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Sanjay Sethi,1 Brendan Clark,2 Lindsay GS Bengtson,3 Erin K Buysman,3 Swetha Palli,2 Andrew Sargent,3 Asif Shaikh,2 Gary T Ferguson4 1Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, NY, USA; 2Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 3Optum Life Sciences, Eden Prairie, MN, USA; 4Department of Medicine, Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USACorrespondence: Brendan Clark, Boehringer Ingelheim Pharmaceuticals, Inc, 900 Ridgebury Road, Ridgefield, CT, 06877, USA, Email brendan.clark@boehringer-ingelheim.comBackground: ATS and GOLD guidelines recommend treating low-exacerbation risk COPD patients with dual (LAMA/LABA) agents and reserving triple therapy (TT; LAMA/LABA and inhaled corticosteroids [ICS]) for severe cases with higher-exacerbation risk. However, TT often is prescribed across the COPD spectrum. This study compared COPD exacerbations, pneumonia diagnosis, healthcare resource utilization, and costs for patients initiating tiotropium bromide/olodaterol (TIO/OLO) and a TT, fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI), stratified by exacerbation history.Methods: COPD patients who initiated TIO/OLO or FF/UMEC/VI between 06/01/2015— 11/30/2019 (index date=first pharmacy fill-date with ≥ 30 consecutive treatment days) were identified from the Optum Research Database. Patients were ≥ 40 years old and continuously enrolled for 12 months during the baseline period and ≥ 30 days during follow-up. Patients were stratified into GOLD A/B (0– 1 baseline non-hospitalized exacerbation), No exacerbation (subset of GOLD A/B), and GOLD C/D (≥ 2 non-hospitalized and/or ≥ 1 hospitalized baseline exacerbation). Baseline characteristics were balanced with propensity score matching (1:1). Adjusted risks of exacerbation, pneumonia diagnosis, and COPD and/or pneumonia-related utilization and costs were evaluated.Results: Adjusted exacerbation risk was similar in GOLD A/B and No exacerbation subgroups, and lower in GOLD C/D for FF/UMEC/VI versus TIO/OLO initiators (hazard ratio: 0.87; 95% CI: 0.78, 0.98, p=0.020). Adjusted pneumonia risk was similar between cohorts across the GOLD subgroups. Adjusted COPD and/or pneumonia-related population annualized pharmacy costs were significantly higher for FF/UMEC/VI versus TIO/OLO initiators across subgroups, p< 0.001. Adjusted COPD and/or pneumonia-related population annualized total healthcare costs were significantly higher for FF/UMEC/VI versus TIO/OLO initiators in the GOLD A/B and No exacerbation, subgroups, p< 0.001 (cost ratio [95% CI]: 1.25 [1.13, 1.38] and 1.21 [1.09, 1.36], respectively), but similar in the GOLD C/D subgroup.Conclusion: These real-world results support ATS and GOLD recommendations for treating low-exacerbation risk COPD patients with dual bronchodilators and TT for more severe, higher-exacerbation risk COPD patients.Keywords: COPD, tiotropium bromide/olodaterol, fluticasone furoate/umeclidinium/vilanterol, exacerbation history, healthcare resource utilization, cost, clinical outcomes

Jill A Ohar,1 Gary T Ferguson,2 Donald A Mahler,3 M Bradley Drummond,4 Rajiv Dhand,5 Roy A Pleasants,4,6 Antonio Anzueto,7 David MG Halpin,8 David B Price,9,10 Gail S Drescher,11 Haley M Hoy,12 John Haughney,9 Michael W Hess,13 Omar S Usmani14 1Section of Pulmonary, Critical Care, Allergy, and Immunology, School of Medicine, Wake Forest University, Winston-Salem, NC, USA; 2Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA; 3Geisel School of Medicine at Dartmouth, Hanover, NH, USA; 4Division of Pulmonary Diseases and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; 5Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Tennessee Graduate School of Medicine, Knoxville, TN, USA; 6Department of Quality, University of Michigan, Ann Arbor, MI, USA; 7Pulmonology Section, University of Texas Health, and South Texas Veterans Health Care System, San Antonio, TX, USA; 8University of Exeter Medical School, College of Medicine and Health, University of Exeter, Exeter, UK; 9Academic Primary Care, Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK; 10Observational and Pragmatic Research Institute, Singapore; 11Pulmonary Services Department, MedStar Washington Hospital Center, Washington, DC, USA; 12Transplant Center, Vanderbilt University Medical Center, Nashville, TN, USA; 13COPD Foundation, Kalamazoo, MI, USA; 14National Heart and Lung Institute, Imperial College London and Royal Brompton Hospital, London, UKCorrespondence: Jill A OharSection of Pulmonary, Critical Care, Allergy, and Immunology, School of Medicine, Wake Forest University, 1834 Wake Forest Road, Winston-Salem, NC 27109, USATel +1 336-716-8426Fax +1 336-716-7277Email johar@wakehealth.eduAbstract: Dry powder inhalers (DPIs) are breath actuated, and patients using DPIs need to generate an optimal inspiratory flow during the inhalation maneuver for effective drug delivery to the lungs. However, practical and standardized recommendations for measuring peak inspiratory flow (PIF)—a potential indicator for effective DPI use in chronic obstructive pulmonary disease (COPD)—are lacking. To evaluate recommended PIF assessment approaches, we reviewed the Instructions for Use of the In-Check™ DIAL and the prescribing information for eight DPIs approved for use in the treatment of COPD in the United States. To evaluate applied PIF assessment approaches, we conducted a PubMed search from inception to August 31, 2021, for reports of clinical and real-life studies where PIF was measured using the In-Check™ DIAL or through a DPI in patients with COPD. Evaluation of collective sources, including 47 applicable studies, showed that instructions related to the positioning of the patient with their DPI, instructions for exhalation before the inhalation maneuver, the inhalation maneuver itself, and post-inhalation breath-hold times varied, and in many instances, appeared vague and/or incomplete. We observed considerable variation in how PIF was measured in clinical and real-life studies, underscoring the need for a standardized method of PIF measurement. Standardization of technique will facilitate comparisons among studies. Based on these findings and our clinical and research experience, we propose specific recommendations for PIF measurement to standardize the process and better ensure accurate and reliable PIF values in clinical trials and in daily clinical practice.Keywords: chronic obstructive pulmonary disease, dry powder inhalers, peak inspiratory flow

Donald A Mahler,1,2 Andrea Ludwig-Sengpiel,3 Gary T Ferguson,4 Alberto de la Hoz,5 John Ritz,6 Asif Shaikh,7 Henrik Watz8 1Geisel School of Medicine at Dartmouth, Hanover, NH, USA; 2Section of Pulmonary Medicine, Valley Regional Hospital, Claremont, NH, USA; 3KLB Gesundheitsforschung Lübeck GmbH, Lübeck, Germany; 4Department of Medicine, Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA; 5Cardio-Metabolism and Respiratory, Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany; 6Biostatistics, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 7Clinical Development & Medical Affairs, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA; 8Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, GermanyCorrespondence: Donald A MahlerMedicine, Geisel School of Medicine at Dartmouth, Hanover, NH, USATel +1 603 542-6777Fax +1 603 543-5613Email mahlerdonald@gmail.comBackground: Inhaled bronchodilator therapy is currently the mainstay of treatment for patients with chronic obstructive pulmonary disease (COPD). Some inhalers require patients to achieve certain inhalation efforts either to activate the device or to deliver medication to the site of action. For dry powder inhalers, low peak inspiratory flow (PIF) can result in poor medication delivery but the clinical significance of this is not well understood.Methods: TRONARTO was a 4-week, randomized, double-blind, placebo-controlled, multicenter, parallel-group study which stratified patients with moderate-to-severe COPD according to their PIF against medium-low resistance at screening. Patients were randomized to receive tiotropium/olodaterol (5 μg/5 μg) or matched placebo delivered via the Respimat® Soft Mist™ inhaler (SMI). After 4 weeks of treatment, we assessed change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve 0– 3 hours (FEV1 AUC0– 3h) and trough FEV1.Results: Overall, 213 patients were randomized, of whom 106 received tiotropium/olodaterol (PIF < 60 L/min, 55; PIF ≥ 60 L/min, 51) and 107 received placebo (PIF < 60 L/min, 55; PIF ≥ 60 L/min, 52). For FEV1 AUC0– 3h, the adjusted mean change from baseline versus placebo was 336 mL (95% confidence interval [CI] 246– 425 mL; P< 0.0001) in the PIF < 60 L/min group and 321 mL (95% CI 233– 409 mL; P< 0.0001) in the PIF ≥ 60 L/min group. For trough FEV1, the adjusted mean change from baseline versus placebo was 201 mL (95% CI 117– 286 mL; P< 0.0001) in the PIF < 60 L/min group and 217 mL (95% CI 135– 299 mL; P< 0.0001) in the PIF ≥ 60 L/min group.Conclusion: In the TRONARTO study, which included patients with moderate-to-severe COPD and varying inspiratory flow abilities, treatment with tiotropium/olodaterol resulted in significant lung function improvements versus placebo. This SMI can be used irrespective of the PIF that a patient can generate.Keywords: inhaler, tiotropium/olodaterol, peak inspiratory flow, SMI, lung function

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

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

Fernando J Martinez,1 Gary T Ferguson,2 Eric Bourne,3 Shaila Ballal,4 Patrick Darken,5 Magnus Aurivillius,6 Paul Dorinsky,3 Colin Reisner4 1Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY, USA; 2Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA; 3AstraZeneca, Durham, NC, USA; 4AstraZeneca, Morristown, NJ, USA; 5AstraZeneca, Wilmington, DE, USA; 6AstraZeneca, Gothenburg, SwedenCorrespondence: Fernando J MartinezJoan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, New York, NY 10065, USATel +1 646 962 2748Email fjm2003@med.cornell.eduPurpose: In the Phase III, 24-week KRONOS study (NCT02497001), triple therapy with budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) reduced exacerbation rates versus glycopyrrolate/formoterol fumarate (GFF) MDI in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) and no requirement for a history of exacerbations. We report a post hoc analysis investigating whether the benefits observed were driven by patients with ≥ 1 exacerbation in the 12 months prior to the study.Patients and Methods: Patients received BGF MDI 320/18/9.6 μg, GFF MDI 18/9.6 μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12 μg twice-daily. Post hoc analyses were conducted on exacerbation and lung function results from patients with and without a documented exacerbation in the 12 months prior to the study.Results: Overall, 74% (1411/1896) of the modified-intent-to-treat (mITT) population had no moderate/severe exacerbations in the 12 months prior to the study. BGF MDI reduced exacerbation rates versus GFF MDI in the prior (58%; unadjusted p=0.0003) and no prior (48%; unadjusted p=0.0001) exacerbations subgroups. The magnitude of reduction in exacerbation rates was generally similar within subgroups for BGF MDI versus BFF MDI and BUD/FORM DPI. In the prior exacerbations subgroup, risk during treatment for time to first exacerbation was lower with BGF MDI versus GFF MDI (p=0.0022) and BFF MDI (p=0.0110); excluding the first 30 days of data yielded similar results. The magnitude of reduction in exacerbation rates for BGF MDI compared with GFF MDI increased with eosinophil count.Conclusion: In patients with or without a history of exacerbations in the 12 months prior to the study, BGF MDI reduced exacerbation rates versus GFF MDI, suggesting results observed in the overall population were not driven by the small subgroup with a prior history of exacerbations.Keywords: fixed-dose combination, COPD, exacerbations of COPD

Gary T Ferguson,1 Tor Skärby,2 Lars H Nordenmark,2 Rosa Lamarca,3 Audrone Aksomaityte,4 Dan Lythgoe,4 Ileen Gilbert,5 Frank Trudo5 1Department of Medicine, Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA; 2BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden; 3BioPharmaceuticals R&D, AstraZeneca, Barcelona, Spain; 4Statistics Department, Phastar, London, UK; 5BioPharmaceuticals Medical – US, AstraZeneca LP, Wilmington, DE, USACorrespondence: Gary T FergusonMD, Pulmonary Research Institute of Southeast Michigan, 29255 West 10 Mile Road, Suite A, Farmington Hills, MI 48336, USATel +1 248 478 6561Email garytferguson@msn.comPurpose: Moderate and severe COPD exacerbations are a significant health-care burden, but patients also experience “mild” exacerbations, or COPD symptom-related attacks, which often go unreported. We aimed to define and then determine the incidence of COPD symptom-related attacks and their impact on future risk of moderate/severe exacerbations, health-related quality of life (HRQoL), and lung function. The effect of COPD maintenance therapy on the attack definition was then evaluated by comparing budesonide/formoterol with formoterol alone.Patients and Methods: This post hoc analysis of the RISE study defined COPD symptom-related attacks as ≥ 2 consecutive days of both worsening symptoms and increased daily rescue medication use based upon thresholds of > 2 and > 4 short-acting β2-agonist (SABA) inhalations/day above baseline. The impact of these events on subsequent moderate/severe exacerbation risk was estimated using a time-varying Cox proportional hazards model. The effects of COPD symptom-related attacks on St George’s Respiratory Questionnaire (SGRQ) total score and pre-bronchodilator forced expiratory volume in 1 second (FEV1) were evaluated as average changes from baseline to first post-attack measurement. Rates of attacks were compared between treatment groups using negative binomial regression models.Results: COPD symptom-related attacks elevated the risk of subsequent moderate/severe exacerbations at both > 2 and > 4 inhalations/day above baseline (HR 1.86 and 2.21, respectively; p< 0.0001), with a cumulative increase in risk with increasing attacks. HRQoL and lung function were reduced for patients with ≥ 1 versus no COPD symptom-related attacks at both rescue medication thresholds. There were fewer COPD symptom-related attacks with budesonide/formoterol versus formoterol alone, with no increased risk of pneumonia and lower respiratory tract infections.Conclusion: COPD symptom-related attacks are common and typically unreported. Importantly, these attacks can account for considerable morbidity and should not be regarded as “mild”. Detection of such exacerbations may be valuable in identifying patients at greater risk and guiding preventive therapeutic interventions.Keywords: COPD, exacerbation, symptoms, rescue inhaler, mild COPD exacerbations

Gary T Ferguson,1 Asif Shaikh,2 Kay Tetzlaff,3 Achim Mueller,3 Helgo Magnussen,4 Henrik Watz4 1Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA; 2Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, USA; 3Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany; 4Pulmonary Research Institute at Lung Clinic Grosshansdorf, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Grosshansdorf, GermanyCorrespondence: Gary T FergusonPulmonary Research Institute of Southeast Michigan, Suite A, 29255 W 10 Mile Road, Farmington Hills, MI, USATel +1 248-478-6561Fax +1 248-478-6908Email garytferguson@msn.comPurpose: In the Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management (WISDOM) trial, inhaled corticosteroid (ICS) withdrawal in patients with chronic obstructive pulmonary disease receiving triple therapy (long-acting β2-agonist+long-acting muscarinic antagonist+ICS) did not change moderate/severe exacerbation risk. However, many patients were not taking triple therapy before study participation. This analysis was conducted to eliminate the impact of non-ICS users on WISDOM results by re-analyzing the data using only the subset of patients who were taking triple therapy at screening.Patients and Methods: The effect of ICS withdrawal on moderate/severe exacerbation risk in the subgroup of WISDOM patients taking triple therapy before enrolling in the study was evaluated in this post hoc analysis. Additionally, the effect of ICS withdrawal in patients with a history of ≥ 2 exacerbations in the previous year and various blood eosinophil counts was assessed.Results: Overall, 39.0% (n=970: ICS continuation, 479; ICS withdrawal, 491) of the WISDOM trial population were taking triple therapy at screening. Baseline characteristics were generally similar between groups. Moderate/severe exacerbation risk between the ICS withdrawal and continuation groups (hazard ratio [HR], 1.05; 95% confidence interval [CI]: 0.89– 1.25) was not increased in patients taking triple therapy at screening versus the overall trial population (HR [95% CI]: 1.06 [0.94– 1.19]). However, in patients with a history of ≥ 2 exacerbations, exacerbation risk (HR [95% CI]) increased nominally with blood eosinophil count from 1.07 [0.81– 1.41] (≥ 100 cells/μL) to 1.45 [0.58– 3.60] (≥ 400 cells/μL).Conclusion: Consistent with results from the overall WISDOM trial population, ICS withdrawal did not increase exacerbation risk in patients taking triple therapy at screening. Patients with a history of frequent exacerbations and higher blood eosinophil counts could benefit from continuation of ICS-based therapy.Keywords: COPD, dual bronchodilator, glucocorticoid, triple therapy

J Mark FitzGerald,1 Eugene R Bleecker,2 Arnaud Bourdin,3 William W Busse,4 Gary T Ferguson,5 Laura Brooks,6 Peter Barker,6 Ubaldo J Martin6 1Centre for Heart and Lung Health, The Lung Centre Vancouver General Hospital, UBC Institute for Heart and Lung Health, Vancouver, BC, Canada; 2Divisions of Pharmacogenomics and Genetics, Genomics and Precision Medicine, University of Arizona College of Medicine, Tucson, AZ, United States; 3Department of Respiratory Diseases, Hôpital Arnaud De Villeneuve, Montpellier, France; 4Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United States; 5Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, United States; 6AstraZeneca, Gaithersburg, MD, United StatesCorrespondence: J Mark FitzGeraldThe Lung Centre, Vancouver General Hospital, Gordon and Leslie Diamond Health Care Centre, 2775 Laurel Street, Vancouver BC V5Z 1M9, CanadaTel +1604-875-4122Email mark.fitzgerald@vch.caBackground: Benralizumab is an interleukin-5 receptor alpha–directed cytolytic monoclonal antibody. Treatment with benralizumab significantly reduces exacerbations and improves lung function after 1 year for patients with severe, uncontrolled eosinophilic asthma.Objective: We explored whether benralizumab efficacy was sustained after an additional year of treatment while maintaining an acceptable safety profile.Methods: Data from the pivotal 48-week SIROCCO and 56-week CALIMA studies were integrated with data from the predefined 56-week adult phase of the BORA extension study to provide a 2-year integrated efficacy and safety analysis of benralizumab. BORA enrolled patients who had completed SIROCCO or CALIMA. Patients receiving benralizumab 30 mg subcutaneously, either every 4 weeks (Q4W) or every 8 weeks (Q8W; first three doses Q4W), were assessed. Efficacy was evaluated based on baseline blood eosinophil counts from the pivotal studies (≥300 and Results: Mean treatment exposures were 24.3 (Q4W, n=518) and 24.6 (Q8W, n=512) months. Exacerbation frequency reductions observed in SIROCCO/CALIMA were maintained; 50% of the patients had no exacerbations during the 2-year study period (crude exacerbation rate, Q8W: 0.56 exacerbations/year for patients with blood eosinophil counts ≥300 cells/μL). Lung function improvements with benralizumab were maintained for 2 years, as represented by increases in mean prebronchodilator forced expiratory volume in 1 second from baseline of 0.343 L and 0.364 L with 1 and 2 years of benralizumab Q8W treatment, respectively, for patients with blood eosinophil counts ≥300 cells/μL. Health-related quality of life improvements with benralizumab observed in the pivotal studies were also sustained. Adverse events and serious adverse event rates were similar between the BORA extension and SIROCCO/CALIMA periods, with no new or unexpected occurrence of adverse events.Conclusion: This benralizumab 2-year integrated analysis further supports long-term use of benralizumab for patients with severe, uncontrolled eosinophilic asthma.Keywords: asthma, benralizumab, clinical features, eosinophilic inflammation, interleukin-5 receptor, safety

Masakazu Ichinose,1 Yasushi Fukushima,2 Yoshikazu Inoue,3 Osamu Hataji,4 Gary T Ferguson,5 Klaus F Rabe,6 Nobuya Hayashi,7 Hiroshi Okada,7 Mami Takikawa,7 Eric Bourne,8 Shaila Ballal,9 Kiernan DeAngelis,10 Magnus Aurivillius,11 Paul Dorinsky,8 Colin Reisner9 1Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; 2Department of Internal Medicine, Fukuwa Clinic, Tokyo, Japan; 3Clinical Research Center, National Hospital Organization, Kinki-Chuo Chest Medical Center, Osaka, Japan; 4Respiratory Center, Matsusaka Municipal Hospital, Matsusaka, Japan; 5Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA; 6LungenClinic Grosshansdorf and Christian-Albrechts University Kiel, Airway Research Center North, Member of the German Center for Lung Research (DZL), Grosshansdorf, Germany; 7AstraZeneca K.K., Osaka, Japan; 8AstraZeneca, Durham, NC, USA; 9AstraZeneca, Morristown, NJ, USA; 10Formerly of AstraZeneca, Durham, NC, USA; 11AstraZeneca, Gothenburg, SwedenCorrespondence: Masakazu IchinoseDepartment of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, JapanTel +81-22-717-8534Email ichinose@rm.med.tohoku.ac.jpBackground: KRONOS, a Phase III, multicenter, randomized, double-blind study (NCT02497001) conducted in Canada, China, Japan, and the USA, assessed the efficacy and safety of budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI), a triple fixed-dose combination therapy, relative to dual therapies in patients with moderate-to-very severe COPD. Here we present findings from the Japanese subgroup of KRONOS.Methods: Patients received BGF MDI 320/18/9.6μg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12μg twice-daily for 24 weeks. The primary endpoint was the change from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) over Weeks 12–24. Symptoms, quality of life, exacerbations, and safety were also assessed.Results: In total, 416 Japanese patients (21.9% of the global KRONOS population) were randomized and treated with BGF MDI (n=139), GFF MDI (n=138), BFF MDI (n=70), or BUD/FORM DPI (n=69). Nominally significant improvements in the change from baseline in morning pre-dose trough FEV1 over Weeks 12–24 were observed for BGF MDI vs GFF MDI (least squares mean [LSM] difference 37 mL, 95% confidence interval [CI] 3, 72; P=0.0337) and BFF MDI (67 mL; 95% CI 25, 109; P=0.0020). Treatment with BGF MDI led to a nominally significant reduction in the rate of moderate/severe exacerbations vs GFF MDI (rate ratio 0.40, 95% CI 0.19, 0.83; P=0.0142). Compared with dual therapies, numerical improvements were observed with BGF MDI for Transition Dyspnea Index focal score and the change from baseline in Evaluating Respiratory Symptoms in COPD total score (P≤0.3899). All treatments were generally well tolerated.Conclusion: BGF MDI nominally significantly improved lung function and numerically improved symptoms vs GFF MDI and BFF MDI. BGF MDI nominally significantly reduced exacerbations vs GFF MDI in Japanese patients with COPD. Efficacy and safety findings were generally comparable to those in the global KRONOS population.Keywords: co-suspension delivery technology, ICS/LAMA/LABA, inhaled corticosteroid, long-acting muscarinic antagonist, long-acting β2-agonist, Japan

Masakazu Ichinose,1 Yasushi Fukushima,2 Yoshikazu Inoue,3 Osamu Hataji,4 Gary T Ferguson,5 Klaus F Rabe,6 Nobuya Hayashi,7 Hiroshi Okada,7 Mami Takikawa,7 Eric Bourne,8 Shaila Ballal,9 Kiernan DeAngelis,10 Magnus Aurivillius,11 Colin Reisner,9 Paul Dorinsky8 1Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan; 2Department of Internal Medicine, Fukuwa Clinic, Tokyo, Japan; 3Clinical Research Center, National Hospital Organization, Kinki-Chuo Chest Medical Center, Osaka, Japan; 4Respiratory Center, Matsusaka Municipal Hospital, Matsusaka, Japan; 5Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA; 6LungenClinic Grosshansdorf and Christian-Albrechts University Kiel, Airway Research Center North, Member of the German Center for Lung Research (DZL), Großhansdorf, Germany; 7AstraZeneca K.K., Osaka, Japan; 8AstraZeneca, Durham, NC, USA; 9AstraZeneca, Morristown, NJ, USA; 10Formerly of AstraZeneca, Durham, NC, USA; 11AstraZeneca, Gothenburg, SwedenCorrespondence: Masakazu IchinoseDepartment of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, JapanTel +81-22-717-8534Email ichinose@rm.med.tohoku.ac.jpBackground: Budesonide/glycopyrrolate/formoterol fumarate metered dose inhaler (BGF MDI) is a triple fixed-dose combination for COPD. The long-term safety of triple therapy for COPD has not been investigated in Japanese patients. In this 28-week extension study (NCT03262012), we investigated the long-term safety and tolerability of BGF MDI in Japanese patients with moderate-to-very severe COPD who completed the 24-week Phase III randomized, double-blind, multicenter KRONOS study (NCT02497001).Materials and methods: Patients randomized to BGF MDI 320/18/9.6 μg, glycopyrrolate/formoterol fumarate (GFF) MDI 18/9.6 μg, budesonide/formoterol fumarate (BFF) MDI 320/9.6 μg, or budesonide/formoterol fumarate dry powder inhaler (BUD/FORM DPI) 400/12 μg twice-daily in KRONOS continued treatment for up to 28 additional weeks. Safety was evaluated over 52 weeks via adverse event (AE) monitoring, electrocardiograms, clinical laboratory testing, and vital sign measurements.Results: The safety population included 416 patients who received BGF MDI (n=139), GFF MDI (n=138), BFF MDI (n=70), or BUD/FORM DPI (n=69). Treatment-emergent AE (TEAE) rates were similar across treatment groups (range: 82.6–82.9%). The most frequent TEAEs overall were nasopharyngitis (32.2%) and bronchitis (9.9%). The incidence of major adverse cardiovascular events was low across groups (range: 0.0–2.9%). Over 52 weeks, the incidence of confirmed pneumonia was 9.4% (BGF MDI), 3.6% (GFF MDI), 5.7% (BFF MDI), and 2.9% (BUD/FORM DPI); in the 28-week extension period, rates were comparable across groups (range: 2.9–5.7%). Six deaths were reported (0.7–2.2% per group); none were considered treatment-related. No clinically meaningful trends were observed in electrocardiograms, laboratory parameters, or vital signs over time in any of the treatment groups.Conclusion: All treatments were well tolerated over 52 weeks, and the safety profile of BGF MDI was generally comparable to dual long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) and inhaled corticosteroid (ICS)/LABA therapies. These findings support the long-term tolerability of BGF MDI in Japanese patients with COPD.Keywords: co-suspension delivery technology, ICS/LAMA/LABA, inhaled corticosteroid, long-acting muscarinic antagonist, long-acting β2-agonist, Japan

Gary T Ferguson,1 Jeremy Cole,2 Magnus Aurivillius,3 Paul Roussel,4 Peter Barker,4 Ubaldo J Martin4 On behalf of the GRECO study investigators1Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA; 2OK Clinical Research, LLC, Edmond, OK, USA; 3AstraZeneca, Mölndal, Sweden; 4AstraZeneca, Gaithersburg, MD, USACorrespondence: Gary T FergusonPulmonary Research Institute of Southeast Michigan, 29255 West 10 Mile Road, Suite A, Farmington Hills, MI 48336, USATel +1-248-478-6806Fax +1-248-478-6908Email garytferguson@msn.comPurpose: Accessorized prefilled syringes (APFS) have demonstrated functionality and reliability for subcutaneous (SC) delivery, including self-administration, of benralizumab 30 mg in the clinic or at home. The multicenter, open-label GRECO study (NCT02918071) assessed functionality and reliability of a single-use autoinjector (AI) for at-home benralizumab administration by patients or their caregivers.Patients and methods: Adults with severe asthma received benralizumab SC injections at the study site at Weeks 0, 4, and 8. The first dose was administered by health care providers. Patients/caregivers had the option of administering the second dose and were required to administer the third dose under supervision. At Weeks 12 and 16, patients/caregivers administered benralizumab via AI at home. After each administration, patients/caregivers completed questionnaires concerning administration and device functioning. All AI devices used were returned for evaluation.Results: A total of 595 AIs were used for 121 patients (mean age 48.5 years; 64% female) in the clinic and at home. Of 116 participants, 113 (97.4%; 95% confidence interval [CI]: 92.63–99.46) and 112 (96.6%; 95% CI: 91.41–99.05) successfully administered benralizumab at home at Weeks 12 and 16, respectively; 108 (93.1%; 95% CI: 86.86–96.98) were successful on both occasions. Throughout the study, 10 (1.7%) AI administrations were unsuccessful: 8 (1.3%) because of user error, 1 (0.2%) with undetermined cause, and 1 (0.2%) because of a manufacturing defect. Benralizumab efficacy (assessed by Asthma Control Questionnaire 6 score) and pharmacokinetics for patients using the AI were comparable to published results for patients receiving benralizumab via syringe in a clinical setting. No new or unexpected safety findings were observed.Conclusion: AIs were functional, reliable, and performed well in the clinic and at home. Nearly all patients and caregivers successfully administered SC benralizumab via AI. Benralizumab availability in AI and APFS could provide patients with choices for self-administration.Keywords: Autoinjector, benralizumab, biologic, clinical trial, delivery system, eosinophil, prefilled syringe, subcutaneous

Sanjay Sethi,1 Edward Kerwin,2 Henrik Watz,3 Gary T Ferguson,4 Robert M Mroz,5,6 Rosa Segarra,7 Eduard Molins,7 Diana Jarreta,7 Esther Garcia Gil7 1Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, SUNY, Buffalo, NY, USA; 2Clinical Research Institute, Medford, OR, USA; 3Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany; 4Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA; 5Centrum Medycyny Oddechowej, Białystok, Poland; 6Medical University of Białystok, Białystok, Poland; 7AstraZeneca, Barcelona, Spain Background: AMPLIFY assessed the efficacy and safety of aclidinium bromide/formoterol fumarate (AB/FF) vs its monocomponents and tiotropium (TIO) in patients with moderate-to-very severe symptomatic COPD (NCT02796677).Methods: In this 24-week, Phase III, double-dummy, active-controlled study, symptomatic patients (COPD Assessment Test score ≥10) were randomized to twice-daily AB/FF 400/12 µg, AB 400 µg, or FF 12 µg, or once-daily TIO 18 µg. Co-primary endpoints were change from baseline at week 24 in 1-hour morning post-dose FEV1 (AB/FF vs AB) and in pre-dose (trough) FEV1 (AB/FF vs FF). Non-inferiority of AB vs TIO in pre-dose FEV1 was also an objective. Normalized area under the curve (AUC)0–3/3 h FEV1 and nighttime and early morning symptoms were also assessed. A subgroup participated in a 24-hour serial spirometry sub-study.Results: A total of 1,594 patients were randomized; 566 entered the sub-study. At week 24, 1-hour post-dose FEV1 significantly improved with AB/FF vs AB, FF, and TIO (84, 84, and 92 mL; all P

Fernando J Martinez,1 Roger A Abrahams,2,3 Gary T Ferguson,4 Leif Bjermer,5 Lars Grönke,6 Florian Voß,7 Dave Singh8 1Division of Pulmonary and Critical Care Medicine, Weill Cornell Medical College, New York, NY, USA; 2Morgantown Pulmonary Clinical Research, Morgantown, WV, USA; 3Department of Pulmonary & Critical Care, Mon Health Care, Morgantown, WV, USA; 4Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA; 5Department of Respiratory Medicine and Allergology, Lund University, Lund, Sweden; 6Biotechnology, CSL Behring, Wiesbaden, Germany; 7Biostatistics + Data Sciences Corp., Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, Germany; 8Medicines Evaluation Unit, University of Manchester, Manchester, UK Rationale: In symptomatic patients with COPD, the decision whether to initiate maintenance treatment with a single agent or a combination of long-acting bronchodilators remains unclear. Objective: To investigate whether baseline symptomatic status influences response to tiotropium/olodaterol treatment. Materials and methods: Post hoc analysis of the randomized OTEMTO® studies (NCT01964352; NCT02006732), in which patients with moderate-to-severe COPD received placebo, tiotropium 5 µg, tiotropium/olodaterol 2.5/5 µg, or tiotropium/olodaterol 5/5 µg once daily for 12 weeks via the Respimat® inhaler (Boehringer Ingelheim, Ingelheim am Rhein, Germany). Impact of baseline symptomatic status (modified Medical Research Council [mMRC] score) on response to treatment with tiotropium/olodaterol 5/5 µg, tiotropium 5 µg, or placebo at Week 12 was assessed by St George’s Respiratory Questionnaire (SGRQ) total score and response rate, transition dyspnea index (TDI) focal score and response rate, and trough forced expiratory volume in 1 second response. Results: Tiotropium/olodaterol improved SGRQ total scores and response rates compared with placebo and tiotropium for patients with baseline mMRC scores 0–1 and ≥2. For tiotropium/olodaterol vs tiotropium, greater improvements were observed for patients with mMRC ≥2 (SGRQ score adjusted mean treatment difference -3.44 [95% CI: -5.43, -1.46]; P=0.0007; SGRQ response rate ORs 2.09 [95% CI: 1.41, 3.10]; P=0.0002). Dyspnea, measured by TDI score, was consistently improved with tiotropium/olodaterol vs placebo for patients with mMRC scores 0–1 and ≥2 (adjusted mean treatment difference 1.63 [95% CI: 1.06, 2.20]; P

Eric T Wittbrodt,1 Lauren A Millette,1 Kristin A Evans,2 Machaon Bonafede,2 Joseph Tkacz,2 Gary T Ferguson3 1Medical Affairs, AstraZeneca, Wilmington, DE, USA; 2Life Sciences, Value-Based Care, IBM Watson Health, Cambridge, MA, USA; 3Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA Purpose: The aim of this study was to examine real-world differences in health care resource use (HRU) and costs among COPD patients in the USA treated with a dry powder inhaler (DPI) or pressurized metered-dose inhaler (pMDI) following a COPD-related hospitalization. Methods: This retrospective analysis used the Truven MarketScan® databases. Eligibility criteria included 1) age ≥40 years, 2) COPD diagnosis, 3) inpatient admission with a diagnosis of COPD exacerbation, 4) inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA) prescription within 10 days of hospital discharge (index date), and 5) continuous enrollment for 12 months preindex and 90 days postindex. Outcomes included pre- and postindex HRU and costs. DPI and pMDI groups were compared on postindex outcomes via multivariate models controlling for demographic and baseline characteristics. Results: The sample included 1,960 DPI and 1,086 pMDI ICS/LABA patients. During the preindex period, pMDI patients were significantly more likely to be prescribed a short-acting β-agonist, experienced more COPD exacerbation-related hospital days, and had a greater number of pulmonologist visits compared to DPI patients (P

Gary T Ferguson,1 Adel H Mansur,2 Joshua S Jacobs,3 Jacques Hebert,4 Corbin Clawson,5 Wenli Tao,6 Yanping Wu,6 Mitchell Goldman6 On behalf of the GREGALE study investigators 1Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA; 2Department of Respiratory Medicine, Birmingham Heartlands Hospital, University of Birmingham, Birmingham, UK; 3Allergy & Asthma Clinical Research, Walnut Creek, CA, USA; 4Clinique Spécialisée en Allergie de la Capitale, Allergie et Immunologie, CHU de Québec, Québec, QC, Canada; 5MedImmune LLC, Gaithersburg, MD, USA; 6AstraZeneca, Gaithersburg, MD, USA Background: Patients prefer at-home subcutaneous administration of biologics across different diseases, yet no biologic is approved for at-home use for severe, uncontrolled asthma. Objective: We assessed at-home functionality, reliability, and performance of an accessorized pre-filled syringe (APFS) for subcutaneous benralizumab administration, an anti-eosinophil monoclonal antibody indicated for add-on maintenance treatment of patients with severe eosinophilic asthma. Materials and methods: Patients (N=116) with severe, uncontrolled asthma despite receiving medium- or high-dosage inhaled corticosteroids and long-acting β2-agonists received up to 5 APFS-administered subcutaneous doses (Weeks 0, 4, 8, 12, and 16) of benralizumab 30 mg. The first 3 doses were administered at the study sites. The patient/caregiver administered the last 2 doses at home. Endpoints included the percentage of dispensed APFS that were used successfully blood eosinophil counts, Asthma Control Questionnaire 6, and safety. Results: Nearly all dispensed APFS were successfully used in the clinic and at home (Week 0: 116/116, 100%; Week 4: 116/117, 99%; Week 8: 115/115, 100%; Week 12: 112/114, 98%; Week 16: 108/109, 99%). Only 1 APFS malfunctioned out of 573 dispensed. Two at-home administrations were unsuccessful because of patient-use error. One unreturned APFS was recorded as nonfunctional. Mean Asthma Control Questionnaire 6 scores decreased from baseline through all post-baseline time points, and nearly complete depletion of eosinophils was observed at the end of treatment. The most common adverse events were nasopharyngitis, upper respiratory tract infection, headache, and sinusitis. Five patients (4%) experienced transient mild or moderate injection-site reactions. Conclusion: The APFS was functional, reliable, and performed equally well in the clinic and at home. Keywords: biologic, subcutaneous, eosinophil, asthma, treatment, patient preference

Gary T Ferguson,1 Roberto Rodriguez-Roisin,2 Colin Reisner,3,4 Andrea Maes,3 Shahid Siddiqui,4 Ubaldo J Martin4 1Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA; 2Universitat de Barcelona, Hospital Clínic-The August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; 3Pearl – A member of the AstraZeneca Group, Morristown, NJ, USA; 4AstraZeneca, Gaithersburg, MD, USA Purpose: The efficacy and tolerability of GFF MDI (Bevespi Aerosphere®), a fixed-dose combination of glycopyrronium (GP)/formoterol fumarate dihydrate (FF) 14.4/10 µg (equivalent to glycopyrrolate/formoterol fumarate 18/9.6 µg) delivered by metered dose inhaler (MDI) using innovative co-suspension delivery technology, has been investigated in a Phase III clinical trial program (NCT01854645, NCT01854658, NCT01970878) in patients with COPD. Here, we present findings from a pharmacokinetic (PK) sub-study of NCT01854645 (PINNACLE-1).Methods: PINNACLE-1 was a multicenter, randomized, double-blind, parallel-group, 24 wk chronic-dosing, placebo- and active-controlled study. The PK sub-study assessed the systemic accumulation of glycopyrronium and formoterol following administration of GFF MDI 14.4/10 µg, GP MDI 14.4 µg, or FF MDI 10 µg (all BID) for 12 wks. Plasma for PK analysis was collected for up to 12 h after dosing, on Day 1 and Week 12.Results: Of 2,103 patients randomized in PINNACLE-1, 292 participated in the PK sub-study. The plasma concentration–time profiles of glycopyrronium were similar following treatment with GFF MDI or GP MDI, both after single dosing and at Week 12. Accumulation at Week 12 relative to Day 1 was up to 2.30-fold for glycopyrronium. The plasma concentration–time profiles of formoterol were similar following treatment with GFF MDI or FF MDI, both after single dosing and at Week 12. Accumulation at Week 12 relative to Day 1 was up to 1.62-fold for formoterol.Conclusion: Overall, the results have characterized the accumulation of glycopyrronium and formoterol associated with GFF MDI, GP MDI, and FF MDI, and indicated that there were no meaningful PK interactions, whether drug–drug or due to formulation, between glycopyrronium and formoterol following treatment with GFF MDI formulated using co-suspension delivery technology. Keywords: COPD, glycopyrronium, formoterol fumarate dihydrate, metered dose inhaler, co-suspension delivery technology, pharmacokinetics

Gary T Ferguson,1 Jill P Karpel,2 Emmanuelle Clerisme-Beaty,3 Lars Grönke,4 Florian Voß,4 Roland Buhl5 1Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, 2North Shore Medical Arts LLP, Great Neck, NY, 3Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA; 4Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, 5Pulmonary Department, Mainz University Hospital, Mainz, Germany Background: Increasing age is associated with poor prognosis in patients with COPD. Objective: This analysis from the replicate Phase III OTEMTO® and TONADO® studies examined the efficacy and safety of tiotropium, a long-acting anticholinergic, combined with olodaterol, a long-acting β2-agonist, compared to monotherapies and placebo in patients with COPD aged 40 years to

Gary T Ferguson,1 Gregory J Feldman,2 Peter Hofbauer,3 Alan Hamilton,4 Lisa Allen,5 Lawrence Korducki,5 Paul Sachs6 1Pulmonary Research Institute of Southeast Michigan, Livonia, MI, 2S Carolina Pharmaceutical Research, Spartanburg, SC, USA; 3Pneumologie, Weinheim, Germany; 4Boehringer Ingelheim, Burlington, ON, Canada; 5Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, 6Pulmonary Associates of Stamford, Stamford, CT, USA Background: Olodaterol is a long-acting β2-agonist with a 24-hour bronchodilator profile. Two replicate, randomized, double-blind, placebo-controlled, parallel-group, Phase III trials were performed as part of a comprehensive clinical program to investigate the long-term safety and efficacy of olodaterol in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) receiving usual-care background therapy. Methods: Patients received olodaterol 5 µg or 10 µg or placebo once daily for 48 weeks. Coprimary end points were forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 3 hours (AUC0–3) response (change from baseline), and trough FEV1 response at 12 weeks. Secondary end points included additional lung function assessments, use of rescue medications, FEV1 AUC response from 0 to 12 hours, and Patient Global Rating over 48 weeks. Results: Overall, 624 and 642 patients were evaluated in studies 1222.11 and 1222.12, respectively. In both studies, olodaterol 5 µg and 10 µg significantly improved the FEV1 AUC0–3 response (P

Gary T Ferguson,1 Mo Ghafouri,2 Luyan Dai,2 Leonard J Dunn31Pulmonary Research Institute of Southeast Michigan, Livonia, MI, USA; 2Boehringer Ingelheim Pharmaceuticals, Inc, Ridgefield, CT, USA; 3Clinical Research of West Florida, Inc, Clearwater, FL, USABackground: Ipratropium bromide/albuterol Respimat inhaler (CVT-R) was developed as an environmentally friendly alternative to ipratropium bromide/albuterol metered-dose inhaler (CVT-MDI), which uses a chlorofluorocarbon propellant.Objective: The objective of this study was to evaluate patient satisfaction, device usage, and long-term safety of CVT-R compared to CVT-MDI, and to the simultaneous administration of ipratropium bromide hydrofluoroalkane (HFA; I) and albuterol HFA (A) metered-dose inhalers as dual monotherapies (I + A).Design: This is a 48-week, open-label, randomized, active-controlled, parallel-group study (n = 470) comparing CVT-R to CVT-MDI and to I + A.Participants: Patients were at least 40 years of age, diagnosed with chronic obstructive pulmonary disease (COPD), and current or exsmokers.Interventions: Patients were randomized to receive: (1) CVT-R, one inhalation four times daily (QID); or (2) CVT-MDI, two inhalations QID; or (3) I + A two inhalations of each inhaler QID.Main measures: Patient Satisfaction and Preference Questionnaire (PASAPQ) performance score (primary endpoint) and adverse events.Key results: PASAPQ performance score was significantly higher (CVT-R versus CVT-MDI, 9.6; and CVT-R versus I + A, 6.2; both P < 0.001) when using CVT-R compared to CVT-MDI or I + A at all visits starting from week 3, while CVT-MDI and I + A treatment groups were similar. Time to first COPD exacerbation was slightly longer in the CVT-R group compared to the other treatment groups, although it did not reach statistical significance (CVT-R versus CVT-MDI, P = 0.57; CVT-R versus I + A, P = 0.22). Rates of withdrawal and patient refusal to continue treatment were lower in CVT-R compared with CVT-MDI and I + A groups (CVT-R versus CVT-MDI, P = 0.09; CVT-R versus I + A, P = 0.005). The percentage of patients reporting adverse events and serious adverse events was similar across all three treatment groups.Conclusion: CVT-R is an effective, environmentally friendly inhaler that provides patients with a high level of user satisfaction and may positively impact clinical outcomes while having no adverse impacts on patients using the device.Keywords: COPD, consumer satisfaction, consumer preference, inhalers

Douglas W Mapel1, Anand A Dalal2, Christopher M Blanchette3,4, Hans Petersen3, Gary T Ferguson5 1Lovelace Clinic Foundation, Albuquerque, NM, USA; 2US Health Outcomes, GlaxoSmithKline, Research Triangle Park, NC, USA; 3Lovelace Respiratory Research Institute, Kannapolis, NC, USA; 4University of North Carolina Eshelmen School of Pharmacy, Chapel Hill, NC, USA; 5Pulmonary Research Institute of Southeast Michigan, Livonia, MI, USA Purpose: This study was conducted to determine COPD severity at the time of diagnosis as confirmed by spirometry in patients treated in a US managed care setting. Patients and methods: All patients with one or more inpatient stays, one or more emergency department visits, or two or more outpatient visits with diagnosis codes for COPD during 1994–2006 were identified from the Lovelace Patient Database. From this group, a subset of continuously enrolled patients with evidence in claims of a first available pulmonary function test or pulmonary clinic visit and a confirmatory claim for a COPD diagnosis was selected. Medical chart abstraction was undertaken for this subset to gather information for diagnosis and severity staging of each patient based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria for COPD. Results: Of the 12,491 patients with a primary or secondary COPD diagnosis between 1994 and 2006, there were 1520 continuously enrolled patients who comprised the study cohort. Among the 648 eligible records from patients with evidence of a pulmonary function test, 366 were identified by spirometry as having COPD of GOLD stage I or higher (average percentage of predicted forced expiratory volume in 1 second: 60%): 19% were diagnosed at the stage of mild disease (GOLD stage I); 50% at moderate disease (GOLD stage II); and 31% at severe or very severe disease (GOLD stage III or IV, respectively). The majority of patients in these groups were not receiving maintenance treatment. Conclusion: The results demonstrate a very low incidence of early-stage diagnosis, confirmed by a pulmonary function test, of COPD in a large US sample and support calls for increased screening for COPD and treatment upon diagnosis. Keywords: lung function, Global Initiative for Chronic Obstructive Lung Disease (GOLD), detection, early treatment