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Claus F Vogelmeier,1 Ian P Naya,2,3 François Maltais,4 Leif Bjermer,5 Edward M Kerwin,6 Lee Tombs,7 Paul W Jones,2 Chris Compton,2 David A Lipson,8,9 Isabelle H Boucot2,10 1Department of Medicine, Pulmonary and Critical Care Medicine, University Medical Center Giessen and Marburg, Philipps-Universität Marburg, Member of the German Center for Lung Research (DZL), Marburg, Germany; 2Global Specialty & Primary Care, GSK, Brentford, Middlesex, UK; 3RAMAX Ltd, Bramhall, Cheshire, UK; 4Centre De Pneumologie, Institut Universitaire De Cardiologie Et De Pneumologie De Québec, Université Laval, Québec, Canada; 5Respiratory Medicine and Allergology, Lund University, Lund, Sweden; 6Altitude Clinical Consulting and Clinical Research Institute of Southern Oregon, Medford, OR, USA; 7Precise Approach Ltd, Contingent Worker on Assignment at GSK, Brentford, Middlesex, UK; 8Respiratory Clinical Sciences, GSK, Collegeville, PA, USA; 9Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 10Medical Emerging Markets, GSK, Brentford, Middlesex, UKCorrespondence: Claus F VogelmeierUniversity Medical Center Giessen and Marburg, Philipps-Universität Marburg, Member of the German Center for Lung Research (DZL), Baldingerstraße, Marburg, 35043, GermanyTel +49 6421/58-66451Email claus.vogelmeier@med.uni-marburg.deIntroduction: This post hoc analysis of the “Early MAXimization of bronchodilation for improving COPD stability” (EMAX) trial investigated whether patients achieving early clinically important improvement (CII) sustained longer-term improvements and lower risk of clinically important deterioration (CID).Methods: Patients were randomized to umeclidinium/vilanterol, umeclidinium, or salmeterol for 24 weeks. The patient-reported outcomes (PROs) Transition Dyspnea Index (TDI), Evaluating Respiratory Symptoms, St George’s Respiratory Questionnaire (SGRQ) and COPD Assessment Test (CAT) were assessed. CII, defined as attaining minimum clinically important differences (MCID) in ≥ 2 PROs, was assessed at Weeks 4, 12 and 24. CID was defined as a deterioration in CAT, SGRQ, TDI by the MCID and/or a moderate/severe exacerbation from Day 30.Results: Of 2425 patients, 50%, 53% and 51% achieved a CII at Weeks 4, 12 and 24, respectively. Patients with a CII at Week 4 versus those without had significantly greater odds of achieving a CII at Weeks 12 and 24 (odds ratio: 5.57 [95% CI: 4.66, 6.66]; 4.09 [95% CI: 3.44, 4.86]). The risk of a CID was higher in patients who did not achieve a CII at Week 4 compared with patients who did (hazard ratio [95% CI]: 2.09 [1.86, 2.34]). Patients treated with umeclidinium/vilanterol versus either monotherapy had significantly greater odds of achieving CII at Weeks 4, 12 and 24.Conclusion: Achieving a CII at Week 4 was associated with longer-term improvement in PROs and a reduced risk of deterioration. Further research is required to investigate the importance of an early response to treatment on the long-term disease course.Keywords: bronchodilator, clinically important improvement, clinically important deterioration, COPD symptoms, early improvement, patient-reported outcomes

Gary T Ferguson,1 Edward M Kerwin,2 Tara Rheault,3 Thomas Bengtsson,4 Kathleen Rickard3 1Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA; 2Altitude Clinical Consulting, Medford, OR, USA; 3Verona Pharma, Plc, Raleigh, NC, USA; 4Stat Mind AB, Lund, SwedenCorrespondence: Tara RheaultVerona Pharma, 8045 Arco Corporate Drive, Suite 130, Raleigh, NC, 27617, USATel +1 646-530-2126Email tara.rheault@veronapharma.comPurpose: Ensifentrine is an inhaled dual inhibitor of phosphodiesterase (PDE) 3 and 4 that has shown bronchodilatory effects and symptom improvement in clinical studies in patients with chronic obstructive pulmonary disease (COPD), and anti-inflammatory effects in healthy volunteers in a model of COPD-like inflammation. This manuscript reports on the results of the clinical study examining if ensifentrine provides meaningful improvements in lung function when added on to tiotropium over 4 weeks in patients with COPD who have impaired lung function and symptoms despite treatment with tiotropium.Patients and Methods: This randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study recruited patients with moderate-to-severe COPD. Patients were randomized to open-label tiotropium once daily (QD) plus (+) blinded escalating doses of ensifentrine or placebo twice daily (BID). Effects on lung function, symptoms and quality of life (QoL) were assessed over 4 weeks.Results: A total of 416 COPD patients were randomized and 413 received at least one dose of blinded study medication + tiotropium. All ensifentrine doses produced a significant and dose-dependent increase in peak forced expiratory volume in 1 second (FEV1) from baseline to Week 4, with placebo-corrected differences of 77.5 mL when added to tiotropium (0.375 mg; 95% CI: 4.8, 150.1 mL; p=0.037) to 124.2 mL (3 mg; 95% CI: 51.0, 196.8 mL; p< 0.001). A significant increase in average FEV1 (0– 12h) was shown at Week 4 with the 3 mg dose (87.3 mL; 95% CI: 20.0, 154.5 mL; p=0.011). Clinically meaningful and statistically significant improvements in the St. George’s Respiratory Questionnaire – COPD (SGRQ-C) additive to tiotropium were observed at Week 4, exceeding the minimally clinically important difference of 4 units with the 1.5 and 3 mg doses. Adverse events were similar in frequency between the ensifentrine and placebo arms.Conclusion: This clinical study demonstrated that nebulized ensifentrine added on to tiotropium produced clinically important improvements in lung function and QoL over 4 weeks in COPD patients receiving tiotropium who demonstrated symptoms and lung function impairment, with a safety profile similar to placebo.Keywords: dual PDE3 and 4 inhibitor, phosphodiesterase, COPD, tiotropium, bronchodilation

Edward M Kerwin,1 Lindsey Murray,2 Xiaoli Niu,3 Carole Dembek3 1Clinical Research Institute of Southern Oregon, Medford, OR, USA; 2Evidera, Bethesda, MD, USA; 3Sunovion Pharmaceuticals Inc., Marlborough, MA, USACorrespondence: Xiaoli NiuSunovion Pharmaceuticals Inc., 84 Waterford Dr, Marlborough, MA 01752, USATel +1 508 357 7863Email xiaoli.niu@sunovion.comPurpose: Using a composite endpoint, pooled data from two 12-week Phase III placebo-controlled trials (GOLDEN 3, NCT02347761; GOLDEN 4, NCT02347774) were analyzed to determine whether glycopyrrolate inhalation solution (25 mcg and 50 mcg) administered twice daily (BID) via the eFlow® Closed System nebulizer (GLY) reduced the risk of clinically important deterioration (CID) in patients with moderate-to-very-severe COPD.Methods: CID was defined as ≥ 100-mL decrease from baseline in post-bronchodilator trough forced expiratory volume in one second (FEV1), or ≥ 4-unit increase in baseline St. George’s Respiratory Questionnaire (SGRQ) total score, or moderate/severe exacerbation. The relative treatment effect of GLY versus placebo on the odds of CID (any and by component endpoints) was expressed as the odds ratio (OR) and 95% confidence interval (CI). Subgroups categorized by age (< 65/≥ 65 years), sex, smoking status (current/former), long-acting beta agonist (LABA) use, FEV1 (< 50%/≥ 50%), and peak inspiratory flow rate (PIFR) (< 60 L/min/≥ 60 L/min) were analyzed.Results: Compared to placebo, GLY 25 mcg and 50 mcg BID over 12 weeks significantly reduced the risk of CID by 50% (OR: 0.50 [0.37– 0.68]) and 40% (OR: 0.60 [0.44– 0.80]), respectively. Subjects treated with GLY 25 mcg BID were 59% less likely to experience CID in FEV1 (OR: 0.41 [0.27– 0.62]) and 48% less likely to perceive CID in health status (OR: 0.52 [0.37– 0.73]). Statistically significant reductions were also observed at the higher dose. The incidence of moderate/severe exacerbations was low and comparable among the cohorts. GLY 25 mcg BID was significantly more effective than placebo (p< 0.05) in preventing CID irrespective of age, smoking status, LABA use, COPD severity, or PIFR. Subjects < 65 years (OR 0.45 [0.29– 0.68]) and those with PIFR < 60 L/min (OR 0.36 [0.20– 0.67]) exhibited the largest benefit.Conclusion: Nebulized GLY over 12 weeks significantly reduced the risk of CID and provided greater short-term stability in patients with moderate-to-very-severe COPD.Keywords: nebulized glycopyrrolate, clinically important deterioration, composite measure

Judith J Stephenson,1 Carole Dembek,2 Amanda Caldwell-Tarr,3 Rebecca M Conto,1 Mark Paullin,1 Edward M Kerwin4 1HealthCore Inc., Wilmington, DE, USA; 2Sunovion Pharmaceuticals Inc., Marlborough, MA, USA; 3HealthCore Inc., Watertown, MA, USA; 4Clinical Research Institute of Southern Oregon, Medford, OR, USACorrespondence: Judith J Stephenson Tel +1 302 230 2142Email jstephenson@healthcore.comPurpose: To assess clinical characteristics and device satisfaction of patients with chronic obstructive pulmonary disease (COPD) treated with glycopyrrolate/eFlow® Closed System (CS) nebulizer (further referred to as eFlow) under real-world conditions.Participants and Methods: Patients with COPD currently using eFlow were identified by the study sponsor. Consenting patients who met study inclusion criteria completed a cross-sectional survey that included a device satisfaction questionnaire. Means, medians, and standard deviations were calculated.Results: Sixty-six patients met inclusion criteria and completed the survey. Participants’ mean ± standard deviation age was 64.9 ± 11.9 years and the majority were white (86.4%) and female (59.1%). Almost two-thirds were former smokers. Thirty-nine (59.1%) reported their COPD to be severe/very severe and 38 (57.6%) reported a COPD exacerbation resulting in a hospitalization, ER visit, or medication modification over the past 12 months. Among 55 participants who had previously used another type of nebulizer, 44 (80%) were overall “much more”/“somewhat more” satisfied with the eFlow compared with their previous nebulizer(s). Regardless of prior nebulizer use, 60 (90.9%) participants were “satisfied”/“very satisfied” overall with the eFlow. Assembly and disassembly, operation, and cleaning were perceived as being “easy”/“very easy” by at least 65% of participants. Among all participants, 57 (86.4%) were “confident”/“very confident” of glycopyrrolate administration. On a Likert scale of 1 (“I don’t like it”) to 7 (“I like it a lot”), mean scores were at least 5.9 for portability, ease of cleaning, size, weight, short administration time, and relative silence of the device. Over 80% of participants said they “probably”/"definitely" would continue to use eFlow.Conclusion: Based on this real-world study, the majority of patients were highly satisfied with, and confident in, using eFlow.Keywords: device satisfaction, cross-sectional, survey, nebulizer, COPD

Donald P Tashkin,1 Alpesh N Amin,2 Edward M Kerwin3 1The Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA, USA; 2Department of Medicine, School of Medicine University of California, Irvine, CA, USA; 3Crisor, LLC Clinical Research Institute of Southern Oregon, Medford, OR, USACorrespondence: Donald P TashkinDavid Geffen School of Medicine, University of California, Los Angeles, CA 90095, USATel +1 310 825 3163Fax +1 310 206 5088Email dtashkin@mednet.ucla.eduAbstract: Analytic epidemiological studies cover a large spectrum of study methodologies, ranging from noninterventional observational studies (population-based, case–control, or cohort studies) to interventional studies (clinical trials). Herein, we review the different research methodologies or study designs and discuss their advantages and disadvantages in the context of chronic obstructive pulmonary disease (COPD) pharmacotherapy. Although randomized controlled trials (RCTs) are considered the “gold standard” for evaluating the efficacy and safety of an intervention, observational studies conducted in a real-world scenario are useful in providing evidence on the effectiveness of the intervention in clinical practice; understanding both efficacy and effectiveness is important from the clinician’s perspective. Pragmatic clinical trials that use real-world data while retaining randomization bridge the gap between explanatory RCTs and noninterventional observational studies. Overall, different study designs have their associated advantages and disadvantages; together, findings from all types of studies bring about progress in clinical research as elucidated through examples from COPD research in this paper.Keywords: clinical trials, COPD, pharmacotherapy, study designs

Reynold A Panettieri Jr,1 Tobias Welte,2 Kartik V Shenoy,3 Stephanie Korn,4 Margret Jandl,5 Edward M Kerwin,6 Rosa Feijoo,7 Peter Barker,8 Richard F Olsson,9 Ubaldo J Martin8 On behalf of the SOLANA Study Investigators1Pulmonary, Allergy and Critical Care Division, University of Pennsylvania, Philadelphia, PA, USA; 2Department of Respiratory Medicine, Member of the German Center of Lung Research, Medizinische Hochschule Hannover, Hannover, Germany; 3Department of Thoracic Medicine and Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA; 4Pulmonary Department, Universitätsmedizin Mainz, Langenbeckstr, Mainz, Germany; 5Hamburger Institut Für Therapieforschung, Hamburg, Germany; 6Clinical Trials Division, Clinical Research Institute of Southern Oregon (Crisor), Medford, OR, USA; 7Departamento De Medicina Interna Oriente, Universidad De Chile, Santiago, Chile; 8Research and Development, AstraZeneca, Gaithersburg, MD, USA; 9R&D, Innovative Medicines and Early Development, Early Clinical Development, AstraZeneca, Gothenburg, SwedenCorrespondence: Reynold A PanettieriUniversity of Pennsylvania, 125 South 31st Street, Philadelphia, PA 19104, USATel +1 215 573-9860Fax +1 215 746-1224Email rp865@rbhs.rutgers.eduObjective: In the SOLANA trial, we sought to physiologically characterize benralizumab’s onset of effect and maintenance of that effect for patients with severe eosinophilic asthma.Methods: SOLANA (NCT02869438) was a multicenter, randomized, double-blind, parallel-group, placebo-controlled, Phase IIIb study conducted at 49 centers in six countries (Chile, Germany, Hungary, the Philippines, South Korea, and the United States). Eligible patients with baseline blood eosinophil counts ≥ 300 cells/μL were randomized to subcutaneous benralizumab (30 mg) or placebo administered at Days 0, 28, and 56. The primary endpoint was the average change from baseline in prebronchodilator forced expiratory volume in 1 s (pre-BD FEV1) during the Day 28‒Day 84 period for benralizumab vs placebo. Secondary endpoints included patient-reported outcomes (PROs). A subset of patients participated in a whole-body plethysmography substudy. Safety was also assessed.Results: In total, 233 patients were randomized to benralizumab (n=118) or placebo (n=115). Improvement from baseline in pre-BD FEV1 with benralizumab 30 mg was not statistically significant compared with placebo (least-squares mean change difference [95% confidence interval] 57 mL [− 22 to 135]; p=0.16). Compared with placebo, benralizumab demonstrated early (Day 7) nonstatistically significant improvements in whole-body plethysmography assessments of hyperinflation and clinically meaningful improvements in PRO measures (Asthma Control Questionnaire 6 at Day 14 and St. George’s Respiratory Questionnaire at Day 28), which were maintained over the treatment period. Benralizumab’s safety profile was commensurate with previously reported studies.Conclusion: The observed early changes in lung volume despite relatively small improvements in airflow obstruction suggest that the anti-inflammatory effect of benralizumab may be manifested as deflation over time for patients with hyperinflation, who potentially have a greater degree of airway remodeling. This early effect could partially explain the rapid PRO improvements observed for certain patients.Keywords: anti–IL-5Rα, benralizumab, interleukin-5, randomized controlled trial, eosinophilic, severe asthma

Dave Singh,1 Anthony D D’Urzo,2 James F Donohue,3 Edward M Kerwin,4 Eduard Molins,5 Ferran Chuecos,5 Anna Ribera,5 Diana Jarreta5 1Medicines Evaluation Unit, University of Manchester, Manchester University NHS Foundation Trust, Manchester, UK; 2Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada; 3Division of Pulmonary Diseases and Critical Care Medicine, University of North Carolina Pulmonary Critical Medicine, Chapel Hill, NC, USA; 4Clinical Research Institute, Medford, OR, USA; 5BioPharmaceuticals R&D, AstraZeneca, Barcelona, SpainCorrespondence: Dave SinghMedicines Evaluation Unit, University of Manchester, Manchester University NHS Foundation Trust, Manchester M23 9QZ, UK Tel +44 161 946 4073Fax +44 161 946 1459Email DSingh@meu.org.ukBackground: Ideally, treatment recommendations for maintenance therapy-naïve patients with COPD should be based on studies conducted specifically in this population. We have reviewed evidence from previous studies of pharmacological treatments in maintenance therapy-naïve patients with COPD and performed a new post-hoc analysis of dual bronchodilator treatment in this population, aiming to assess the effectiveness of these interventions.Materials and methods: A literature review identified clinical trials that included analyses of patients with COPD who were maintenance therapy-naïve with long-acting β2-agonists (LABA) or long-acting muscarinic antagonists (LAMA). Additionally, a post-hoc subgroup analysis was conducted for maintenance therapy-naïve patients with COPD in two large phase III, randomized, double-blind, 24-week trials investigating the efficacy of aclidinium bromide/formoterol fumarate (AB/FF) fixed-dose combination versus monotherapy or placebo (ACLIFORM [NCT01462942] and AUGMENT [NCT01437397]).Results: Treatment-naïve patients with COPD often represent a population of patients at the earliest stage at which most patients seek treatment. Of nine relevant studies identified, all reported positive findings for efficacy of LABA, LAMA, or LABA/LAMA treatment in maintenance therapy-naïve populations. Improvements were observed in lung function, symptoms, and health status versus monotherapy or placebo. Post-hoc analysis of ACLIFORM and AUGMENT demonstrated that AB/FF was effective in improving lung function in patients who had received no prior maintenance therapy. AB/FF showed improvements in 1 hr post-dose FEV1, trough FEV1, and patient-reported outcomes versus placebo and monotherapies. Combined with reviews of previous studies in maintenance therapy-naïve patients, these findings suggest that earlier intervention with a dual bronchodilator maintenance therapy, such as AB/FF, may provide significantly greater benefits than LAMA or LABA mono-bronchodilator therapy as a first maintenance treatment for COPD.Conclusion: These data show that therapeutic intervention is effective in treatment-naïve patients. Intervention with dual bronchodilator therapy as a first maintenance treatment for COPD may provide greater benefits than LAMA or LABA monotherapy.Keywords: COPD, treatment-naïve, LAMA, LABA

Courtney Crim,1 Michael L Watkins,1 Eric D Bateman,2 Gregory J Feldman,3 Isabelle Schenkenberger,4 Edward M Kerwin,5 Catriona Crawford,6 Krishna Pudi,7 Shuyen Ho,8 Charlotte Baidoo,9 Ramiro Castro-Santamaria10 1GSK, Research and Development, Research Triangle Park, NC, USA; 2Division of Pulmonology, Department of Medicine, University of Cape Town, Cape Town, South Africa; 3S. Carolina Pharmaceutical Research, Spartanburg, SC, USA; 4Klinische Forschung Berlin GbR, Berlin, Germany; 5Clinical Trials Division, Crisor LLC, Clinical Research Institute, Medford OR, USA; 6GSK, Global Medical, Stockley Park, Uxbridge, Middlesex, UK; 7Upstate Pharmaceutical Research, Greenville, SC, USA; 8PAREXEL International, Durham, NC, USA; 9GSK, Clinical Statistics, Stockley Park, Uxbridge, Middlesex, UK; 10GSK, Research and Development, Collegeville, PA, USA Background: Batefenterol is a novel bifunctional muscarinic antagonist β2-agonist in development for COPD. The primary objective of this randomized, double-blind, placebo-controlled, active comparator, Phase IIb study was to model the dose–response of batefenterol and select a dose for Phase III development.Patients and methods: Patients aged ≥40 years with COPD and FEV1 ≥30% and ≤70% predicted normal were randomized equally to batefenterol 37.5, 75, 150, 300, or 600 µg, placebo, or umeclidinium/vilanterol (UMEC/VI) 62.5/25 µg once daily. The primary and secondary endpoints were weighted-mean FEV1 over 0–6 hours post-dose and trough FEV1, analyzed by Bayesian and maximum likelihood estimation Emax of dose–response modeling, respectively, on day 42.Results: In the intent-to-treat population (N=323), all batefenterol doses demonstrated statistically and clinically significant improvements from baseline vs placebo in the primary and secondary endpoints (191.1–292.8 and 182.2–244.8 mL, respectively), with a relatively flat dose–response. In the subgroup reversible to salbutamol, there were greater differences between batefenterol doses. Lung function improvements with batefenterol ≥150 µg were comparable with those with UMEC/VI. Batefenterol was well tolerated and no new safety signals were observed.Conclusion: Batefenterol 300 µg may represent the optimal dose for Phase III studies. Keywords: bifunctional, bronchodilator, dual-pharmacophore, dose–response, muscarinic antagonist β2-agonist

Anthony D D’Urzo,1 Dave Singh,2 James F Donohue,3 Edward M Kerwin,4 Anna Ribera,5 Eduard Molins,5 Ferran Chuecos,5 Diana Jarreta,5 Esther Garcia Gil5 1Department of Family and Community Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; 2Medicines Evaluation Unit, Manchester University NHS Foundation Trust, Manchester, UK; 3Division of Pulmonary Diseases & Critical Care Medicine, University of North Carolina School of Medicine at Chapel Hill, Chapel Hill, NC, USA; 4Clinical Research Institute of Southern Oregon, Medford, OR, USA; 5AstraZeneca, Barcelona, Spain Background: Aclidinium/formoterol 400/12 µg is a twice-daily maintenance bronchodilator for COPD. This post hoc study evaluated aclidinium/formoterol vs aclidinium 400 µg, formoterol 12 µg, or placebo in patient subgroups. Patients and methods: Data were pooled from two 24-week Phase III clinical trials (ACLIFORM and AUGMENT). Patients (N=3,394) were analyzed by baseline airflow obstruction severity (moderate/severe), age (

Edward M Kerwin,1 Robert Tosiello,2 Barry Price,2 Shahin Sanjar,2 Thomas Goodin2 1Clinical Research Institute of Southern Oregon, Inc., Medford, OR, USA; 2Sunovion Pharmaceuticals Inc., Marlborough, MA, USA Background: Phase III studies demonstrated efficacy and safety of nebulized glycopyrrolate inhalation solution (GLY) in subjects with COPD. Secondary analyses were performed to examine the effect of background long-acting beta2-agonist (LABA) use on the efficacy and safety of nebulized GLY. Methods: In two 12-week placebo-controlled studies (GOLDEN 3 and GOLDEN 4) and one 48-week, open-label active-controlled study (GOLDEN 5), a total of 2,379 subjects were stratified by background LABA use (LABA-yes: n=861; LABA-no: n=1,518) and randomized to placebo vs GLY 25 or 50 µg twice daily, or GLY 50 µg twice daily vs tiotropium (TIO) 18 µg once daily. Lung function, patient-reported outcomes, exacerbations, and safety were assessed. Results: Compared with placebo, pooled data from the 12-week studies showed significant improvements from baseline with GLY 25 and 50 µg across LABA subgroups in trough FEV1 (LABA-yes: 0.101 and 0.110 L; LABA-no: 0.092 and 0.101 L, respectively; P

Colin Reisner,1,2 James Pearle,3 Edward M Kerwin,4 Earl St Rose,1 Patrick Darken1 1Pearl – a member of the AstraZeneca Group, Morristown, NJ, USA; 2AstraZeneca, Gaithersburg, MD, USA; 3California Research Medical Group, Inc., Fullerton, CA, USA; 4Clinical Research Institute of Southern Oregon, Medford, OR, USA Purpose: To determine the efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI 36/9.6, 36/7.2, 18/9.6, 9/9.6 μg) using innovative co‑suspension delivery technology, compared with glycopyrrolate (GP) MDI 36 μg and formoterol fumarate (FF) MDI 9.6 μg, in patients with moderate-to-severe COPD. Methods: In this Phase IIb, randomized, double-blind, balanced incomplete-block, two-period, cross-over study (NCT01349816), patients received treatment twice-daily for 7 days. The primary efficacy endpoint was forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 12 hours (AUC0–12) on Day 7. Secondary efficacy endpoints were peak change from baseline in FEV1 through 2 hours; time to onset of action (≥10% improvement in mean FEV1); proportion of patients achieving ≥12% improvement in FEV1 on Day 1; peak change from baseline in inspiratory capacity (IC) on Days 1 and 7; change from baseline in morning pre-dose FEV1; peak change from baseline in FEV1 through 6 hours; and change from baseline in mean evening 12-hour post-dose trough FEV1 on Day 7. Safety was assessed. Results: All 185 randomized patients received treatment. All doses of GFF MDI significantly improved the primary endpoint compared with GP MDI 36 μg (all P≤0.0137). For peak change in FEV1 and IC and time to onset of action secondary endpoints, ≥2 doses of GFF MDI demonstrated superiority to GP MDI 36 μg. No significant differences were observed between GFF MDI and FF MDI 9.6 μg for primary and secondary endpoints. The incidence of adverse events was similar between treatments. Conclusion: While all doses of GFF MDI were superior to GP MDI 36 μg for the primary endpoint, in this study neither superiority of GFF MDI to FF MDI 9.6 μg nor a clear dose-response was observed. All treatments were well tolerated with no unexpected safety findings. Keywords: bronchodilator, chronic obstructive pulmonary disease, co-suspension delivery technology, fixed-dose combination, LAMA/LABA, long-acting β2-agonist, long-acting muscarinic antagonist

Edward M Kerwin,1 Thomas M Siler,2 Samir Arora,3 Patrick Darken,4 Earl St Rose,4 Colin Reisner4,5 1Clinical Research Institute of Southern Oregon, Medford, OR, USA; 2Midwest Chest Consultants, St Charles, MO, USA; 3Aventiv Research, Columbus, OH, USA; 4Pearl – a member of the AstraZeneca Group, Morristown, NJ, USA; 5AstraZeneca, Gaithersburg, MD, USA Purpose: This study investigated the efficacy, safety, and pharmacokinetics of the inhaled corticosteroid/long-acting β2-agonist fixed-dose combination budesonide/formoterol fumarate (BFF) metered dose inhaler (MDI), compared with the monocomponents budesonide (BD) MDI and formoterol fumarate (FF) MDI, in patients with moderate-to-severe COPD. Materials and methods: In this Phase IIb, randomized, double-blind, four-period, five-treatment, incomplete-block, crossover study (NCT02196077), all patients received BFF MDI 320/9.6 μg and FF MDI 9.6 μg, and two of either BFF MDI 160/9.6 μg, BFF MDI 80/9.6 μg, or BD MDI 320 μg twice daily for 28 days. The primary efficacy endpoint was forced expiratory volume in 1 second area under the curve from 0 to 12 hours on Day 29. Secondary efficacy endpoints included additional lung function assessments, and evaluation of dyspnea and rescue medication use. Safety was monitored throughout. The systemic exposure to budesonide and formoterol was assessed on Day 29. Results: Overall, 180 patients were randomized. For forced expiratory volume in 1 second area under the curve from 0 to 12 hours on Day 29, all BFF MDI doses showed significant improvements versus BD MDI 320 μg (least squares mean differences 186–221 mL; all p

Edward M Kerwin,1 Thomas J Ferro,2 Rinat Ariely,3 Debra E Irwin,4 Ruchir Parikh3 1Clinical Trials Division, Clinical Research Institute of Southern Oregon, PC, Medford, OR, 2Global Medical Affairs, 3Global Health Economics and Outcome Research, Teva Pharmaceuticals, Frazer, PA, 4Outcomes Research, Truven Health Analytics, Durham, NC, USA Background: Accurate tracking of the administered dose of asthma rescue inhalers is critical for optimal disease management and is related to reductions in rates of unscheduled health care utilization in asthma patients. There are few published data on the real-world impact of rescue inhalers with integrated dose counters (IDCs) on health care resource utilization (HRU) for asthma patients. This study evaluates HRU among users of ProAir® hydrofluoroalkane (HFA) (albuterol sulfate inhalation aerosol), with IDC versus without IDC, in asthma patients.Methods: This was a retrospective administrative claims study of asthma patients receiving a new prescription for albuterol inhalation aerosol without IDC during 2 years (January 2011–December 2012) or with IDC during the first full year after IDC implementation in the USA (July 2013–July 2014). Six months of continuous enrollment with medical and prescription drug benefits were required before and after the first prescription during the study period. Data on respiratory-related hospitalizations and emergency department (ED) visits were collected during the follow-up period.Results: A total of 135,305 (32%) patients used albuterol inhalation aerosol with IDC, and 287,243 (68%) patients received albuterol inhalation aerosol without IDC. After adjusting for baseline confounding factors, the odds ratio (OR) for experiencing a respiratory-related hospitalization (OR=0.92; 95% confidence interval [CI] 0.88–0.96) or ED visit (OR=0.92; 95% CI 0.90–0.94) was significantly lower among patients using albuterol inhalation aerosol with IDC versus without IDC.Conclusion: In a real-world setting, asthma patients using ProAir HFA with IDC experienced significantly fewer hospitalizations and ED visits compared with patients using ProAir HFA without IDC. Dosage information provided by IDCs may allow providers to better understand patients’ disease severity and aid in titrating controller medications and also decrease the likelihood that the canister will be empty when needed, thereby enhancing disease management and reducing HRU. Keywords: asthma, ProAir, integrated dose counters, respiratory-related hospitalizations, emergency department visits, lower respiratory tract infections-related outpatient visits

Edward M Kerwin,1 Chris J Kalberg,2 Dmitry V Galkin,2 Chang-Qing Zhu,3 Alison Church,2 John H Riley,4 William A Fahy4 1Clinical Research Institute of Southern Oregon, Medford, OR, 2Respiratory Department, GlaxoSmithKline, Research Triangle Park, NC, USA; 3Clinical Statistics, GlaxoSmithKline, Stockley Park, Uxbridge, Middlesex, 4Respiratory Department, GlaxoSmithKline, Stockley Park, Uxbridge, Middlesex, UK Introduction: Patients with COPD who remain symptomatic on long-acting bronchodilator monotherapy may benefit from step-up therapy to a long-acting bronchodilator combination. This study evaluated the efficacy and safety of umeclidinium (UMEC)/vilanterol (VI) in patients with moderate COPD who remained symptomatic on tiotropium (TIO). Methods: In this randomized, blinded, double-dummy, parallel-group study (NCT01899742), patients (N=494) who were prescribed TIO for ≥3 months at screening (forced expiratory volume in 1 s [FEV1]: 50%–70% of predicted; modified Medical Research Council [mMRC] score ≥1) and completed a 4-week run-in with TIO were randomized to UMEC/VI 62.5/25 µg or TIO 18 µg for 12 weeks. Efficacy assessments included trough FEV1 at Day 85 (primary end point), 0–3 h serial FEV1, rescue medication use, Transition Dyspnea Index (TDI), St George’s Respiratory Questionnaire (SGRQ), and COPD Assessment Test (CAT). Safety evaluations included adverse events (AEs). Results: Compared with TIO, UMEC/VI produced greater improvements in trough FEV1 (least squares [LS] mean difference: 88 mL at Day 85 [95% confidence interval {CI}: 45–131]; P

Anthony D D’Urzo,1 Edward M Kerwin,2 Kenneth R Chapman,3 Marc Decramer,4 Robert DiGiovanni,5 Peter D’Andrea,6 Huilin Hu,6 Pankaj Goyal,5 Pablo Altman6 1Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada; 2Clinical Research Institute of Southern Oregon, PC, Medford, USA; 3Asthma and Airway Centre, University Health Network, Toronto Western Hospital, Toronto, ON, Canada; 4Respiratory Division, University of Leuven, Leuven, Belgium; 5Novartis Pharma AG, Basel, Switzerland; 6Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA Background: Chronic use of inhaled anticholinergics by patients with chronic obstructive pulmonary disease (COPD) has raised long-term safety concerns, particularly cardiovascular. Glycopyrronium is a once-daily anticholinergic with greater receptor selectivity than previously available agents. Methods: We assessed the safety of inhaled glycopyrronium using data pooled from two analysis sets, involving six clinical studies and over 4,000 patients with COPD who received one of the following treatments: glycopyrronium 50 µg, placebo (both delivered via the Breezhaler® device), or tiotropium 18 µg (delivered via the HandiHaler® device). Data were pooled from studies that varied in their duration and severity of COPD of the patients (ie, ≤12 weeks duration with patients having moderate or severe COPD; and >1 year duration with patients having severe and very severe COPD). Safety comparisons were made for glycopyrronium vs tiotropium or placebo. Poisson regression was used to assess the relative risk for either active drug or placebo (and between drugs where placebo was not available) for assessing the incidence of safety events. During post-marketing surveillance (PMS), safety was assessed by obtaining reports from various sources, and disproportionality scores were computed using EMPIRICA™. In particular, the cardiac safety of glycopyrronium during the post-marketing phase was evaluated.Results: The overall incidence of adverse events and deaths was similar across groups, while the incidence of serious adverse events was numerically higher in placebo. Furthermore, glycopyrronium did not result in an increased risk of cerebro-cardiovascular events vs placebo. There were no new safety reports during the PMS phase that suggested an increased risk compared to results from the clinical studies. Moreover, the cardiac safety of glycopyrronium during the PMS phase was also consistent with the clinical data.Conclusion: The overall safety profile of glycopyrronium was similar to its comparators indicating no increase in the overall risk for any of the investigated safety end points. Keywords: COPD, drug safety, glycopyrronium, post-marketing surveillance

This review addresses outstanding questions regarding initial pharmacological management of chronic obstructive pulmonary disease (COPD). Optimizing initial treatment improves clinical outcomes in symptomatic patients, including those with low exacerbation risk. Long-acting muscarinic antagonist/long-acting β 2 -agonist (LAMA/LABA) dual therapy improves lung function versus LAMA or LABA monotherapy, although other treatment benefits have been less consistently observed. The benefits of dual bronchodilation in symptomatic patients with COPD at low exacerbation risk, and its duration of efficacy and cost effectiveness in this population, are not yet fully established. Questions remain on the impact of baseline symptom severity, prior treatment, degree of reversibility to bronchodilators, and smoking status on responses to dual bronchodilator treatment. Using evidence from EMAX (NCT03034915), a 6-month trial comparing the LAMA/LABA combination umeclidinium/vilanterol with umeclidinium and salmeterol monotherapy in symptomatic patients with COPD at low exacerbation risk who were inhaled corticosteroid-naïve, we describe how these findings can be applied in primary care., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: EMK has served on advisory boards, speaker panels or received travel reimbursement for Amphastar, AstraZeneca, Boehringer Ingelheim, Connect Biopharma, GSK, Mylan, Novartis, Pearl, Sunovion, Teva and Theravance, and has received consulting fees from Cipla and GSK. PWJ is an Emeritus Professor of Respiratory Medicine at St George’s, University of London, and a former full-time employee of GSK at the time of protocol development and contributed to study design and protocol on behalf of GSK. He is a part-time consultant at GSK and holds stocks/shares. IHB, DAL and CC are employees of GSK and hold stock and shares in GSK. LHB has received honoraria for giving a lecture or attending an advisory board for Airsonett, ALK-Abelló, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Meda, Novartis and Teva. FM has received research grants for participating in multicenter trials for AstraZeneca, Boehringer Ingelheim, GSK, Sanofi and Novartis, and has received unrestricted research grants and personal fees from Boehringer Ingelheim, Grifols and Novartis. IPN was an employee of GSK at the time of the EMAX trial, holds stocks and shares in GSK, and was a contingent worker on assignment at AstraZeneca. LT is a contingent worker on assignment at GSK. CFV has received grants from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Grifols, Mundipharma, Novartis, and the German Federal Ministry of Education and Research (BMBF) Competence Network Asthma and COPD (ASCONET), and has received personal fees from AstraZeneca, Boehringer Ingelheim, Berlin Chemie/Menarini, Chiesi, CSL Behring, GSK, Grifols, MedUpdate, Novartis and Teva. DISKUS and ELLIPTA are owned by/licensed to the GSK group of companies.

Early MAXimisation of bronchodilation for improving COPD stability (EMAX) was a large, multicentre, multi-national, randomised, double-blind, 24-week trial. EMAX evaluated the efficacy and safety of dual bronchodilator therapy with umeclidinium bromide (UMEC)/vilanterol (VI) versus monotherapy with either UMEC or salmeterol (SAL) in symptomatic patients with chronic obstructive pulmonary disease (COPD) at low exacerbation risk who were not taking concomitant inhaled corticosteroid (ICS). EMAX generated evidence covering a wide range of patient-centred endpoints in COPD in addition to measures of lung function, clinical deterioration and safety. In addition, prospective and post hoc secondary analyses have generated clinically valuable information regarding the effects of baseline patient characteristics on treatment outcomes. Importantly, as concomitant ICS use was not permitted in this study, EMAX compared dual long-acting muscarinic antagonist (LAMA)/long-acting β 2 -agonist (LABA) therapy with LAMA or LABA monotherapy without potential confounding due to concurrent ICS use or withdrawal. EMAX demonstrated beneficial treatment effects of UMEC/VI over UMEC or SAL monotherapy as maintenance treatment across a range of different patient characteristics, with no forfeit in safety. Thus, the trial provided novel insights into the role of LAMA/LABA versus LABA and LAMA monotherapies as maintenance therapy for patients with symptomatic COPD at low risk of exacerbations. This article will explore the clinical implications of the main findings to date of the EMAX trial and consider the key learnings this trial offers for future trial design in COPD., Competing Interests: Disclosures FM has received research grants for participating in multicentre trials for AstraZeneca, Boehringer Ingelheim, GSK, Sanofi and Novartis, and has received unrestricted research grants and personal fees from Boehringer Ingelheim, Grifols and Novartis. CFV has received grants from AstraZeneca, Boehringer Ingelheim, GSK, Grifols and Novartis, and has received lecturing and personal fees from AstraZeneca, Boehringer Ingelheim, Berlin Chemie/Menarini, Chiesi, CSL Behring, GSK, Grifols, MedUpdate, Novartis, Aerogen and Nuvaira. EMK has served on advisory boards, speaker panels or received travel reimbursement for Amphastar, AstraZeneca, Boehringer Ingelheim, Connect Biopharma, GSK, Mylan, Novartis, Pearl, Sunovion, Teva and Theravance, and has received consulting fees from Cipla and GSK. LHB has received honoraria for giving a lecture or attending an advisory board for Airsonett, ALK-Abelló, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Meda, Novartis and Teva. PWJ, IHB, DAL and CC are GSK employees and hold shares and stocks in GSK. LT is a contingent worker on assignment at GSK. IPN was an employee of GSK at the time of the EMAX trial, holds stocks and shares in GSK, and was a contingent worker on assignment at AstraZeneca., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In patients with chronic obstructive pulmonary disease (COPD), the relationship between short-term bronchodilator reversibility and longer-term response to bronchodilators is unclear. Here, we investigated whether the efficacy of long-acting bronchodilators is associated with reversibility of airflow limitation in patients with COPD with a low exacerbation risk not receiving inhaled corticosteroids., Methods: The double-blind, double-dummy EMAX trial randomised patients to umeclidinium/vilanterol 62.5/25 µg once daily, umeclidinium 62.5 µg once daily, or salmeterol 50 µg twice daily. Bronchodilator reversibility to salbutamol was measured once at screening and defined as an increase in forced expiratory volume in 1 s (FEV 1 ) of ≥ 12% and ≥ 200 mL 10-30 min post salbutamol. Post hoc, fractional polynomial (FP) modelling was conducted using the degree of reversibility (mL) at screening as a continuous variable to investigate its relationship to mean change from baseline in trough FEV 1 and self-administered computerised-Transition Dyspnoea Index (SAC-TDI) at Week 24, Evaluating Respiratory Symptoms-COPD (E-RS) at Weeks 21-24, and rescue medication use (puffs/day) over Weeks 1-24. Analyses were conducted across the full range of reversibility (-850-896 mL); however, results are presented for the range -100-400 mL because there were few participants with values outside this range., Results: The mean (standard deviation) reversibility was 130 mL (156) and the median was 113 mL; 625/2425 (26%) patients were reversible. There was a trend towards greater improvements in trough FEV 1 , SAC-TDI, E-RS and rescue medication use with umeclidinium/vilanterol with higher reversibility. Improvements in trough FEV 1 and reductions in rescue medication use were greater with umeclidinium/vilanterol compared with either monotherapy across the range of reversibility. Greater improvements in SAC-TDI and E-RS total scores were observed with umeclidinium/vilanterol versus monotherapy in the middle of the reversibility range., Conclusions: FP analyses suggest that patients with higher levels of reversibility have greater improvements in lung function and symptoms in response to bronchodilators. Improvements in lung function and rescue medication use were greater with umeclidinium/vilanterol versus monotherapy across the full range of reversibility, suggesting that the dual bronchodilator umeclidinium/vilanterol may be an appropriate treatment for patients with symptomatic COPD, regardless of their level of reversibility., (© 2021. The Author(s).)

Introduction: Limited prospective evidence is available to guide selection of first-line maintenance therapy in patients with COPD. This pre-specified analysis of the EMAX trial explored the efficacy and safety of dual- versus mono-bronchodilator therapy in maintenance-naïve and maintenance-treated patients., Methods: The 24-week EMAX trial evaluated lung function, symptoms (including rescue medication use), exacerbations, and safety with umeclidinium/vilanterol, umeclidinium, and salmeterol in symptomatic patients at low exacerbation risk who were not receiving inhaled corticosteroids. Maintenance-naïve and maintenance-treated subgroups were defined by maintenance bronchodilator use 30 days before screening., Results: The analysis included 749 (31%) maintenance-naïve and 1676 (69%) maintenance-treated patients. For both subgroups, improvements from baseline in trough FEV 1 at Week 24 (primary endpoint) were greater with umeclidinium/vilanterol versus umeclidinium (mean difference [95% CI]; maintenance-naïve: 44 mL [1, 87]; maintenance-treated: 77 mL [50, 104]), and salmeterol (maintenance-naïve: 128 mL [85, 171]; maintenance-treated: 145 mL [118, 172]), and in rescue medication inhalations/day over 24 weeks versus umeclidinium (maintenance-naïve: -0.44 [-0.73, -0.16]; maintenance-treated: -0.28 [-0.45, -0.12]) and salmeterol (maintenance-naïve: -0.37 [-0.66, -0.09]; maintenance-treated: -0.25 [-0.41, -0.08]). In maintenance-naïve patients, umeclidinium/vilanterol numerically improved scores at Week 24 for Transition Dyspnea Index versus umeclidinium (0.37 [-0.21, 0.96]) and versus salmeterol (0.47 [-0.10, 1.05]) and Evaluating Respiratory Symptoms-COPD versus umeclidinium (-0.26 [-1.04, 0.53]) and versus salmeterol (-0.58 [-1.36, 0.20]), with similar improvements seen in maintenance-treated patients. All treatments were well tolerated across both subgroups., Conclusion: Similar to maintenance-treated patients, maintenance-naïve patients receiving umeclidinium/vilanterol showed greater improvements in lung function and symptoms compared with patients receiving umeclidinium or salmeterol. These findings provide support for the consideration of dual bronchodilator treatment in symptomatic maintenance-naïve patients with COPD., Competing Interests: IHB, DAL, CC, and PWJ are employees of GSK and hold stocks and shares in GSK. IHB’s current affiliation is Medical Emerging Markets, GSK, Brentford, Middlesex, UK. IPN was an employee of GSK at the time of the study, holds stocks and shares in GSK, and was a contingent worker on assignment at AstraZeneca. IPN’s current affiliation is RAMAX Ltd, Bramhall, Cheshire, UK. LT is a contingent worker on assignment at GSK. FM has received research grants for participating in multicenter trials for AstraZeneca, Boehringer Ingelheim, GSK, Sanofi, and Novartis, and has received unrestricted research grants and personal fees from Boehringer Ingelheim, Grifols, and Novartis. LB has received honoraria for giving a lecture or attending an advisory board for Airsonett, ALK-Abello, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Meda, Novartis and Teva. EMK has served on advisory boards, speaker panels or received travel reimbursement from for Amphastar, AstraZeneca, Boehringer Ingelheim, Connect Biopharma, GSK, Mylan, Novartis, Pearl, Sunovion, Teva, and Theravance and has received consulting fees from Cipla and GSK. CFV has received grants from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Grifols, Novartis, and the German Federal Ministry of Education and Research (BMBF) Competence Network Asthma and COPD (ASCONET), and has received personal fees from AstraZeneca, Boehringer Ingelheim, Berlin Chemie/Menarini, Chiesi, CSL Behring, GSK, Grifols, MedUpdate, Novartis, Nuvaira, and Teva. The authors report no other conflicts of interest in this work., (© 2021 Bjermer et al.)

Background: Short-acting β 2 -agonist (SABA) bronchodilators help alleviate symptoms in chronic obstructive pulmonary disease (COPD) and may be a useful marker of symptom severity. This analysis investigated whether SABA use impacts treatment differences between maintenance dual- and mono-bronchodilators in patients with COPD., Methods: The Early MAXimisation of bronchodilation for improving COPD stability (EMAX) trial randomised symptomatic patients with low exacerbation risk not receiving inhaled corticosteroids 1:1:1 to once-daily umeclidinium/vilanterol 62.5/25 μg, once-daily umeclidinium 62.5 μg or twice-daily salmeterol 50 μg for 24 weeks. Pre-specified subgroup analyses stratified patients by median baseline SABA use (low, < 1.5 puffs/day; high, ≥1.5 puffs/day) to examine change from baseline in trough forced expiratory volume in 1 s (FEV 1 ), change in symptoms (Transition Dyspnoea Index [TDI], Evaluating Respiratory Symptoms-COPD [E-RS]), daily SABA use and exacerbation risk. A post hoc analysis used fractional polynomial modelling with continuous transformations of baseline SABA use covariates., Results: At baseline, patients in the high SABA use subgroup (mean: 3.91 puffs/day, n = 1212) had more severe airflow limitation, were more symptomatic and had worse health status versus patients in the low SABA use subgroup (0.39 puffs/day, n = 1206). Patients treated with umeclidinium/vilanterol versus umeclidinium demonstrated statistically significant improvements in trough FEV 1 at Week 24 in both SABA subgroups (59-74 mL; p < 0.001); however, only low SABA users demonstrated significant improvements in TDI (high: 0.27 [p = 0.241]; low: 0.49 [p = 0.025]) and E-RS (high: 0.48 [p = 0.138]; low: 0.60 [p = 0.034]) scores. By contrast, significant reductions in mean SABA puffs/day with umeclidinium/vilanterol versus umeclidinium were observed only in high SABA users (high: - 0.56 [p < 0.001]; low: - 0.10 [p = 0.132]). Similar findings were observed when comparing umeclidinium/vilanterol and salmeterol. Fractional polynomial modelling showed baseline SABA use ≥4 puffs/day resulted in smaller incremental symptom improvements with umeclidinium/vilanterol versus umeclidinium compared with baseline SABA use < 4 puffs/day., Conclusions: In high SABA users, there may be a smaller difference in treatment response between dual- and mono-bronchodilator therapy; the reasons for this require further investigation. SABA use may be a confounding factor in bronchodilator trials and in high SABA users; changes in SABA use may be considered a robust symptom outcome., Funding: GlaxoSmithKline (study number 201749 [NCT03034915]).

Purpose: To assess clinical characteristics and device satisfaction of patients with chronic obstructive pulmonary disease (COPD) treated with glycopyrrolate/eFlow ® Closed System (CS) nebulizer (further referred to as eFlow) under real-world conditions., Participants and Methods: Patients with COPD currently using eFlow were identified by the study sponsor. Consenting patients who met study inclusion criteria completed a cross-sectional survey that included a device satisfaction questionnaire. Means, medians, and standard deviations were calculated., Results: Sixty-six patients met inclusion criteria and completed the survey. Participants' mean ± standard deviation age was 64.9 ± 11.9 years and the majority were white (86.4%) and female (59.1%). Almost two-thirds were former smokers. Thirty-nine (59.1%) reported their COPD to be severe/very severe and 38 (57.6%) reported a COPD exacerbation resulting in a hospitalization, ER visit, or medication modification over the past 12 months. Among 55 participants who had previously used another type of nebulizer, 44 (80%) were overall "much more"/"somewhat more" satisfied with the eFlow compared with their previous nebulizer(s). Regardless of prior nebulizer use, 60 (90.9%) participants were "satisfied"/"very satisfied" overall with the eFlow. Assembly and disassembly, operation, and cleaning were perceived as being "easy"/"very easy" by at least 65% of participants. Among all participants, 57 (86.4%) were "confident"/"very confident" of glycopyrrolate administration. On a Likert scale of 1 ("I don't like it") to 7 ("I like it a lot"), mean scores were at least 5.9 for portability, ease of cleaning, size, weight, short administration time, and relative silence of the device. Over 80% of participants said they "probably"/"definitely" would continue to use eFlow., Conclusion: Based on this real-world study, the majority of patients were highly satisfied with, and confident in, using eFlow., Competing Interests: Carole Dembek is an employee of Sunovion Pharmaceuticals Inc. Edward M Kerwin has received consultancy and advisory fees from Amphastar, AstraZeneca, Boehringer Ingelheim, Cipla, GlaxoSmithKline, Mylan, Novartis, Oriel, Pearl, Sunovion, Teva, and Theravance. The authors report no other conflicts of interest in this work., (© 2020 Stephenson et al.)

Background: Inhaler errors among patients with chronic obstructive pulmonary disease (COPD) can reduce treatment efficacy., Methods: This randomized, open-label, crossover study evaluated correct use of ELLIPTA versus DISKUS plus HandiHaler. Participants with COPD attended at least 3 study visits (Day 1 [Visit 1], Day 28 [Visit 2], and Day 56 [Visit 3]). Inhalers contained placebo; usual maintenance medication was continued. Participants were randomized to an inhaler sequence (ELLIPTA then DISKUS plus HandiHaler, or the reverse) and preference questionnaire at Visit 1. Participants read the instructions for use in the approved prescribing information for their inhaler(s) and correct use was assessed at Visit 1 (verbal guidance provided if required). Correct use was reassessed at Visit 2, and with the next inhaler(s) at Visit 3. Primary endpoint was the proportion of participants demonstrating correct use (0 errors) with the assigned inhaler(s) after 28 days., Results: A greater proportion of study participants (n = 217) correctly used ELLIPTA (96%) versus DISKUS plus HandiHaler (87%) after 28 days. The odds of demonstrating correct use with ELLIPTA were 6.88 times that of DISKUS plus HandiHaler ( p < 0.001). Overall, > 99% of participants made 0 critical errors (errors leading to no or significantly reduced medication inhaled) with ELLIPTA versus 89% with DISKUS plus HandiHaler after 28 days. ELLIPTA was the patient-preferred option versus DISKUS plus HandiHaler or no preference ( p < 0.001)., Conclusions: Delivery of COPD maintenance therapy via ELLIPTA demonstrates higher correct use rates and lower critical error rates compared with DISKUS plus HandiHaler., Competing Interests: EMK has participated in consulting, advisory boards, speaker panels, or received travel reimbursement from Amphastar, AstraZeneca, Boehringer Ingelheim, Chiesi, Cipla, GlaxoSmithKline plc., Mylan, Novartis, Oriel, Pearl, Sunovion, Teva, and Theravance. He has conducted multicenter clinical research trials for approximately 40 pharmaceutical companies. SS has been a principal investigator for 20 years and has conducted clinical research trials for a large number of pharmaceutical companies. He has also participated as a consultant and on advisory boards and speaker panels for pharmaceutical companies including AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline plc., Mylan, Menlo, Novartis, Pearl, Sunovion, Teva, and Theravance. MZ, VM, RJ, KC, and RS are employees of, and own shares in, GlaxoSmithKline plc. Editorial support (in the form of writing assistance, collating author comments, assembling tables and/or figures, grammatical editing, fact checking, and referencing) was provided by Matthew Hallam, MSc(Res) and Joanna Wilson, PhD, of Gardine—Caldwell Communications (Macclesfield, UK) and was funded by GlaxoSmithKline plc. Trademarks are the property of their respective owners., (JCOPDF © 2020.)

Background: In chronic obstructive pulmonary disease (COPD), both the time needed for patients to gain symptom improvement with long-acting bronchodilator therapy and whether an early response is predictive of a sustained response is unknown. This study aimed to investigate how quickly meaningful symptom responses are seen in patients with COPD with bronchodilator therapy and whether these responses are sustained., Methods: Early MAXimisation of bronchodilation for improving COPD stability (EMAX) was a 24-week, double-blind, double-dummy, parallel-group trial that randomised patients to umeclidinium/vilanterol (UMEC/VI), umeclidinium or salmeterol. Daily Evaluating Respiratory Symptoms in COPD (E-RS:COPD) score and rescue salbutamol use were captured via an electronic diary and analysed initially in 4-weekly periods. Post hoc analyses assessed change from baseline in daily E-RS:COPD score and rescue medication use weekly (Weeks 1-8), and association between E-RS:COPD responder status at Weeks 1-4 and later time points., Results: In the intent-to-treat population ( n  = 2425), reductions from baseline in E-RS:COPD scores and rescue medication use were apparent from Day 2 with all treatments. Treatment differences for UMEC/VI versus either monotherapy plateaued by Week 4-8 and were sustained at Weeks 21-24; improvements were consistently greater with UMEC/VI. For all treatments, most patients (60-85%) retained their Weeks 1-4 E-RS:COPD responder/non-responder status at Weeks 21-24. Among patients receiving UMEC/VI who were E-RS:COPD responders at Weeks 1-4, 70% were responders at Weeks 21-24., Conclusion: Patients with symptomatic COPD had greater potential for early symptom improvements with UMEC/VI versus either monotherapy. This benefit was generally maintained for 24 weeks. Early monitoring of treatment response can provide clinicians with an early indication of a patient's likely longer-term response to prescribed bronchodilator treatment and will facilitate appropriate early adjustments in care., Clinical Trial Registration: NCT03034915, 2016-002513-22 (EudraCT Number). The reviews of this paper are available via the supplemental material section.

Rationale: Symptom relief is a key treatment goal in patients with chronic obstructive pulmonary disease (COPD). However, there are limited data available on the response to bronchodilator therapy in patients at low risk of exacerbations with different levels of symptom severity. This study compared treatment responses in patients with a range of symptom severities as indicated by baseline COPD assessment test (CAT) scores., Methods: The 24-week EMAX trial evaluated the benefits of umeclidinium/vilanterol versus umeclidinium or salmeterol in symptomatic patients at low exacerbation risk who were not receiving inhaled corticosteroids. This analysis assessed lung function, symptoms, health status, and short-term deterioration outcomes in subgroups defined by a baseline CAT score [<20 ( post hoc ) and ⩾20 (pre-specified)]. Outcomes were also assessed using post hoc fractional polynomial modelling with continuous transformations of baseline CAT score covariates., Results: Of the intent-to-treat population ( n  = 2425), 56% and 44% had baseline CAT scores of <20 and ⩾20, respectively. Umeclidinium/vilanterol demonstrated favourable improvements compared with umeclidinium and salmeterol for the majority of outcomes irrespective of the baseline CAT score, with the greatest improvements generally observed in patients with CAT scores <20. Fractional polynomial analyses revealed consistent improvements in lung function, symptoms and reduction in rescue medication use with umeclidinium/vilanterol versus umeclidinium and salmeterol across a range of CAT scores, with the largest benefits seen in patients with CAT scores of approximately 10-21., Conclusions: Patients with symptomatic COPD benefit similarly from dual bronchodilator treatment with umeclidinium/vilanterol. Fractional polynomial analyses demonstrated the greatest treatment differences favouring dual therapy in patients with a CAT score <20, although benefits were seen up to scores of 30. This suggests that dual bronchodilation may be considered as initial therapy for patients across a broad range of symptom severities, not only those with severe symptoms (CAT ⩾20). Trial registration: NCT03034915, 2016-002513-22 (EudraCT number). The reviews of this paper are available via the supplemental material section.

Background: Prospective evidence is lacking regarding incremental benefits of long-acting dual- versus mono-bronchodilation in improving symptoms and preventing short-term disease worsening/treatment failure in low exacerbation risk patients with chronic obstructive pulmonary disease (COPD) not receiving inhaled corticosteroids., Methods: The 24-week, double-blind, double-dummy, parallel-group Early MAXimisation of bronchodilation for improving COPD stability (EMAX) trial randomised patients at low exacerbation risk not receiving inhaled corticosteroids, to umeclidinium/vilanterol 62.5/25 μg once-daily, umeclidinium 62.5 μg once-daily or salmeterol 50 μg twice-daily. The primary endpoint was trough forced expiratory volume in 1 s (FEV 1 ) at Week 24. The study was also powered for the secondary endpoint of Transition Dyspnoea Index at Week 24. Other efficacy assessments included spirometry, symptoms, heath status and short-term disease worsening measured by the composite endpoint of clinically important deterioration using three definitions., Results: Change from baseline in trough FEV 1 at Week 24 was 66 mL (95% confidence interval [CI]: 43, 89) and 141 mL (95% CI: 118, 164) greater with umeclidinium/vilanterol versus umeclidinium and salmeterol, respectively (both p < 0.001). Umeclidinium/vilanterol demonstrated consistent improvements in Transition Dyspnoea Index versus both monotherapies at Week 24 (vs umeclidinium: 0.37 [95% CI: 0.06, 0.68], p = 0.018; vs salmeterol: 0.45 [95% CI: 0.15, 0.76], p = 0.004) and all other symptom measures at all time points. Regardless of the clinically important deterioration definition considered, umeclidinium/vilanterol significantly reduced the risk of a first clinically important deterioration compared with umeclidinium (by 16-25% [p < 0.01]) and salmeterol (by 26-41% [p < 0.001]). Safety profiles were similar between treatments., Conclusions: Umeclidinium/vilanterol consistently provides early and sustained improvements in lung function and symptoms and reduces the risk of deterioration/treatment failure versus umeclidinium or salmeterol in symptomatic patients with low exacerbation risk not receiving inhaled corticosteroids. These findings suggest a potential for early use of dual bronchodilators to help optimise therapy in this patient group.

Background: Long-term use of inhaled corticosteroids (ICSs) has been associated with increased risk of bone and ocular comorbidities. We evaluated the effects of the triple fixed-dose combination budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI), formulated using co-suspension delivery technology, on bone mineral density (BMD) and ocular safety in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD)., Methods: In this extension study, a subset of patients from the 24-week, phase III, randomized, double-blind KRONOS study (NCT02497001) continued treatment (BGF MDI 320/18/9.6 μg, budesonide/formoterol fumarate [BFF] MDI 320/9.6 μg or glycopyrrolate/formoterol fumarate [GFF] MDI 18/9.6 μg, as a non-steroidal comparator) for an additional 28 weeks. Primary endpoints were percentage change from baseline in lumbar spine BMD and change from baseline in lens opacities classification system III posterior subcapsular cataract (P) score, both at Week 52. Adverse events were also assessed., Results: In total, 456 patients were included in the safety population (53.1% male, mean age 62.8 years). Changes from baseline in lumbar spine BMD (least squares mean [LSM] range - 0.12 to 0.38%) and P score (LSM range 0.02-0.15) were small for all treatments. Both BGF MDI and BFF MDI were non-inferior to GFF MDI using margins of -2% (BMD) and 0.5 units (P score). The incidence of treatment-emergent adverse events (TEAEs)  was generally similar among groups. Rates of confirmed pneumonia were low overall (2.4%) and highest in the GFF MDI group (3.4%), followed by BGF MDI (2.1%) and BFF MDI (1.1%). There were no cumulative adverse effects of treatment over time as the incidence and types of TEAEs, were generally similar in the first 24 weeks of the study and after Week 24., Conclusions: In patients with COPD, both ICS-containing therapies were non-inferior to GFF MDI for the primary BMD and ophthalmological endpoints. Changes from baseline in all three treatment groups over 52 weeks were small and not clinically meaningful. All treatments were well tolerated with no new or unexpected safety findings., Trial Registration: ClinicalTrials.gov NCT02536508. Registered 27 August 2015.

There is increasing focus on understanding the nature of chronic obstructive pulmonary disease (COPD) during the earlier stages. Mild COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 1 or the now-withdrawn GOLD stage 0) represents an early stage of COPD that may progress to more severe disease. This review summarises the disease burden of patients with mild COPD and discusses the evidence for treatment intervention in this subgroup.Overall, patients with mild COPD suffer a substantial disease burden that includes persistent or potentially debilitating symptoms, increased risk of exacerbations, increased healthcare utilisation, reduced exercise tolerance and physical activity, and a higher rate of lung function decline versus controls. However, the evidence for treatment efficacy in these patients is limited due to their frequent exclusion from clinical trials. Careful assessment of disease burden and the rate of disease progression in individual patients, rather than a reliance on spirometry data, may identify patients who could benefit from earlier treatment intervention.

Introduction: Handheld spirometers for home use by patients allow longitudinal spirometry data to be collected daily and may overcome some of the limitations of in-clinic spirometry (long intervals between measurements, results can be affected by site-based coaching and patient's asthma status during a given visit)., Objectives: To determine the relationship between spirometry values measured by clinic-based and handheld spirometers during a clinical trial., Methods: A post hoc correlation analysis of data from a 6-week phase 3 study of beclomethasone dipropionate (BDP; delivered by breath-actuated inhaler: BAI) versus placebo in patients aged ≥12 years with persistent asthma. During the study, forced expiratory volume in 1 s (FEV 1 ) was assessed by both office-based spirometry at Weeks 2, 4 and 6, and daily by handheld spirometer as a secondary study endpoint., Results: There was a high correlation between FEV 1 values measured at home and in-clinic (overall correlation coefficient = 0.8393, R = 0.81921, 0.85927, 0.85369 and 0.83734 for BAI 320 μg/day, BAI 640 μg/day, BDP metered dose inhaler 320 μg/day and placebo treatment groups, respectively), with the scatterplot showing an upward trend for all treatment groups. Nearly all patients achieved home FEV 1 values close to clinic FEV 1 values, with very few outliers., Conclusions: Clinic-based and handheld spirometry demonstrated comparable treatment effects relative to placebo, suggesting that home spirometry could be used to help patients monitor their asthma severity. Daily measurement of FEV 1 provides more comprehensive data than can be achieved through clinic visits, and may lead to a new approach to clinical trial design., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Phase III studies demonstrated efficacy and safety of nebulized glycopyrrolate inhalation solution (GLY) in subjects with COPD. Secondary analyses were performed to examine the effect of background long-acting beta 2 -agonist (LABA) use on the efficacy and safety of nebulized GLY., Methods: In two 12-week placebo-controlled studies (GOLDEN 3 and GOLDEN 4) and one 48-week, open-label active-controlled study (GOLDEN 5), a total of 2,379 subjects were stratified by background LABA use (LABA-yes: n=861; LABA-no: n=1,518) and randomized to placebo vs GLY 25 or 50 µg twice daily, or GLY 50 µg twice daily vs tiotropium (TIO) 18 µg once daily. Lung function, patient-reported outcomes, exacerbations, and safety were assessed., Results: Compared with placebo, pooled data from the 12-week studies showed significant improvements from baseline with GLY 25 and 50 µg across LABA subgroups in trough FEV 1 (LABA-yes: 0.101 and 0.110 L; LABA-no: 0.092 and 0.101 L, respectively; P <0.001) and St George's Respiratory Questionnaire total score (SGRQ; LABA-yes: -2.957 and -3.888; LABA-no: -3.301 and -2.073, respectively; P <0.05). Incidence of treatment-emergent adverse events (TEAEs) was similar in LABA subgroups, and lower in GLY 25 µg vs placebo. In the 48-week active-controlled study, GLY and TIO both showed improvement from baseline across LABA subgroups in FEV 1 (LABA-yes: 0.106 and 0.092 L; LABA-no: 0.096 and 0.096 L, respectively) and in SGRQ total score (LABA-yes: -5.190 and -3.094; LABA-no: -4.368 and -4.821, respectively). Incidence of TEAEs was similar between GLY and TIO, and across LABA subgroups. Exacerbation rates were similar across treatments and LABA subgroups, and cardiovascular events of special interest were more frequent in the LABA-no subgroup. Nebulized GLY, combined with LABA, did not generate any additional safety signals., Conclusion: Nebulized GLY demonstrated efficacy and was well tolerated up to 48 weeks in subjects with COPD with/without background LABA., Competing Interests: Disclosure EMK has participated in consulting, advisory boards, speaker panels, or received travel reimbursement for Amphastar, AstraZeneca, Forest, Mylan, Novartis, Oriel, Pearl, Sunovion, Teva, and Theravance. He has conducted multicenter clinical research trials for ~40 pharmaceutical companies. RT, BP, SS, and TG are employees of Sunovion Pharmaceuticals Inc. The authors report no other conflicts of interest in this work.

TELOS compared budesonide (BD)/formoterol fumarate dihydrate (FF) metered dose inhaler (BFF MDI), formulated using innovative co-suspension delivery technology that enables consistent aerosol performance, with its monocomponents and budesonide/formoterol fumarate dihydrate dry powder inhaler (DPI) in patients with moderate to very severe chronic obstructive pulmonary disease (COPD), without a requirement for an exacerbation history.In this phase III, double-blind, parallel-group, 24-week study (NCT02766608), patients were randomised to BFF MDI 320/10 µg (n=664), BFF MDI 160/10 µg (n=649), FF MDI 10 µg (n=648), BD MDI 320 µg (n=209) or open-label budesonide/formoterol DPI 400/12 µg (n=219). Primary end-points were change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV 1 ) and FEV 1 area under the curve from 0-4 h (AUC 0-4 ). Time to first and rate of moderate/severe exacerbations were assessed.BFF MDI 320/10 µg improved pre-dose trough FEV 1 versus FF MDI (least squares mean (LSM) 39 mL; p=0.0018), and BFF MDI 320/10 µg and 160/10 µg improved FEV 1 AUC 0-4 versus BD MDI (LSM 173 mL and 157 mL, respectively; both p<0.0001) at week 24. BFF MDI 320/10 µg and 160/10 µg improved time to first and rate of moderate/severe exacerbations versus FF MDI. Treatments were well tolerated, with pneumonia incidence ranging from 0.5-1.4%.BFF MDI improved lung function versus monocomponents and exacerbations versus FF MDI in patients with moderate to very severe COPD., Competing Interests: Conflict of interest: G.T. Ferguson reports grants, personal fees and non-financial support from AstraZeneca, during the conduct of the study; and grants, personal fees and non-financial support from Boehringer Ingelheim, Novartis, AstraZeneca, Pearl (a member of the AstraZeneca Group) and Sunovion, grants and personal fees from Theravance, and personal fees from Verona, Mylan, Innoviva, GlaxoSmithKline and Circassia, outside the submitted work. Conflict of interest: A. Papi reports board membership, consultancy, payment for lectures, grants for research and travel expenses reimbursement from Chiesi, AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Mundipharma and TEVA, payment for lectures and travel expenses reimbursement from Menarini, Novartis and Zambon, board membership, payment for lectures, grants for research and travel expenses reimbursement from Pfizer, and grants for research from Sanofi, outside the submitted work. Conflict of interest: A. Anzueto reports institutional grants from GSK, and personal fees for consultancy from GSK, AstraZeneca, Novartis and BI, outside the submitted work. Conflict of interest: E.M. Kerwin is an employee of Crisor LLC Research, has served on advisory boards, speaker panels, or received travel reimbursement from Novartis, AstraZeneca, Amphastar, Forest, Pearl (a member of the AstraZeneca Group), Sunovion, Teva and Theravance, has served on a medical advisory board for Mylan, and has undertaken consultancy for GSK, outside the submitted work. Conflict of interest: C. Cappelletti is a full-time employee of Pearl (a member of the AstraZeneca Group). Conflict of interest: E.A. Duncan is a full-time employee of Pearl (a member of the AstraZeneca Group). Conflict of interest: J. Nyberg is a full-time employee of Pearl (a member of the AstraZeneca Group). Conflict of interest: P. Dorinsky is a full-time employee of Pearl (a member of the AstraZeneca Group)., (Copyright ©ERS 2018.)

Background: Symptoms of chronic obstructive pulmonary disease (COPD) may diminish patients' health-related quality of life (HRQoL). We report effects of Longhala™ Magnair™ (glycopyrrolate) Inhalation Solution, a drug/device combination of the long-acting antimuscarinic glycopyrrolate administered using the eFlow® closed system (eFlow CS) nebulizer, on HRQoL from the Glycopyrrolate for Obstructive Lung Disease Via Electronic Nebulizer (GOLDEN) clinical studies. Methods: Data consisted of a pooled analysis of 2 phase 3, 12-week efficacy studies (GOLDEN-3 and -4) of glycopyrrolate/eFlow CS (25 or 50 mcg twice daily [BID]) versus placebo, and a 48-week, open-label safety study (GOLDEN-5) of glycopyrrolate/eFlow CS 50 mcg BID versus tiotropium 18 mcg once daily in patients with moderate to very severe COPD. Change from baseline in HRQoL was measured via the St George's Respiratory Questionnaire (SGRQ). Results are provided as mean changes in SGRQ Total score and as response analysis (≥4-point improvement [responder], no change, and ≥4-point worsening in Total score) using analysis of covariance or logistic regression, as applicable. Results: Atotal of 1293 patients were evaluated from GOLDEN-3 and -4 and 1086 from GOLDEN-5. Glycopyrrolate/eFlow CS significantly improved SGRQ Total and component scores. The percentage of SGRQ responders in pooled GOLDEN-3/4 was 46.8% for glycopyrrolate/eFlow CS 25 mcg, 41.7% for glycopyrrolate/eFlow CS 50 mcg, and 34.5% for placebo. SGRQ Total and component score improvements were similar between glycopyrrolate/eFlow CS and tiotropium in GOLDEN-5. Conclusions: The drug/device combination of glycopyrrolate/eFlow CS significantly improved HRQoL, as measured by the SGRQ, offering a potential maintenance treatment option in patients with moderate to very severe COPD. ClinicalTrials.gov: NCT02347761, NCT02347774, NCT02276222., Competing Interests: Sunovion Pharmaceuticals Inc., provided funding for this research. G. Ferguson receives consultancy and advisory fees from Sunovion Pharmaceuticals Inc., E.M. Kerwin receives consultancy and advisory fees from Amphastar, AstraZeneca, Mylan, Novartis, Pearl, Sunovion, Teva, and Theravance. He has conducted multicenter clinical research trials for approximately 40 pharmaceutical companies. J. Donohue receives consultancy and advisory fees from Sunovion Pharmaceuticals Inc. R. Tosiello, V Ganapathy, and K. Rajagopalan are full-time employees of Sunovion Pharmaceuticals Inc. V. Bollu was a former full-time employee of Sunovion Pharmaceuticals Inc., and currently receives consultancy fees from Sunovion.

Background: Long-acting muscarinic antagonist (LAMA) and long-acting β 2 -agonist (LABA) bronchodilators are key to the pharmacologic treatment of chronic obstructive pulmonary disease (COPD). This Phase IIb study investigated the safety and efficacy of four doses of the LAMA glycopyrronium (GP) delivered using co-suspension delivery technology via metered dose inhaler (MDI). The study was part of a wider clinical trial program performed to determine the optimal dose of GP MDI, the LABA formoterol fumarate dihydrate (FF) MDI, and glycopyrronium/formoterol fumarate dihydrate (GFF) MDI fixed-dose combination to be taken forward into Phase III studies., Methods: In this randomized, double-blind, 7-day chronic-dosing, three-period incomplete block, cross-over study, patients with moderate-to-severe COPD received two of the four doses of GP MDI (28.8 μg, 14.4 μg, 7.2 μg, and 3.6 μg) twice daily (BID), and either placebo MDI BID or open-label ipratropium MDI 34 μg four times daily. The primary efficacy endpoint was forced expiratory volume in 1 s (FEV 1 ) area under the curve from 0 to 12 h (AUC 0-12 ) relative to baseline on Day 7. Secondary and exploratory efficacy endpoints were assessed on Days 1 and 7. Safety and tolerability were evaluated throughout the study., Results: All GP MDI treatments were superior to placebo MDI for the primary efficacy endpoint (all p < 0.0001). However, only GP MDI 28.8 μg and 14.4 μg demonstrated statistical superiority to placebo MDI for all secondary efficacy endpoints analyzed in this study, with the exception of GP MDI 14.4 μg versus placebo MDI for the proportion of patients achieving ≥12% improvement in FEV 1 . No nominally significant differences were observed between GP MDI 28.8 μg and GP MDI 14.4 μg for any of the endpoints. All doses of GP MDI were well tolerated, with no unexpected safety findings., Conclusions: This study indicated that there was no advantage of GP MDI 28.8 μg compared with GP MDI 14.4 μg. It therefore added to the evidence from the Phase I/II clinical trial program, which identified GP MDI 14.4 μg as the most appropriate dose for use in the Phase III clinical studies., Trial Registration: ClinicalTrials.gov (NCT01350128). Registered May 09, 2011.

Background: Accurate tracking of the administered dose of asthma rescue inhalers is critical for optimal disease management and is related to reductions in rates of unscheduled health care utilization in asthma patients. There are few published data on the real-world impact of rescue inhalers with integrated dose counters (IDCs) on health care resource utilization (HRU) for asthma patients. This study evaluates HRU among users of ProAir ® hydrofluoroalkane (HFA) (albuterol sulfate inhalation aerosol), with IDC versus without IDC, in asthma patients., Methods: This was a retrospective administrative claims study of asthma patients receiving a new prescription for albuterol inhalation aerosol without IDC during 2 years (January 2011-December 2012) or with IDC during the first full year after IDC implementation in the USA (July 2013-July 2014). Six months of continuous enrollment with medical and prescription drug benefits were required before and after the first prescription during the study period. Data on respiratory-related hospitalizations and emergency department (ED) visits were collected during the follow-up period., Results: A total of 135,305 (32%) patients used albuterol inhalation aerosol with IDC, and 287,243 (68%) patients received albuterol inhalation aerosol without IDC. After adjusting for baseline confounding factors, the odds ratio (OR) for experiencing a respiratory-related hospitalization (OR=0.92; 95% confidence interval [CI] 0.88-0.96) or ED visit (OR=0.92; 95% CI 0.90-0.94) was significantly lower among patients using albuterol inhalation aerosol with IDC versus without IDC., Conclusion: In a real-world setting, asthma patients using ProAir HFA with IDC experienced significantly fewer hospitalizations and ED visits compared with patients using ProAir HFA without IDC. Dosage information provided by IDCs may allow providers to better understand patients' disease severity and aid in titrating controller medications and also decrease the likelihood that the canister will be empty when needed, thereby enhancing disease management and reducing HRU., Competing Interests: Disclosure Edward M Kerwin has served on advisory boards and speaker panels, or received travel reimbursement, from Amphastar, AstraZeneca, Forest, Ironwood, Merck, Mylan, Novartis, Pearl, Pfizer, Sanofi Aventis, Sunovion, Targacept, Teva, and Theravance, and has conducted multicenter clinical research trials for ~40 pharmaceutical companies including Teva. Thomas J Ferro, Rinat Ariely, and Ruchir Parikh are employees of Teva Pharmaceuticals. Debra E Irwin discloses that her institution receives funding from all major pharmaceutical companies to conduct research studies, but she does not personally receive any support. The authors report no other conflicts of interest in this work.

Background: The long-term safety and efficacy of a novel Co-Suspension™ Delivery Technology glycopyrrolate (GP)/formoterol fumarate (FF) 18/9.6 μg fixed-dose combination metered dose inhaler (GFF MDI) were investigated in a 28-week safety extension study (PINNACLE-3, NCT01970878) of two randomized controlled Phase III trials (PINNACLE-1 and -2; NCT01854645 and NCT01854658) in subjects with moderate-to-very severe chronic obstructive pulmonary disease (COPD)., Methods: Subjects completing 24 weeks' treatment with GFF MDI, GP MDI, FF MDI (all twice-daily) or open-label tiotropium 18 μg (once-daily) in PINNACLE-1 or -2 were randomly selected to continue treatment for 28 weeks. The target enrollment for PINNACLE-3 was 850 subjects. Safety and efficacy were evaluated over 52 weeks., Results: Of 3274 subjects randomized to active treatment in PINNACLE-1 or -2, 892 entered PINNACLE-3. Incidences of adverse events, serious adverse events and major adverse cardiovascular events were similar across treatment groups with no unexpected safety findings. For change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV 1 ), treatment differences for GFF MDI versus GP MDI, FF MDI and open-label tiotropium over 52 weeks were 57, 65 and 25 mL, respectively (p ≤ 0.0117). Average daily rescue medication use was significantly reduced for GFF MDI versus GP MDI and open-label tiotropium (p ≤ 0.0002). Statistically significant improvements were observed with GFF MDI versus monocomponents in Self-Administered Computerized Transition Dyspnea Index focal score, and in St George's Respiratory Questionnaire total score versus GP MDI., Conclusions: Results confirmed the long-term safety and tolerability of GFF MDI 18/9.6 μg twice-daily in subjects with moderate-to-very severe COPD. Improvements in efficacy endpoints were also sustained over 52 weeks., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Long-acting muscarinic antagonist/long-acting β 2 -agonist combinations are recommended for patients whose chronic obstructive pulmonary disease (COPD) is not managed with monotherapy. We assessed the efficacy and safety of glycopyrrolate (GP)/formoterol fumarate (FF) fixed-dose combination delivered via a Co-Suspension™ Delivery Technology-based metered dose inhaler (MDI) (GFF MDI)., Methods: This was a Phase IIb randomized, multicenter, placebo-controlled, double-blind, chronic-dosing (7 days), crossover study in patients with moderate-to-very severe COPD ( NCT01085045 ). Treatments included GFF MDI twice daily (BID) (GP/FF 72/9.6 μg or 36/9.6 μg), GP MDI 36 μg BID, FF MDI 7.2 and 9.6 μg BID, placebo MDI, and open-label formoterol dry powder inhaler (FF DPI) 12 μg BID or tiotropium DPI 18 μg once daily. The primary endpoint was forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV 1 AUC 0-12 ) on Day 7 relative to baseline FEV 1 . Secondary endpoints included pharmacokinetics and safety., Results: GFF MDI 72/9.6 μg or 36/9.6 μg led to statistically significant improvements in FEV 1 AUC 0-12 after 7 days' treatment versus monocomponent MDIs, placebo MDI, tiotropium, or FF DPI (p ≤ 0.0002). GFF MDI 36/9.6 μg was non-inferior to GFF MDI 72/9.6 μg and monocomponent MDIs were non-inferior to open-label comparators. Pharmacokinetic results showed glycopyrrolate and formoterol exposure were decreased following administration via fixed-dose combination versus monocomponent MDIs; however, this was not clinically meaningful. GFF MDI was well tolerated., Conclusions: GFF MDI 72/9.6 μg and 36/9.6 μg BID improve lung function and are well tolerated in patients with moderate-to-very severe COPD., Trial Registration: ClinicalTrials.gov NCT01085045 . Registered 9 March 2010.

Background: This study forms part of the first complete characterization of the dose-response curve for glycopyrrolate (GP) delivered using Co-Suspension™ Delivery Technology via a metered dose inhaler (MDI). We examined the lower GP MDI dose range to determine an optimal dose for patients with moderate-to-severe chronic obstructive pulmonary disease (COPD)., Methods: This randomized, double-blind, chronic-dosing, balanced incomplete-block, placebo-controlled, crossover study compared six doses of GP MDI (18, 9, 4.6, 2.4, 1.2, and 0.6 μg, twice daily [BID]) with placebo MDI BID and open-label tiotropium dry powder inhaler (18 μg, once daily [QD]) in patients with moderate-to-severe COPD. Patients were randomized into 1 of 120 treatment sequences. Each sequence included 4 of 8 treatments administered for 14-day periods separated by 7- to 21-day washout periods. The primary efficacy endpoint was change from baseline in forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV1 AUC0-12) on Day 14. Secondary efficacy endpoints included peak change from baseline (post-dose) in FEV1 and inspiratory capacity (IC) on Days 1, 7, and 14; change from baseline in morning pre-dose trough FEV1 on Days 7 and 14; change from baseline in 12-h post-dose trough FEV1 on Day 14; time to onset of action (≥10 % improvement in mean FEV1) and the proportion of patients achieving ≥12 % improvement in FEV1 on Day 1; and pre-dose trough IC on Days 7 and 14. Safety and tolerability were also assessed., Results: GP MDI 18, 9, 4.6, and 2.4 μg demonstrated statistically significant and clinically relevant increases in FEV1 AUC0-12 compared with placebo MDI following 14 days of treatment (modified intent-to-treat population = 120). GP MDI 18 μg was non-inferior to open-label tiotropium for peak change in FEV1 on Day 1 and morning pre-dose trough FEV1 on Day 14. All doses of GP MDI were well tolerated with no unexpected safety findings., Conclusions: These efficacy and safety results support GP MDI 18 μg BID as the most appropriate dose for evaluation in Phase III trials in patients with moderate-to-severe COPD., Trial Registration: ClinicalTrials.gov NCT01566773 . Registered 27 March 2012.

Background: Chronic use of inhaled anticholinergics by patients with chronic obstructive pulmonary disease (COPD) has raised long-term safety concerns, particularly cardiovascular. Glycopyrronium is a once-daily anticholinergic with greater receptor selectivity than previously available agents., Methods: We assessed the safety of inhaled glycopyrronium using data pooled from two analysis sets, involving six clinical studies and over 4,000 patients with COPD who received one of the following treatments: glycopyrronium 50 μg, placebo (both delivered via the Breezhaler device), or tiotropium 18 μg (delivered via the HandiHaler device). Data were pooled from studies that varied in their duration and severity of COPD of the patients (ie, ≤12 weeks duration with patients having moderate or severe COPD; and >1 year duration with patients having severe and very severe COPD). Safety comparisons were made for glycopyrronium vs tiotropium or placebo. Poisson regression was used to assess the relative risk for either active drug or placebo (and between drugs where placebo was not available) for assessing the incidence of safety events. During post-marketing surveillance (PMS), safety was assessed by obtaining reports from various sources, and disproportionality scores were computed using EMPIRICA. In particular, the cardiac safety of glycopyrronium during the post-marketing phase was evaluated., Results: The overall incidence of adverse events and deaths was similar across groups, while the incidence of serious adverse events was numerically higher in placebo. Furthermore, glycopyrronium did not result in an increased risk of cerebro-cardiovascular events vs placebo. There were no new safety reports during the PMS phase that suggested an increased risk compared to results from the clinical studies. Moreover, the cardiac safety of glycopyrronium during the PMS phase was also consistent with the clinical data., Conclusion: The overall safety profile of glycopyrronium was similar to its comparators indicating no increase in the overall risk for any of the investigated safety end points.

Background: Combining two long-acting bronchodilators with complementary mechanisms of action may provide treatment benefits to patients with chronic obstructive pulmonary disease (COPD) that are greater than those derived from either treatment alone. The efficacy and safety of a fixed-dose combination (FDC) of aclidinium bromide, a long-acting muscarinic antagonist, and formoterol fumarate, a long-acting β2-agonist, in patients with moderate to severe COPD are presented., Methods: In this 24-week double-blind study, 1692 patients with stable COPD were equally randomized to twice-daily treatment with FDC aclidinium 400 μg/formoterol 12 μg (ACL400/FOR12 FDC), FDC aclidinium 400 μg/formoterol 6 μg (ACL400/FOR6 FDC), aclidinium 400 μg, formoterol 12 μg, or placebo administered by a multidose dry powder inhaler (Genuair®/Pressair®)*. Coprimary endpoints were change from baseline to week 24 in 1-hour morning postdose FEV1 (FDCs versus aclidinium) and change from baseline to week 24 in morning predose (trough) FEV1 (FDCs versus formoterol). Secondary endpoints were change from baseline in St. George's Respiratory Questionnaire (SGRQ) total score and improvement in Transition Dyspnea Index (TDI) focal score at week 24. Safety and tolerability were also assessed., Results: At study end, improvements from baseline in 1-hour postdose FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC or ACL400/FOR6 FDC compared with aclidinium (108 mL and 87 mL, respectively; p < 0.0001). Improvements in trough FEV1 were significantly greater in patients treated with ACL400/FOR12 FDC versus formoterol (45 mL; p = 0.0102), a numerical improvement of 26 mL in trough FEV1 over formoterol was observed with ACL400/FOR6 FDC. Significant improvements in both SGRQ total and TDI focal scores were observed in the ACL400/FOR12 FDC group at study end (p < 0.0001), with differences over placebo exceeding the minimal clinically important difference of ≥4 points and ≥1 unit, respectively. All treatments were well tolerated, with safety profiles of the FDCs similar to those of the monotherapies., Conclusions: Treatment with twice-daily aclidinium 400 μg/formoterol 12 μg FDC provided rapid and sustained bronchodilation that was greater than either monotherapy; clinically significant improvements in dyspnea and health status were evident compared with placebo. Aclidinium/formoterol FDC may be an effective and well tolerated new treatment option for patients with COPD., Trial Registration: Clinicaltrials.gov NCT01437397.

Inhaled corticosteroids (ICSs) improve asthma disease control; once-daily ICS administration may have advantages for patients. Our objective was to assess the efficacy and safety of the novel ICS fluticasone furoate (FF) over 24 weeks versus placebo. This was a 24-week double-blind, double-dummy, placebo- and active-controlled study (NCT01159912) of 343 asthma patients (≥12 years) not controlled by their current ICS. Patients were randomised (1:1:1) to FF100 μg, placebo (both administered once-daily [OD] via ELLIPTA™ dry powder inhaler in the evening) or fluticasone propionate (FP) 250 μg (administered twice-daily (BD) via DISKUS™/ACCUHALER™). Primary endpoint was change from baseline in pre-dose evening forced expiratory volume in 1s (FEV1) at Week 24; change from baseline in % rescue-free 24-h periods was a powered secondary endpoint. Adverse events (AEs) were assessed. FF100 μg OD and FP250 μg BD significantly improved pre-dose evening FEV1 compared with placebo at Week 24 (+146 ml [p = 0.009] and +145 ml [p = 0.011], respectively). Percentage of rescue-free 24-h periods was increased with FF100 μg OD (+14.8%) and FP250 μg BD (+17.9%) compared to placebo (both p < 0.001). On-treatment AEs were reported by 53% (FF100 μg OD), 42% (FP250 μg BD) and 40% (placebo) of patients. On-treatment severe asthma exacerbations were lower with FF100 μg OD (3%) and FP250 μg BD (2%) than placebo (7%). There was significant suppression of urinary cortisol at week 24 with FF100 μg OD (p = 0.030) and FP250 μg BD (p = 0.036) relative to placebo. FF100 μg OD, administered in the evening, achieves significant improvements in lung function and rescue inhaler use over 24 weeks, comparable to FP250 μg BD with similar safety profile., (Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Fluticasone furoate (FF)/vilanterol (VI) is a novel once-daily inhaled corticosteroid/long-acting β2-agonist combination therapy for COPD. We aimed to assess the efficacy and safety of two strengths of FF/VI (100/25 μg; 50/25 μg) vs. individual components (FF 100 μg, VI 25 μg) and placebo over 24 weeks., Methods: Multicentre, randomised, placebo-controlled, double-blind, parallel-group study of patients (N = 1030) with moderate-to-severe COPD. All medication was administered once daily in the morning. Co-primary efficacy endpoints were: (1) weighted mean (wm) FEV1 (0-4 h post-dose on day 168) to assess acute lung function effects; and (2) trough FEV1 (23-24 h post-dose on day 169) to assess long-lasting effects. Symptom-related outcomes were analysed and adverse events (AEs) assessed., Results: Main findings were: (1) the combination of FF/VI at a strength of 100/25 μg significantly (p < 0.001) improved wm FEV1 (173 ml) and trough FEV1 (115 ml) vs. placebo. Similar effects were observed with FF/VI 50/25 μg; (2) no significant difference was seen between FF/VI 100/25 μg and VI 25 μg for trough FEV1 (48 ml, p = 0.082), while an effect was observed between FF/VI 100/25 μg and FF 100 μg for wm FEV1 (120 ml, p < 0.001); (3) VI 25 μg over 24 weeks improved lung function vs. placebo significantly for wm FEV1 (103 ml, p < 0.001) and trough FEV1 (67 ml, p = 0.017); and (4) no safety signal was observed., Conclusions: In subjects with moderate-to-severe COPD, FF/VI 100/25 μg provides rapid and significant sustained bronchodilation at 24 weeks. Lung function is improved to a similar extent with FF/VI 50/25 μg and to a somewhat lesser extent with VI 25 μg. All treatments were well tolerated. GSK study number: HZC112206. ClinicalTrials.gov: NCT01053988., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: The twice daily administration of an inhaled corticosteroid (ICS) and long-acting beta(2)-agonist (LABA) has been shown to be effective in achieving asthma control. The once daily administration of an ICS/LABA may be a treatment option for some patients., Objective: To assess the effectiveness of fluticasone propionate (FP)/salmeterol via a single inhaler (FSC) administered once daily compared with FP once daily, FSC twice daily, or placebo., Methods: A 12-week, randomized, double-blind multicenter study conducted in 844 patients > or = 12 years of age who were symptomatic while using a short-acting beta(2)-agonist alone. Blinded treatments included: FSC 250/50 mcg once daily in the evening (FSC 250/50 QD), FP 250 mcg once daily in the evening (FP 250 QD), FSC 100/50 mcg twice daily (FSC 100/50 mcg BID), or placebo. All treatments were delivered via the Diskus device., Results: All treatments demonstrated greater improvements in efficacy measures compared with placebo. Overall, the greatest improvements were observed in the patients receiving FSC, either once or twice daily, compared with the FP 250 QD group. The two FSC treatments were similar except that QD dosing did not maintain improvements in lung function for 24h compared with twice daily dosing. All treatments were well tolerated. No suppression of HPA axis, as assessed by 24-h urinary cortisol excretion, was observed in any of the active treatment groups., Conclusion: In patients symptomatic on a short-acting beta(2)-agonist alone, FSC 100/50 mcg BID was shown to provide better efficacy than a higher strength (FSC 250/50 mcg) administered once daily. However, a once daily regimen was effective and may be a valuable treatment option for some patients. Registered at (http://ctr.gsk.co.uk/welcome.asp) (SAS30022).