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Nanshan Zhong,1 Jinping Zheng,1 Sang Haak Lee,2 David A Lipson,3 Xin Du,4 Shunquan Wu4 1State Key Laboratory of Respiratory Disease, National Clinical Research Centre of Respiratory Disease, Guangzhou Institute of Respiratory Health, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, the Catholic University of Korea, Seoul, South Korea; 3GSK, Collegeville, and Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 4GSK, Shanghai, People’s Republic of ChinaCorrespondence: Jinping Zheng Email jpzhenggy@163.comPurpose: Previous studies demonstrating efficacy and safety of once-daily umeclidinium (UMEC) in patients with chronic obstructive pulmonary disease (COPD) have included few Asian patients. This study evaluated efficacy and safety of UMEC 62.5 mcg versus placebo in Asian patients with COPD.Patients and Methods: A Phase III, randomized, double-blind, parallel-group study. Patients (aged ≥ 40 years with COPD, pre-, and post-albuterol forced expiratory volume in 1 s [FEV1]/forced vital capacity ratio < 0.70 and low risk of exacerbations) were randomized 2:1 to once-daily UMEC 62.5 mcg or placebo via the ELLIPTA inhaler for 24 weeks. Primary endpoint was change from baseline (CFB) in trough FEV1 on Day 169. Secondary endpoints were weighted mean FEV1 over 0– 6 hrs post-dose on Day 1 and CFB in Transition Dyspnea Index (TDI) focal score on Day 168.Results: A total of 306 patients were included in the modified intent-to-treat population (UMEC: 205; placebo: 101). UMEC versus placebo provided a statistically significant improvement in least squares (LS) mean trough FEV1 between baseline and Day 169 (154 mL [95% confidence interval (CI): 113, 194]; p< 0.001). A clinically meaningful difference of 125 mL in favor of UMEC (95% CI: 103, 147; p< 0.001) was also seen in LS weighted mean FEV1 0– 6 hrs post-dose on Day 1. A LS mean treatment difference in TDI focal score of 0.9 units in favor of UMEC was seen on Day 168 (95% CI: 0.3, 1.5; p=0.004). Incidence of on-treatment adverse events (AEs) was lower in the placebo (55%) versus UMEC arm (60%); non-fatal serious AEs, drug-related AEs, and AEs leading to withdrawal were similar with UMEC and placebo.Conclusion: Once-daily UMEC 62.5 mcg resulted in statistically significant and clinically meaningful improvements in lung function and dyspnea, compared with placebo, in Asian patients with COPD, with no new safety concerns observed.Keywords: Asia, chronic obstructive pulmonary disease, forced expiratory volume in 1 second, Transition Dyspnea Index, umeclidinium

Additional file 1: Supplementary Table 1. SMQs, sub-SMQs, and Preferred Terms for on-treatment CVAESI that were reported in the IMPACT study Supplementary Table 2. Summary of on-treatment CVAESI by baseline CV risk factors (ITT population)

Supplemental material, Supplementary_Figures_and_Table for Impact of baseline COPD symptom severity on the benefit from dual versus mono-bronchodilators: an analysis of the EMAX randomised controlled trial by Claus F. Vogelmeier, Edward M. Kerwin, Leif H. Bjermer, Lee Tombs, Paul W. Jones, Isabelle H. Boucot, Ian P. Naya, David A. Lipson, Chris Compton, Neil Barnes and François Maltais in Therapeutic Advances in Respiratory Disease

Supplemental material, Reviewer_1_v.1 for Early and sustained symptom improvement with umeclidinium/vilanterol versus monotherapy in COPD: a post hoc analysis of the EMAX randomised controlled trial by Edward M Kerwin, Isabelle H Boucot, Claus F Vogelmeier, Francois Maltais, Ian P Naya, Lee Tombs, Paul W Jones, David A Lipson, Tom Keeley and Leif Bjermer in Therapeutic Advances in Respiratory Disease

Additional file 1. Full inclusion and exclusion criteria and supplementary figures 1–5.

Supplemental material, Reviewer_2_v.1 for Efficacy of FF/UMEC/VI compared with FF/VI and UMEC/VI in patients with COPD: subgroup analysis of the Spain cohort in IMPACT by José M. Marín, Luis Mateos, Juan Roldán, José M. Echave-Sustaeta, Sergi Pascual-Guardia, Maria V. Pardo, Beatriz Velasco, C. Elaine Jones, Sally Kilbride and David A. Lipson in Therapeutic Advances in Respiratory Disease

Supplemental material, Supp_Figure_2_HR for Early and sustained symptom improvement with umeclidinium/vilanterol versus monotherapy in COPD: a post hoc analysis of the EMAX randomised controlled trial by Edward M Kerwin, Isabelle H Boucot, Claus F Vogelmeier, Francois Maltais, Ian P Naya, Lee Tombs, Paul W Jones, David A Lipson, Tom Keeley and Leif Bjermer in Therapeutic Advances in Respiratory Disease

Supplemental material, Author_Response for Early and sustained symptom improvement with umeclidinium/vilanterol versus monotherapy in COPD: a post hoc analysis of the EMAX randomised controlled trial by Edward M Kerwin, Isabelle H Boucot, Claus F Vogelmeier, Francois Maltais, Ian P Naya, Lee Tombs, Paul W Jones, David A Lipson, Tom Keeley and Leif Bjermer in Therapeutic Advances in Respiratory Disease

Supplemental material, Reviewer_1_v.1 for Impact of baseline COPD symptom severity on the benefit from dual versus mono-bronchodilators: an analysis of the EMAX randomised controlled trial by Claus F. Vogelmeier, Edward M. Kerwin, Leif H. Bjermer, Lee Tombs, Paul W. Jones, Isabelle H. Boucot, Ian P. Naya, David A. Lipson, Chris Compton, Neil Barnes and François Maltais in Therapeutic Advances in Respiratory Disease

Supplemental material, Author_Response_1 for Impact of baseline COPD symptom severity on the benefit from dual versus mono-bronchodilators: an analysis of the EMAX randomised controlled trial by Claus F. Vogelmeier, Edward M. Kerwin, Leif H. Bjermer, Lee Tombs, Paul W. Jones, Isabelle H. Boucot, Ian P. Naya, David A. Lipson, Chris Compton, Neil Barnes and François Maltais in Therapeutic Advances in Respiratory Disease

International audience

Globally, soils store two to three times as much carbon as currently resides in the atmosphere, and it is critical to understand how soil greenhouse gas (GHG) emissions and uptake will respond to ongoing climate change. In particular, the soil-to-atmosphere CO(2)flux, commonly though imprecisely termed soil respiration (R-S), is one of the largest carbon fluxes in the Earth system. An increasing number of high-frequencyR(S)measurements (typically, from an automated system with hourly sampling) have been made over the last two decades; an increasing number of methane measurements are being made with such systems as well. Such high frequency data are an invaluable resource for understanding GHG fluxes, but lack a central database or repository. Here we describe the lightweight, open-source COSORE (COntinuous SOil REspiration) database and software, that focuses on automated, continuous and long-term GHG flux datasets, and is intended to serve as a community resource for earth sciences, climate change syntheses and model evaluation. Contributed datasets are mapped to a single, consistent standard, with metadata on contributors, geographic location, measurement conditions and ancillary data. The design emphasizes the importance of reproducibility, scientific transparency and open access to data. While being oriented towards continuously measuredR(S), the database design accommodates other soil-atmosphere measurements (e.g. ecosystem respiration, chamber-measured net ecosystem exchange, methane fluxes) as well as experimental treatments (heterotrophic only, etc.). We give brief examples of the types of analyses possible using this new community resource and describe its accompanying R software package.

Motokazu Kato,1 Keisuke Tomii,2 Kenichi Hashimoto,3 Yasuko Nezu,3 Takeo Ishii,4 C Elaine Jones,5 Sally Kilbride,6 Annette S Gross,7 Christine S Clifton,7 David A Lipson8,9 1Chest Disease Clinical and Research Institute, Kishiwada City Hospital, Kishiwada, Japan; 2Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan; 3Evidence Generation Department, GlaxoSmithKline K.K., Tokyo, Japan; 4MA Respiratory Department, GlaxoSmithKline K.K., Tokyo, Japan; 5Development, R&D, GlaxoSmithKline, Research Triangle Park, NC, USA; 6Biostatistics, GlaxoSmithKline, Uxbridge, Middlesex, UK; 7Clinical Pharmacology Modelling & Simulation, GlaxoSmithKline R&D, Sydney, Australia; 8Clinical Sciences, GlaxoSmithKline, Collegeville, PA, USA; 9Pulmonary, Allergy and Critical Care Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USACorrespondence: Yasuko NezuEvidence Generation Department, Respiratory Medical Affairs & Development GlaxoSmithKline K.K., Akasaka Intercity AIR 1-8-1 Akasaka, Minato-Ku, Tokyo 107-0052, JapanTel +81 3 4231 5064Fax +81 3 4231 5994Email yasuko.2.nezu@gsk.comPurpose: The Informing the Pathway of COPD Treatment (IMPACT) study demonstrated that single-inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) reduces moderate/severe exacerbation rates and improves lung function and health status versus FF/VI or UMEC/VI dual therapy in patients with symptomatic COPD and a history of exacerbations. This analysis evaluated the efficacy and safety of FF/UMEC/VI in patients enrolled in Japan.Patients and methods: IMPACT was a 52-week, randomized, double-blind, multicenter study comparing FF/UMEC/VI 100/62.5/25 μg with FF/VI 100/25 μg or UMEC/VI 62.5/25 μg in patients ≥40 years with symptomatic COPD and ≥1 moderate/severe exacerbation in the previous year. Endpoints included annual rate of on-treatment moderate/severe exacerbations (primary endpoint), time-to-first on-treatment moderate/severe exacerbation and change from baseline at Week 52 in trough FEV1, post-bronchodilator FEV1, St. George’s Respiratory Questionnaire, and COPD Assessment Test score. Safety was also assessed.Results: The Japan subgroup accounted for only 4% (378/10,355) of the overall IMPACT intent-to-treat (ITT) population. In the Japan subgroup, FF/UMEC/VI reduced the annual rate of on-treatment moderate/severe exacerbations by 15% (95% CI: −20, 40) versus FF/VI (compared with 15% [10, 20] in the ITT) and 36% (95% CI: 6, 57) versus UMEC/VI (compared with 25% [19, 30] in the ITT). FF/UMEC/VI reduced moderate/severe exacerbation risk (time-to-first), improved lung function and health status at Week 52 versus both dual therapies. These results were in the same direction and of a generally similar magnitude to those seen in the overall ITT population. No new safety signals were identified in the Japan subgroup compared with the ITT population. Pneumonia incidence was higher with FF/UMEC/VI and FF/VI versus UMEC/VI.Conclusion: These results highlight the favorable benefit–risk profile of FF/UMEC/VI single-inhaler triple therapy compared with FF/VI or UMEC/VI dual therapy in patients in Japan with symptomatic COPD and ≥1 exacerbation in the prior year.Keywords: triple therapy, fluticasone furoate, Japan, umeclidinium, vilanterol, COPD exacerbation