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Additional file 1. Plain language summary.

Additional file 1: Table 1. Baseline characteristics and demographics by treatment and Week 16 fibrinogen quartile. Table 2. Baseline characteristics and demographics by treatment and Week 16 fibrinogen 3.5 g/L threshold. Table 3. COPD exacerbation history by treatment group and by withdrawal status at Week 16 (ITT population). Table 4. Analysis of fibrinogen levels at Week 16 by treatment group. Table 5. Incidence and rates of AESIs by fibrinogen quartile. Figure 1. Rate of on-treatment moderate/severe exacerbations from Week 16 by continuous fibrinogen level at Week 16; (A) moderate exacerbations; (B) moderate/severe exacerbations; (C) severe exacerbations. Figure 2. Time-to-first on-treatment COPD exacerbation from Week 16 by Week 16 fibrinogen 3.5 g/L threshold: (A) moderate exacerbations; (B) moderate/severe exacerbations; (C) severe exacerbations.

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, Supp_Figure_1_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, Reviewer_2_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, Supplementary_data 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_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, Reviewer_2_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

Safety endpoints. (DOCX 18 kb)

Additional file 2: Table S2. UMEC versus salmeterol comparisons for all outcomes. aSymptom severity outcomes presented for Week 24 for SAC-TDI and global assessment of disease severity, for Weeks 21–24 for E-RS, and for Weeks 1–24 for rescue salbutamol use; bdata are LS mean (95% CI); cSAC-TDI responders were defined as a ≥ 1-unit improvement from baseline; dE-RS responders were defined as a reduction of ≥2 from baseline; eoverall assessment of change in COPD severity was rated using a seven-point Likert scale (‘Much Better’, ‘Slightly Better’, ‘Better’, ‘No Change’, ‘Slightly Worse’, ‘Worse’, ‘Much Worse’). Ordered response ratios were reported as odds of better response category; fSGRQ responders were defined as a ≥ 4-point reduction from baseline; gCAT responders were defined as a ≥ 2-unit improvement from baseline. CAT, COPD Assessment Test; CI, confidence interval; CID, clinically important deterioration; COPD, chronic obstructive pulmonary disease; E-RS, Evaluating Respiratory Symptoms-COPD; FEV1, trough forced expiratory volume in 1 sec; LS, least squares; n, number of responders/patients with an event; N, number of patients with analysable data; SAC-TDI, self-administered computerised Transition Dyspnoea Index; SAL, salmeterol; SGRQ, St George’s Respiratory Questionnaire; UMEC, umeclidinium; VI, vilanterol.

Forest plot of TDI focal score at Day 168, active treatments versus PBO. (DOCX 101 kb)

Supplemental material, Bigelow_SI_for_Holocene for Dust deposition drives microbial metabolism in a remote, high-elevation catchment by Amy Bigelow, Natalie Mladenov, David Lipson and Mark Williams in The Holocene

Additional file 3: Table S3. Proportion of responders for symptom severity and health status outcomes – additional timepoints. aSAC-TDI responders were defined as a ≥ 1-unit improvement from baseline; bE-RS responders were defined as a reduction of ≥2 from baseline; coverall assessment of change in COPD severity was rated using a seven-point Likert scale (‘Much Better’, ‘Slightly Better’, ‘Better’, ‘No Change’, ‘Slightly Worse’, ‘Worse’, ‘Much Worse’). Ordered response ratios were reported as odds of better response category; dSGRQ responders were defined as a ≥ 4-point reduction from baseline; eCAT responders were defined as a ≥ 2-unit improvement from baseline. CAT, COPD Assessment Test; CI, confidence interval; COPD, chronic obstructive pulmonary disease; e-diary, electronic diary; E-RS, Evaluating Respiratory Symptoms-COPD; n/N, number of responders/number of patients with analysable data; SAC-TDI, self-administered computerised Transition Dyspnoea Index; SAL, salmeterol; SGRQ, St George’s Respiratory Questionnaire; UMEC, umeclidinium; VI, vilanterol.

TDI focal score profile (ITT population). (DOCX 78 kb)

Additional file 1: Table S1. Patient-reported outcomes. aSAC-TDI responders were defined as a ≥ 1-unit improvement from baseline; btotal score and subscales (breathlessness, cough and sputum, chest); cE-RS responders were defined as a reduction of ≥2 from baseline; dSGRQ responders were defined as a ≥ 4-point reduction from baseline; eCAT responders were defined as a ≥ 2-unit improvement from baseline. CAT, COPD Assessment Test; COPD, chronic obstructive pulmonary disease; E-RS, Evaluating Respiratory Symptoms-COPD; LS, least squares; SAC-TDI, self-administered computerised-Transition Dyspnoea Index; SGRQ, St George’s Respiratory Questionnaire.

Additional file 5: Table S5. List of investigators.

Introduction: Recruitment and activation of inflammatory cells contributes to the pathophysiology of Cystic Fibrosis (CF). Recruitment is initiated, in part, by engagement of the CXCR2 receptor on neutrophils and other inflammatory cells. Materials and Methods: Levels of CXCR2 agonists (CXCL 1, 3, 5, 7, 8), and systemic biomarkers of inflammation (fibrinogen, CC-16, SP-D, IL-1β, and MMP-9) were measured in the serum of stable outpatients with cystic fibrosis compared to normal healthy age-, gender, and racially-matched non-smoking control subjects. Secondary objectives included characterization of pulmonary function assessed by spirometry, Impulse Oscillometry (IOS), R5-R15 peripheral resistance, R5 total resistance and R25 large airway resistance; frequency dependent reactance as indicators of reactive capacitance properties of the lung (X5, resonant frequency, Fres, AX) in patients with CF compared with controls. Health outcomes scores in patients with CF were assessed using the Cystic Fibrosis Questionnaire. Population: Single center, prospective, two visit study. 48 subjects were enrolled. Forty-two subjects (28 patients with CF and 14 healthy controls matched 2:1 (age, gender, and race) were evaluable. Results: Blood fibrinogen levels in CF patients were significantly elevated compared with controls (3.9 g/L vs. 3.0 g/L [p=0.0004]); similar differences were seen in levels of CXCL8 (CF patients=10.2 pg/mL and controls=5.9 pg/mL [p=0.0065]). A trend was noted for CC-16, CXCL1, and SP-D. As expected, lung functions assessed by spirometry and IOS values were significantly different in the patient population compared to the control group. Mean FEV1 and mean reactance were 2.4L (67% predicted) vs. 3.5L (99% predicted) and 0.174 kPa/(L/sec) vs. –0.085 kPa/(L/sec) in CF patients vs, controls, respectively(p=0.0002 and p

Introduction We report the results of the first direct comparison of the once-daily fixed-dose long-acting muscarinic antagonist/long-acting β2-agonist (LAMA/LABA) combinations umeclidinium/vilanterol (UMEC/VI) and tiotropium/olodaterol (TIO/OLO) in patients with COPD. Methods This was a randomized, two-period crossover open-label study in symptomatic patients with COPD [age 40 years or older, postbronchodilator forced expiratory volume in 1 s (FEV1) of 70% or less and 50% or more of predicted normal values, and modified Medical Research Council Dyspnoea Scale score of 2 or greater] not receiving inhaled corticosteroid therapy. Patients were randomized to receive UMEC/VI (62.5/25 µg once daily) via a multidose dry powder inhaler (ELLIPTA) followed by TIO/OLO (5/5 µg once daily) via a soft mist inhaler (Respimat), each for 8 weeks with an interim 3-week washout or vice versa. The primary end point was the change from baseline in trough FEV1 at week 8 with a noninferiority margin of − 50 mL in the per-protocol (PP) population. The incidence of adverse events was also assessed. Results In total, 236 patients (mean age 64.4 years, 60% male) were included in the intent-to-treat population and 227 were included in the PP population. UMEC/VI treatment was noninferior in the PP population and superior in the intent-to-treat population to TIO/OLO treatment with regard to trough FEV1 at week 8 [FEV1 change from baseline 180 mL vs 128 mL; difference 52 mL (95% confidence interval 28–77 mL); p