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Martin Anderson,1 Kathryn Collison,2 M Bradley Drummond,3 Melanie Hamilton,4 Renu Jain,2 Neil Martin,5,6 Richard A Mularski,7 Mike Thomas,8 Chang-Qing Zhu,9 Gary T Ferguson10 1Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; 2Respiratory Therapy Area, GSK, Research Triangle Park, NC, USA; 3Pulmonary and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 4R&D, GSK, Ware, Hertfordshire, UK; 5Global Medical Affairs, GSK, Brentford, Middlesex, UK; 6Institute for Lung Health, University of Leicester, Leicester, Leicestershire, UK; 7Department of Pulmonary and Critical Care Medicine, Kaiser Permanente Northwest Center for Health Research, Portland, OR, USA; 8Primary Care Research, University of Southampton, Southampton, UK; 9Biostatistics, GSK, Stockley Park West, Uxbridge, Middlesex, UK; 10Pulmonary Research, Institute of Southeast Michigan, Farmington Hills, MI, USACorrespondence: Gary T FergusonPulmonary Research, Institute of Southeast Michigan, Farmington Hills, MI, USATel +1 248-478-6561Email garytferguson@msn.comBackground: The influence of peak inspiratory flow (PIF) on dose delivery from dry powder inhalers (DPIs) and association with treatment efficacy in patients with chronic obstructive pulmonary disease (COPD) has not been fully determined. In vitro studies have demonstrated adequate dose delivery through ELLIPTA DPI at PIF ≥ 30 L/min. This analysis of two clinical trials and a real-world population of COPD patients determined spirometric PIF distribution, and explored the relationship between PIF and outcomes in the trials.Methods: The replicate Phase IV, 12-week, randomized, double-blind 207608/207609 (NCT03478683/NCT03478696) trials evaluated fluticasone furoate/umeclidinium/vilanterol via ELLIPTA DPI versus budesonide/formoterol+tiotropium in COPD patients. This post hoc analysis assessed spirometric PIF distribution at screening and relationship between PIF and lung function outcomes in the pooled 207608/207609 population. Spirometric PIF distributions in a real-world population of COPD patients were evaluated by retrospective analysis of the Kaiser Permanente Northwest (KPNW) database to assess similarities between clinical trial and real-world populations.Results: A total of 1460 (207608/207609) and 3282 (KPNW) patients were included. There was considerable overlap between spirometric PIF distributions for both populations. Overall, 99.7% and 99.8% of the 207608/207609 and KPNW populations, respectively, reported spirometric PIF ≥ 50 L/min, estimated as equivalent to ELLIPTA PIFR ≥ 30 L/min. In the 207608/207609 combined analysis, there was no significant interaction between spirometric PIF and treatment for lung function endpoints, indicating treatment effect is independent of PIF.Conclusion: Nearly all COPD patients in the 207608/207609 and KPNW populations achieved spirometric PIF values estimated as equivalent to PIFR of ≥ 30 L/min through the ELLIPTA DPI. Lack of correlation between spirometric PIF at screening and treatment efficacy aligns with consistent dose performance from the ELLIPTA DPI across a wide range of PIFs, achieved by patients with COPD of all severities.Keywords: COPD, inhaled triple therapy, patient outcomes, real-world studies, peak inspiratory flow rate, DPI

Background: In asthma, persistent airflow limitation (PAL) is associated with poorer control, lung function decline and exacerbations. Using post‐hoc analyses we evaluated: the relationship between post‐salbutamol PAL at screening, airflow limitation (AL) during 52 weeks treatment with extrafine beclometasone dipropionate/formoterol fumarate/glycopyrronium (BDP/FF/G) versus BDP/FF and the risk of moderate/severe asthma exacerbations. Methods: TRIMARAN and TRIGGER were double‐blind studies comparing BDP/FF/G with BDP/FF (TRIMARAN medium‐dose ICS; TRIGGER high‐dose) in adults with uncontrolled asthma. Patients were subgrouped according to post‐salbutamol PAL status at screening, and AL over the 52‐week treatment period. Results: Most patients with post‐salbutamol PAL at screening had AL at all on‐treatment visits (TRIMARAN 62.8%; TRIGGER 66.8%). A significantly higher proportion of patients had normalised airflow on ≥1 follow‐up visit when receiving BDP/FF/G than BDP/FF (TRIMARAN 44.1 vs. 33.1% [p = 0.003]; TRIGGER 40.1 vs. 26.0% [p < 0.001]). In patients with post‐salbutamol PAL at screening and normalised AL at ≥1 follow‐up visit, exacerbation rates were 15% (p = 0.105) and 19% (p = 0.039) lower in TRIMARAN and TRIGGER versus those with AL on all visits. There was a trend to lower exacerbation rates in patients receiving BDP/FF/G than BDP/FF, particularly in patients in whom AL was normalised. Conclusion: In these analyses, AL in asthma was associated with an increased exacerbation incidence. Inhaled triple therapy with extrafine BDP/FF/G was more likely to normalise airflow, and was associated with a trend to a lower exacerbation rate than BDP/FF, particularly in the subgroup of patients in whom treatment was associated with airflow normalisation. ClinicalTrials.gov: TRIMARAN, NCT02676076; TRIGGER, NCT02676089. [ABSTRACT FROM AUTHOR]

Use of propellants with high global warming potential (such as HFA-134a) for pressurised metered-dose inhalers (pMDIs) is being phased down. Switching to dry-powder inhalers may not be clinically feasible for all patients; an alternative is reformulation using propellants with low global warming potential. The combination of beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB) is available for asthma or chronic obstructive pulmonary disease via pMDI using HFA-134a as propellant. This is being reformulated using the low global warming potential propellant HFA-152a. This manuscript reports three studies comparing BDP/FF/GB pharmacokinetics delivered via pMDI using HFA-152a vs HFA-134a. The studies were four-way crossover, single-dose, randomised, double-blind, in healthy volunteers. In Studies 1 and 2, subjects inhaled four puffs of BDP/FF/GB (Study 1: 100/6/12.5 μg [medium-strength BDP]; Study 2: 200/6/12.5 μg [high-strength]), ingesting activated charcoal in two of the periods (once per propellant). In Study 3, subjects inhaled medium- and high-strength BDP/FF/GB using a spacer. All three studies compared HFA-152a vs HFA-134a in terms of lung availability and total systemic exposure of beclometasone-17-monopropionate (B17MP; active metabolite of BDP), BDP, formoterol and GB. Bioequivalence was concluded if the 90 % confidence intervals (CIs) of the ratios between formulations of the geometric mean maximum plasma concentration (C max) and area under the plasma concentration–time curve between time zero and the last quantifiable timepoint (AUC 0–t) for the analytes were between 80 and 125 %. In Studies 1 and 2, systemic exposure bioequivalence (i.e., comparisons without charcoal block) was demonstrated, except for GB C max in Study 2 (upper 90 % CI 125.11 %). For lung availability (i.e., comparisons with charcoal block), B17MP and formoterol demonstrated bioequivalence in both studies, as did BDP in Study 2; in Study 1, BDP upper CIs were 126.96 % for C max and 127.34 % for AUC 0–t). In Study 1, GB AUC 0–t lower CI was 74.54 %; in Study 2 upper limits were 135.64 % for C max and 129.12 % for AUC 0–t. In Study 3, the bioequivalence criteria were met for BDP, B17MP and formoterol with both BDP/FF/GB strengths, and were met for GB AUC 0–t , although not for C max. Both formulations were similarly well tolerated in all three studies. Overall, while formal bioequivalence cannot be concluded for all analytes, these data suggest therapeutic equivalence of the new formulation with the existing BDP/ FF /GB pMDI formulation, therefore supporting reformulation using a propellant with low global warming potential. • Use of propellants with high global warming potential (such as HFA-134a) inpMDIs is being phased down. • The combination of BDP/FF/GB is now being reformulated using the low global warming potential propellant HFA-152a. • These three studies compared BDP/FF/GB pharmacokinetics when delivered via pMDI using HFA-152a vs HFA-134a as propellant. • Overall, these data suggest therapeutic equivalence of the new formulation and the existing BDP/FF/GB pMDI formulation. [ABSTRACT FROM AUTHOR]

Dave Singh,1 Massimo Corradi,2 Monica Spinola,3 Alberto Papi,4 Omar S Usmani,5 Mario Scuri,3 Stefano Petruzzelli,3 Jørgen Vestbo1 1Division of Infection, Immunity and Respiratory Medicine, University of Manchester, Manchester, UK; 2Department of Medicine and Surgery, University of Parma, Parma, Italy; 3Chiesi Farmaceutici SpA, Parma, Italy; 4Department of Medical Sciences, Research Centre on Asthma and COPD, University of Ferrara, Ferrara, Italy; 5National Heart and Lung Institute, Imperial College London, London, UK Abstract: The goals of COPD therapy are to prevent and control symptoms, reduce the frequency and severity of exacerbations, and improve exercise tolerance. The triple combination therapy of inhaled corticosteroids (ICSs), long-acting beta2 agonists (LABAs), and long-acting muscarinic antagonists (LAMAs) has become an option for maintenance treatment of COPD and as a “step-up” therapy from single or double combination treatments. There is evidence that triple combination ICS/LABA/LAMA with different inhalers improves lung function, symptoms, and health status and reduces exacerbations. A new triple fixed-dose combination of extrafine beclomethasone dipropionate (100 µg/puff)/formoterol fumarate (6 µg/puff)/glycopyrronium bromide (12.5 µg/puff) has been developed as a hydrofluoroalkane pressurized metered dose inhaler. Two large pivotal studies showed that this extrafine fixed ICS/LABA/LAMA triple combination is superior to fixed ICS/LABA combined therapy and also superior to the LAMA tiotropium in terms of lung function and exacerbation prevention in COPD patients at risk of exacerbation. This review considers the new information provided by these clinical trials of extrafine triple therapy and the implications for the clinical management of COPD patients. Keywords: COPD, inhaled triple therapy, beclomethasone dipropionate, formoterol fumarate and glycopyrronium bromide