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Christian Gessner,1 Frederik Trinkmann,2,3 Sanaz Bahari Javan,4 Raimund Hövelmann,4 Valentina Bogoevska,4 George Georges,5 Elena Nudo,6 Carl-Peter Criée7 1Pneumologische Praxis Leipzig, Universitätsklinikum Leipzig, Institut für Klinische Immunologie, Leipzig, Germany; 2Pneumology and Critical Care Medicine, Thoraxklinik at University Hospital Heidelberg, Translational Lung Research Center Heidelberg (TLRC), Member of German Center for Lung Research (DZL), Heidelberg, Germany; 3Department of Biomedical Informatics (DBMI) at the Center for Preventive Medicine and Digital Health Baden-Württemberg (CPD-BW), University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Heidelberg, Germany; 4Department of Medical Affairs, Chiesi GmbH, Hamburg, Germany; 5Corporate R&D, Chiesi USA Inc., Cary, NC, USA; 6Global Medical Affairs, Chiesi Farmaceutici S.p.A., Parma, Italy; 7Department of Sleep and Respiratory Medicine, Evangelical Hospital Goettingen-Weende, Bovenden, GermanyCorrespondence: Christian Gessner, Pneumologische Praxis Leipzig, Universitätsklinikum Leipzig, Institut für Klinische Immunologie, Tauchaer Straße 12, Leipzig, 04357, Germany, Tel +49 341 60 20 960, Email ch.gessner@pneumologe-leipzig.dePurpose: Real-word evidence on the effectiveness of switching from dual therapies or triple therapies (multiple inhalers) to extrafine single-inhaler triple therapy (efSITT), which consists of the inhaled corticosteroid (ICS) beclomethasone, the long-acting β2-agonist (LABA) formoterol and the long-acting muscarinic antagonist (LAMA) glycopyrronium, in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) is limited. The impact of switching to efSITT on health-related quality of life (HRQoL), COPD specific symptoms, lung function and treatment adherence were assessed in routine clinical care.Patients and Methods: Patients were recruited at 148 sites in Germany between 2017 and 2020 in this multicenter, non-interventional observational study. Demographics, clinical data and treatment history were collected at baseline. HRQoL (measured by COPD Assessment Test [CAT]), lung function and adherence (measured by Test of Adherence to Inhalers [TAI]) were assessed at baseline and after six months. Descriptive analyses were conducted by prior treatment and GOLD groups as well as for the overall population.Results: 55.1% of the 2623 included patients were male. Mean age was 65.8 years. 57.5% of the patients were previously treated with ICS+LABA+LAMA (multiple inhalers), 23.9% with ICS/LABA (single or two inhalers) and 18.6% with LAMA/LABA (single or two inhalers). After six months, largest mean improvements in the total CAT score were observed in the ICS/LABA (− 3.9) and LAMA/LABA (− 3.9) prior treatment groups as well as in patients in GOLD group B (− 2.9). In the overall population, the CAT items for cough, phlegm, and dyspnea decreased on average by − 0.4 points each. After six months, FEV1 increased by 2.0 percentage points in relation to predicted values. The percentages of measured sRtot and RV of predicted values decreased by 24.5 and 4.4 percentage points, respectively. The percentage of patients with good adherence increased from 67.8% to 76.5%.Conclusion: Treatment switch to efSITT resulted in an improvement of HRQoL, COPD specific symptoms, lung function parameters and adherence under real-world conditions.Keywords: COPD, extrafine single inhaler triple therapy, treatment adherence, CAT score

Background: An extrafine formulation triple therapy combination of beclomethasone dipropionate (BDP), formoterol fumarate (FF), and glycopyrronium bromide (GB) has been developed for the maintenance treatment of asthma and chronic obstructive pulmonary disease. This study used gamma scintigraphy to evaluate the intrapulmonary and extrapulmonary in vivo deposition of BDP/FF/GB, and the intrapulmonary regional distribution of the deposited formulation.Methods: This open-label uncontrolled nonrandomized single-dose study recruited 10 healthy volunteers and 9 patients with asthma. After a krypton-81m (Kr-81m) ventilation scan was conducted, subjects inhaled study drug (four inhalations of BDP/FF/GB 100/6/12.5 mu g radiolabeled using technetium-99 m [Tc-99m]) through pressurized metered-dose inhaler, and a series of scintigraphic images were taken. The primary objective was to evaluate intrapulmonary drug deposition of BDP/FF/GB, determined as the percentage of nominal (i.e., metered) dose. Secondary endpoints included central/peripheral deposition ratio (C/P), and the standardized central/peripheral ratio (sC/P; Tc-99m aerosol C/P/Kr-81m gas C/P).Results: All participants completed the study, with all scintigraphy procedures performed at one site. In patients with asthma, mean +/- standard deviation intrapulmonary deposition was 25.50% +/- 6.81%, not significantly different to that in healthy volunteers (22.74% +/- 9.19%; p = 0.4715). Approximately half of the lung dose was deposited in the peripheral region of the lung (fraction deposited 0.52 +/- 0.07 and 0.49 +/- 0.06 in healthy volunteers and patients with asthma, respectively), resulting in C/P ratios of 0.94 +/- 0.25 and 1.06 +/- 0.25, respectively, with sC/P ratios of 1.80 +/- 0.40 and 1.94 +/- 0.38. Deposition patterns were similar in the two populations. BDP/FF/GB was well tolerated.Conclusions: This study confirmed that the extrafine particles delivered by BDP/FF/GB penetrate the peripheral areas of the lungs, with a similar proportion of particles deposited in the central and peripheral regions. Importantly, the deposition patterns were similar in healthy volunteers and patients with asthma, suggesting that disease characteristics are unlikely to impact drug deposition.Clinical Trial Registration number: NCT03795350.

Introduction: This manuscript describes a Phase II, dose-ranging, randomized, double-blind, placebo- and active-controlled, parallel-group study conducted to identify the appropriate dose of beclom...

Kai-Michael Beeh,1 Piotr Kuna,2 Massimo Corradi,3 Isabelle Viaud,4 Alessandro Guasconi,4 George Georges4 1Insaf Respiratory Research Institute, Wiesbaden, Germany; 2Division of Internal Medicine, Asthma and Allergy, Barlicki University Hospital, Łódź, Poland; 3Department of Medicine and Surgery, University of Parma, Parma, Italy; 4Global Clinical Development, Chiesi Farmaceutici SpA, Parma, ItalyCorrespondence: Kai-Michael BeehInsaf Respiratory Research Institute, Wiesbaden, GermanyTel +49 611 9854347Email k.beeh@insaf-wi.deBackground: Three 52-week studies in COPD have assessed the efficacy and safety of single-inhaler extrafine formulation triple therapy combining beclomethasone dipropionate (BDP), formoterol fumarate (FF) and glycopyrronium (G) delivered via pressurized metered-dose inhaler (pMDI). BDP/FF/G is now being developed for delivery via multi-dose dry-powder inhaler (DPI; NEXThaler). This study aimed to demonstrate non-inferiority of BDP/FF/G DPI vs pMDI for lung function.Methods: Multicenter, randomized, double-blind, double-dummy, active-controlled, three-way cross-over study in patients with COPD and post-bronchodilator forced expiratory volume in 1 second (FEV1) 30– 80% predicted. Patients received BDP/FF/G 100/6/10μg via DPI and pMDI, and BDP/FF 100/6μg via pMDI, all two inhalations twice daily for four weeks, with treatments separated by two-week washout. The two co-primary objectives were to demonstrate non-inferiority between the two BDP/FF/G formulations for FEV1 area under the curve between 0 and 12 hours post-dose (AUC0-12h) normalized by time and trough FEV1 at 24 hours, both on Day 28. EudraCT 2017– 004405-41.Results: Of 449 patients screened, 366 were randomized, with 342 (93.4%) completing all three treatment periods. The primary objectives were met, with changes from baseline in FEV1 AUC0– 12h and trough FEV1 on Day 28 similar for the two BDP/FF/G formulations, and the confidence intervals for the difference lying entirely within the pre-specified non-inferiority criterion (– 50mL): – 20 (– 35, – 6) mL and 3 (– 15, 20) mL for AUC0– 12h and trough FEV1, respectively. BDP/FF/G pMDI and DPI were statistically superior to BDP/FF for these endpoints (p< 0.001). A similar proportion of patients experienced adverse events with each treatment (15.5%, 18.7% and 15.4% with BDP/FF/G DPI and pMDI, and BDP/FF, respectively); the majority were mild or moderate, with few related to treatment.Conclusion: Extrafine BDP/FF/G DPI and pMDI demonstrated similar efficacy and safety in patients with COPD, supporting the DPI formulation as a valid alternative.Keywords: adrenergic beta-2 receptor agonists, muscarinic antagonists, steroids, respiratory function tests, chronic obstructive pulmonary disease

Omar S Usmani,1 Nicola Scichilone,2 Benjamin Mignot,3 Dennis Belmans,3 Cedric Van Holsbeke,3 Jan De Backer,3 Roberta De Maria,4 Erika Cuoghi,4 Eva Topole,4 George Georges4 1Airway Disease Section, National Heart and Lung Institute, Imperial College, London, UK; 2PROMISE Department of Medicine, University of Palermo, Palermo, Italy; 3FLUIDDA, Kontich, Belgium; 4Chiesi Farmaceutici, SpA, Parma, ItalyCorrespondence: George GeorgesChiesi USA Inc., 175 Regency Woods Place, Ste. 600, Cary, NC 27518, USATel +1 (919) 678 6611 x1536Email george.georges@chiesi.comIntroduction: There is a clear correlation between small airways dysfunction and poor clinical outcomes in patients with chronic obstructive pulmonary disease (COPD), and it is therefore important that inhalation therapy (both bronchodilator and anti-inflammatory) can deposit in the small airways. Two single-inhaler triple therapy (SITT) combinations are currently approved for the maintenance treatment of COPD: extrafine formulation beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB), and non-extrafine formulation fluticasone furoate/vilanterol/umeclidinium (FluF/VI/UMEC). This study evaluated the lung deposition of the inhaled corticosteroid (ICS), long-acting β2-agonist (LABA), and long-acting muscarinic antagonist (LAMA) components of these two SITTs.Materials and Methods: Lung deposition was estimated in-silico using functional respiratory imaging, a validated technique that uses aerosol delivery performance profiles, patients’ high-resolution computed tomography (HRCT) lung scans, and patient-derived inhalation profiles to simulate aerosol lung deposition.Results: HRCT scan data from 20 patients with COPD were included in these analyses, who had post-bronchodilator forced expiratory volume in 1 second (FEV1) ranging from 19.3% to 66.0% predicted. For intrathoracic deposition (as a percentage of the emitted dose), deposition of the ICS component was higher from BDP/FF/GB than FluF/VI/UMEC; the two triple therapies had similar performance for both the LABA component and the LAMA component. Peripheral deposition of all three components was higher with BDP/FF/GB than FluF/VI/UMEC. Furthermore, the ratios of central to peripheral deposition for all three components of BDP/FF/GB were < 1, indicating greater peripheral than central deposition (0.48± 0.13, 0.48± 0.13 and 0.49± 0.13 for BDP, FF and GB, respectively; 1.96± 0.84, 0.97± 0.34 and 1.20± 0.48 for FluF, VI and UMEC, respectively).Conclusions: Peripheral (small airways) deposition of all three components (ICS, LABA, and LAMA) was higher from BDP/FF/GB than from FluF/VI/UMEC, based on profiles from patients with moderate to very severe COPD. This is consistent with the extrafine formulation of BDP/FF/GB.Keywords: tomography, X-ray computed, metered dose inhalers, dry powder inhalers, inhaled corticosteroid, long-acting beta2 agonist, long-acting muscarinic antagonist

Price DB, Henley W, Cançado JED, et al. Int J Chron Obstruct Pulmon Dis. 2022;17:355–370 On page 356, last paragraph of the Introduction section, the paragraph should be corrected from “ …Collectively, there is a requirement for a real- world study comparing the use of extrafine particle fixed dose combination beclometasone dipropionate (ef-FDC-BDP; with a MMAD of 1.1μm in FOSTER® and TRIMBOW® NEXTHALER® DPIs and 1.3μm in FOSTER® pMDI) with other ICSs, such as fine particle fluticasone (fp-FDC-F; with a MMAD of 3.9μm and 3.2μm for propionate (SERETIDE® DISKUS®) and furoate (RELVAR® ELLIPTA®) esters respectively).21–23 to “ …Collectively, there is a requirement for a real-world study comparing the use of extrafine particle fixed dose combination beclometasone dipropionate (ef-FDC-BDP; with a MMAD of 1.1µm in TRIMBOW® pMDI and 1.3µm in FOSTER® pMDI) with other ICSs, such as fine particle fluticasone (fp-FDC-F; with a MMAD of 3.9µm and 3.2µm for propionate (SERETIDE® DISKUS®) and furoate (RELVAR® ELLIPTA®) esters respectively).21-23 The authors apologize for this error and advise they do not affect the results of the paper. Read the original article

David B Price,1,2 William Henley,1,3 José Eduardo Delfini Cançado,4 Leonardo M Fabbri,5 Huib AM Kerstjens,6 Alberto Papi,7 Nicolas Roche,8 Elif &Scedil;en,9 Dave Singh,10 Claus F Vogelmeier,11 Sara Barille,12 Elena Nudo,12 Victoria Carter,1 Derek Skinner,1 Rebecca Vella,1 George Georges13 1Observational and Pragmatic Research Institute, Singapore; 2Centre of Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; 3Health Statistics Group, Institute of Health Research, University of Exeter Medical School, Exeter, UK; 4Santa Casa de São Paulo Medical School, São Paulo, Brazil; 5Respiratory Medicine, Department of Translational Medicine, University of Ferrara, Ferrara, Italy; 6Department of Pulmonary Diseases, University of Groningen and University Medical Centre Groningen, and Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, Netherlands; 7Respiratory Medicine, University of Ferrara, Ferrara, Italy; 8Department of Respiratory Medicine, APHP-Centre University of Paris, Cochin Institute, Paris, France; 9Department of Pulmonary Medicine, Ankara University School of Medicine, Ankara, Turkey; 10Division of Infection, Immunity & Respiratory Medicine, University of Manchester, Manchester University NHS Foundation Trust, Manchester, UK; 11Department of Internal Medicine, Pulmonary and Critical Care Medicine, University of Marburg, Member of the German Centre for Lung Research (DZL), Marburg, Germany; 12Global Medical Affairs, Chiesi Farmaceutici, S.p.A., Parma, Italy; 13Global Clinical Development, Chiesi Farmaceutici, S.p.A., Parma, ItalyCorrespondence: David B Price, Observational and Pragmatic Research Institute, 22 Sin Ming Lane, #06-76, Midview City, 573969, Singapore, Email dprice@opri.sgBackground: Inhaled corticosteroids (ICS) afford therapeutic benefits in some COPD patients, but their widespread use is cautioned due to an increased risk of developing pneumonia. Subclass variations exist, and the risk profile differs for individual ICS. Formulation particle size has been identified as a potential effect modifier. The present study compared the risk of pneumonia among new COPD users of fixed-dose combination inhalers containing fine-particle fluticasone (fp-FDC-F) versus extrafine particle beclometasone (ef-FDC-BDP).Methods: A propensity matched historical cohort study was conducted using data from the Optimum Patient Care Research Database. COPD patients aged ≥ 40 years with ≥ 1 year of continuous medical data who initiated fp-FDC-F or ef-FDC-BDP were compared. The primary outcome was time to pneumonia event, as treated, using either sensitive (physician diagnosed) or specific (physician diagnosed and x-ray or hospital admission confirmed) definitions.Results: A total of 13,316 patients were matched. Initiation of fp-FDC-F (mean dosage furoate 99 μg; propionate 710 μg) was associated with an increased risk of pneumonia versus ef-FDC-BDP (mean beclometasone dose 395 μg), irrespective of definition (sensitive HR 1.38 95% CI 1.14– 1.68; specific HR 1.31 95% CI 1.05– 1.62).Conclusion: In the current investigation, we found that in comparison to extrafine beclomethasone, commencing a formulation containing fluticasone is associated with an increased risk of developing pneumonia. These observations support the idea that not all ICS are equal in their adverse effects and subclass variations exist and should be carefully considered in the treatment choice.Keywords: inhaled corticosteroids, pneumonia, COPD, extrafine beclomethasone, fluticasone

Purpose A number of single-inhaler, fixed-dose, triple combinations are available for the management of chronic obstructive pulmonary disease and/or asthma. One of these is the extrafine formulation beclomethasone dipropionate, formoterol fumarate, glycopyrronium bromide (BDP/FF/GB). Given that differences in ethnicity can result in differences in systemic exposure, we evaluated the relative pharmacokinetic (PK) profiles of BDP/FF/GB in Japanese vs Caucasian healthy volunteers to assess the need for dose adjustment. Methods This randomized, double-blind, single-dose, 4-way crossover study recruited healthy men and women 20 to 55 years of age; for each Japanese person a Caucasian was enrolled who matched in terms of sex, age, and weight. Study treatments included BDP/FF/GB 200/12/25 and 400/12/25 μg (therapeutic), 800/48/100 μg (supratherapeutic), and placebo. PK blood samples were taken up to 24 hours for evaluation of BDP, beclomethasone 17-monopropionate (B17MP, an active metabolite of BDP), and formoterol and up to 48 h for GB. The primary objective was to characterize the PK profiles of BDP, FF, and GB after administration of a single dose of BDP/FF/GB in Caucasian and Japanese healthy volunteers in terms of the AUC0–t and Cmax of B17MP, formoterol, and GB. Findings Of the 32 recruited participants (16 Japanese and 16 Caucasian ), 30 completed the study. A clear plasma exposure dose-response relationship was found for all 4 molecules. B17MP Cmax geometric mean ratios for Japanese vs Caucasian participants for the 3 study treatments ranged from 1.17 to 1.26, and AUC0–t ratios ranged from 1.16 to 1.22; thus, the findings were comparable between the ethnicities. Formoterol exposure was higher in Japanese than Caucasian participants (Cmax, 1.22–1.53; AUC0–t, 1.23–1.40). The GB Cmax with BDP/FF/GB 400/12/25 μg (1.09) and AUC0–t values for all three doses (0.98–1.17) were comparable in the 2 populations, but Cmax with 200/12/25 and 800/48/100 μg were higher in Japanese participants (1.32 and 1.42, respectively). Pharmacodynamic (cortisol, potassium, glucose, blood pressure, heart rate, and QT interval with the Fridericia correction) and safety profile results were similar in the 2 ethnicities, with most patients not experiencing any adverse events. Implications Exposure to BDP/FF/GB pressurized metered dose inhaler at therapeutic and supratherapeutic doses was associated with higher plasma levels in Japanese versus Caucasian healthy volunteers. These PK differences did not translate into meaningful differences in the safety or pharmacodynamic parameters assessed in this study and were consistent with the results of other long-term (52-week) published studies. Dose adjustments in Japanese people are not deemed necessary. ClinicalTrials.gov identifier NCT03859414.

This Phase II, randomized, parallel group study was conducted as part of US regulatory requirements to identify the most appropriate dose of the long-acting muscarinic antagonist glycopyrronium bromide (GB) for use in a single-inhaler triple-therapy combination with the inhaled corticosteroid beclomethasone dipropionate plus the long-acting β2-agonist formoterol fumarate. Eligible subjects were adults with COPD and post-bronchodilator forced expiratory volume in 1 s (FEV1) 40–80% predicted. Subjects were randomized to receive inhaled double-blind GB 6.25, 12.5, 25 or 50 µg or placebo, all twice daily (BID), or open-label tiotropium 18 µg once daily for six weeks. The primary objective was to evaluate the efficacy of GB versus placebo in terms of FEV1 area under the curve between 0 and 12 h at Week 6. Of 733 subjects randomized, 682 (93.0%) completed the study. For the primary endpoint, all GB doses were superior to placebo (p p

Introduction and Objectives Persistent airflow limitation (PAL) predicts a positive clinical response to add-on long acting muscarinic antagonist in patients with asthma taking inhaled corticosteroids and long-acting β2-receptor agonists. We conducted a post-hoc analysis of the TRIGGER study to evaluate the effect of extrafine BDP/FF/G vs BDP/FF on asthma control and the use of systemic corticosteroids for asthma exacerbations in a subset of patients with PAL. Methods TRIGGER was a phase III, randomized, parallel group trial comparing 52-week treatment with BDP/FF/G 200/6/10µg two inhalations twice daily (BID) to BDP/FF 200/6µg BID and an open-label treatment arm consisting of BDP/FF 200/6µg BID plus tiotropium (BDP/FF+Tio). PAL criteria were a post-bronchodilator FEV1≤80% of predicted normal and FEV1/FVC≤0.7; ACQ-7 response was defined as a change from baseline in ACQ-7 score ≤-0.5 unit, and asthma control days as asthma symptom-free day without using rescue medication. Results 1437 subjects were randomized and 61.2% met the PAL criteria. In this subgroup, there was a significantly higher percentage of ACQ-7 responders on BDP/FF/G compared to BDP/FF at week 26 (60.2% vs 49.4%) and week 52 (60.8% vs 51.7%). In the overall population, the difference in the percentage of ACQ-7 responders was 61.3% vs 55.9% at week 26 and 62.3% vs 58.1% at week 52, for BDP/FF/G and BDP/FF respectively. In patients with PAL, the change from baseline in the asthma control days over 52 weeks was higher in BDP/FF/G compared to BDP/FF (14.5% vs 8.8%), with a smaller difference observed in the overall population (Table 1). Patients treated with BDP/FF/G had less days of systemic corticosteroid use for asthma exacerbations compared to BDP/FF in the PAL subpopulation (34.1% reduction; RR=0.659, 95%CI (0.389–1.118) p=0.122), and in the overall population (24.4% reduction; RR=0.756, 95%CI (0.499–1.145) p=0.186), although not statistically significant. Conclusions In adult asthmatics with PAL, treatment with high ICS dose extrafine BDP/FF/G compared to BDP/FF was associated with greater odds of experiencing asthma control and a higher trend towards a decreased use of systemic corticosteroids for asthma exacerbations, compared to the overall population.

Introduction and Objectives The COPD Assessment Test (CAT) and Saint George Respiratory Questionnaire (SGRQ) are reliable instruments for monitoring health status changes in clinical trials. We present here the interim analysis results of the TRIVERSYTI study on these secondary patient-reported outcome measures in East Asian patients with COPD. Methods TRIVERSYTI is an ongoing phase III multi-centre (China, South Korea and Taiwan), randomized, parallel group trial comparing a 24-week treatment with (BDP/FF/GB) 100/6/12.5 µg pMDI, 2 puffs bid to BUD/FF 160/4.5 µg DPI (Turbuhaler®, AstraZeneca) 2 inhalations bid, in adults with COPD, post-bronchodilator FEV1 Results 614 patients were randomized and included in the interim analysis, of whom 498 (81%) were Chinese. Treatment with BDP/FF/GB resulted in improvement of -1.34 (p=0.005; all patients) and -1.37 points (p=0.010; Chinese participants) vs BUD/FF in the CAT Score, and in improvement of -3.08 (p=0.009; all patients) and -3.37 points (p=0.006; Chinese participants) in the SGRQ Total Score. There were 41.4% SGRQ ‘responders’ in BDP/FF/GB compared to 34.1% in BUD/FF (OR: 1.41; p=0.053) among all patients, and 43.3% SGRQ responders compared to 34.1% in the Chinese participants (OR: 1.50; p=0.040). Conclusions Extra-fine triple therapy with BDP/FF/GB pMDI significantly improves COPD health status compared to ICS/LABA with BUD/FF DPI in Asian and Chinese patients with severe COPD.

Background A single-inhaler extrafine triple combination of beclometasone dipropionate (BDP), formoterol fumarate (FF) and glycopyrronium (G) has been developed for maintenance therapy of chronic obstructive pulmonary disease (COPD). This study evaluated the efficacy and safety of BDP/FF/G in patients in three eastern Asian areas: China, Republic of Korea and Taiwan. Methods TRIVERSYTI was a double-blind, randomised, active-controlled, parallel-group study in patients with COPD, post-bronchodilator forced expiratory volume in 1 s (FEV1) 1 at Week 24 (these were analysed as key secondary objectives in the China subgroup). The rate of moderate/severe COPD exacerbations was a secondary endpoint. Results Of 708 patients randomised, 88.8% completed. BDP/FF/G was superior to BUD/FF for pre-dose and 2-h post-dose FEV1 at Week 24 [adjusted mean differences 62 (95% CI 38, 85) mL and 113 (87, 140) mL; both p p Conclusions In patients with COPD, FEV1 Trial registration CFDA CTR20160507 (registered 7 Nov 2016, http://www.chinadrugtrials.org.cn/index.html).

Background: Functional respiratory imaging (FRI) is a computational fluid dynamics-based technique using three-dimensional models of human lungs and formulation profiles to simulate aerosol deposition. Methods: FRI was used to evaluate lung deposition of extrafine beclomethasone dipropionate (BDP)/formoterol fumarate (FF)/glycopyrronium bromide (GB) and extrafine BDP/FF delivered through pressurized metered dose inhalers and to compare results with reference gamma scintigraphy data. FRI combined high-resolution computed tomography scans of 20 patients with moderate-to-severe chronic obstructive pulmonary disease (mean forced expiratory volume in 1 second 42% predicted) with in silico computational flow simulations, and incorporated drug delivery parameters to calculate aerosol airway deposition. Inhalation was simulated using profiles obtained from real-life measurements. Results: Total lung deposition (proportion deposited in intrathoracic region) was similarly high for both products, with mean ± standard deviation (SD) values of 31.0% ± 5.7% and 28.1% ± 5.2% (relative to nominal dose) for BDP/FF/GB and BDP/FF, respectively. Pairwise comparison of the deposition of BDP and FF gave a mean intrathoracic BDP/FF/GB:BDP/FF deposition ratio of 1.10 (p = 0.0405). Mean intrathoracic, central and peripheral deposition ratios for BDP were 1.09 (95% confidence interval [CI]: 1.05–1.14), 0.92 (95% CI: 0.89–0.96), and 1.20 (95% CI: 1.15–1.26), respectively, and for FF were 1.11 (95% CI: 1.07–1.15), 0.94 (95% CI: 0.91–0.98), and 1.21 (95% CI: 1.15–1.27), within the bioequivalence range (0.80–1.25) for intrathoracic and central regions, and slightly exceeding the upper boundary in the peripheral region. Mean ± SD central:peripheral deposition (C:P) was 0.48 ± 0.13 for BDP/FF/GB and 0.62 ± 0.17 for BDP/FF, indicating a higher proportion of drug deposition in the small airways than in the large airways. Conclusion: FRI demonstrated similar deposition patterns for extrafine BDP/FF/GB and BDP/FF, with both having a high lung deposition. Moreover, the deposition patterns of BDP and FF were similar in both products. Furthermore, the C:P ratios of both products indicated a high peripheral deposition, supporting small airway targeting and delivery of these two extrafine fixed combinations, with a small difference in ratios potentially due to mass median aerodynamic diameters.

Introduction: TriOptimize is the first ongoing real-world study of symptomatic patients with moderate-to-severe COPD treated with extrafine single inhaler triple therapy (efSITT). Methods: In this interim analysis we present the effect of 3-month treatment with efSITT (BDP/FF/G) on lung function (LF) in patients prior on LABA/LAMA, ICS/LABA or multi-inhaler triple therapy (MITT). Data were retrieved from patients’ health records if available. Results: Treatment with efSITT for 3 months resulted in improvement of airflow obstruction, airway resistance and hyperinflation parameters, showing a response pattern depending on prior treatment (Table 1). Summary and Conclusion: Symptomatic patients with moderate-to-severe COPD displayed an improvement in LF after 3 months treatment with efSITT, validating results of Phase III studies in a real-world setting. Furthermore, we report distinct therapeutic benefits of efSITT depending on the addition of a LAMA, or an ICS to prior dual maintenance therapy or possibly the single-inhaler feature compared to MITT. The improvement in LF observed after switching from MITT to single-inhaler triple therapy indicates enhanced adherence and the positive impact of using a single inhaler rather than multiple inhalers with different inhalation techniques.

Introduction: The CODEX (age-adjusted Charlson comorbidity score, Obstruction, Dyspnea, and severe EXacerbations) index has shown to be useful at predicting survival and COPD readmissions, with a prognostic capacity superior to other indices. Its validation in randomized clinical trials has not been performed. Aims and Objectives: To explore the performance of the CODEX in a cohort from pooled multinational randomized pharmacological intervention clinical trials, in comparison to the BODEX, DOSE and ADO indices. Methods: TRILOGY, TRINITY, and TRIBUTE were phase III randomized clinical trials that evaluated 1-yr treatment with extra fine BDP/FF/GB versus other maintenance therapies in symptomatic patients with severe COPD and a history of exacerbations. Patients from the intent-to-treat population of each study were considered, those with missing data for any of the variables involved in the derivation of the COPD multivariate indices were excluded. Results: 5588 patients were considered, 5584 entered the analysis. 565 (10.1%) of patients experienced death or a severe exacerbation. The mean (SD) CODEX index was 5.7 (1.15), with 82.6% of patients scoring between 5-9 on a 0-10 scale. For patients with a score ≥5, the Hazard Ratio (HR) for either death or a severe exacerbation was 2.6 (95%CI: 1.9 – 3.5, p Conclusion: A high CODEX index is significantly associated with mortality or severe exacerbation outcomes in a pooled cohort from randomized interventional clinical trials.

Introduction: A DPI formulation (NEXThaler®) of the extra fine BDP/FF/GB triple therapy has been developed as an alternative to pMDI to meet patients’ preference and to provide treatment options. Aims and Objectives: To demonstrate the non-inferiority of the DPI versus pMDI formulations of extra fine BDP/FF/GB on lung function. Methods: TRI-D was a, randomized, double-blind, double-dummy, active controlled, 3-way cross-over trial comparing 4 weeks of treatment with BDP/FF/GB 100/6/12.5 µg DPI and pMDI and BDP/FF 100/6 µg pMDI each delivered as 2 inhalations bid, separated by 2-week wash-outs in patients with stable, moderate-to-severe COPD. The co-primary efficacy endpoints were the change from baseline in FEV1 AUC0-12h normalised by time and in trough FEV1 at 24 hours on Day 28. Treatment-emergent adverse events (TEAEs) were collected. Results: 366 patients were randomized. Non-inferiority of BDP/FF/GB DPI vs pMDI was demonstrated for both co‑primary endpoints, with the lower limits of confidence interval of the adjusted mean differences falling above the non-inferiority threshold of -50 mL (-35 mL and -15 mL). Both DPI and pMDI triple therapies significantly improved FEV1 AUC0‑12h vs BDP/FF pMDI by 85 and 105 mL, respectively (p Conclusion: DPI and pMDI formulations of extra fine BDP/FF/GB demonstrated similar efficacy and safety in patients with COPD supporting the new DPI formulation as a valid option for both patient and physician.

Introduction: Asthma exacerbations cluster by seasons with peaks in the autumn, winter and spring. Aims and Objectives: We evaluated the effect of extra-fine beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB) pressurized metered dose inhaler (pMDI) on asthma exacerbation rates during the four seasons. Methods: This was a post-hoc analysis of pooled data from two phase III multinational, randomized, parallel group trial comparing a 52-week treatment with BDP/FF/GB 400/24/50 µg/d to BDP/FF 400/24 µg/d (TRIMARAN study) and BDP/FF/GB 800/24/50 µg/d to BDP/FF 800/24 µg/d (TRIGGER study) in adult patients with uncontrolled asthma on medium or high dose ICS/LABA and a history of exacerbation in the past year. Patients with persistent airflow limitation (PAL) were identified based on FEV1 ≤80% of predicted normal and FEV1/FVC ≤0.7 after 400 μg salbutamol pMDI. Asthma exacerbations were assigned to the month corresponding to the start of the event. Seasons were normalized across northern and southern hemispheres. Results: 2291 patients were considered in this analysis, of whom 1361 had PAL. The number and rate of moderate-severe exacerbations were highest in the winter followed by autumn and spring. Reductions of moderate-severe asthma exacerbation rates with BDP/FF/GB were 11% and 23% (winter), 21% and 23% (autumn), 14% and 21% (spring), and 5 and 13% (summer) in the overall and PAL populations respectively, compared to BDP/FF. Conclusions: Treatment with extra-fine BDP/FF/GB reduces seasonal peaks of asthma exacerbations in adults with asthma uncontrolled on BDP/FF, particularly in those with PAL.

Introduction: TriOptimize is the first real-world (RW) study collecting data from patients treated with extrafine single inhaler triple therapy (efSITT). Here, we present an interim analysis of changes in health-related quality of life (HRQoL) after 3 months treatment with efSITT. Methods: Changes in HRQoL measured by the COPD assessment test (CAT) were retrieved from health records of 1866 patients with moderate to severe COPD treated with efSITT (BDP/FF/G) for 3 months, stratified by COPD pre-therapy. Results: For patients previously treated with LABA/LAMA (n= 324), average CAT score improved after 3 months treatment with efSITT from 21.0 to 17.8 with -3.3 points (p Summary and Conclusion: TriOptimize is the first RW study to report a significant clinically meaningful improvement in HRQoL following a switch from ICS/LABA, LAMA/LABA or MITT to efSITT with BDP/FF/G in patients with moderate to severe COPD.

Introduction: Severe COPD exacerbations requiring hospitalizations or resulting in death clearly impose a serious prognostic and economic impact on patients and healthcare systems who seek to prevent and treat them. Aims and Objectives: We evaluated the effect of triple therapy with extra-fine beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB) pressurized metered dose inhaler (pMDI) on reducing the severe COPD exacerbation rate compared to non-triple (non-TT) including non-ICS-containing maintenance inhalation therapies. Methods: Analysis of pooled data from 3 phase III multinational, randomized, parallel group trials comparing 52 weeks treatment with BDP/FF/GB 100/6/12.5 µg 2 inhalations bid to BDP/FF (TRILOGY), tiotropium (TRINITY) and indacaterol/glycopyrronium (TRIBUTE) in symptomatic patients on prior non-TT with severe or very severe COPD and history of moderate or severe exacerbation in the past year. Results: 445 patients experienced 535 severe exacerbations and were considered in this analysis. 202 received BDP/FF/GB, 243 received non-TT (BDP/FF, TIO, IND/GLY), and of those, 168 received non-ICS-containing therapies (TIO, IND/GLY). The adjusted rate ratio of severe exacerbation with BDP/FF/GB was 0.769 (95%CI: 0.632, 0.936, p=0.009) vs non-TT and 0.745 (95%CI: 0.592, 0.937, p=0.012) vs non-ICS-containing therapies. Conclusions: Treatment with extra-fine BDP/FF/GB pMDI effectively reduced the rate of severe COPD exacerbations vs non-triple (by 23.1%) and non-ICS containing (by 25.5%) therapies in symptomatic patients.

Background A number of single-inhaler triple therapies are being developed for asthma, including the extrafine formulation of beclometasone dipropionate (BDP), formoterol fumarate (FF), and glycopyrronium (G). Given asthma is a heterogenous disease, we investigated whether the clinical response to the addition of the long-acting muscarinic antagonist component within inhaled triple therapy was impacted by a range of clinical characteristics. Methods These were pre-specified and post-hoc sub-group analyses of TRIMARAN and TRIGGER, which were double-blind, 52-week studies comparing medium-strength (100/6/10 µg; TRIMARAN) and high-strength (200/6/10 µg; TRIGGER) BDP/FF/G with the respective BDP/FF strengths in adults with uncontrolled asthma and a history of ≥ 1 exacerbation. Co-primary endpoints were pre-dose forced expiratory volume in 1 s (FEV1) at Week 26 and the rate of moderate-to-severe exacerbations over 52 weeks. Key secondary endpoints: peak FEV1 at Week 26 and average morning peak expiratory flow over the first 26 weeks in each study, and severe exacerbation rate over 52 weeks (pooled data). Results Baseline clinical characteristics (pre-specified analyses) had no consistent effect on the lung function improvements with BDP/FF/G. For the exacerbation endpoints, sub-groups with higher reversibility gained greatest relative benefit from BDP/FF/G versus BDP/FF. In post-hoc analyses with patients sub-grouped by screening blood eosinophil values, in TRIMARAN the greatest relative effect of BDP/FF/G versus BDP/FF on the lung function endpoints was in the ≤ 300 cells/µL group; in TRIGGER, eosinophil levels did not markedly influence the relative efficacy of BDP/FF/G versus BDP/FF. Eosinophil levels did not influence relative efficacy on moderate-to-severe or severe exacerbations. Conclusion Overall, the relative efficacy of extrafine BDP/FF/G versus BDP/FF was not influenced by a range of clinical characteristics. However, some patient sub-groups gained additional benefit from BDP/FF/G for certain endpoints. In particular, for exacerbations the relative efficacy of BDP/FF/G was greater in more reversible patients. Trial registration ClinicalTrials.gov: TRIMARAN, NCT02676076 (registered February 8, 2016, https://clinicaltrials.gov/ct2/show/NCT02676076?term=NCT02676076&draw=2&rank=1,); TRIGGER, NCT02676089 (registered February 8, 2016, https://clinicaltrials.gov/ct2/show/NCT02676089?term=NCT02676089&draw=2&rank=1)

The addition of a long-acting muscarinic antagonist (LAMA) is a recognised treatment option for patients whose asthma is uncontrolled with an inhaled corticosteroid (ICS) plus long-acting β2-agonist (LABA) combination [1]. The data supporting this recommendation were provided from studies in which the LAMA tiotropium was added to ICS/LABA combinations using separate inhalers [2, 3]. The use of separate inhalers, most often of different design, with contrasting instructions for use and dosing regimens is not only inconvenient for patients and healthcare providers who provide instruction on correct inhaler use, but can negatively impact treatment adherence and persistence – and therefore outcomes [4–7]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Singh reports personal fees from Chiesi, during the conduct of the study; personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi, personal fees from Cipla, personal fees from Genentech, personal fees from GlaxoSmithKline, personal fees from Glenmark, personal fees from Menarini, personal fees from Mundipharma, personal fees from Novartis, personal fees from Peptinnovate, personal fees from Pfizer, personal fees from Pulmatrix, personal fees from Theravance, personal fees from Verona, outside the submitted work. Conflict of interest: Dr. Vele reports and I am an employee of Chiesi, the sponsor of the two studies. Conflict of interest: Dr. Kots reports and I am an employee of Chiesi, the sponsor of the two studies. Conflict of interest: Dr. Georges reports other from Chiesi USA, Inc., during the conduct of the study; other from Chiesi USA, Inc., outside the submitted work. Conflict of interest: Dr. Papi reports grants, personal fees, non-financial support and other from Chiesi, grants, personal fees, non-financial support and other from Astrazeneca, grants, personal fees, non-financial support and other from GlaxoSmithKline, grants, personal fees, non-financial support and other from Boehringer Ingelheim, personal fees and non-financial support from Menarini, personal fees and non-financial support from Novartis, personal fees and non-financial support from Zambon, grants, personal fees, non-financial support and other from Mundipharma, grants, personal fees, non-financial support and other from TEVA, personal fees and non-financial support from Sanofi, outside the submitted work. Conflict of interest: Dr. Canonica reports personal fees from A. Menarini, personal fees from Alk-Abello, personal fees from Allergy Therapeutics, personal fees from AstraZeneca-Medimmune, personal fees from Boehringer Ingelheim, personal fees from Chiesi Farmaceutici, personal fees from Genentech, personal fees from Guidotti-Malesci, personal fees from GlaxoSmithKline, personal fees from Hal Allergy, personal fees from Merck Sharp & Dome, personal fees from Mundipharma, personal fees from Novartis, personal fees from Orion, personal fees from Sanofi-Aventis, personal fees from Sanofi Genzyme/Regeneron, personal fees from Stallergenes-Greer, personal fees from Uriach Pharma, personal fees from Teva, personal fees from Valeas, personal fees from ViforPharma, outside the submitted work. Conflict of interest: Dr. Virchow reports personal fees from Chiesi , during the conduct of the study; and In the past J. Christian Virchow has ectured and received honoraria fromUstraZeneca, Avontec, Bayer, Bencard, Bionorica, Boehringer-Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, Leti, MEDA, Merck, MSD, Mundipharma, Novartis, Nycomed/Altana, Pfizer, Revotar, Sanofi/Regeneron, Sandoz-Hexal, Stallergens, TEVA, UCB/Schwarz-Pharma, Zydus/Cadila and possibly othersUnd participated in advisory boards and received honoraria fromUvontec, Boehringer-Ingelheim, Chiesi, Essex/Schering-Plough, GSK, Janssen-Cilag, MEDA, MSD, Mundipharma, Novartis, Paul-Ehrlich Institut, Regeneron, Revotar, Roche, Sanofi-Aventis, Sanofi/Regeneron, Sandoz-Hexal, TEVA, UCB/Schwarz-Pharma and possibly othersUnd received funding for research from Ýeutsche Forschungsgesellschaft, Land Mecklenburg-Vorpommern, GSK, MSDUnd has advised the Bemeinsame Bundesausschuss (GBA).

Introduction: FRI is a validated computational fluid dynamics (CFD)-based technique using aerosol delivery performance profile, patients’ high-resolution lung CT scans and patient-derived inhalation profiles to simulate aerosol lung deposition. Aims and Objectives: To evaluate lung deposition patterns of extrafine beclometasone dipropionate/formoterol fumarate/glycopyrronium [BDP/FF/G; TRIMBOW®] pressurized metered dose inhaler (pMDI) and non-extrafine fluticasone furoate/vilanterol/umeclidinium [FluF/VI/UMEC; TRELEGY® ELLIPTA®] dry powder inhaler (DPI) in patients with stable COPD and moderate to very severe airflow obstruction. Methods: Intrathoracic depositions of the inhaled corticosteroid (ICS), long-acting β2 receptor agonist (LABA), and long-acting muscarinic antagonist (LAMA) components were calculated for each inhaler in 20 patients. Inhalation was simulated in silico using a per-patient profile derived from real life measurement. Results: Pulmonary deposition [% delivered dose] was higher for extrafine BDP than FluF (35.9 ± 6.7% vs 23.3± 4.6%) and comparable between FF and VI and between G and UMEC. Central to peripheral ratios were markedly lower for BDP, FF, and G compared to FluF, VI and UMEC, respectively (Table 1). Conclusions: FRI data indicate a higher peripheral lung (small airways) deposition with extrafine BDP/FF/G than with FluF/VI/UMEC. This may be attributed to the lower Mass Median Aerodynamic Diameter (MMAD) of BDP/FF/G.

Introduction: Persistent airflow limitation (PAL) may predict a positive clinical response to add-on long-acting muscarinic antagonist (LAMA) in asthmatics on inhaled corticosteroids and long-acting β2-receptor agonists (ICS/LABA) Objectives: We evaluated the effect of extrafine HS beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB) on asthma exacerbations in a subset of patients with PAL Methods: TRIGGER was a phase III randomized, parallel group trial comparing 52-week treatment with BDP/FF/GB 800/24/50 µg/d to BDP/FF 800/24 µg/d via pressurized metered dose inhalers (pMDI) and open-label treatment consisting of BDP/FF plus tiotropium Respimat® 5 μg/d (TioR) in adult patients with uncontrolled asthma on high-dose ICS/LABA and a history of exacerbation in the past year. PAL criteria were FEV1 ≤80% of predicted normal and FEV1/FVC ≤0.7 after 400 μg salbutamol pMDI Results: 1437 subjects were randomized in 2:2:1 ratio; 880 (61.2%) met PAL criteria on BDP/FF/GB (n=357), BDP/FF (n=346), and BDP/FF+TioR (n=177), respectively. Treatment of this subgroup with BDP/FF/GB compared to BDP/FF resulted in a 25.9% and 31.8% reduction in annual moderate-severe and severe asthma exacerbations rates, respectively, (RR [95% CI] = 0.741 [0.611, 0.900], p=0.002; 0.682 [0.494; 0.940], p=0.019), vs. 12% and 20.5% reductions in the entire study population. There were no significant differences between BDP/FF/GB and BDP/FF+TioR. Conclusions: PAL is associated with a greater response to triple therapy with extrafine HS BDP/FF/GB in patients with asthma uncontrolled on high dose ICS/LABA