Publications by authors named "James F Donohue"

119 Publications

Future concepts in bronchodilation for COPD: dual- monotherapy.

Eur Respir Rev 2021 Jun 1;30(160). Epub 2021 Jun 1.

Weill Cornell Medical College, New York, NY, USA.

Most patients with COPD are recommended to initiate maintenance therapy with a single long-acting bronchodilator, such as a long-acting muscarinic antagonist or long-acting β-agonist. However, many patients receiving mono-bronchodilation continue to experience high symptom burden, suggesting that patients are frequently not receiving optimal treatment. Treatment goals for COPD are often broad and not individually tailored, making initial treatment response assessments difficult. A personalised approach to initial maintenance therapy, based upon an individual's symptom burden and exacerbation risk, may be more appropriate.An alternative approach would be to maximise bronchodilation early in the disease course of all patients with COPD. Evidence suggests that dual bronchodilation has greater and consistent efficacy for lung function and symptoms than mono-bronchodilation, whilst potentially reducing the risk of exacerbations and disease deterioration, with a similar safety profile to mono-bronchodilators. Improvements in lung function and symptoms between dual- and mono-bronchodilation have also been demonstrated in maintenance-naïve patients, who are most likely to resemble those at first presentation in a clinical setting. Despite promising results, there are several evidence gaps that need to be addressed to allow decision makers to evaluate the merits of a widespread earlier introduction of dual bronchodilation.
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http://dx.doi.org/10.1183/16000617.0023-2021DOI Listing
June 2021

Aclidinium bromide/formoterol fumarate as a treatment for COPD: an update.

Expert Rev Respir Med 2021 09 17;15(9):1093-1106. Epub 2021 Jun 17.

School of Medicine, Johns Hopkins University, Baltimore, MD, USA.

: Aclidinium/formoterol is a long-acting muscarinic antagonist (LAMA) and long-acting β-agonist (LABA) dual bronchodilator used as a maintenance treatment for patients with chronic obstructive pulmonary disease (COPD). The efficacy of aclidinium/formoterol has been demonstrated consistently in patients with moderate-to-severe COPD versus placebo and monocomponents, with a comparable safety profile.: This review examines recent research findings that expand our understanding of the impact of aclidinium/formoterol on the burden of COPD. Reviewed outcomes include improvements in lung function, respiratory symptoms, health-related quality of life, exercise tolerance, exacerbation rates, and clinically important deteriorations. In addition, the reported cardiovascular safety of aclidinium and current LAMA/LABA treatment recommendations are discussed.: Aclidinium/formoterol reduces disease burden in patients with COPD, including those that are treatment-naïve, without a significant increase in safety risk compared with monotherapies. Furthermore, evidence supports an improvement in lung function over a 24-hour period with aclidinium/formoterol treatment versus monotherapy and placebo, which may offer an advantage over some once-daily LAMA/LABA combinations. In summary, the recent evidence discussed in this review adds weight to the use of LAMA/LABA combinations as an initial therapy for certain patients newly diagnosed with COPD.
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http://dx.doi.org/10.1080/17476348.2021.1920403DOI Listing
September 2021

FEV Minimum Important Difference versus Minimal Detectable Difference? In Search of the Unicorn.

Am J Respir Crit Care Med 2021 06;203(12):1573-1576

University of North Carolina at Chapel Hill Chapel Hill, North Carolina.

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http://dx.doi.org/10.1164/rccm.202012-4322LEDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483219PMC
June 2021

Wixela Inhub: A Generic Equivalent Treatment Option for Patients with Asthma or COPD.

Pulm Ther 2021 Jun 7;7(1):47-57. Epub 2020 Dec 7.

Mylan Pharma UK Ltd., Sandwich, Kent, UK.

Purpose: The purpose of this review is to discuss the development of Wixela™ Inhub™, a generic equivalent of Advair Diskus, a fixed-dose combination of fluticasone propionate/salmeterol powder for oral inhalation for patients with asthma whose symptoms are not controlled with inhaled corticosteroids alone and for those with chronic obstructive pulmonary disease (COPD) who are at a high risk for exacerbations. We provide an overview of the Inhub device and the bioequivalence studies that have been conducted to date. Briefly, the in vitro performance, improvements in forced expiratory volume in 1 s, and the fluticasone propionate/salmeterol dose strengths for Wixela Inhub and Advair Diskus were comparable.

Conclusion: The bioequivalence demonstrated by the totality of clinical and in vitro data supports the use of Wixela Inhub and provides a treatment option for patients with asthma or COPD.
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http://dx.doi.org/10.1007/s41030-020-00142-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137747PMC
June 2021

Pharmacotherapy for Chronic Obstructive Pulmonary Disease: Molecules and Delivery Are Equally Important.

Am J Respir Crit Care Med 2020 11;202(10):1482

University of North Carolina School of Medicine Chapel Hill, North Carolina.

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http://dx.doi.org/10.1164/rccm.202004-1489LEDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667917PMC
November 2020

Efficacy of revefenacin, a long-acting muscarinic antagonist for nebulized therapy, in patients with markers of more severe COPD: a post hoc subgroup analysis.

BMC Pulm Med 2020 May 11;20(1):134. Epub 2020 May 11.

Theravance Biopharma US, Inc., 901 Gateway Blvd, South San Francisco, CA, 94080, USA.

Background: Revefenacin, a once-daily, long-acting muscarinic antagonist delivered via standard jet nebulizer, increased trough forced expiratory volume in 1 s (FEV) in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in prior phase 3 trials. We evaluated the efficacy of revefenacin in patients with markers of more severe COPD.

Methods: A post hoc subgroup analysis of two replicate, randomized, phase 3 trials was conducted over 12 weeks. Endpoints included least squares change from baseline in trough FEV, St. George's Respiratory Questionnaire (SGRQ) responders, and transition dyspnea index (TDI) responders at Day 85. This analysis included patient subgroups at high risk for COPD exacerbations and compared patients who received revefenacin 175 μg and placebo: severe and very severe airflow limitation (percent predicted FEV 30%-< 50% and < 30%), 2011 Global Initiative for Chronic Obstructive Lung Disease (GOLD) D, reversibility (≥ 12% and ≥ 200 mL increase in FEV) to short-acting bronchodilators, concurrent use of long-acting β agonists and/or inhaled corticosteroids, older age (> 65 and > 75 years), and comorbidity risk factors.

Results: Revefenacin demonstrated significant improvements in FEV versus placebo at Day 85 among the intention-to-treat (ITT) population and all subgroups. Additionally, there was a greater number of SGRQ and TDI responders in the ITT population and the majority of subgroups analyzed among patients who received revefenacin versus placebo. For the SGRQ responders, the odds of response (odds ratio > 2.0) were significantly greater in the revefenacin arm versus the placebo arm among the severe airflow obstruction, very severe airflow obstruction and 2011 GOLD D subgroups. For the TDI responders, the odds of response (odds ratio > 2.0) were significantly greater among the severe airflow obstruction subgroup and patients aged > 75 years.

Conclusions: Revefenacin showed significantly greater improvements in FEV versus placebo in the ITT population and all subgroups. Furthermore, there were a greater number of SGRQ and TDI responders in the ITT population, and in the majority of patient subgroups among patients who received revefenacin versus placebo. Based on the data presented, revefenacin could be a therapeutic option among patients with markers of more severe COPD.

Trial Registration: Clinical trials registered with www.clinicaltrials.gov (Studies 0126 [NCT02459080; prospectively registered 22 May 2015] and 0127 [NCT02512510; prospectively registered 28 July 2015]).
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http://dx.doi.org/10.1186/s12890-020-1156-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216337PMC
May 2020

The Effect of Baseline Rescue Medication Use on Efficacy and Safety of Nebulized Glycopyrrolate Treatment in Patients with COPD from the GOLDEN 3 and 4 Studies.

Int J Chron Obstruct Pulmon Dis 2020 14;15:745-754. Epub 2020 Apr 14.

Sunovion Pharmaceuticals Inc., Marlborough, MA, USA.

Purpose: Rescue medication use is common in chronic obstructive pulmonary disease (COPD) patients and tends to increase with symptoms and disease severity. An analysis of baseline rescue medication use was conducted to inform on patient phenotypes and subsequent effects on lung function, symptoms, and safety following 12 weeks of nebulized glycopyrrolate (GLY) 25 µg twice daily or placebo in patients with moderate-to-very-severe COPD.

Patients And Methods: Pooled data from the 12-week, placebo-controlled GOLDEN 3 and 4 studies (n=781) were used to assign patients into quarters based on baseline rescue medication use (ie, average puffs-per-day) during the run-in period. Placebo-adjusted trough forced expiratory volume in 1 second (FEV), St. George's Respiratory Questionnaire (SGRQ) total score and EXAcerbations of COPD Tool-Respiratory Symptoms (EXACT-RS) total score data were reported; safety was evaluated by reviewing the incidence of adverse events (AEs) and serious AEs (SAEs).

Results: Baseline rescue medication use was a proxy for disease severity, evidenced by decreased lung function, increased health status scores, symptom scores and use of background long-acting β2-agonists and inhaled corticosteroids across quarters and treatment groups. Treatment with GLY led to greater improvements from baseline in trough FEV, SGRQ and EXACT-RS scores compared with placebo in all rescue medication use quarters. Additionally, the SGRQ and EXACT-RS exhibited greater improvement with increased baseline rescue medication use with GLY treatment. In the Q4 patients, SGRQ (≥4-unit reduction) or EXACT-RS (≥2-unit reduction) responders were significantly greater with GLY compared with placebo. AE and SAE incidences were similar across quartiles.

Conclusion: These results suggest that baseline rescue medication use assessments may be useful in the management of COPD. Treatment with nebulized GLY improved lung function and symptom scores, regardless of baseline rescue medication use. These results support the use of nebulized GLY for the treatment of COPD, independent of baseline rescue medication use.
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http://dx.doi.org/10.2147/COPD.S242767DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7166066PMC
June 2021

Efficacy and safety of revefenacin for nebulization in patients with chronic obstructive pulmonary disease taking concomitant ICS/LABA or LABA: subgroup analysis from phase III trials.

Ther Adv Respir Dis 2020 Jan-Dec;14:1753466620905278

Theravance Biopharma US, Inc., South San Francisco, CA 94080, USA.

Background: Combinations of a long-acting muscarinic receptor antagonist (LAMA), long-acting β-agonist (LABA), and inhaled corticosteroid (ICS) are used for patients with persistent chronic obstructive pulmonary disease (COPD) exacerbations on bronchodilator monotherapy. In this prespecified subgroup analysis, we assessed the efficacy and safety of the LAMA revefenacin in patients with COPD taking concomitant LABA, including ICS/LABA (LABA subgroup).

Methods: Efficacy data were obtained from two 12-week, replicate, placebo-controlled trials and safety data were pooled from the 12-week and a 52-week tiotropium-controlled trial. Patients received revefenacin 175 µg or placebo in the 12-week or tiotropium 18 µg in the 52-week studies. The efficacy endpoint was least squares (LS) mean change from baseline in trough forced expiratory volume in 1 second (FEV). Clinical health outcomes were assessed using the St. George's Respiratory Questionnaire (SGRQ).

Results: Revefenacin produced similar improvements from baseline in trough FEV in the non-LABA and LABA subgroups [placebo-adjusted LS mean change (95% confidence interval) in day 85 trough FEV, 150.9 (110.3-191.6) ml and 139.2 (82.9-195.5) ml;  < 0.0001 placebo]. Similar improvements were observed in SGRQ scores in the non-LABA and LABA subgroups [-3.3 (-5.4 to -1.2) and -3.4 (-6.3 to -0.6)]. Improvements in lung function and health outcomes were observed regardless of airflow obstruction severity. Revefenacin was well tolerated with more adverse events reported in the LABA than the non-LABA subgroup.

Conclusions: Once daily revefenacin for nebulization can be an effective and well-tolerated treatment for patients who require concomitant use of LABA with or without ICS.

Clinicaltrials.gov Identifiers: NCT02512510, NCT02459080, NCT02518139
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http://dx.doi.org/10.1177/1753466620905278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052452PMC
June 2021

Inhaler Devices for Delivery of LABA/LAMA Fixed-Dose Combinations in Patients with COPD.

Pulm Ther 2019 Jun 13;5(1):23-41. Epub 2019 Mar 13.

Centre of Academic Primary Care, University of Aberdeen, Aberdeen, UK.

Inhaled fixed-dose combinations (FDCs) of a long-acting β-agonist (LABA) and a long-acting muscarinic antagonist (LAMA) have become the cornerstone for the maintenance treatment of symptomatic COPD patients. In this regard, global COPD treatment guidelines have recognized the importance of inhaler devices as integral contributors to the effectiveness of LABA/LAMA FDCs and recommend regular assessment of inhaler device use by the patients in order to improve long-term clinical outcomes. Optimal disease control is also highly dependent upon patient preferences and adherence to inhaler devices. This review objectively examines and compares the major inhaler devices used to deliver different LABA/LAMA FDCs, discusses the inhaler device characteristics that determine drug deposition in the airways, real-life preference for inhaler devices, and handling of inhaler devices that impact the results of the long-term management of COPD. The introduction of new LABA/LAMA FDCs, new inhaler devices, and more clinical studies have created confusion among physicians in choosing the optimal inhaled therapy for COPD patients; in this context, this review attempts to provide an evidence-based framework for informed decision-making with a particular focus on the inhaler devices.Funding. The preparation of this manuscript was funded by Novartis Pharma AG.
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http://dx.doi.org/10.1007/s41030-019-0090-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6967354PMC
June 2019

Revefenacin: A Once-Daily, Long-Acting Bronchodilator For Nebulized Treatment Of COPD.

Int J Chron Obstruct Pulmon Dis 2019 19;14:2947-2958. Epub 2019 Dec 19.

University at Buffalo, State University of New York, Buffalo, NY, USA.

Bronchodilation with muscarinic antagonists, β-agonists, and inhaled corticosteroids remains the foundation of pharmaceutical treatment for patients with stable COPD. These drugs are delivered from a variety of devices, including dry powder inhalers, pressurized metered-dose inhalers, soft-mist inhalers, or nebulizers. Nebulized delivery is often preferable in patients who are elderly, are cognitively impaired, are unable to generate sufficient inspiratory force to use their inhaler, have difficulty coordinating hand-breath activity, are too dyspneic to hold their breath for a sufficient time, and/or may be acutely ill. Revefenacin, a once-daily long-acting muscarinic antagonist for nebulization recently approved by the US FDA for the treatment of patients with COPD, was discovered and developed using "duration and lung selectivity-by-design." This strategy selected a molecule with a high lung-selective index to maximize bronchodilation and limit systemic anti-muscarinic side effects. In early-phase clinical studies, revefenacin for nebulization led to a rapid onset of bronchodilation that was sustained for 24 hrs in patients with moderate to severe COPD. Revefenacin also demonstrated minimal systemic exposure and good tolerability in these studies. Statistically and clinically significant improvements in lung function (ie, peak and/or trough FEV) relative to placebo were observed with revefenacin in Phase III clinical trials of up to 3 months in patients with moderate to very severe COPD. Revefenacin was well tolerated in Phase III clinical trials with a low incidence of systemic antimuscarinic adverse events, which is consistent with its lung-selective design. There was no evidence of an increased risk of major cardiovascular events. Patient-reported outcome data from clinical trials indicated statistically significant improvements in several disease-specific measures. Revefenacin 175 μg for nebulization provides an effective once-daily treatment option for patients with moderate to very severe COPD who require or prefer nebulized therapy.
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http://dx.doi.org/10.2147/COPD.S157654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927563PMC
July 2020

An Evaluation Of Single And Dual Long-Acting Bronchodilator Therapy As Effective Interventions In Maintenance Therapy-Naïve Patients With COPD.

Int J Chron Obstruct Pulmon Dis 2019 6;14:2835-2848. Epub 2019 Dec 6.

BioPharmaceuticals R&D, AstraZeneca, Barcelona, Spain.

Background: 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 β-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 FEV, trough FEV, 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.
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http://dx.doi.org/10.2147/COPD.S217710DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6902852PMC
April 2020

Maintained therapeutic effect of revefenacin over 52 weeks in moderate to very severe Chronic Obstructive Pulmonary Disease (COPD).

Respir Res 2019 Oct 30;20(1):241. Epub 2019 Oct 30.

Theravance Biopharma US, Inc., 901 Gateway Boulevard, South San Francisco, CA, 94080, USA.

Background: Revefenacin is a long-acting muscarinic antagonist that was recently approved for the nebulized treatment of chronic obstructive pulmonary disease (COPD). Although shorter duration studies have documented the efficacy of revefenacin in COPD, longer-term efficacy has not been described. In a recent 52-week safety trial, revefenacin was well tolerated and had a favorable benefit-risk profile. Here we report exploratory efficacy and health outcomes in patients receiving revefenacin 175 μg or 88 μg daily during the 52-week trial.

Methods: In this randomized, parallel-group, 52-week trial (NCT02518139), 1055 participants with moderate to very severe COPD received revefenacin 175 μg or 88 μg in a double-blind manner, or open-label active control tiotropium.

Results: Over the 52-week treatment period, both doses of revefenacin, as well as tiotropium, elicited significant (all p < 0.0003) improvements from baseline in trough forced expiratory volume in 1 s (FEV). The trough FEV profile (least squares mean change from baseline) for revefenacin 175 μg ranged from 52.3-124.3 mL and the trough FEV profile for tiotropium ranged from 79.7-112.8 mL. In subgroup comparisons, the effect of revefenacin on trough FEV was comparable in patients taking concomitant long-acting β-agonists, with or without inhaled corticosteroids, with patients who were not taking these medications. There were statistically significant (p < 0.05) improvements in all measured health status outcomes (evaluated using St. George's Respiratory Questionnaire, COPD Assessment Test, Clinical COPD Questionnaire and Baseline and Transition Dyspnea Index) from 3 months onward, in all treatment arms.

Conclusions: Significant sustained improvements from baseline in trough FEV and respiratory health outcomes were demonstrated for 175-μg revefenacin over 52 weeks, further supporting its use as a once-daily bronchodilator for the nebulized treatment of patients with COPD.

Trial Registration: NCT02518139 ; Registered 5 August 2015.
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http://dx.doi.org/10.1186/s12931-019-1187-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6822411PMC
October 2019

The Role of Guaifenesin in the Management of Chronic Mucus Hypersecretion Associated with Stable Chronic Bronchitis: A Comprehensive Review.

Chronic Obstr Pulm Dis 2019 Oct;6(4)

Internal Medicine & Pulmonology, Charlotte Lung & Health Center, Charlotte, North Carolina.

Chronic obstructive pulmonary disease is the third leading cause of death and disease burden worldwide. It includes a spectrum of diseases including chronic bronchitis which is characterized by overproduction, hypersecretion and decreased elimination of mucus. Chronic bronchitis has numerous clinical consequences, including predisposition to lower respiratory tract infections, accelerated decline in lung function, increased exacerbation rate and decreased health-related quality of life.

Although the inflammatory mechanisms responsible for mucus cell metaplasia in chronic obstructive pulmonary disease and stable chronic bronchitis are poorly understood, the main goals of therapy are to decrease mucus hypersecretion by controlling inflammation and to increase mucus clearance. Non-pharmacological measures include smoking cessation and chest physiotherapy. Pharmacological interventions include expectorants and mucolytics together with long-acting beta2-adrenergic receptor agonists, anticholinergics, glucocorticoids, phosphodiesterase-4 inhibitors, antioxidants, and antibiotics.

Guaifenesin is an expectorant that is thought to increase hydration and decrease viscosity of mucus leading to improved clearance of accumulated secretions from the upper and lower airway. Although guaifenesin has a Food and Drug Administration Over-the-Counter (OFC) Monograph indication to "help loosen phlegm (mucus) and thin bronchial secretions in patients with stable chronic bronchitis," there is limited published evidence of either mechanism of action or clinical efficacy in this disease state. Here we review the pathophysiology and consequences of chronic mucus hypersecretion and examine the evidence for the use of guaifenesin in patients with stable chronic bronchitis.
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http://dx.doi.org/10.15326/jcopdf.6.4.2019.0139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7006698PMC
October 2019

Weighing the evidence for pharmacological treatment interventions in mild COPD; a narrative perspective.

Respir Res 2019 Jul 8;20(1):141. Epub 2019 Jul 8.

Clinical Research Institute, Medford, Oregon, USA.

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.
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http://dx.doi.org/10.1186/s12931-019-1108-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615221PMC
July 2019

Cardiovascular safety of revefenacin, a once-daily, lung-selective, long-acting muscarinic antagonist for nebulized therapy of chronic obstructive pulmonary disease: Evaluation in phase 3 clinical trials.

Pulm Pharmacol Ther 2019 08 30;57:101808. Epub 2019 May 30.

Theravance Biopharma US, Inc., South San Francisco, 901 Gateway Boulevard, CA, 94080, USA. Electronic address:

The cardiovascular safety of revefenacin, an anticholinergic indicated for the maintenance treatment of patients with chronic obstructive lung disease (COPD), was evaluated in phase 3 trials in patients with moderate to very severe COPD. No clinically meaningful changes in 12-lead electrocardiogram recordings were observed with up to 52 weeks of once-daily revefenacin 88 or 175 μg. In a pooled analysis of Studies 0126 and 0127, the incidence of prolonged QT interval corrected for heart rate using the Fridericia correction formula (QTcF; >450 msec) for revefenacin 88 μg (n = 23, 5.6%) and revefenacin 175 μg (n = 23, 5.9%) was similar to that for placebo (n = 22, 5.3%). In Study 0128, the incidence of prolonged QTcF was similar in the revefenacin 175 μg (n = 25, 7.7%) and tiotropium (n = 26, 7.3%) groups and lower in the revefenacin 88 μg (n = 15, 4.2%) group. There were four major adverse cardiac events (MACEs) in Study 0126 (one, two, and one in the placebo, revefenacin 88 μg, and revefenacin 175 μg groups, respectively), no MACEs in Study 0127 and 26 MACEs in Study 0128 (9, 10 and 7 in the revefenacin 88 μg, revefenacin 175 μg and tiotropium groups, respectively). In Study 0128, only one MACE was considered possibly/probably related to revefenacin (atrial fibrillation in the revefenacin 175 μg group). Thus, revefenacin may provide beneficial nebulized therapy for patients with COPD without further elevating their risk of cardiovascular events.
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http://dx.doi.org/10.1016/j.pupt.2019.101808DOI Listing
August 2019

Revefenacin, a once-daily, lung-selective, long-acting muscarinic antagonist for nebulized therapy: Safety and tolerability results of a 52-week phase 3 trial in moderate to very severe chronic obstructive pulmonary disease.

Respir Med 2019 07 23;153:38-43. Epub 2019 May 23.

Theravance Biopharma US, Inc., 901 Gateway Boulevard, South San Francisco, CA, 94080, USA. Electronic address:

Background: Prior replicate 12-week phase 3 trials demonstrated that once-daily doses of revefenacin inhalation solution at 88 μg and 175 μg produced significant bronchodilation over 24 h post dose in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). The objective was to characterize the safety profile of revefenacin 88 μg and 175 μg over 52 weeks of treatment.

Methods: In this randomized, parallel-group, 52-week trial (NCT02518139), 1055 participants with moderate to very severe COPD received revefenacin 88 μg or 175 μg in a double-blind manner, or open-label active control tiotropium.

Results: Treatment-emergent adverse events (AEs) were comparable across all treatment groups (n [%] patients; revefenacin 88 μg, 272 [74.7%]; 175 μg, 242 [72.2%]; tiotropium, 275 [77.2%]). Numerically fewer COPD exacerbations (n [%] patients) were observed with revefenacin 175 μg (73 [21.8%]) than with 88 μg (107 [29.4%]) or tiotropium (100 [28.1%]). Serious AEs were comparable with revefenacin 88 μg (58 [15.9%] and tiotropium (58 [16.3%]), but were lower with revefenacin 175 μg (43 [12.8%]), and mortality was low. In patients using revefenacin 88 μg or tiotropium with a concurrent long-acting β-agonist (LABA) product, the incidence of AEs was slightly higher than without concurrent LABA. LABA did not affect the incidence of AEs for patients who received revefenacin 175 μg.

Conclusions: Revefenacin was generally well tolerated over 52 weeks of treatment, and had a safety profile that supports its use as a long-term once-daily bronchodilator for the nebulized treatment of COPD.
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http://dx.doi.org/10.1016/j.rmed.2019.05.010DOI Listing
July 2019

Aclidinium bromide in fixed-dose combination with formoterol fumarate in the management of COPD: an update on the evidence base.

Ther Adv Respir Dis 2019 Jan-Dec;13:1753466619850725

Asthma and Airway Center, Toronto Western Hospital, Toronto, ON, Canada.

Aclidinium bromide/formoterol fumarate (AB/FF) 400/12 µg is a twice-daily long-acting muscarinic receptor antagonist and long-acting β agonist (LAMA/LABA) dual-bronchodilator maintenance therapy used to relieve symptoms and reduce future risk of exacerbations in adults with chronic obstructive pulmonary disease (COPD). To date, there have been several clinical studies and post hoc analyses of AB/FF, assessing treatment outcomes in patients with moderate-to-severe COPD. These studies have looked at a range of outcomes, including lung function parameters, patient-reported symptom scores, quality-of-life measures assessing impaired health and perceived well-being, and the frequency, duration, and severity of exacerbations. In light of the major 2017 revision to the Global initiative for chronic Obstructive Lung Disease (GOLD) recommendations, and the subsequent updates, we present an update on the latest evidence supporting the efficacy and safety of AB/FF. This review discusses the clinical relevance of the improvements in lung function, symptoms, quality of life, and exacerbations in patients with COPD reported in the phase III and IV trials of AB/FF. Given the current concerns over unnecessary inhaled corticosteroid (ICS) use in COPD, we also touch briefly on the use of blood eosinophils as a biomarker for identifying those patients with COPD already using LAMA/LABA therapy for whom the addition of ICS might be of benefit.
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http://dx.doi.org/10.1177/1753466619850725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6535700PMC
November 2019

Prevalence and factors associated with suboptimal peak inspiratory flow rates in COPD.

Int J Chron Obstruct Pulmon Dis 2019;14:585-595. Epub 2019 Mar 1.

Division of Pulmonary Diseases and Critical Medicine, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA,

Purpose: Adequate peak inspiratory flow rate (PIFR) is required for drug dispersion with dry powder inhalers (DPIs). Prevalence of PIFR discordance (suboptimal PIFR with prescribed inhalers) and factors influencing device-specific PIFR are unclear in COPD. The objective of this study was to determine the prevalence of PIFR discordance and associated clinical factors in a stable COPD population.

Patients And Methods: An observational, single-center, cohort study was conducted including 66 outpatients with COPD. PIFR was measured using the In-Check™ Dial with applied resistance of prescribed inhalers. Participants were defined as discordant if measured PIFR was <30 L/min and <60 L/min for high and low-medium resistance devices, respectively, using an inspiratory effort the participant normally used with their prescribed DPI.

Results: The median age of the COPD participants was 69.4 years, 92% were white and 47% were female. A total of 48% were using low-medium resistance DPIs (Diskus/Ellipta) and 76% used high-resistance DPI (Handihaler). A total of 40% of COPD participants were discordant to prescribed inhalers. Female gender was the only factor consistently associated with lower PIFR. Shorter height was associated with reduced PIFR for low-medium resistance (=0.44; =0.01), but not high resistance (=0.20; =0.16). There was no correlation between PIFR by In-Check™ dial and PIFR measured by standard spirometer.

Conclusion: PIFR is reduced in stable COPD patients, with female gender being the only factor consistently associated with reduced PIFR. Discordance with prescribed inhalers was seen in 40% of COPD patients, suggesting that many COPD patients do not generate adequate inspiratory force to overcome prescribed DPIs resistance in the course of normal use.
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http://dx.doi.org/10.2147/COPD.S195438DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402615PMC
July 2019

Efficacy of aclidinium/formoterol 400/12 µg, analyzed by airflow obstruction severity, age, sex, and exacerbation history: pooled analysis of ACLIFORM and AUGMENT.

Int J Chron Obstruct Pulmon Dis 2019;14:479-491. Epub 2019 Feb 26.

AstraZeneca, 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 (<65/≥65 years), sex, and exacerbation history (0/≥1 exacerbation in the previous 12 months). Changes from baseline vs placebo and mono-therapies were evaluated: morning pre-dose (trough) and morning 1-hour post-dose FEV, Transition Dyspnea Index (TDI), and moderate/severe exacerbation rates (healthcare resource utilization [HCRU] and EXAcerbations of Chronic pulmonary disease Tool [EXACT] criteria).

Results: Aclidinium/formoterol improved the post-dose FEV vs placebo and monotherapy in all subgroups (all <0.01) and trough FEV vs placebo (<0.001) and formoterol (<0.05) across all subgroups. Improvements in trough FEV were observed vs aclidinium in patients with severe airflow obstruction, patients aged <65 years, males, and patients with exacerbation history (<0.05). Improvements in TDI were observed vs placebo in all subgroups (all <0.001), monotherapies for patients with moderate (formoterol <0.05) or severe airflow obstruction (aclidinium <0.05), patients aged <65 years (aclidinium <0.01, formoterol <0.05), males (formoterol <0.05), and patients with no exacerbation history (formoterol <0.05). HCRU exacerbation rates were lower for aclidinium/formoterol vs placebo in patients with no exacerbation history (<0.01). EXACT exacerbation rates were lower for aclidinium/formoterol in patients with moderate airflow obstruction vs placebo and aclidinium, patients aged <65 years vs placebo and ≥65 years vs formoterol, males vs placebo, and patients with no exacerbation history vs placebo (all <0.05).

Conclusion: Aclidinium/formoterol significantly improved post-dose FEV, trough FEV, and TDI vs placebo across all subgroups and vs monotherapy in many subgroups. These findings further support the benefits of aclidinium/formoterol for all patients with COPD.
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http://dx.doi.org/10.2147/COPD.S185502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396834PMC
July 2019

Use of a Cross-Sectional Survey in the Adult Population to Characterize Persons at High-Risk for Chronic Obstructive Pulmonary Disease.

Healthcare (Basel) 2019 Jan 18;7(1). Epub 2019 Jan 18.

Division of Pulmonary, Critical Care and Sleep Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.

Rationale/Objective: The Behavioral Risk Factor Surveillance System (BRFSS) health survey has been used to describe the epidemiology of chronic obstructive pulmonary disease (COPD) in the US. Through addressing respiratory symptoms and tobacco use, it could also be used to characterize COPD risk.

Methods: Four US states added questions to the 2015 BRFSS regarding productive cough, shortness of breath, dyspnea on exertion, and tobacco duration. We determined COPD risk categories: provider-diagnosed COPD as self-report, high-risk for COPD as ≥10 years tobacco smoking and at least one significant respiratory symptom, and low risk was neither diagnosed COPD nor high risk. Disease burden was defined by respiratory symptoms and health impairments. Data were analyzed using multiple logistic regression models with age as a covariate.

Results: Among 35,722 adults ≥18 years, the overall prevalence of COPD and high-risk for COPD were 6.6% and 5.1%. Differences among COPD risk groups were evident based on gender, race, age, geography, tobacco use, health impairments, and respiratory symptoms. Risk for disease was seen early where 3.75% of 25⁻34 years-old met high-risk criteria. Longer tobacco duration was associated with an increased prevalence of COPD, particularly >20 years. Seventy-nine percent of persons ≥45 years-old with frequent shortness of breath (SOB) reported having or being at risk of COPD, reflecting disease burden.

Conclusion: These data, representing nearly 18% of US adults, indicates those at high risk for COPD share many, but not all of the characteristics of persons diagnosed with the disease and demonstrates the value of the BRFSS as a tool to define lung health at a population level.
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http://dx.doi.org/10.3390/healthcare7010012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473439PMC
January 2019

Health-Related Quality of Life Improvements in Moderate to Very Severe Chronic Obstructive Pulmonary Disease Patients on Nebulized Glycopyrrolate: Evidence from the GOLDEN Studies.

Chronic Obstr Pulm Dis 2018 Jun 6;5(3):193-207. Epub 2018 Jun 6.

Sunovion Pharmaceuticals Inc., Marlborough, Massachusetts.

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. 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. 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. 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. NCT02347761, NCT02347774, NCT02276222.
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http://dx.doi.org/10.15326/jcopdf.5.3.2017.0178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296788PMC
June 2018

Satisfaction with the Use of eFlow Closed-System Nebulizer in Patients with Moderate-to-Very Severe Chronic Obstructive Pulmonary Disease: Findings from a Long-Term Safety Study.

J Aerosol Med Pulm Drug Deliv 2019 02 17;32(1):24-33. Epub 2018 Nov 17.

4 Sunovion Pharmaceuticals, Inc., Marlborough, Massachusetts.

Background: Effective delivery of inhaled drugs in chronic obstructive pulmonary disease (COPD) depends on patients' ability to correctly use an inhalation device. Nebulized delivery may be appropriate for COPD patients who cannot coordinate breath with inhalation or generate adequate inhalational force. Until recently, long-acting muscarinic antagonists (LAMAs), used for maintenance treatment of COPD, were available for delivery only via handheld inhalers. Lonhala™ Magnair™ (glycopyrrolate inhalation solution) is a LAMA delivered via the eFlow closed-system (eFlow CS) vibrating membrane nebulizer. We assessed patient-reported ease of use and satisfaction with the eFlow CS nebulizer in the GOLDEN (Glycopyrrolate for Obstructive Lung Disease via Electronic Nebulizer)-5 study.

Methods: GOLDEN-5, a phase 3, randomized, open-label trial, evaluated the safety and efficacy of glycopyrrolate/eFlow CS 50 μg twice daily versus tiotropium 18 μg once daily (administered via HandiHaler™) in patients with moderate-to-very severe COPD. Only patients in the glycopyrrolate/eFlow CS group completed a study-specific device use questionnaire, evaluating patients' perceptions about ease of use, confidence in drug delivery, and overall device satisfaction at week 48 or end of study. Responses were summarized by counts and percentages.

Results: Of 620 patients who received glycopyrrolate/eFlow CS, 454 completed the questionnaire (mean age [standard deviation, SD] 63.3 [8.5] years; mean BMI [SD] 28.45 [6.208] kg/m). Based on patient-reported perceptions, most patients (83%) were "confident" to "very confident" that the drug was delivered into their lungs with the eFlow CS; >70% rated the eFlow CS as "easy" or "very easy" to assemble, operate, and clean. Most (75%) patients ranked themselves as being "satisfied" or "very satisfied" overall with the eFlow CS nebulizer.

Conclusions: High levels of satisfaction, confidence, and ease of use were reported with the eFlow CS nebulizer in this study. These findings support the use of the eFlow CS for maintenance treatment of COPD with glycopyrrolate inhalation solution.
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http://dx.doi.org/10.1089/jamp.2018.1477DOI Listing
February 2019

An Update on the Global Initiative for Chronic Obstructive Lung Disease 2017 Guidelines With a Focus on Classification and Management of Stable COPD.

Respir Care 2018 Jun;63(6):749-758

Division of Pulmonary Diseases and Critical Care Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

The 2017 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines offer important changes to the assessment and management of stable COPD of importance to practitioners, respiratory therapists, pharmacists, and nurses who care for patients with COPD. Therapies are now chosen based on the burden of symptoms and the history of COPD exacerbations, and inhaler regimens are modifiable based on continual clinical reassessment. Although identifying the degree of airway obstruction remains important for informing the clinical status of the patient with COPD, FEV is no longer used to direct the therapeutic approach. Therapies and modes of inhaled medication delivery for each GOLD grouping have been modified and reflect the need for reevaluation of patient symptoms and COPD exacerbation history as an indicator to add or withdraw therapies. As the knowledge of this important disease continues to expand, exacerbation and symptom prevention in patients with stable COPD will remain as an important target of COPD therapies and research. Novel drug combinations and delivery devices are sure to positively affect the practitioner's approach to patients with stable COPD. The new 2017 GOLD guidelines represent a step toward personalized care of the patient with COPD.
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http://dx.doi.org/10.4187/respcare.06174DOI Listing
June 2018

Long-term health-related quality-of-life and symptom response profiles with arformoterol in COPD: results from a 52-week trial.

Int J Chron Obstruct Pulmon Dis 2018 5;13:499-508. Epub 2018 Feb 5.

Section of Pulmonary and Critical Care Medicine, Baylor College of Medicine, Houston, TX, USA.

Background: Symptom severity is the largest factor in determining subjective health in COPD. Symptoms (eg, chronic cough, dyspnea) are associated with decreased health-related quality of life (HRQoL). We evaluated the impact of arformoterol on HRQoL in COPD patients, measured by St George's Respiratory Questionnaire (SGRQ). Post hoc growth mixture model (GMM) analysis examined symptom response profiles.

Methods: We examined data from a randomized, double-blind, parallel-group, 12-month safety trial of twice-daily nebulized arformoterol 15 µg (n=420) versus placebo (n=421). COPD severity was assessed by Global Initiative for Chronic Obstructive Lung Disease (GOLD) status. GMM analysis identified previously unknown patient subgroups and examined the heterogeneity in response to SGRQ Symptoms scores.

Results: SGRQ Total score improved by 4.24 points with arformoterol and 2.02 points with placebo (=0.006). Significantly greater improvements occurred for arformoterol versus placebo in SGRQ Symptoms (6.34 vs 4.25, =0.031) and Impacts (3.91 vs 0.97, =0.001) scores, but not in Activity score (3.57 vs 1.75, =0.057). GMM identified responders and nonresponders based on the SGRQ Symptoms score. End-of-study mean difference in SGRQ Symptoms scores between these latent classes was 20.7 points (<0.001; 95% confidence interval: 17.6-23.9). Compared with nonresponders, responders were more likely current smokers (55.52% vs 44.02%, =0.0021) and had more severe COPD (forced expiratory volume in 1 second [FEV]: 1.16 vs 1.23 L, =0.0419), more exacerbations (0.96 vs 0.69, =0.0018), and worse mean SGRQ Total (59.81 vs 40.57, <0.0001), Clinical COPD Questionnaire (3.29 vs 2.05, <0.0001), and Modified Medical Research Council Dyspnea Scale (3.13 vs 2.75, <0.0001) scores. Arformoterol-receiving responders exhibited significantly greater improvements in FEV (0.09 vs 0.008, =0.03) and fewer hospitalizations (0.13 vs 0.24, =0.02) than those receiving placebo.

Conclusion: In this study, arformoterol treatment significantly improved HRQoL reflected by SGRQ. For the analysis performed on these data, arformoterol may be particularly effective in improving lung function and reducing hospitalizations among patients who are unable to quit smoking or present with more severe symptoms.
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http://dx.doi.org/10.2147/COPD.S141729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5804733PMC
September 2018

Correlations between FEV1 and patient-reported outcomes: A pooled analysis of 23 clinical trials in patients with chronic obstructive pulmonary disease.

Pulm Pharmacol Ther 2018 04 19;49:11-19. Epub 2017 Dec 19.

Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.

Background: In clinical trials of inhaled bronchodilators, chronic obstructive pulmonary disease (COPD) guidelines recommend that patient-reported outcomes (PROs) are assessed alongside lung function. How these endpoints are related is unclear.

Methods: Pooled longitudinal data from 23 randomised controlled COPD studies were analyzed (N = 23,213). Treatments included long-acting β agonists, long-acting muscarinic antagonists (LABAs or LAMAs) and the LABA/LAMA combination QVA149. Outcome measures were Transition Dyspnoea Index (TDI) and St. George's Respiratory Questionnaire (SGRQ) scores, COPD exacerbation frequency and rescue medication use. Relationships between changes in trough forced expiratory volume in one second (ΔFEV) and outcomes following treatment were assessed using correlations of data summaries and model-based analysis: generalized linear mixed-effect regression modelling to determine if ΔFEV could predict patient outcomes with different treatments.

Results: Mean age was 64 years, 73% were male, and most had moderate (45%) or severe (52%) disease. Statistically significant correlations were observed between ΔFEV and each outcome measure (exacerbations Rs = 0.05; rescue medication, SGRQ, TDI, r = 0.11-0.16; all p < .001). Patients with greater improvements in trough FEV had on average better SGRQ and TDI scores, fewer exacerbations, and used less rescue medication. For SGRQ and TDI scores, minimal clinically important differences were observed over the range of pooled ΔFEV values. Model-based predictions confirmed the treatment effect was partly explained by changes in FEV from baseline with improvements in PROs observed across all treatments when trough FEV improved. Across all endpoints active treatments were better than placebo (p < .0001), and LABA/LAMA treatment resulted in numerically better treatment outcomes than either monocomponent.

Conclusions: These data suggest that FEV improvements post-bronchodilation correlate with PRO improvements. Further improvements in patient outcomes may be expected by maximizing lung function improvements.

Trial Registration: Registration details for the 23 randomised controlled studies used in this pooled analysis are supplied in Additional File 4.
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http://dx.doi.org/10.1016/j.pupt.2017.12.005DOI Listing
April 2018

Dose selection for glycopyrrolate/eFlow phase III clinical studies: results from GOLDEN (Glycopyrrolate for Obstructive Lung Disease via Electronic Nebulizer) phase II dose-finding studies.

Respir Res 2017 12 4;18(1):202. Epub 2017 Dec 4.

Sunovion Pharmaceuticals Inc., Marlborough, MA, USA.

Background: Long-acting muscarinic antagonists (LAMAs) are recommended for the treatment of chronic obstructive pulmonary disease (COPD). Glycopyrrolate/eFlow® is an investigational drug-device combination of the LAMA glycopyrrolate administered by an eFlow® Closed System (eFlow® CS) nebulizer. The GOLDEN 2 (NCT01706536) and GOLDEN 6 (NCT02038829) Phase II, multicenter studies were conducted to inform dose selection for the GOLDEN Phase III clinical trials. Bronchodilator responses and safety assessments supported dose selection.

Methods: Subjects with moderate-to-severe COPD were randomized into 28-day parallel-group (GOLDEN 2) or 7-day crossover (GOLDEN 6) studies and received placebo, glycopyrrolate (3, 6.25, 12.5, 25, 50 or 100 μg twice daily [BID]) or aclidinium bromide 400 μg BID. The primary endpoint of both studies was change from baseline in trough forced expiratory volume in 1 s (FEV). Safety assessments included the incidence of treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events, and discontinuation due to TEAE. Lung function data collected in both studies were pooled.

Results: The combined GOLDEN 2 (n = 282) and GOLDEN 6 (n = 96) studies included 378 subjects. On Days 7 and 28 there were dose-ordered, statistically significant and clinically important lung function improvements in glycopyrrolate treatment groups. Specifically, on Day 7, glycopyrrolate produced >0.100 L placebo-adjusted changes from baseline in trough FEV (12.5 μg BID: 0.122 L; 25 μg BID: 0.123 L; 50 μg BID: 0.137 L) and FEV AUC (12.5 μg BID: 0.145 L; 25 μg BID: 0.178 L; 50 μg BID: 0.180 L). The improvements in lung function for the glycopyrrolate 25 and 50 μg BID doses were comparable to those with aclidinium bromide 400 μg BID (FEV: 0.149 L; FEV AUC: 0.172 L). Acceptable safety profiles were observed across all groups in both studies.

Conclusions: The efficacy and safety findings supported selection of glycopyrrolate 25 and 50 μg BID doses for the Phase III GOLDEN studies and provided preliminary evidence for the use of nebulized glycopyrrolate as a maintenance therapy for COPD.
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http://dx.doi.org/10.1186/s12931-017-0681-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5715551PMC
December 2017

Efficacy and safety of glycopyrrolate/eFlow CS (nebulized glycopyrrolate) in moderate-to-very-severe COPD: Results from the glycopyrrolate for obstructive lung disease via electronic nebulizer (GOLDEN) 3 and 4 randomized controlled trials.

Respir Med 2017 Nov 19;132:238-250. Epub 2017 Jul 19.

Pulmonary Research Institute of Southeast Michigan, Farmington Hills, MI, USA.

Background: SUN-101 is a combination of glycopyrrolate delivered through an innovative, electronic nebulizer, intended for the treatment of patients with COPD. The objective of this study was to assess the efficacy and safety of this new drug device combination.

Methods: Replicate Phase III randomized, double-blind, placebo-controlled studies were conducted to evaluate the efficacy and safety of glycopyrrolate solution administered by an investigational eFlow Closed System (eFlow CS) nebulizer in subjects with moderate-to-very-severe COPD, including those with continued background use of a long-acting beta-agonist ± inhaled corticosteroid and/or history of cardiovascular (CV) disease. Subjects were randomized in a 1:1:1 ratio to receive placebo or glycopyrrolate (25 μg or 50 μg twice daily [BID]) for 12 weeks. The primary efficacy endpoint was the change from baseline in trough forced expiratory volume in 1 s (FEV) at Week 12 compared with placebo. Secondary endpoints included change from baseline in forced vital capacity (FVC) after 12 weeks, change from baseline in health status measured by St George's Respiratory Questionnaire (SGRQ) at 12 weeks/end of study (EOS), and change in rescue medication use, as well as change from baseline in FEV area under the curve from 0 to 12 h after 12 weeks in the GOLDEN 3 sub-study. Daytime and night-time symptoms were recorded using an electronic diary. Safety was monitored throughout the study, including major adverse cardiovascular events.

Results: A total of 653 subjects were randomized in GOLDEN 3 and 641 in GOLDEN 4. Treatment with glycopyrrolate 25 μg BID and 50 μg BID resulted in statistically significant and clinically important changes from baseline in trough FEV compared with placebo at Week 12 (GOLDEN 3: 0.105 L and 0.126 L; p ≤ 0.0001; GOLDEN 4: 0.084 L and 0.082 L; p ≤ 0.0001). Nebulized glycopyrrolate 25 μg BID and 50 μg BID also resulted in improvements in FVC change from baseline versus placebo at Week 12 (GOLDEN 3: 0.149 L and 0.167 L, p < 0.001; GOLDEN 4: 0.130 L and 0.113 L, p < 0.01), and in SGRQ change from baseline score versus placebo at Week 12/EOS (GOLDEN 3: -3.072 [p < 0.05] and -1.848; GOLDEN 4: -3.585 and -3.557, p < 0.01). LS mean change from baseline in EXACT-respiratory symptoms total score at Week 12 for placebo and nebulized glycopyrrolate 25 and 50 μg BID were -0.936, -1.903 and -1.502 for GOLDEN 3 and -0.376, -1.647 and -1.532 for GOLDEN 4. Rescue medication use was unchanged. Nebulized glycopyrrolate was well tolerated at both doses based on the incidence of adverse events and CV events.

Conclusions: The results of these studies demonstrated statistically significant and clinically important improvements in pulmonary function and patient-reported health outcomes, with an acceptable safety profile, support the use of glycopyrrolate/eFlow CS as a potential maintenance treatment for moderate-to-very-severe COPD.
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http://dx.doi.org/10.1016/j.rmed.2017.07.011DOI Listing
November 2017

Long-term safety and efficacy of glycopyrrolate/formoterol metered dose inhaler using novel Co-Suspension™ Delivery Technology in patients with chronic obstructive pulmonary disease.

Respir Med 2017 05 12;126:105-115. Epub 2017 Mar 12.

Pearl Therapeutics Inc., Morristown, NJ, USA; AstraZeneca, Morristown, NJ, USA.

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), 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.
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http://dx.doi.org/10.1016/j.rmed.2017.03.015DOI Listing
May 2017
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