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

BMC Pulmonary Medicine

Anne Leselbaum⁸  Esther Garcia Gil⁶  Cynthia Caracta⁵  Eduard Molins⁶  Cristina Serra³  Stephanie Korn¹  Eric D Bateman²  Paul W Jones⁷  Dave Singh⁴ 

[1] Pulmonary Department, Mainz University Hospital, Mainz, Germany;Division of Pulmonology, Department of Medicine, University of Cape Town, Cape Town, South Africa;Almirall R&D Centre, Almirall, Barcelona, Spain;University of Manchester, Medicines Evaluation Unit, Langley Building, University Hospital of South Manchester NHS Foundation Trust, Southmoor Road, Manchester M23 9QZ, UK;Formerly of Forest Research Institute, Forest Laboratories LLC, a subsidiary of Actavis, Jersey City, NJ, USA;AstraZeneca PLC, Barcelona, Spain;Infection and Immunity Institute, St George’s, University of London, London, UK;Formerly of Almirall S.A., Barcelona, Spain

关键词: Fixed-dose combination;    Chronic obstructive pulmonary disease;    Aclidinium bromide/formoterol fumarate;   

Others  :  1091380
DOI  :  10.1186/1471-2466-14-178

 received in 2014-06-13, accepted in 2014-11-03,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Singh et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Global Initiative for Chronic Obstructive Lung Disease: Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease. 2014. http://www.goldcopd.org/uploads/users/files/GOLD_Report_2013_Feb20.pdf webcite
• [2]Cazzola M, Calzetta L, Matera MG: beta(2) -adrenoceptor agonists: current and future direction. Br J Pharmacol 2011, 163:4-17.
• [3]Cazzola M, Page CP, Calzetta L, Matera MG: Pharmacology and therapeutics of bronchodilators. Pharmacol Rev 2012, 64:450-504.
• [4]IMS Health LS: IMS Data 5/2011-4/2012. Danbury, CT, US: IMS Health Incorporated; 2012.
• [5]Tashkin DP, Ferguson GT: Combination bronchodilator therapy in the management of chronic obstructive pulmonary disease. Respir Res 2013, 14:49. BioMed Central Full Text
• [6]Rudolf M, Tashkin DP: Bronchodilators - future role in the management of chronic obstructive pulmonary disease. Eur Respir Dis 2012, 8:108-115.
• [7]Cazzola M, Rogliani P, Matera MG: Aclidinium bromide/formoterol fumarate fixed-dose combination for the treatment of chronic obstructive pulmonary disease. Expert Opin Pharmacother 2013, 14:775-781.
• [8]Partridge MR, Karlsson N, Small IR: Patient insight into the impact of chronic obstructive pulmonary disease in the morning: an internet survey. Curr Med Res Opin 2009, 25:2043-2048.
• [9]Global Initiative for Chronic Obstructive Lung Disease: Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease. 2010. http://www.goldcopd.org/Guidelines/guideline-2010-gold-report.html webcite
• [10]Leidy NK, Wilcox TK, Jones PW, Murray L, Winnette R, Howard K, Petrillo J, Powers J, Sethi S: Development of the EXAcerbations of Chronic obstructive pulmonary disease Tool (EXACT): a patient-reported outcome (PRO) measure. Value Health 2010, 13:965-975.
• [11]Leidy NK, Wilcox TK, Jones PW, Roberts L, Powers JH, Sethi S: Standardizing measurement of chronic obstructive pulmonary disease exacerbations: reliability and validity of a patient-reported diary. Am J Respir Crit Care Med 2011, 183:323-329.
• [12]Leidy NK, Murray LT: Patient-reported outcome (PRO) measures for clinical trials of COPD: the EXACT and E-RS. COPD 2013, 10:393-398.
• [13]Leidy NK, Murray LT, Jones P, Sethi S: Performance of the EXAcerbations of Chronic pulmonary disease Tool patient-reported outcome measure in three clinical trials of chronic obstructive pulmonary disease. Ann Am Thorac Soc 2014, 11:316-325.
• [14]European Medicines Agency: Guideline on Clinical Development of Fixed Combination Medicinal Products (CHMP/EWP/240/95) Rev.1. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003686.pdf webcite
• [15]US Food and Drug Administration: Code of Federal Regulations. Title 21. Section 300.50. Fixed-Combination Prescription Drugs for Humans. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=300.50 webcite
• [16]Benhamou D, Cuvelier A, Muir JF, Leclerc V, Le Gros V, Kottakis J, Bourdeix I: Rapid onset of bronchodilation in COPD: a placebo-controlled study comparing formoterol (Foradil Aerolizer) with salbutamol (Ventodisk). Respir Med 2001, 95:817-821.
• [17]Tashkin DP, Fabbri LM: Long-acting beta-agonists in the management of chronic obstructive pulmonary disease: current and future agents. Respir Res 2010, 11:149. BioMed Central Full Text
• [18]Kerwin EM, D’Urzo AD, Gelb AF, Lakkis H, Garcia Gil E, Caracta CF, ACCORD I study investigators: Efficacy and safety of a 12-week treatment with twice-daily aclidinium bromide in COPD patients (ACCORD COPD I). COPD 2012, 9:90-101.
• [19]Jones PW, Singh D, Bateman ED, Agusti A, Lamarca R, de Miquel G, Segarra R, Caracta C, Garcia Gil E: Efficacy and safety of twice-daily aclidinium bromide in COPD patients: the ATTAIN study. Eur Respir J 2012, 40:830-836.
• [20]Aalbers R, Maleki-Yazdi MR, Hamilton A, Waitere-Wijker S, Pivovarova A, Schmidt O, Bjermer L: Dose-Finding Study for Tiotropium and Olodaterol When Administered in Combination via the Respimat® Inhaler in Patients with COPD. Vienna, Austria: Poster presented at the European Respiratory Society Annual Congress; 2012.
• [21]Bateman ED, Ferguson GT, Barnes N, Gallagher N, Green Y, Henley M, Banerji D: Dual bronchodilation with QVA149 versus single bronchodilator therapy: the SHINE study. Eur Respir J 2013, 42:1484-1494.
• [22]Donohue JF, Maleki-Yazdi MR, Kilbride S, Mehta R, Kalberg C, Church A: Efficacy and safety of once-daily umeclidinium/vilanterol 62.5/25 mcg in COPD. Respir Med 2013, 107:1538-1546.
• [23]Maltais F, Beck E, Webster D, Maleki-Yazdi MR, Seibt J-V, Arnoux A, Hamilton A: Four weeks once daily treatment with tiotropium+olodaterol (BI 1744) fixed dose combination compared with tiotropium in COPD patients [abstract]. Eur Respir J 2010, 36:1014s.
• [24]Reisner C, Fogarty C, Spangenthal S, Dunn L, Kerwin EM, Quinn D, Seale JP, Thomas M, St Rose E, Orevillo C: Novel combination of glycopyrrolate and formoterol MDI (GFF-MDI) provides superior bronchodilation compared to its components administered alone, tiotropium DPI, and formoterol DPI in a randomized, double-blind, placebo-controlled Phase 2b study in patients with COPD [abstract]. Am J Resp Crit Care Med 2011, 183:A6435.
• [25]Jones PW, Beeh KM, Chapman KR, Decramer M, Mahler DA, Wedzicha JA: Minimal clinically important differences in pharmacological trials. Am J Respir Crit Care Med 2014, 189:250-255.
• [26]Donohue JF: Minimal clinically important differences in COPD lung function. COPD 2005, 2:111-124.
• [27]Kaptchuk TJ, Friedlander E, Kelley JM, Sanchez MN, Kokkotou E, Singer JP, Kowalczykowski M, Miller FG, Kirsch I, Lembo AJ: Placebos without deception: a randomized controlled trial in irritable bowel syndrome. PLoS One 2010, 5:e15591.
• [28]Westwood M, Bourbeau J, Jones PW, Cerulli A, Capkun-Niggli G, Worthy G: Relationship between FEV1 change and patient-reported outcomes in randomised trials of inhaled bronchodilators for stable COPD: a systematic review. Respir Res 2011, 12:40. BioMed Central Full Text
• [29]Rabe KF, Fabbri LM, Vogelmeier C, Kogler H, Schmidt H, Beeh KM, Glaab T: Seasonal distribution of COPD exacerbations in the prevention of exacerbations with tiotropium in COPD trial. Chest 2013, 143:711-719.
• [30]Kessler R, Partridge MR, Miravitlles M, Cazzola M, Vogelmeier C, Leynaud D, Ostinelli J: Symptom variability in patients with severe COPD: a pan-European cross-sectional study. Eur Respir J 2011, 37:264-272.
• [31]Kew KM, Mavergames C, Walters JA: Long-acting beta2-agonists for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2013, 10:CD010177.
• [32]Jansat JM, Lamarca R, Garcia Gil E, Ferrer P: Safety and pharmacokinetics of single doses of aclidinium bromide, a novel long-acting, inhaled antimuscarinic, in healthy subjects. Int J Clin Pharmacol Ther 2009, 47:460-468.
• [33]Sentellas S, Ramos I, Albertí J, Salvà M, Antón F, Miralpeix M, Beleta J, Gavaldà A: Aclidinium bromide, a new, long-acting, inhaled muscarinic antagonist: in vitro plasma inactivation and pharmacological activity of its main metabolites. Eur J Pharm Sci 2010, 39:283-290.