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A dose-ranging study of the bronchodilator effects of abediterol (LAS100977), a long-acting β2-adrenergic agonist, in asthma; a Phase II, randomized study

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      Abstract

      Background

      Long-acting β 2-adrenergic agonists (LABAs) are recommended in combination with inhaled corticosteroids (ICSs) for asthma management. Abediterol is a novel, selective, potent, once-daily LABA in development for treatment of asthma and chronic obstructive pulmonary disease. This study aimed to determine abediterol doses with similar peak bronchodilatory effect to salbutamol 400 μg, and duration of action compatible with once-daily dosing in patients with persistent, stable asthma.

      Methods

      This was a Phase II, randomized, double-blind, double-dummy, crossover, placebo-controlled, dose-ranging study (ClinicalTrials.gov NCT01425801) in 62 patients with mild-to-moderate asthma who were also receiving an ICS. Patients received single doses of abediterol 0.313, 0.625, 1.25, or 2.5 μg, salbutamol 400 μg, or placebo in the morning. Spirometry was performed up to 36 h post-dose; safety and tolerability were assessed throughout the study. The primary endpoint was change from baseline in peak forced expiratory volume in 1 s (FEV 1). Additional endpoints included trough FEV 1, normalized area under the FEV 1 curve (FEV 1 AUC) up to 24 h post-dose, and peak and trough forced vital capacity (FVC).

      Results

      Abediterol produced dose-dependent improvements in peak FEV 1 from baseline compared with placebo, from 0.274 (95% CI 0.221, 0.327) to 0.405 L (95% CI 0.353, 0.458) for abediterol 0.313 to 2.5 μg, respectively (p < 0.0001 all doses). Abediterol 0.625, 1.25, and 2.5 μg had similar magnitude of peak FEV 1 effect to salbutamol. Dose-dependent changes from baseline in trough FEV 1 versus placebo were 0.219 (95% CI 0.136, 0.302) to 0.400 L (95% CI 0.317, 0.483) for abediterol 0.313 to 2.5 μg, respectively (p < 0.0001). All abediterol doses achieved significant improvements versus placebo in FEV 1 AUC 0–6, 0–12, and 0–24 h, and peak and trough FVC (p < 0.05). Less than 10% of patients experienced treatment-related adverse events for each dose of abediterol; most were mild to moderate in intensity and the most common were headache and nasopharyngitis. There were no clinically relevant changes in heart rate.

      Conclusions

      Abediterol 0.625–2.5 μg provided dose-dependent, clinically and statistically significant bronchodilation versus placebo in patients with asthma, with a peak effect similar to salbutamol and duration of action compatible with once-daily dosing. All doses of abediterol were well tolerated.

      Electronic supplementary material

      The online version of this article (doi:10.1186/1471-2466-14-176) contains supplementary material, which is available to authorized users.

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      Most cited references 24

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      Interpretative strategies for lung function tests.

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        Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society.

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          Adherence to inhaled therapies, health outcomes and costs in patients with asthma and COPD.

          Suboptimal adherence to pharmacological treatment of asthma and chronic obstructive pulmonary disease (COPD) has adverse effects on disease control and treatment costs. The reasons behind non-adherence revolve around patient knowledge/education, inhaler device convenience and satisfaction, age, adverse effects and medication costs. Age is of particular concern given the increasing prevalence of asthma in the young and increased rates of non-adherence in adolescents compared with children and adults. The correlation between adherence to inhaled pharmacological therapies for asthma and COPD and clinical efficacy is positive, with improved symptom control and lung function shown in most studies of adults, adolescents and children. Satisfaction with inhaler devices is also positively correlated with improved adherence and clinical outcomes, and reduced costs. Reductions in healthcare utilisation are consistently observed with good adherence; however, costs associated with general healthcare and lost productivity tend to be offset only in more adherent patients with severe disease, versus those with milder forms of asthma or COPD. Non-adherence is associated with higher healthcare utilisation and costs, and reductions in health-related quality of life, and remains problematic on an individual, societal and economic level. Further development of measures to improve adherence is needed to fully address these issues. Copyright © 2013. Published by Elsevier Ltd.
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            Author and article information

            Affiliations
            [ ]University of Manchester, Medicines Evaluation Unit Ltd, The Langley Building, Southmoor Road, Wythenshawe, Manchester M23 9QZ UK
            [ ]Almirall Research and Development Centre, Barcelona, Spain
            Contributors
            dsingh@meu.org.uk
            helena.pujol@almirall.com
            anna.ribera@almirall.com
            beatriz.seoane@almirall.com
            eric.massana@almirall.com
            carol.astbury@almirall.com
            sandrine.ruiz@almirall.com
            gonzalo.demiquel@almirall.com
            Journal
            BMC Pulm Med
            BMC Pulm Med
            BMC Pulmonary Medicine
            BioMed Central (London )
            1471-2466
            14 November 2014
            2014
            : 14
            : 1
            25398689 4320624 647 10.1186/1471-2466-14-176
            © Singh et al.; licensee BioMed Central. 2014

            This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

            Categories
            Research Article
            Custom metadata
            © The Author(s) 2014

            Respiratory medicine

            chronic respiratory disease, laba, asthma, dose-finding, bronchodilation

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