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

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          Abstract

          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 2-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 1, trough FEV 1, 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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          Efficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study

           Dave Singh,  Paul W Jones,  Eric D Bateman … (2014)
          Background Aclidinium/formoterol is a twice-daily (BID) fixed-dose combination (FDC) in development for chronic obstructive pulmonary disease (COPD). The efficacy and safety of aclidinium/formoterol versus monotherapy and placebo in patients with COPD was assessed. Methods In this 24-week double-blind, parallel-group, active- and placebo-controlled, multicentre Phase III study, patients (≥40 years, post-bronchodilator forced expiratory volume in 1 second [FEV1]/forced vital capacity <70% and FEV1 ≥30% but <80% predicted normal) were randomised 2:2:2:2:1 to aclidinium/formoterol 400/12 μg (n = 385) or 400/6 μg (n = 381), aclidinium 400 μg (n = 385), formoterol 12 μg (n = 384) or placebo (n = 194) BID via Genuair®/Pressair®a. Results At Week 24, aclidinium/formoterol 400/12 μg and 400/6 μg lead to significant improvements from baseline in 1-hour post-dose FEV1 versus aclidinium (125 mL [95% CI: 90, 160; p < 0 · 001] and 69 mL [95% CI: 34, 105; p < 0.001], respectively) and trough FEV1 versus formoterol (85 mL [95% CI: 51, 119; p < 0.001] and 53 mL [95% CI: 19, 87; p < 0.01], respectively; co-primary endpoints). Additionally, aclidinium/formoterol 400/12 μg and 400/6 μg provided significant improvements in Transition Dyspnoea Index (TDI) focal score versus placebo (1.29 units [95% CI: 0.73, 1.86; p < 0.001] and 1.16 units [95% CI: 0.59, 1.73; p < 0.001], respectively; secondary endpoint). All treatments were well tolerated, with safety profiles of the FDCs similar to those of placebo and monotherapy. Conclusions Both aclidinium/formoterol BID doses significantly improved bronchodilation versus monotherapy, and dyspnoea versus placebo, with no increase in safety risk. Aclidinium/formoterol may be an effective treatment for patients with COPD. Trial registration ClinicalTrials.gov: NCT01462942. Electronic supplementary material The online version of this article (doi:10.1186/1471-2466-14-178) contains supplementary material, which is available to authorized users.
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            The MCID of the transition dyspnea index is a total score of one unit.

             Donald Mahler,  T J Witek (2005)
            The Baseline (BDI) and Transition (TDI) Dyspnea Indexes provide interview-based measurements of breathlessness related to activities of daily living. The BDI is a discriminative instrument that includes specific criteria for each of three components at a single point in time. The TDI is an evaluative instrument that includes specific criteria for each of three components to measure changes from a baseline state. Observational studies have shown that patients with COPD generally experience a gradual progression of breathing difficulty as measured by the TDI over time. Randomized controlled trials have demonstrated excellent measurement characteristics of the TDI; these include responsiveness (ability to detect change) and construct validity (a change in the TDI correlates with changes in other variables). Supporting evidence for one unit as the minimal clinically important difference (MCID) of the TDI is based on: expert preference; use of the physician's global evaluation score as an anchor; and distribution estimates (standard error of measurement and 0.5 of the standard deviation). As an alternative to the interview process, self-administered computerized (SAC) versions of the BDI/TDI have been developed to provide direct patient-reported ratings of dyspnea. To further establish the MCID of the interview-administered and/or the SAC TDI, we recommend that a patient's report of global ratings of change by used as an independent standard or anchor.
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              Aclidinium bromide and formoterol fumarate as a fixed-dose combination in COPD: pooled analysis of symptoms and exacerbations from two six-month, multicentre, randomised studies (ACLIFORM and AUGMENT)

               Eric D Bateman,  Kenneth Chapman,  Dave Singh … (2015)
              Background The combination of aclidinium bromide, a long-acting anticholinergic, and formoterol fumarate, a long-acting beta2-agonist (400/12 μg twice daily) achieves improvements in lung function greater than either monotherapy in patients with chronic obstructive pulmonary disease (COPD), and is approved in the European Union as a maintenance treatment. The effect of this combination on symptoms of COPD and exacerbations is less well established. We examined these outcomes in a pre-specified analysis of pooled data from two 24-week, double-blind, parallel-group, active- and placebo-controlled, multicentre, randomised Phase III studies (ACLIFORM and AUGMENT). Methods Patients ≥40 years with moderate to severe COPD (post-bronchodilator forced expiratory volume in 1 s [FEV1]/forced vital capacity <70 % and FEV1 ≥30 % but <80 % predicted normal) were randomised (ACLIFORM: 2:2:2:2:1; AUGMENT: 1:1:1:1:1) to twice-daily aclidinium/formoterol 400/12 μg or 400/6 μg, aclidinium 400 μg, formoterol 12 μg or placebo via Genuair™/Pressair®. Dyspnoea (Transition Dyspnoea Index; TDI), daily symptoms (EXAcerbations of Chronic pulmonary disease Tool [EXACT]-Respiratory Symptoms [E-RS] questionnaire), night-time and early-morning symptoms, exacerbations (Healthcare Resource Utilisation [HCRU] and EXACT definitions) and relief-medication use were assessed. Results The pooled intent-to-treat population included 3394 patients. Aclidinium/formoterol 400/12 μg significantly improved TDI focal score versus placebo and both monotherapies at Week 24 (all p < 0.05). Over 24 weeks, significant improvements in E-RS total score, overall night-time and early-morning symptom severity and limitation of early-morning activities were observed with aclidinium/formoterol 400/12 μg versus placebo and both monotherapies (all p < 0.05). The rate of moderate or severe HCRU exacerbations was significantly reduced with aclidinium/formoterol 400/12 μg compared with placebo (p < 0.05) but not monotherapies; the rate of EXACT-defined exacerbations was significantly reduced with aclidinium/formoterol 400/12 μg versus placebo (p < 0.01) and aclidinium (p < 0.05). Time to first HCRU or EXACT exacerbation was longer with aclidinium/formoterol 400/12 μg compared with placebo (all p < 0.05) but not the monotherapies. Relief-medication use was reduced with aclidinium/formoterol 400/12 μg versus placebo and aclidinium (p < 0.01). Conclusions Aclidinium/formoterol 400/12 μg significantly improves 24-hour symptom control compared with placebo, aclidinium and formoterol in patients with moderate to severe COPD. Furthermore, aclidinium/formoterol 400/12 μg reduces the frequency of exacerbations compared with placebo. Trial registration NCT01462942 and NCT01437397 (ClinicalTrials.gov) Electronic supplementary material The online version of this article (doi:10.1186/s12931-015-0250-2) contains supplementary material, which is available to authorized users.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Int J Chron Obstruct Pulmon Dis
                Journal ID (iso-abbrev): Int J Chron Obstruct Pulmon Dis
                Journal ID (publisher-id): COPD
                Journal ID (pmc): copd
                Title: International Journal of Chronic Obstructive Pulmonary Disease
                Publisher: Dove
                ISSN (Print): 1176-9106
                ISSN (Electronic): 1178-2005
                Publication date (Electronic): 06 December 2019
                Publication date Collection: 2019
                Volume: 14
                Pages: 2835-2848
                Affiliations
                [1 ]Medicines Evaluation Unit, University of Manchester, Manchester University NHS Foundation Trust , Manchester, UK
                [2 ]Department of Family and Community Medicine, University of Toronto , Toronto, ON, Canada
                [3 ]Division of Pulmonary Diseases and Critical Care Medicine, University of North Carolina Pulmonary Critical Medicine , Chapel Hill, NC, USA
                [4 ]Clinical Research Institute , Medford, OR, USA
                [5 ]BioPharmaceuticals R&D, AstraZeneca , Barcelona, Spain
                Author notes
                Correspondence: Dave Singh Medicines Evaluation Unit, University of Manchester, Manchester University NHS Foundation Trust , ManchesterM23 9QZ, UKTel +44 161 946 4073Fax +44 161 946 1459 Email DSingh@meu.org.uk
                Article
                Publisher ID: 217710
                DOI: 10.2147/COPD.S217710
                PMC ID: 6902852
                Copyright statement: © 2019 Singh et al.
                License:

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 5, Tables: 2, References: 30, Pages: 14
                Categories
                Subject: Review

                Data availability:

                ScienceOpen disciplines: Respiratory medicine

                Keywords: copd, treatment-naïve, lama, laba

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