMA/LABA or ICS/LABA. The pulmonary, extrathoracic, and regional lung deposition patterns of a radiolabeled ICS/LAMA/LABA triple fixed-dose combination budesonide/glycopyrrolate/formoterol fumarate (BGF 320/18/9.6 μg), delivered via a single Aerosphere metered dose inhaler (MDI) were previously assessed in healthy volunteers and showed good deposition to the central and peripheral airways (whole lung deposition: 37.7%). Here, we report the findings assessing BGF in patients with moderate-to-very severe COPD. Methods This phase I, single-dose, open-label gamma scintigraphy imaging study (NCT03906045) was conducted in patients with moderate-to-very severe COPD. Patients received two actuations of BGF MDI (160/9/4.8 μg per actuation) radiolabeled with technetium‑99‑pertechnetate, not exceeding 5 MBq per actuation. Immediately following each inhalation, patients performed a breath-hold of up to 10 s, then exhaled into an exhalation filter. Gamma scintigraphy imaging of the anterior and posterior views of the lungs and stomach, and a lateral head and neck view, were performed immediately after exhalation. The primary objective of the study was to assess the pulmonary deposition of BGF. Secondary objectives assessed the deposited dose of radiolabeled BGF in the oropharyngeal and stomach regions, on the actuator, and on the exhalation filter in addition to regional airway deposition patterns in the lungs. Results The mean BGF emitted dose deposited in the lungs was 32.1% (standard deviation [SD] 15.6) in patients with moderate-to-very severe COPD, 35.2% (SD 12.8) in patients with moderate COPD, and 28.7% (SD 18.4) in patients with severe/very severe COPD. Overall, the mean normalized outer/inner ratio was 0.55 (SD 0.19), while the standardized central/peripheral ratio was 2.21 (SD 1.64). Conclusions Radiolabeled BGF 320/18/9.6 μg was efficiently delivered and deposited throughout the entire lung, including large and small airways, in patients with moderate-to-very severe COPD, with similar deposition in patients with moderate COPD and patients with severe/very severe COPD. Trial registration: ClinicalTrials.gov, NCT03906045. Registered 8 April 2019, https://clinicaltrials.gov/ct2/show/NCT03906045

1. Martinez FJ, Rabe KF, Ferguson GT, Wedzicha JA, Singh D, Wang C, et al.; ETHOS Investigators. Reduced all-cause mortality in the ETHOS trial of budesonide/glycopyrrolate/formoterol for COPD: a randomized, double-blind, multicenter parallel-group study. Am J Respir Crit Care Med [online ahead of print] 30 Nov 2020; DOI: 10.1164/rccm.202006-2618OC. 2. Rabe KF, Martinez FJ, Ferguson GT, Wang C, Singh D, Wedzicha JA, et al.; ETHOS Investigators. Triple inhaled therapy at two glucocorticoid doses in moderate-to-very-severe COPD. N Engl J Med 2020;383:35–48. 3. Sullivan KM, Dean A, Soe MM. OpenEpi: a web-based epidemiologic and statistical calculator for public health. Public Health Rep 2009; 124:471–474. 4. Lipson DA, Barnhart F, Brealey N, Brooks J, Criner GJ, Day NC, et al. Once-daily single-inhaler triple versus dual therapy in patients with COPD. N Engl J Med 2018;378:1671–1680. 5. Scichilone N, Basile M, Battaglia S, Bellia V. What proportion of chronic obstructive pulmonary disease outpatients is eligible for inclusion in randomized clinical trials? Respiration 2014;87:11–17. 6. Keene ON, Vestbo J, Anderson JA, Calverley PM, Celli B, Ferguson GT, et al. Methods for therapeutic trials in COPD: lessons from the TORCH trial. Eur Respir J 2009;34:1018–1023.