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Cristina Rebordosa,1 Estel Plana,2 Annalisa Rubino,3 Jaume Aguado,2 David Martinez,2 Alejhandra Lei,4 Sami Daoud,5 Nuria Saigi-Morgui,1 Susana Perez-Gutthann,1 Elena Rivero-Ferrer1 1Department of Epidemiology and Risk Management, RTI Health Solutions, Barcelona, Spain; 2Department of Biometrics, RTI Health Solutions, Barcelona, Spain; 3Epidemiology, Respiratory and Immunology, AstraZeneca, Cambridge, UK; 4Patient Safety Biopharma, AstraZeneca, Barcelona, Spain; 5BioPharmaceuticals Research and Development, Late-Stage Development Respiratory and Immunology, AstraZeneca, Gaithersburg, MD, USACorrespondence: Cristina Rebordosa, RTI Health Solutions, Department of Epidemiology and Risk Management, Av. Diagonal, 605, 9-1, Barcelona, 08028, Spain, Tel +34.93.362.2807, Fax +34.93.760.8507, Email crebordosa@rti.orgBackground: The long-acting muscarinic antagonist (LAMA) aclidinium was approved in Europe in 2012 to relieve symptoms in adult patients with chronic obstructive pulmonary disease (COPD). A post-authorization safety study was initiated to assess potential cardiovascular risks associated with LAMAs versus long-acting beta2-agonists.Purpose: To estimate incidence rates and adjusted incidence rate ratios (IRRs) for acute myocardial infarction (AMI), stroke, and major adverse cardiac events (MACE) in new users of aclidinium, aclidinium/formoterol, tiotropium, other LAMA, long-acting beta-agonists/inhaled corticosteroids (LABA/ICS), and LAMA/LABA compared with initiators of LABA.Patients and Methods: This population-based cohort study included patients with COPD aged ≥ 40 years initiating COPD medications in the UK Clinical Practice Research Datalink (CPRD) Aurum database from 2012 to 2019. Poisson regression models were used to estimate the IRR for AMI, stroke, and MACE in users of COPD medications versus LABA, adjusting for clinically relevant covariables.Results: The study included 11,121 new users of aclidinium, 4804 of aclidinium/formoterol, 56,198 of tiotropium, 23,856 of other LAMA, 17,450 of LAMA/LABA, 70,289 of LABA/ICS, and 13,716 of LABA. During periods of continuous medication use after initiation (current use), crude incidence rates per 1000 person-years for AMI ranged from 8.7 (aclidinium/formoterol) to 12.4 (LAMA/LABA), for stroke ranged from 4.8 (aclidinium/formoterol) to 7.2 (LAMA/LABA), and for MACE ranged from 13.5 (aclidinium/formoterol) to 19.3 (LAMA/LABA). Using LABA as reference, adjusted IRRs [95% confidence intervals] were close to 1 for all study drugs for AMI (lowest for aclidinium/formoterol, 0.95 [0.60– 1.52], and highest for LAMA/LABA, 1.23 [0.91– 1.67]), stroke (lowest for aclidinium/formoterol, 0.64 [0.39– 1.06], and highest for tiotropium, 1.02 [0.81– 1.27] for tiotropium) and for MACE (lowest for aclidinium, 0.93 [0.75– 1.16], and highest for LAMA/LABA, 1.24 [0.97– 1.59]).Conclusion: Risks of AMI, stroke, and MACE in current users of aclidinium, aclidinium/formoterol, tiotropium, other LAMA, LAMA/LABA, or LABA/ICS were similar to the risks among current users of LABA.Keywords: aclidinium, acute myocardial infarction, LAMA, stroke, United Kingdom

Abstract Background Beta-blocker therapies for cardiovascular comorbidities are often withheld in patients with chronic obstructive pulmonary disease (COPD) due to potential adverse effects on airway obstruction. We carried out a post hoc analysis to determine the efficacy and safety of aclidinium in patients with moderate-to-very severe COPD and increased cardiovascular risk receiving beta-blockers at baseline versus non-users. Methods ASCENT-COPD was a Phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group study. Patients were randomized 1:1 to aclidinium or placebo twice-daily for up to 3 years. Outcomes included risk of (time to first) major adverse cardiovascular events (MACE), all-cause mortality, and lung function over 3 years, and exacerbations over 1 year. Results Of 3589 patients, 1269 (35.4%) used beta-blockers and 2320 (64.6%) were non-users at baseline. Aclidinium did not statistically increase the risk of MACE (beta-blocker user: hazard ratio 1.01 [95% CI 0.62–1.64]; non-user: 0.80 [0.51–1.24]; interaction P = 0.48) or all-cause mortality (beta-blocker user: 1.13 [0.78–1.64]; non-user: 0.89 [0.62–1.26]; interaction P = 0.35), in patients using beta-blockers. Aclidinium reduced annualized rate of moderate-to-severe COPD exacerbation (beta-blocker user: rate ratio 0.75 [95% CI 0.60–0.94, P = 0.013]; non-user: 0.79 [0.67–0.93, P = 0.005]), delayed time to first exacerbation, and improved lung function versus placebo. There was greater trough FEV1 benefit in beta-blocker users versus non-users (least squares mean difference at 52 weeks: 111 mL [95% CI 74 mL–147 mL] versus 69 mL [42 mL–97 mL]; interaction P = 0.041). Conclusions This post hoc analysis supports long-acting anti-muscarinic use with concomitant beta-blockers in patients with moderate-to-very severe COPD and cardiovascular comorbidity. Trial registration: ClinicalTrials.gov, NCT01966107, Registered 16 October 2013, https://clinicaltrials.gov/ct2/show/NCT01966107 .

Cristina Rebordosa, 1 Estel Plana, 1 Annalisa Rubino, 2 Jaume Aguado, 1 Alejhandra Lei, 3 Sami Daoud, 4 Nuria Saigi-Morgui, 1 Susana Perez-Gutthann, 1 Elena Rivero-Ferrer 1 1RTI Health Solutions, Barcelona, Spain; 2Epidemiology, Respiratory and Immunology, AstraZeneca, Cambridge, UK; 3Patient Safety Biopharma, AstraZeneca, Barcelona, Spain; 4BioPharmaceuticals Research and Development, Late-Stage Development Research and Innovation, AstraZeneca, Gaithersburg, MD, USACorrespondence: Cristina RebordosaRTI Health Solutions, Av. Diagonal, 605, 9-1, Barcelona, 08028, SpainTel +34 93 241 7766Fax +34 93 760 8507Email crebordosa@rti.orgBackground: The long-acting anticholinergic (LAMA) aclidinium was approved in Europe in 2012 to relieve symptoms in adults with chronic obstructive pulmonary disease (COPD). A Post-Authorisation Safety Study (PASS) was initiated to assess potential cardiovascular safety concerns for aclidinium.Objective: To estimate the adjusted incidence rate ratio (IRR) for hospitalisation for heart failure in patients with COPD who were new users of aclidinium, tiotropium, other LAMA, long-acting beta-agonists/inhaled corticosteroids (LABA/ICS), and LAMA/LABA were compared with initiators of LABA.Methods: This population-based cohort study included patients with COPD aged ≥ 40 years initiating COPD medications in the Clinical Practice Research Datalink (CPRD) GOLD in the United Kingdom from 2012 to 2017. Medications were identified via general practice prescriptions. The first-ever hospitalisations for heart failure were identified in the Hospital Episode Statistics, and general practitioner records from the CPRD. Poisson regression models were used to estimate the IRR for hospitalisation for heart failure in users of COPD medications versus LABA, adjusting for clinically relevant covariates.Results: The study included 4350 new users of aclidinium, 23,405 of tiotropium, 6977 of other LAMAs, 3122 of LAMA/LABA, 26,093 of LABA/ICS, and 5678 of LABA. Mean age was 69– 70 years across medication groups. Aclidinium users had the highest proportion of severe COPD, and LABA users had the lowest (35% vs 19%, respectively). Crude incidence rates per 1000 person-years for the first-ever hospitalisation for heart failure ranged from 6.9 in LABA to 9.5 in aclidinium. Using LABA as reference, adjusted IRRs (95% confidence interval) for first-ever hospitalisation for heart failure were 0.90 (0.53– 1.53) for aclidinium, 1.02 (0.69– 1.51) for tiotropium, 0.86 (0.50– 1.47) for other LAMAs, 1.09 (0.41– 2.92) for LAMA/LABA, and 1.01 (0.69, 1.48) for LABA/ICS.Conclusion: The study did not find increased risks of hospitalisations for heart failure in new users of aclidinium, tiotropium, other LAMAs, LAMA/LABA, and LABA/ICS compared with LABA.Keywords: aclidinium, LAMA, heart failure, United Kingdom

Robert A Wise,1 Kenneth R Chapman,2 Benjamin M Scirica,3,4 Sami Z Daoud,5 Dan Lythgoe,6 Esther Garcia-Gil7 1Medicine, Pulmonary and Critical Care, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Department of Medicine, University of Toronto, Toronto, ON, Canada; 3Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA; 4Department of Medicine, Harvard Medical School, Boston, MA, USA; 5Late-Stage Respiratory and Immunology, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA; 6Statistics, Phastar, Chiswick, London, UK; 7Respiratory & Immunology, BioPharmaceuticals Medical, AstraZeneca, Barcelona, SpainCorrespondence: Robert A WiseMedicine, Pulmonary and Critical Care, Johns Hopkins University School of Medicine, 5501 Hopkins Bayview Circle, Baltimore, MD, 21224, USAEmail rwise@jhmi.eduPurpose: Chronic obstructive pulmonary disease (COPD) exacerbations are associated with increased risk of major adverse cardiovascular events (MACE) and mortality. Here, we investigate whether the safety and efficacy of aclidinium bromide differ due to exacerbation history in patients with COPD and increased cardiovascular risk.Patients and Methods: ASCENT-COPD was a Phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group study of patients with moderate-to-very severe COPD and increased cardiovascular risk. Patients were randomized 1:1 to receive aclidinium or placebo twice daily for up to 3 years. Outcomes included time to first MACE and all-cause mortality over 3 years, exacerbation rate during the first year on-treatment, and change in baseline pre-dose forced expiratory volume in 1 second (FEV1) over 3 years. This pre-specified subgroup analysis compared outcomes in patients receiving aclidinium vs placebo. The comparison of patients with vs without an exacerbation history was added following a protocol amendment to increase enrollment in the primary study.Results: Of 3589 patients, 2156 (60.1%) had ≥ 1 moderate or severe exacerbations in the prior year, compared with 1433 (39.9%) without prior exacerbations. Although patients with an exacerbation history had numerically higher rates of MACE and mortality regardless of treatment, aclidinium did not increase risk of MACE (≥ 1: hazard ratio [HR] 0.79, 95% confidence interval [CI]: 0.54– 1.16; none: HR 1.27, 95% CI: 0.65– 2.47; interaction P=0.233) or all-cause mortality (≥ 1: HR 1.08, 95% CI: 0.81– 1.43; none: HR 0.66, 95% CI: 0.36– 1.22; interaction P=0.154), regardless of exacerbation history. Aclidinium reduced the exacerbation rate vs placebo irrespective of exacerbation history (≥ 1: rate ratio [RR] 0.80, 95% CI: 0.68– 0.94; none: RR 0.69, 95% CI: 0.54– 0.89; interaction P=0.340) and improved FEV1 (interaction P=0.633).Conclusion: In patients with moderate-to-very severe COPD and increased cardiovascular risk, aclidinium did not increase risk of MACE or mortality and reduced exacerbation rate vs placebo, regardless of exacerbation history.Clinical Trial Registration: ClinicalTrials.gov Identifier: NCT01966107.Keywords: COPD, COPD exacerbation, aclidinium, MACE, mortality

Konstantinos Kostikas,1 Theodoros I Vassilakopoulos,2,3 Nikos Tzanakis,4 Athanasios K Konstantinidis,1 Epameinondas N Kosmas,5 Spyros Papiris,6 Paschalis Steiropoulos,7 Effrosyni D Manali,6 Stylianos A Michaelides8,†, Grigorios Daskos9 1Respiratory Medicine Department, University Hospital of Ioannina, Ioannina, Greece; 2Pulmonary and Critical Care Medicine, Medical School, National and Kapodistrian University of Athens, Athens, Greece; 3Third Department of Critical Care Medicine, Evgenideio Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece; 4Department of Respiratory Medicine, University Hospital of Heraklion, Medical School, University of Crete, Crete, Greece; 5Department of Pulmonary Medicine, Metropolitan Hospital, Athens, Greece; 6Second Pulmonary Medicine Department, General University Hospital “Attikon”, Medical School, National and Kapodistrian University of Athens, Athens, Greece; 7Pulmonology Clinic Medical School, Democritus University of Thrace/University General Hospital, Alexandroupolis, Greece; 8Department of Occupational Lung Disease and Tuberculosis, “Sismanogleio-Amalia Fleming” General Hospital, Athens, Greece; 9MENARINI HELLAS, Athens, Greece†Stylianos A Michaelides passed away on September 14, 2019Correspondence: Konstantinos KostikasRespiratory Medicine Department, University of Ioannina School of Medicine, Leoforos Stavrou Niarchou, Ioannina 45500, GreeceTel +30-2651007536Email ktkostikas@gmail.comPurpose: This multicenter, prospective, observational study aimed to supplement real-world evidence on the effects of aclidinium bromide on the quality of life (QoL), symptoms, and activity impairment of patients with COPD.Patients and Methods: Eligible patients were ≥ 40 years of age, newly initiated on aclidinium bromide as monotherapy or add-on therapy according to the product’s approved label. Patient-reported COPD assessment test (CAT), the severity of symptoms and their impact on daily activities, and the features of the Genuair® inhaler device were assessed at enrollment and at 12 weeks post-treatment onset.Results: Between 13 March 2015 and 29 January 2016, 285 eligible consenting patients (76.3% males; median age: 69.0 years; 26.0% newly diagnosed with COPD) were enrolled by 15 hospital-based respiratory medicine specialists in Greece. Aclidinium bromide was initiated as add-on therapy to other inhaled maintenance medications in 73.1% of evaluable patients. The median (interquartile range [IQR]) baseline CAT score decreased from 14.0 (9.0– 20.0) to 10.0 (6.0– 15.0) points (p< 0.001) after 12 weeks of treatment, with 76.5% of the patients achieving a ≥ 2-point decrease. The severity of night-time and early-morning symptoms, assessed using a 5-point Likert-type scale, decreased from a median (IQR) of 1.0 (0.0– 2.0) to 0.0 (0.0– 1.0), and from 2.0 (1.0– 2.0) to 1.0 (1.0– 2.0), respectively (p< 0.001 for both). In patients with paired data, the prevalence of at least moderate night-time symptoms, early-morning symptoms, and daily activity impairment decreased from 28.2% to 19.1%, from 63.6% to 34.2%, and from 59.5% to 38.7%, respectively (p< 0.001 for all). Inhaler device features were assessed as “very good”/“good” by more than 90% of the patients. The adverse drug reaction rate was 1.4%.Conclusion: The study provides real-world evidence on the beneficial effects of aclidinium bromide on the patients’ QoL, symptom severity, and daily activity impairment, which are complemented by a favorable safety profile and high patient satisfaction with the inhaler device.Keywords: aclidinium, chronic obstructive pulmonary disease, COPD assessment test, daily activities, quality of life, symptoms

Background: Beta-blocker therapies for cardiovascular comorbidities are often withheld in patients with chronic obstructive pulmonary disease (COPD) due to potential adverse effects on airway obstruction. We carried out a post hoc analysis to determine the efficacy and safety of aclidinium in patients with moderate-to-very severe COPD and increased cardiovascular risk receiving beta-blockers at baseline versus non-users.Methods: ASCENT-COPD was a Phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group study. Patients were randomized 1:1 to aclidinium or placebo twice-daily for up to 3 years. Outcomes included risk of (time to first) major adverse cardiovascular events (MACE), all-cause mortality, and lung function over 3 years, and exacerbations over 1 year.Results: Of 3589 patients, 1269 (35.4%) used beta-blockers and 2320 (64.6%) were non-users at baseline. Aclidinium did not statistically increase the risk of MACE (beta-blocker user: hazard ratio 1.01 [95% CI 0.62-1.64]; non-user: 0.80 [0.51-1.24]; interaction P = 0.48) or all-cause mortality (beta-blocker user: 1.13 [0.78-1.64]; non-user: 0.89 [0.62-1.26]; interaction P = 0.35), in patients using beta-blockers. Aclidinium reduced annualized rate of moderate-to-severe COPD exacerbation (beta-blocker user: rate ratio 0.75 [95% CI 0.60-0.94, P = 0.013]; non-user: 0.79 [0.67-0.93, P = 0.005]), delayed time to first exacerbation, and improved lung function versus placebo. There was greater trough FEV1 benefit in beta-blocker users versus non-users (least squares mean difference at 52 weeks: 111 mL [95% CI 74 mL-147 mL] versus 69 mL [42 mL-97 mL]; interaction P = 0.041).Conclusions: This post hoc analysis supports long-acting anti-muscarinic use with concomitant beta-blockers in patients with moderate-to-very severe COPD and cardiovascular comorbidity.Trial Registration: ClinicalTrials.gov, NCT01966107, Registered 16 October 2013, https://clinicaltrials.gov/ct2/show/NCT01966107 . [ABSTRACT FROM AUTHOR]

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

The article presents an analytical review of the use of aclidinium, formoterol, and combination of aclidinium and formoterol to treat chronic obstructive pulmonary disease (COPD) using a metered-dose dry powder inhaler Genuair® to administer a fixeddose combination. It is noted that twelve hours’ double bronchodilating effect has some advantages including the rapid elimination of drugs having minimal systemic effects, significant effect on dyspnoea and exhalation rates, profitability of using this drug. It is proven that Genuair® is a new, patient-friendly, easy to administer at any age powder inhaler with an informative feedback mechanism. All this makes it possible to consider a new fixed-dose combination of bronchodilators in the innovative device to be a promising basic therapy for COPD.

Relevant publications related to medicinal and toxic aerosols are discussed in this review. Treatment of COPD includes a combination of long-acting bronchodilators and long-acting muscarinic antagonists. A combination of aclidinium bromide and formoterol fumarate was approved in the United States. The combination was superior to its components alone, as well as tiotropium and a salmeterol-fluticasone combination. Increased risk of an asthma exacerbation was reported in children exposed to electronic nicotine delivery systems. A smart inhaler capable of recording inspiratory flow was approved in the United States. The use of as-needed budesonide-formoterol was reported to be superior to scheduled budesonide and as-needed terbutaline for the treatment of adults with mild-to-moderate asthma. A survey among teens with asthma and their caregivers revealed a disagreement in the number of inhaled controller medications the teen was taking. Treatment with inhaled hypertonic saline resulted in a decreased lung clearance index in infants and preschool children with cystic fibrosis. Surgical masks were well tolerated and significantly decreased the burden of aerosolized bacteria generated by coughing in adults with cystic fibrosis. Inhaled liposomal amikacin in addition to guidelinebased therapy was reported to be superior to guideline-based therapy alone in achieving negative sputum cultures in adult subjects with Mycobacterium avium complex pulmonary disease. During 2019, lung injury associated to e-cigarette or vaping was reported, including 60 casualties. [ABSTRACT FROM AUTHOR]

Henrik Watz,1 Thierry Troosters,2 Kai M Beeh,3 Judith Garcia-Aymerich,4–6 Pierluigi Paggiaro,7 Eduard Molins,8 Massimo Notari,9 Antonio Zapata,10 Diana Jarreta,8 Esther Garcia Gil8 1Pulmonary Research Institute at LungenClinic Grosshansdorf, Airway Research Center North, German Center for Lung Research, Grosshansdorf, Germany; 2Department of Rehabilitation Sciences, Pulmonary Rehabilitation and Respiratory Division, University Hospital Leuven, KU Leuven, Leuven, Belgium; 3insaf Respiratory Research Institute GmbH, Wiesbaden, Germany; 4Barcelona Institute of Global Health (ISGlobal), Barcelona, Spain; 5Universitat Pompeu Fabra (UPF), Barcelona, Spain; 6CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain; 7Department of Surgery, Medicine, Molecular Biology and Critical Care, University of Pisa, Pisa, Italy; 8AstraZeneca PLC, Barcelona, Spain; 9A. Menarini Farmaceutica Internazionale S.R.L., Firenze, Italy; 10Laboratorios Menarini, S.A., Badalona, Spain Abstract: The Phase IV, 8-week, randomized, double-blind, placebo-controlled ACTIVATE study (NCT02424344) evaluated the effect of aclidinium/formoterol (AB/FF) 400/12 µg twice daily on lung hyperinflation, exercise capacity, and physical activity in patients with moderate-to-severe COPD. Patients received AB/FF (n=134) or placebo (n=133) (1:1) via the Genuair™/Pressair® dry powder inhaler for 8 weeks. From Weeks 5 to 8, all patients participated in behavioral intervention (BI; daily messages providing step goals). The primary end point was trough functional residual capacity (FRC) at Week 4. Exercise endurance time and physical activity were assessed at Week 4 (pharmacotherapy only) and at Week 8 (8 weeks of pharmacotherapy plus 4 weeks of BI). Other end points included post-dose FRC, residual volume, and inspiratory capacity (IC) at rest and during exercise. After 4 weeks, trough FRC improved with AB/FF versus placebo but did not reach significance (125 mL; P=0.0690). However, post-dose FRC, residual volume, and IC at rest improved significantly with AB/FF at Week 4 versus placebo (all P

Aclidinium bromide/formoterol fumarate (AB/FF) 400/12 µg is a twice-daily long-acting muscarinic receptor antagonist and long-acting β2 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. [ABSTRACT FROM AUTHOR]

Marco Contoli,1 Paolo Solidoro,2 Fabiano Di Marco,3,4 Nicola Scichilone,5 Angelo Corsico,6 Fulvio Braido,7 Pierachille Santus4,8 1Research Centre on Asthma and COPD, Department of Medical Sciences, University of Ferrara, Ferrara, Italy; 2Cardiovascular and Thoracic Department, Città della Salute, Turin, Italy; 3Department of Health Sciences, University of Milan, Milan, Italy; 4Respiratory Unit, San Paolo Hospital, Milan, Italy; 5Department of Internal Medicine, Section of Pulmonology (DIBIMIS), University of Palermo, Palermo, Italy; 6Department of Molecular Medicine, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; 7Allergy and Respiratory Diseases Clinic, DIMI, University of Genoa, IRCS AOU San Martino-IST, Genoa, Italy; 8Pulmonary Rehabilitation Unit, Fondazione Salvatore Maugeri, Scientific Institute of Milan-IRCCS, Milan, Italy Abstract: The pathophysiology of chronic obstructive pulmonary disease (COPD) includes persistent airflow limitation, altered gas exchange, and enhanced chronic inflammatory response. According to disease severity in individual patients, exacerbations and comorbidities frequently occur. The overall nocturnal and daily symptoms have a strong impact on patient quality of life and clinical outcomes. Bronchodilators, by targeting two important aspects of COPD pathophysiology, ie, bronchoconstriction and lung hyperinflation, are the mainstay of therapy for COPD. Aclidinium bromide in particular is an anticholinergic molecule, approved for maintenance bronchodilator treatment of stable COPD, that combines high antimuscarinic activity with strong kinetic selectivity for the M3 receptor subtype. Moreover, the elevated plasma clearance of aclidinium has been related to low systemic bioavailability and low incidence of anticholinergic adverse events, whereas the reduced residence time at M2 receptors provides good cardiovascular safety. Altogether, these characteristics result in a high safety and tolerability profile. This review aims to reappraise the contribution of symptoms and of the level of quality of life determinants on COPD severity and to evaluate how therapeutic strategies with aclidinium may positively impact on these specific determinants of disease severity. Keywords: COPD, quality of life, daily symptoms, LAMA, aclidinium

Marc Miravitlles,1 Kenneth R Chapman,2 Ferran Chuecos,3 Anna Ribera,4 Esther Garcia Gil3 1Department of Pneumology, Vall d’Hebron University Hospital, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, Spain; 2Asthma & Airway Centre, University Health Network, Toronto Western Hospital and University of Toronto, Toronto, ON, Canada; 3Global Medicines Development, AstraZeneca PLC, Barcelona, Spain; 4Global Medical Affairs, AstraZeneca PLC, Barcelona, Spain Background: Patients with chronic obstructive pulmonary disease (COPD) experience respiratory symptoms, which impair quality of life. This pooled analysis of two Phase III studies assessed the impact of aclidinium/formoterol on patients with COPD categorized by symptom status.Methods: Data were pooled from two 24-week, randomized, placebo-controlled studies of twice-daily aclidinium/formoterol 400/12 µg in moderate-to-severe COPD (ACLIFORM [NCT01462942] and AUGMENT [NCT01437397]). These post hoc analyses evaluated the efficacy of aclidinium/formoterol versus placebo or monotherapies in patients defined as less/more symptomatic by a) Evaluating Respiratory Symptoms (E-RS™) score ≥10/

Cristoforo Incorvaia,1 Marcello Montagni,2 Elena Makri,1 Erminia Ridolo21Allergy/Pulmonary Rehabilitation, Istituti Clinici di Perfezionamento Hospital, Milan, 2Department of Clinical and Experimental Medicine, University of Parma, Parma, ItalyAbstract: The current guidelines on chronic obstructive pulmonary disease (COPD) recommend the prominent use of bronchodilators, including long-acting β2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs), while inhaled corticosteroids are recommended only in patients with severe disease or frequent exacerbations. LABA–LAMA combinations are indicated when single bronchodilators are insufficient to control COPD. A number of LABA–LAMA combinations are available, based on twice-daily or once-daily administration according to the 12- or 24-hour duration of action, respectively. The aclidinium–formoterol combination is based on the new LAMA aclidinium bromide, which has a high selectivity for M3 muscarinic receptors and a fast onset of action, and the well-known LABA formoterol. Both drugs require twice-daily administration. The fixed-dose combination of aclidinium 400 µg/formoterol 12 µg has shown in randomized controlled trials fast and sustained bronchodilation that was greater than either monotherapy and provided clinically significant improvements in dyspnea and health status compared with placebo, also reducing the use of rescue medications. The overall incidence of adverse events was low and comparable to placebo. These data define the aclidinium–formoterol fixed-dose combination as a new treatment option for patients with COPD. The need for twice-daily administration could be an apparent disadvantage compared to the available once-daily LABA–LAMA combinations, but the immediately perceived benefit in reducing dyspnea due to the fast onset of action, as well as reported correct patient use and satisfaction with the Genuair inhaler might prove useful in favoring adherence.Keywords: bronchodilators, COPD, LABA, LAMA, combination, efficacy, safety, inhalation device

Maria Gabriella Matera,1 Alessandro Sanduzzi,2 Mario Cazzola3 1Department of Experimental Medicine, Second University of Naples, 2Department of Respiratory Diseases, Monaldi Hospital, University Federico II, Naples, 3Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy Abstract: Co-administration of a long-acting β2-agonist and a long acting muscarinic antagonist produces superior bronchodilation compared with their individual effects. Our preclinical data indicated that combining aclidinium bromide (ACLI) and formoterol fumarate (FORM) provides synergistic benefit on smooth muscle relaxation of both large and small human airways. Data from more than 2,000 patients in eleven clinical trials documented that ACLI/FORM, a twice-daily fixed-dose combination, produces a greater degree of bronchodilation than ACLI or FORM monotherapy alone and is safe and well tolerated. Two large key trials have shown that there is a benefit in using ACLI/FORM when the clinical target is the variability of symptoms and mainly nighttime and/or early morning symptoms. ACLI/FORM is the only long acting muscarinic antagonist/long acting β2-agonist fixed-dose combination that has been studied for this therapeutic indication. Keywords: aclidinium, formoterol, fixed-dose combination, COPD, symptoms

Aclidinium, a muscarinic antagonist, is generally used to treat the respiratory system diseases whereas it is not clear whether aclidinium has therapeutic effect in ovarian cancer (OC). The aim of this study was to investigate the impact of aclidinium on OC and its potential mechanism. CCK-8 was employed to test the potential effect of aclidinium on SKOV3 cell proliferation. Transwell migration and invasion assay was performed to assess the influence of aclidinium on SKOV3 cell metastasis and invasion. Furthermore, flow cytometry apoptotic analysis was used to evaluate the effect of aclidinium on cell apoptosis. Finally, western blotting was applied to determine the changes of key proteins in apoptosis and PI3K/AKT/mTOR signaling pathway induced by aclidinium. The study showed that aclidinium had antiproliferative activity on SKOV3 cells. Simultaneously, aclidinium could significantly inhibit the number of migrated and invaded SKOV3 cells and markedly increased the SKOV3 cell apoptosis rate. Mechanistically, the expression of PI3K/AKT/mTOR signaling pathway related proteins were significantly inhibited in aclidinium treated SKOV3 cells. Our findings proposed a clue for further OC studies in preclinical and clinical treatment and aclidinium may be useful for the treatment of OC in the future. [ABSTRACT FROM AUTHOR]

Three simple, accurate and selective spectrophotometric methods were developed to determine aclidinium in the presence of formoterol as interferent compound in Duaklir ® Genuair ® inhalation powder. The methods under study are absorbance subtraction, area under the curve and simultaneous equation. The methods were linear over the concentration range of 5-50 μg/mL for aclidinium and validated according to the ICH guidelines. The accuracy and precision were found to be within the acceptable limits. The specificity of the proposed methods was tested using laboratory prepared mixtures and assessed by applying the standard addition technique. Furthermore, the methods were statistically compared to the RP-HPLC method and good results were obtained. [ABSTRACT FROM AUTHOR]

Evidence-based guidelines recommend inhaled long-acting anti-muscarinic agents (LAMAs) as first-line maintenance therapy for symptomatic patients with COPD. Several LAMAs are now available for use either as monotherapy or in combination with other COPD medications, including long-acting β2-agonists (LABAs) or inhaled corticosteroids (ICS). The efficacy and long-term safety of these medications have been evaluated in multiple clinical trials and real-life studies. This review evaluates the evidence available on the safety of existing LAMAs alone or in combination with LABAs and ICS in patients with COPD. [ABSTRACT FROM AUTHOR]

Background: As emphasized by international recommendations and largely confirmed by clinical experience, long-acting bronchodilators play a central role in the maintenance treatment of chronic obstructive pulmonary disease (COPD) due to their proven efficacy in reducing airflow obstruction and improving symptoms.Main Body: There are some important aspects to define with regard to inhalation therapy for COPD, particularly those concerning the selection criteria and the optimal use of long-acting bronchodilators. First of all, it needs to be determined in which patients and clinical situations monotherapy with one bronchodilator, such as a long-acting muscarinic antagonist (LAMA), should be considered adequate, and in which cases the use of combination therapies, such as the "double bronchodilation" with a LAMA and a long-acting β2-agonist (LABA), should be preferred. Another critical issue concerns the effect of the frequency of daily administration of inhaled agents on the control of symptoms during the 24 h. COPD symptoms are known to exhibit considerable circadian variability with worsening in the early morning, and a significant proportion of patients have disease-related sleep disorders which can adversely affect their quality of life. The worsening of symptoms in the early morning may be due, at least in part, to a reduction in airway caliber caused by an increased "cholinergic tone" at night. As such, the coverage of nighttime and early morning symptoms is a reasonable therapeutic goal, which can be achieved by many patients using LAMAs such as aclidinium bromide twice daily (BID). Therapeutic adherence is known to be a multifactorial phenomenon that is frequently affected by other aspects than dosing frequency, including the technical features and ease of use of the inhalers. To this end, it should be mentioned that certain new-generation inhalers such as Genuair® have been associated in clinical trials with higher patient preference.Conclusion: In this work, in addition to presenting an overview of the main evidence on the efficacy of COPD treatment with the LAMA aclidinium bromide BID, we suggest some selection criteria for the monotherapy with one long-acting bronchodilator or the combination therapy with LAMA and LABA in COPD patients, with particular reference to specific clinical scenarios. [ABSTRACT FROM AUTHOR]

Background Comparisons of the use of aclidinium bromide and tiotropium bromide for the treatment of chronic obstructive pulmonary disease often concentrate on key end points (exacerbations) at the expense of other benefits and risks. Multicriteria decision analysis (MCDA) can help overcome this by using stakeholder preferences to combine multiple end points into an overall value estimate. Objectives To evaluate the use of aclidinium bromide twice daily via Pressair™ (AstraZeneca Pharmaceuticals LP, Wilmington, DE) and of tiotropium once daily via HandiHaler ® (Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT) from the perspective of patients using MCDA. Methods Literature reviews and clinician engagement were used to identify value criteria. Performance of criteria was estimated from a clinical trial and clinician opinion. Scores and swing weights came from six clinicians who, during a 2-day workshop, reflected their patients’ preferences. Scenario and sensitivity analyses were used to explore uncertainty in model designs and inputs. Results Fourteen criteria, covering clinical effectiveness, safety, and convenience of the treatments of chronic obstructive pulmonary disease, were identified. Exacerbations and device preloading were identified as the most important to patients; the least important was rescue medication use. Tiotropium’s higher overall clinical effectiveness score was offset by aclidinium’s better performance on safety and convenience outcomes. The MCDA generated a −42 (worst performance) to 100 (best performance) scale. The net impact of benefits over risks of aclidinium (38.5) exceeded that of tiotropium (13.2), and patients preferred aclidinium 79.7% of the time. Conclusions When considering clinical benefits and risks, aclidinium and tiotropium generate similar value to patients, but when convenience criteria are considered, aclidinium may be preferred. Further work is required to replicate these results, including eliciting preferences directly from patients. [ABSTRACT FROM AUTHOR]

Introduction: Chronic obstructive pulmonary disease (COPD) is a prevalent disease of the airways in which inhaled bronchodilators can be given as monotherapy or fixed dose combination, in order to better control disease symptoms and to reduce its morbidity. A novel bronchodilator approach is represented by bifunctional molecules such as navafenterol, which exert dual synergic bronchodilator effects as a monotherapy. Navafenterol is currently being investigated for COPD., Areas Covered: This review summarizes the preclinical data regarding navafenterol synthesis and in vitro and in vivo testing. Clinical data coming from phase I and II studies are also discussed. Navafenterol was found to improve lung function, dyspnea, and cough severity and was well tolerated, and its effect was comparable with that of fixed-dose combinations in patients with moderate-to-severe COPD., Expert Opinion: Despite clinical evidence of efficacy for navafenterol is still limited, the existing data prompts further clinical evaluation and also consideration of other inhalation approaches such as pressure metered-dose inhalers (pMDIs) or nebulization. Other interesting approach would be combination with another bifunctional molecule such as ensifentrine.

Long-acting muscarinic receptor antagonists (LAMAs) have been reported to attenuate cough in preclinical and clinical studies. The present study was performed on rabbits to compare aclidinium and tiotropium efficacy in the downregulation of the cough reflex. This reflex was evoked by citric acid inhalation in unanesthetized animals and by both citric acid inhalation and mechanical stimulation of the tracheobronchial tree in anesthetized animals 90 min following the inhalation of each drug (nebulizer output always at 1 mL/min). Aclidinium 4 mg/mL and tiotropium 200 μg/mL inhaled in 1 min proved to have similar protective effect on methacholine-induced bronchoconstriction in anesthetized animals. The total dosage employed for aclidinium and tiotropium was 4 mg and 200 μg, respectively. In awake animals, similar reductions in the cough number were observed following 10-min inhalation of each drug with a slight, not significant tendency to higher antitussive effects for aclidinium. In anesthetized animals, 1-min inhalation of each drug caused similar depressant effects on cough responses induced by both mechanical and chemical stimulation. A complete suppression of cough responses to mechanical stimuli was seen in some preparations. The results strongly suggest that the LAMA-induced downregulation of cough may be mediated not only by transient receptor potential vanilloid type 1 channels, as already reported, but also by acid-sensing ion channels and mechanoreceptors. The route of administration along with the more rapid hydrolysis of aclidinium into inactive metabolites minimize potential systemic side effects and give to this drug a very favorable safety profile. [ABSTRACT FROM AUTHOR]

Aclidinium is a twice-daily long-acting muscarinic receptor antagonist (LAMA) with an interesting pharmacological profile. Recent evidence indicates that this LAMA, in addition to causing a significant improvement in lung function and other important supportive outcomes, such as health related quality of life, dyspnea and nighttime/early morning symptoms in patients suffering from COPD, is also able to significantly reduce the rate of exacerbations of any severity, is extremely effective in controlling the COPD symptoms, is able to reduce lung hyperinflation, and has an excellent cardiovascular safety profile. Consequently, aclidinium should be considered a first-line approach at least for the symptomatic treatment of COPD although there are still few head-to-head studies comparing this LAMA with other bronchodilators. In any case, aclidinium can be taken into account in the treatment of different COPD phenotypes (emphysema, chronic bronchitis, exacerbators and patients with overlap COPD asthma). [ABSTRACT FROM PUBLISHER]

Introduction: Long-acting muscarinic antagonists confer improvements in spirometry when used in addition to inhaled corticosteroids and long-acting beta-agonists (ICS/LABA) in COPD. The dual objectives of this proof of concept study were to evaluate trough effects of tiotropium (TIO) or aclidinium (ACL) when used as triple therapy and to assess if impulse oscillometry (IOS) might be more sensitive than spirometry in detecting subtle differences in bronchodilator response. Methods: Patients with moderate to severe COPD already taking ICS/LABA were randomized to receive add-on therapy in cross-over fashion with either TIO 18 µg od or ACL 322 µg bid for 2-3 weeks each. Measurements of IOS, spirometry, 6-min walk test, St George's Respiratory Questionnaire (SGRQ) and Baseline/Transition Dyspnoea Index (TDI) were made at baseline and after chronic dosing at trough (12 h for ACL and 24 h for TIO), in addition to domiciliary diurnal spirometry. Results: 13 patients were completed: mean age 69 years, FEV 52 % predicted, FEV/FVC 0.48, and R5 202 % predicted. There were no differences in any visit-based trough IOS or spirometry outcomes comparing TIO versus ACL. Resonant frequency but not total airway resistance at 5 Hz (R5) significantly improved from baseline with both treatments while peripheral airway resistance (R5-R20) significantly improved with ACL. Visit-based FEV, and forced and relaxed vital capacity were also significantly improved from baseline with both treatments. There were no significant differences in diurnal FEV and FEV profiles between treatments. 6-min walk distance and post-walk fatigue significantly improved from baseline with ACL, while post-walk dyspnea improved with TIO. SGRQ symptom score significantly improved to a similar degree with both treatments. TDI significantly improved with ACL versus TIO by 1.54 units. Conclusion: We observed comparable bronchodilator efficacy at trough with TIO and ACL when used as triple therapy in COPD, while IOS was no more sensitive than spirometry. [ABSTRACT FROM AUTHOR]

Introduction: The objective of this study was to estimate the relative efficacy and safety of fixed-dose combination aclidinium/formoterol 400/12 μg twice daily compared to tiotropium 18 μg once daily in adult patients with moderate-to-severe chronic obstructive pulmonary disease (COPD).Methods: A systematic literature review performed in March 2014, using a predefined search strategy in MEDLINE, EMBASE and Cochrane Library, identified 17 randomized placebo-controlled trials, (tiotropium n = 15; aclidinium/formoterol n = 2). Outcomes of interest were: bronchodilation (peak and trough forced expiratory volume in 1 s (FEV1)), COPD symptoms [Transition Dyspnea Index (TDI) focal score and % of responders (>1 unit improvement)] and Health Related Quality of Life (HRQoL) [St. George's Respiratory Questionnaire (SGRQ) total score and % responders (>4 unit improvement)], % of patients with ≥1 exacerbations, adverse events (AE), serious adverse events (SAE), hospitalization and mortality, all at 24 weeks. In the absence of head-to-head trials between aclidinium/formoterol and tiotropium, a Bayesian indirect treatment comparison (ITC) was used with placebo as common control.Results: Regarding bronchodilation, aclidinium/formoterol was found to be more efficacious than tiotropium at peak FEV1, with mean difference in change from baseline (DCFB) 143 mL [95% credible interval (CrI): 112, 174] and at trough FEV1 [DCFB 26 mL (95% CrI -2, 55)]. Aclidinium/formoterol is expected to be more efficacious than tiotropium in improving dyspnea symptoms measured by TDI [DCFB 0.54 points (95% CrI 0.09, 0.99); odds ratio (OR) of responders 1.51 (95% CrI 1.11, 2.06)]. SGRQ results are comparable for aclidinium/formoterol versus tiotropium [DCFB -0.52 (95% CrI -2.21, 1.17); OR of responders 1.16 (95% CrI 0.47, 2.87)]. The ITC results suggest similar safety profiles regarding AEs, SAEs and hospitalization.Conclusion: Based on the ITC, aclidinium/formoterol is expected to be more efficacious than tiotropium in terms of lung function and symptom control while providing comparable HRQoL results and safety profile.Funding: AstraZeneca. [ABSTRACT FROM AUTHOR]

M antagonist activity was assessed in electrically stimulated human bronchial strips; potency, onset and offset of action of aclidinium, tiotropium and ipratropium were determined. M antagonist activity was assessed in electrically stimulated isolated human left atria; duration of action was calculated. Aclidinium demonstrated competitive antagonism at M receptors with similar potency to comparators. Onset of action of aclidinium was similar to ipratropium and faster than tiotropium ( P < 0.05); duration of action was similar to tiotropium and longer than ipratropium ( P < 0.05). At M receptors, duration of action of aclidinium was shorter than tiotropium and longer than ipratropium. All antagonists exhibited a shorter duration of action at M versus M receptors. Aclidinium exhibited kinetic selectivity for human bronchial versus atrial receptors, supporting a favorable cardiovascular safety profile. [ABSTRACT FROM AUTHOR]

Combined muscarinic receptor antagonists and long acting β 2 -agonists improve symptom control in chronic obstructive pulmonary disease (COPD) significantly. In clinical studies aclidinium bromide achieved better beneficial effects than other bronchodilators; however, the underlying molecular mechanisms are unknown. This study assessed the effect of aclidinium bromide combined with formoterol on COPD lung ( n = 20) and non-COPD lung ( n = 10) derived epithelial cells stimulated with TGF-β 1 + carbachol on: (i) the generation of mesenchymal cells in relation to epithelial cells, (II) extracellular matrix (ECM) deposition, and (iii) the interaction of ECM on the generation of epithelial and mesenchymal cells. TGF-β 1 + carbachol enhanced the generation of mesenchymal cells, which was significantly reduced by aclidinium bromide or formoterol. The effect of combined drugs was additive. Inhibition of p38 MAP kinase and Smad by specific inhibitors or aclidinium bromide reduced the generation of mesenchymal cells. In mesenchymal cells, TGF-β 1 + carbachol induced the deposition of collagen-I and fibronectin which was prevented by both drugs dose-dependently. Formoterol alone reduced collagen-I deposition via cAMP, this however, was overruled by TGF-β 1 + carbachol and rescued by aclidinium bromide. Inhibition of fibronectin was cAMP independent, but involved p38 MAP kinase and Smad. Seeding epithelial cells on ECM collagen-I and fibronectin induced mesenchymal cell generation, which was reduced by aclidinium bromide and formoterol. Our results suggest that the beneficial effect of aclidinium bromide and formoterol involves cAMP affecting both, the accumulation of mesenchymal cells and ECM remodeling, which may explain the beneficial effect of the drugs on lung function in COPD. [ABSTRACT FROM AUTHOR]

Preclinical studies suggested that aclidinium and glycopyrronium might have a faster onset of action than tiotropium. In this study we assessed the onset of action of aclidinium and glycopyrronium versus tiotropium, all administered at the approved clinical doses, in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) and in human isolated bronchi by using different concentrations. Sixteen COPD patients inhaled single doses of aclidinium 400 µg, glycopyrronium 50 μg and tiotropium 18 µg and FEV 1 was measured to assess their onset of action. In human isolated bronchi the time to evoke half maximal relaxation of transmural stimulation was tested from 10 nM to 1 µM for each drug. Nine, eight and twelve patients did not achieve 15% increase of FEV 1 after inhalation of aclidinium, glycopyrronium and tiotropium, respectively. Aclidinium (15.6±7.5 min) and glycopyrronium (17.9±10.4 min) enhanced 15% FEV 1 more rapidly than tiotropium (42.5±19.4 min), with no significant difference ( P >0.05). In isolated airways, glycopyrronium elicited a dose-dependent onset of action (10 nM: 8.2±1.3 min, 100 nM: 7.1±2.1 min, 1 μM: 3.4±0.4 min) that was faster compared to that induced by aclidinium (1 μM: 6.4±0.5 min) and tiotropium (1 μM: 8.4±1.1 min) ( P <0.05), that halved the contractile tone only at the highest concentration. Bronchodilation induced by aclidinium and glycopyrronium was faster than that induced by tiotropium, but since our analysis was restricted to the acute effect of these LAMAs and the inhaled doses were not isoeffective, the real differences in their impact on the onset of bronchodilation will be definitely determined after a long-term challenge of these treatments at isoeffective doses in COPD patients. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a major cause of death and disability worldwide. Inhaled bronchodilators are the mainstay of COPD pharmacological treatment. Long-acting muscarinic antagonists (LAMAs) are a major class of inhaled bronchodilators. Some LAMA/device systems with different characteristics and dosing schedules are currently approved for maintenance therapy of COPD and a range of other products are being developed. They improve lung function and patient-reported outcomes and reduce acute bronchial exacerbations with good safety. LAMAs are used either alone or associated with long-acting β2-agonists, eventually in fixed dose combinations. Long-acting β2-agonist/LAMA combinations assure additional benefits over the individual components alone. The reader will obtain a view of the safety and efficacy of the different LAMA/device systems in COPD patients. [ABSTRACT FROM AUTHOR]

Exacerbations of chronic obstructive pulmonary disease (COPD) have important consequences for lung function, health status and mortality. Furthermore, they are associated with high economic costs, predominantly related to hospitalization. They are managed acutely with short-acting bronchodilators, systemic corticosteroids or antibiotics; however, a large proportion of COPD exacerbations are unreported and therefore untreated or self-managed. There is evidence to suggest that these unreported exacerbations also have important consequences for health status; therefore, reducing exacerbation risk is an important goal in the management of COPD.Current guidelines recommend long-acting muscarinic antagonists (LAMAs) as first-line bronchodilator therapy in patients with stable COPD who have a high risk of exacerbation or increased symptoms. To date, three LAMAs, tiotropium bromide, aclidinium bromide and glycopyrronium bromide, have been approved as maintenance bronchodilator treatments for stable COPD. These all provide clinically significant improvements in lung function, reduce symptoms and improve health status compared with placebo in patients with COPD. This paper reviews evidence from randomized, controlled clinical trials demonstrating that tiotropium, aclidinium and glycopyrronium reduce exacerbation risk in patients with COPD. Reductions were seen irrespective of the exacerbation measure used, whether time to first event or annualized exacerbation rate. Furthermore, studies with aclidinium suggest LAMAs can reduce exacerbation risk irrespective of whether exacerbation events are assessed, using an event-based approach or a symptom-based method which includes unreported events. Together these results demonstrate that LAMAs have the potential to provide clinical benefit in the management of exacerbations in patients with stable COPD. [ABSTRACT FROM PUBLISHER]

Chronic obstructive pulmonary disease (COPD) is a complex heterogeneous disease, in which several factors combine to give the final clinical expression. Both early and more recent studies have shown that forced expiratory volume in one second (FEV1), despite being an extremely important parameter to predict the progression of the disease, is a poor surrogate marker for symptoms perception. Accordingly, patient-reported outcomes (PROs) have gained popularity as a measure of the impact of treatment from the patients' perspective, since they represent the individuals' perception of their health status, beyond any physiological limitations. Several such PROs, therefore, are currently included in multidimensional COPD evaluation. This multidimensional approach helps identify different patient types and individualize, up to a certain point, pharmacological treatment. In this multidimensional approach it is important to highlight the importance of long-acting bronchodilators in COPD treatment strategies. Long-acting bronchodilators are cost-effective and have been shown to achieve the greatest functional and clinical improvements in COPD. As a result, long-acting bronchodilators are now the main pharmacological treatment for COPD at all stages of the disease. Until recently, tiotropium was the leading bronchodilator for the treatment of COPD. The clinical development of this medication, unprecedented in inhaled therapy, involved tens of thousands of patients and yielded consistent outcomes in terms of lung function, symptoms, quality of life, exacerbations, and prognosis. However, new long-acting bronchodilators have recently been developed or are currently under development. In this review, we evaluate the effects of aclidinium bromide, a novel long-acting bronchodilator, on PROs in COPD. Aclidinium is a novel long-acting muscarinic antagonist with a good safety profile for the treatment of COPD, and has proven efficacy in both objective functional measurements and PROs. Comparison studies with tiotropium have shown it to have similar lung function improvement and a similar impact on PROs, including quality of life or symptom perception. [ABSTRACT FROM AUTHOR]

Background This study evaluated the effects of aclidinium bromide, a long-acting muscarinic antagonist indicated for maintenance treatment of chronic obstructive pulmonary disease (COPD), on exercise endurance, dyspnea, lung hyperinflation, and physical activity. Methods In this randomized, double-blind, crossover study, patients with moderate-to-severe COPD received aclidinium 400 µg twice daily or placebo via Genuair®/Pressair®a for 3 weeks (2- week washout between treatment periods). The primary endpoint was change from baseline to Week 3 in endurance time, measured by constant work rate cycle ergometry testing at 75% peak incremental work rate. Changes from baseline in intensity of exertional dyspnea (Borg CR10 Scale®) and trough inspiratory capacity were secondary endpoints. Additional endpoints included changes from baseline in other spirometric, plethysmographic, and physical activity (assessed by objective accelerometer measurement) parameters. Efficacy endpoints were analyzed using an analysis of covariance model. Results In total, 112 patients were randomized and treated (mean age 60.3 years; mean postbronchodilator forced expiratory volume in 1 s 1.7 L [56.7% predicted]; mean endurance time 485.7 s). After 3 weeks, endurance time was significantly increased with aclidinium versus placebo (treatment difference 58.5 s; p < 0.05). At Week 3, aclidinium significantly reduced dyspnea intensity at isotime during exercise (treatment difference -0.63; p < 0.05) and improved trough inspiratory capacity (treatment difference 78 mL; p < 0.05) versus placebo. Significant improvements in spirometric, plethysmographic, and some physical activity parameters were observed with aclidinium versus placebo. Conclusions These results suggest that aclidinium significantly improves exercise endurance, exertional dyspnea, hyperinflation, and physical activity in patients with COPD. Trial registration ClinicalTrials.gov identifier: NCT01471171; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

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

This study characterised the in vitro and in vivo profiles of two novel long-acting muscarinic antagonists, aclidinium bromide and glycopyrronium bromide, using tiotropium bromide and ipratropium bromide as comparators. All four antagonists had high affinity for the five muscarinic receptor sub-types (M1-M5); aclidinium had comparable affinity to tiotropium but higher affinity than glycopyrronium and ipratropium for all receptors. Glycopyrronium dissociated faster from recombinant M3 receptors than aclidinium and tiotropium but more slowly than ipratropium; all four compounds dissociated more rapidly from M2 receptors than from M3 receptors. In vitro, aclidinium, glycopyrronium and tiotropium had a long duration of action at native M3 receptors (>8 h versus 42 min for ipratropium). In vivo, all compounds were equi-potent at reversing acetylcholine-induced bronchoconstriction. Aclidinium, glycopyrronium and ipratropium had a faster onset of bronchodilator action than tiotropium. Aclidinium had a longer duration of action than glycopyronnium (time to 50% recovery of effect [t½ offset] = 29 h and 13 h, respectively); these compare with a t½ offset of 64 h and 8 h for tiotropium and ipratropium, respectively. Aclidinium was less potent than glycopyrronium and tiotropium at inhibiting salivation in conscious rats (dose required to produce half-maximal effect [ED50] = 38, 0.74 and 0.88 µg/kg, respectively) and was more rapidly hydrolysed in rat, guinea pig and human plasma compared with glycopyrronium or tiotropium. These results indicate that while aclidinium and glycopyrronium are both potent antagonists at muscarinic receptors with similar kinetic selectivity for M3 receptors versus M2, aclidinium has a longer dissociation half-life at M3 receptors and a longer duration of bronchodilator action in vivo than glycopyrronium. The rapid plasma hydrolysis of aclidinium, coupled to its kinetic selectivity, may confer a reduced propensity for systemic anticholinergic side effects with aclidinium versus glycopyrronium and tiotropium. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is increasing worldwide and is predicted to become the third most frequent cause of death by 2030. Muscarinic receptor antagonists, alone or in combination with long-acting β2-agonists, are frequently used for COPD therapy. Aclidinium bromide is a novel muscarinic receptor antagonist, and clinical studies indicate that its metabolism is more rapid than that of other muscarinic receptor inhibitors, so systemic side effects are expected to occur less frequently. Aclidinium bromide is well tolerated, and when compared with other muscarinic receptor antagonists, the drug achieves better control of lung function, especially night-time symptoms in COPD patients. This review summarizes the safety profile and side effects reported by recent clinical studies using aclidinium bromide alone. [ABSTRACT FROM AUTHOR]

Background: Aclidinium is a novel, long-acting muscarinic antagonist indicated for maintenance treatment of COPD. Methods: In this 52-week, parallel-group, double-blind study, patients with moderate-to- severe COPD were randomized (1:1) to receive aclidinium twice-daily (BID) 200 μg or 400 μg via a novel, dry powder inhaler (Genuair®/Pressair®) [Registered trademarks of Almirall, SA, Barcelona, Spain for use within the European Union, Iceland, Norway, and Switzerland as Genuair® and within the United States as Pressair®]. Safety, the primary objective, was assessed via adverse events (AEs), clinical laboratory tests, vital signs, and 12-lead electrocardiograms. Efficacy was evaluated using spirometry, SGRQ, and rescue medication use. Results: A total of 605 patients were randomized in the study. The percentage of patients reporting any treatment-emergent AE (TEAE) was comparable between groups; most TEAEs were mild or moderate. Anticholinergic TEAEs were reported by low percentages of patients in either treatment group (dry mouth: 200 μg, 1.3%; 400 μg, 2.7%; constipation: 200 μg, 2.9%; 400 μg, 1.7%). Cardiac TEAEs were also reported by a low percentage of patients (<2% for any event in any group) and did not appear to be dose dependent. There were no clinically relevant abnormalities in other safety outcomes. Both aclidinium 200 mg and 400 mg resulted in improvements from baseline to Week 52 in FEV1, with numerically greater increases observed with the higher dose. Clinically important improvements in SGRQ scores and a reduction in rescue medication use were observed throughout the study for both doses. Conclusions: Long-term treatment with aclidinium 200 μg or 400 μg BID was well tolerated, with sustained benefits in lung function and health status in patients with COPD throughout the 1-year study. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality. With the significant toll of the disease, more resources have been invested in developing new treatment modalities. Among these medications, inhalational anticholinergics are widely used for the management of stable COPD. The newer agents, with longer half-lives and better safety profiles, have emerged and helped to improve management of COPD patients. The available data from randomized clinical trials support use of these agents. Multiple randomized clinical trials show safety and efficacy of the newer long-acting inhaled anticholinergics, including tiotropium and aclidinium. A recent meta-analysis of tiotropium delivered with Respimat® raised some safety concerns. A large trial, comparing different doses and delivery methods of inhaled tiotropium, is ongoing to determine the effect on mortality. As clinical trials may not comprehensively represent the entire COPD population, caution should be exercised when these agents are used in higher-risk populations, like individuals with cardiac arrhythmias or urinary obstruction. In this publication, we review the safety of inhalational anticholinergics. [ABSTRACT FROM AUTHOR]

Background: This Phase III study evaluated the efficacy and safety of twice-daily aclidinium 200 μg and 400 μg versus placebo in the treatment of moderate-to-severe COPD. Methods: In this 12-week, double-blind, multicenter trial, patients were randomized (1:1:1) to inhaled twice-daily aclidinium 200 μg, aclidinium 400 μg, or placebo. Primary and secondary endpoints were changes from baseline in trough FEV1 and peak FEV1 at Week 12, respectively. Health status (St. George's Respiratory Questionnaire [[SGRQ]]), COPD symptoms (Transitional Dyspnea Index [[TDI]], night and early morning symptoms), and safety were also assessed. Results: A total of 561 patients (mean age, 64 ± 9 years) with a mean baseline FEV1 of 1.36 ± 0.54 L (47.2%% of predicted value) were randomized. At Week 12, aclidinium 200 μg and 400 μg showed significant improvements from baseline in mean (95%% CI) trough FEV1 compared with placebo by 86 (45, 127) mL and 124 (83,164) mL, respectively, and in peak FEV1 by 146 (101, 190) mL and 192 (148, 236) mL, respectively (p ≤ 0.0001 for all). Both aclidinium doses also provided significant improvements in SGRQ, TDI and almost all COPD symptom scores compared with placebo (p < 0.05 for all). Incidences of adverse events (AEs) were similar across treatment groups. The incidence of anticholinergic AEs was low and similar across groups (dry mouth: 0.5%%-1.6%%; constipation: 0%%-1.1%%). Conclusions: Treatment of moderate-to-severe COPD patients with twice-daily aclidinium 200 μg and 400 μg was associated with significant improvements in bronchodilation, health status, and COPD symptoms. Both doses were well tolerated and had safety profiles similar to placebo. Trial Registration: This ACCORD I study (AClidinium in Chronic Obstructive Respiratory Disease I) was registered on clinicaltrials.gov (NCT00891462) as 'Efficacy and Safety of Aclidinium Bromide for Treatment of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)'. [ABSTRACT FROM AUTHOR]

Abstract: This Phase IIb, double-blind, double-dummy, placebo- and active-comparator-controlled crossover study (ClinicalTrials.gov identifier: NCT01120093) assessed efficacy and safety of three doses of aclidinium bromide in patients with moderate to severe chronic obstructive pulmonary disease. Patients were randomised to one of five treatment sequences each consisting of twice-daily (BID) aclidinium 100 μg, 200 μg, 400 μg (via Genuair®*), formoterol 12 μg (via Aerolizer®) and matched placebo for 7 days, with a 5- to 9-day washout period. Primary endpoint was mean change from baseline in forced expiratory volume in 1 s (FEV1) normalised area under the curve (AUC)0–12 on Day 7. Secondary endpoints were: change from baseline in FEV1 normalised AUC12–24, FEV1 normalised AUC0−24 and morning pre-dose FEV1 on Day 7. Adverse events were monitored throughout the study. Of 79 randomised patients, 68 (86.1%) completed the study. After 7 days of treatment, aclidinium and formoterol produced statistically significantly greater changes from baseline in FEV1 normalised AUC0−12 vs placebo (p < 0.0001). FEV1 normalised AUC12−24, FEV1 normalised AUC0–24, and morning pre-dose FEV1 were also statistically significantly greater with all aclidinium doses vs placebo (p < 0.0001). Improvements in primary and secondary endpoints were statistically significantly greater with aclidinium 400 μg vs 100 μg. The safety profile of aclidinium was comparable to placebo. These results demonstrated that twice-daily aclidinium produced dose-dependent clinically meaningful improvements in FEV1 compared with placebo. This study also confirmed the use of an aclidinium BID dosing regimen and established aclidinium 200 μg and 400 μg as suitable doses for further investigation in Phase III trials. [Copyright &y& Elsevier]

Abstract: Aims: Aclidinium bromide is a novel, long-acting, inhaled muscarinic antagonist currently in registration phase for the treatment of chronic obstructive pulmonary disease. Since urinary difficulty and retention have been reported for anticholinergic agents such as tiotropium and ipratropium, it is important to examine the preclinical urinary and renal safety profile of aclidinium. Main methods: The effect of aclidinium on urine and electrolyte excretion, renal function and voiding cystometry was analysed in conscious water-loaded Wistar rats (10–1000μg/kg, s.c.), anaesthetised Beagle dogs (1000μg/kg, i.v.) and anaesthetised guinea pigs (3–100μg/kg, intratracheally), respectively. Aclidinium plasma levels were determined in an independent study. Active comparators were tiotropium (all studies) and ipratropium (cystometry only). Key findings: Aclidinium 1000μg/kg had no effect on urine excretion in rats, in contrast to tiotropium 100μg/kg which significantly decreased this parameter (p<0.05). Aclidinium 1000μg/kg also had no effect on renal function in Beagle dogs. In guinea pigs, aclidinium 3–100μg/kg had no effect on urinary bladder function, whereas tiotropium and ipratropium 100μg/kg decreased the peak micturition pressure (p<0.05), increased the volume of urine retained in the bladder (p<0.01) and showed a trend to decrease the volume of urine excreted. Significance: Aclidinium had no significant effect on urinary and renal function in the animal models studied. These results, together with the rapid plasma clearance of aclidinium reported previously, suggest a lower propensity to induce urinary retention in humans than tiotropium and ipratropium. [Copyright &y& Elsevier]

Summary: Background: Static and dynamic lung hyperinflation are associated with exercise impairment and poor outcomes in COPD patients. Aclidinium bromide is a novel, long-acting inhaled muscarinic antagonist currently in development for COPD treatment. Methods: Patients with moderate to severe COPD (N = 181) were randomized to once-daily aclidinium 200 μg or placebo for 6 weeks. Constant work rate cycling exercises at 75% of peak work rate were performed at baseline, Day 1, Week 3, and Week 6. The primary efficacy measure was change in exercise endurance time (ET) from baseline to Week 6. Secondary outcomes included changes in trough forced expiratory volume in 1 s (FEV1), inspiratory capacity (IC), IC/total lung capacity (TLC), and functional residual capacity (FRC) from baseline to Day 1, Week 3, and Week 6. Borg dyspnea scores during exercise, locus of symptom limitation, and safety measures were assessed. Results: Aclidinium significantly improved ET on Day 1 (P = 0.0002), and improvements were sustained through Week 3 (P = 0.0007) and Week 6 (P = 0.0042) vs placebo. Compared with placebo, aclidinium improved trough FEV1, IC, and IC/TLC at Weeks 3 and 6 (P < 0.05 for all). Exertional dyspnea scores at isotime were reduced on Day 1, Week 3, and Week 6 for aclidinium vs placebo (P < 0.05). Furthermore, the likelihood of stopping exercise due to breathing discomfort was lower in the aclidinium group at study end (P = 0.0208) compared with placebo. No differences in safety outcomes were reported between treatments. Conclusions: Aclidinium significantly increased exercise tolerance, improved airflow obstruction and lung hyperinflation, and was safe and well tolerated. Registration of Trial: This trial was registered with ClinicalTrials.gov (NCT00500318) under the name “A Study of Exercise Endurance and Lung Hyperinflation in Patients with Moderate to Severe COPD”. [Copyright &y& Elsevier]

Abstract: Airway hyperresponsiveness and inflammation characterize the airways of individuals with asthma and chronic obstructive pulmonary disease (COPD). Hence, therapeutic approaches that attenuate such manifestations may offer promise in the management of these diseases. In the present study, we investigated whether a novel long-acting cholinergic antagonist, aclidinium bromide, modulates airway function and leukocyte trafficking in an Aspergillus fumigatus (Af)-induced murine model of asthma. Nebulized aclidinium (1mg/ml) administration completely abrogated increases in methacholine-induced lung resistance in Af-exposed mice. Parallel assessment of dynamic compliance showed that aclidinium also completely restores methacholine-mediated decreases in naïve and Af-exposed mice. As evidenced by differential cell counts within bronchoalveolar lavage fluid, aclidinium also diminished (51±4%) Af-induced airway eosinophil numbers with no significant change in other immune cell types. Further assessment of cytokine and total protein levels in bronchoalveolar lavage fluid showed that aclidinium had little effect on IL-4 or IL-6 levels in either Af-exposed or naïve mice but markedly decreased total protein levels in bronchoalveolar lavage fluid. These data suggest that aclidinium, a selective muscarinic antagonist, not only acts as a bronchodilator but could also act as an anti-inflammatory agent with potential clinical benefits in the treatment of COPD and asthma. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Long-acting inhaled bronchodilators are central in the symptomatic treatment of patients with chronic obstructive pulmonary disease (COPD). Until now the only long-acting inhaled anticholinergic drug available in the clinic is tiotropium bromide. WHAT THIS STUDY ADDS • Aclidinium bromide is a new anticholinergic drug. In normal volunteers inhalation of this compound induced a long-lasting bronchodilation and offered protection against the bronchoconstrictor effect of inhaled methacholine. Aclidinium bromide is now being developed as a long-acting anticholinergic for patients with COPD. AIM Aclidinium bromide is a muscarinic antagonist in development for the treatment of chronic obstructive pulmonary disease (COPD). This phase I trial in healthy subjects investigated the bronchodilator activity of aclidinium and its ability to reduce methacholine-induced bronchoconstriction. METHODS This double-blind, partial-crossover study randomized 12 subjects to treatment with single doses of aclidinium (50, 300 or 600 µg) or placebo. Drug activity was assessed for 24 h after administration by specific airway conductance (sGaw), airways resistance (Raw) and bronchial responsiveness (PC35 sGaw methacholine). RESULTS Aclidinium significantly increased sGaw compared with placebo at all assessments and doses (sGaw mean ± SD AUC (l kPa−1 h) for placebo 24.4 ± 4.37, for 50 µg 29.0 ± 7.08, for 300 µg 31.2 ± 6.68 and for 600 µg 32.7 ± 7.95) ( P < 0.009), except 50 µg at 1 and 24 h. Significant decreases in Raw were observed with aclidinium 300 and 600 µg compared with placebo at all assessments (Raw mean ± SD AUC (kPa s−1 l−1 h) for placebo 7.7 ± 3.46, for 300 µg 5.8 ± 2.33, for 600 µg 6.3 ± 3.11) ( P < 0.04) except 600 µg at 24 h. Differences between aclidinium 300 and 600 µg vs. placebo in PC35 doubling concentration were significant at all assessments (mean ± SD AUC (mg ml−1 h) for placebo 100.0 ± 30.27, for 50 µg 117.2 ± 33.33, for 300 µg 168.9 ± 28.66 and for 600 µg 179.1 ± 15.73 ( P < 0.0001). For all endpoints, there was a significant difference between aclidinium 50 µg and the higher doses ( P < 0.0001). Aclidinium was not detected in plasma and was well tolerated. CONCLUSION Aclidinium produced statistically significant and sustained bronchodilation over 24 h, suggesting long-acting efficacy and providing a rationale for future studies in patients with COPD. [ABSTRACT FROM AUTHOR]