Efficacy and safety of fixed-dose combinations of aclidinium bromide/formoterol fumarate: the 24-week, randomized, placebo-controlled AUGMENT COPD study

Respiratory Research

Cynthia F Caracta³  Anne R Leselbaum²  Victor Mergel³  Edward M Kerwin⁴  Stephen I Rennard¹  Anthony D D’Urzo⁵ 

[1] University of Nebraska Medical Center, Omaha, NE, USA;R&D Centre, Almirall, Barcelona, Spain;Forest Research Institute, Jersey City, NJ, USA;Clinical Research Institute, Medford, OR, USA;University of Toronto, Toronto, Canada

关键词: Health status;    Dyspnea;    Lung function;    COPD;    Formoterol;    Aclidinium;   

Others  :  1137253
DOI  :  10.1186/s12931-014-0123-0

 received in 2014-06-03, accepted in 2014-09-30,  发布年份 2014

【 摘 要 】

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.

Trial registration

Clinicaltrials.gov NCT01437397 webcite.

*Registered trademarks of Almirall S.A., Barcelona, Spain; for use within the US as Pressair^® and Genuair^® within all other licensed territories.

【 授权许可】

   
2014 D'Urzo et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1][http://www.goldcopd.org/] webcite Global Initiative for Chronic Obstructive Lung Disease (GOLD): Global strategy for the diagnosis, management and prevention of COPD (2014 update). []
• [2]Rabe KF, Timmer W, Sagkriotis A, Viel K: Comparison of a combination of tiotropium plus formoterol to salmeterol plus fluticasone in moderate COPD. Chest 2008, 134:255-262.
• [3]van Noord JA, Aumann JL, Janssens E, Smeets JJ, Verhaert J, Disse B, Mueller A, Cornelissen PJ: Comparison of tiotropium once daily, formoterol twice daily and both combined once daily in patients with COPD. Eur Respir J 2005, 26:214-222.
• [4]Wang J, Jin D, Zuo P, Wang T, Xu Y, Xiong W: Comparison of tiotropium plus formoterol to tiotropium alone in stable chronic obstructive pulmonary disease: a meta-analysis. Respirology 2011, 16:350-358.
• [5]Mahler DA, D'Urzo A, Bateman ED, Ozkan SA, White T, Peckitt C, Lassen C, Kramer B: Concurrent use of indacaterol plus tiotropium in patients with COPD provides superior bronchodilation compared with tiotropium alone: a randomised, double-blind comparison. Thorax 2012, 67:781-788.
• [6]van Noord JA, Aumann JL, Janssens E, Verhaert J, Smeets JJ, Mueller A, Cornelissen PJ: Effects of tiotropium with and without formoterol on airflow obstruction and resting hyperinflation in patients with COPD. Chest 2006, 129:509-517.
• [7]D'Urzo A, Kerwin E, Rennard S, He T, Gil EG, Caracta C: One-year extension study of ACCORD COPD I: safety and efficacy of two doses of twice-daily aclidinium bromide in patients with COPD. COPD 2013, 10:500-510.
• [8]Fuhr R, Magnussen H, Sarem K, Llovera AR, Kirsten AM, Falques M, Caracta CF, Garcia Gil E: Efficacy of aclidinium bromide 400 μg twice daily compared with placebo and tiotropium in patients with moderate to severe COPD. Chest 2012, 141:745-752.
• [9]Gelb AF, Tashkin DP, Make BJ, Zhong X, Garcia Gil E, Caracta C: Long-term safety and efficacy of twice-daily aclidinium bromide in patients with COPD. Respir Med 2013, 107:1957-1965.
• [10]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.
• [11]Kerwin EM, D'Urzo AD, Gelb AF, Lakkis H, Garcia Gil E, Caracta CF: Efficacy and safety of a 12-week treatment with twice-daily aclidinium bromide in COPD patients (ACCORD COPD I). COPD 2012, 9:90-101.
• [12][http://www.merck.com/product/usa/pi_circulars/f/foradil/foradil_pi.pdf] webcite Foradil prescribing information. []
• [13]Maltais F, Celli B, Casaburi R, Porszasz J, Jarreta D, Seoane B, Caracta C: Aclidinium bromide improves exercise endurance and lung hyperinflation in patients with moderate to severe COPD. Respir Med 2011, 105:580-587.
• [14]Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P: Standardisation of spirometry. Eur Respir J 2005, 26:319-338.
• [15]Leidy NK, Murray LT: Patient-reported outcome (PRO) measures for clinical trials of COPD: the EXACT and E-RS. COPD 2013, 10:393-398.
• [16]Hareendran A, Palsgrove A, Mocarski M, Schaefer M, Setyawan J, Carson R, Make BJ: The development of a patient-reported outcome measure for assessing nighttime symptoms of chronic obstructive pulmonary disease. Health Qual Life Outcomes 2013, 11:104-112. BioMed Central Full Text
• [17]Mocarski M, Hareendran A, Jen M-H, Zaiser E, Make BJ: Evaluation of the Psychometric Properties of the Nighttime Symptoms of COPD Instrument (NiSCI) [abstract]. Am J Respir Crit Care Med 2014, 189:A5843.
• [18]Mocarski M, Hareendran A, Jen M-H, Zaiser E, Make BJ: Evaluation of the Psychometric Properties of the Early Morning Symptoms of COPD Instrument (EMSCI) [abstract]. Value Health 2014, 17(3):A179.
• [19]Jones PW: St. George's Respiratory Questionnaire: MCID. COPD 2005, 2:75-79.
• [20]Yu AP, Guerin A, Ponce de Leon D, Ramakrishnan K, Wu EQ, Mocarski M, Blum S, Setyawan J: Therapy persistence and adherence in patients with chronic obstructive pulmonary disease: multiple versus single long-acting maintenance inhalers. J Med Econ 2011, 14:486-496.
• [21]Cazzola M, Molimard M: The scientific rationale for combining long-acting beta2-agonists and muscarinic antagonists in COPD. Pulm Pharmacol Ther 2010, 23:257-267.
• [22]Cazzola M, Di Marco F, Santus P, Boveri B, Verga M, Matera MG, Centanni S: The pharmacodynamic effects of single inhaled doses of formoterol, tiotropium and their combination in patients with COPD. Pulm Pharmacol Ther 2004, 17:35-39.
• [23][http:/ / www.gpo.gov/ fdsys/ pkg/ CFR-2011-title21-vol5/ pdf/ CFR-2011-title21-vol5-sec300-50.pdf] webcite FDA: Code of Federal Regulations (CFR Section 300.50): Fixed-combination prescription drugs for humans. []
• [24]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.
• [25]Singh D, Jones PW, Bateman ED, Korn S, Serra C, Molins E, Caracta C, Garcia Gil E: Evaluation of the efficacy and safety of two doses of aclidinium and formoterol in fixed-dose combination in patients with COPD: the ACLIFORM study [abstract]. Chest 2014, 145(3):Suppl 375A.
• [26]Anderson G: Formorterol: pharmacology, molecular basis of agonism and mechanism of long duration of a highly potent and selective beta2-adrenoceptor agonist bronchodilator. Life Sci 1993, 52:2145-2160.
• [27]Richter K, Stenglein S, Mucke M, Sieder C, Schmidtmann S, Harnest U, Weidinger G, Magnussen H: Onset and duration of action of formoterol and tiotropium in patients with moderate to severe COPD. Respiration 2006, 73:414-419.
• [28]Bourbeau J, Bartlett SJ: Patient adherence in COPD. Thorax 2008, 63:831-838.
• [29]Make BJ: Chronic obstructive pulmonary disease: developing comprehensive management. Respir Care 2003, 48:1225-1234.
• [30]Mahler DA, Weinberg DH, Wells CK, Feinstein AR: The measurement of dyspnea. Contents, interobserver agreement, and physiologic correlates of two new clinical indexes. Chest 1984, 85:751-758.
• [31]Celli B, ZuWallack R, Wang S, Kesten S: Improvement in resting inspiratory capacity and hyperinflation with tiotropium in COPD patients with increased static lung volumes. Chest 2003, 124:1743-1748.
• [32]Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, Stockley RA, Sin DD, Rodriguez-Roisin R: Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2013, 187:347-365.
• [33]Jones P, Beeh K, Chapman K, Decramer M, Mahler DA, Wedzicha J: Minimal Clinically Important Differences in Pharmacological Trials. Am J Respir Crit Care Med 2014, 189:250-255.
• [34]Mahler DA, Decramer M, D'Urzo A, Worth H, White T, Alagappan VK, Chen H, Gallagher N, Kulich K, Banerji D: Dual bronchodilation with QVA149 reduces patient-reported dyspnoea in COPD: the BLAZE study. Eur Respir J 2014, 43:1599-1609.
• [35]Calverley PM, Burge PS, Spencer S, Anderson JA, Jones PW: Bronchodilator reversibility testing in chronic obstructive pulmonary disease. Thorax 2003, 58:659-664.
• [36]Price D, Small M, Milligan G, Higgins V, Gil EG, Estruch J: Impact of night-time symptoms in COPD: a real-world study in five European countries. Int J Chron Obstruct Pulmon Dis 2013, 8:595-603.
• [37]Agusti A, Hedner J, Marin JM, Barbe F, Cazzola M, Rennard S: Night-time symptoms: a forgotten dimension of COPD. Eur Respir Rev 2011, 20:183-194.
• [38]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.
• [39]Tashkin DP, Pearle J, Iezzoni D, Varghese ST: Formoterol and tiotropium compared with tiotropium alone for treatment of COPD. COPD 2009, 6:17-25.
• [40]Rennard SI, Tashkin DP, McElhattan J, Goldman M, Ramachandran S, Martin UJ, Silkoff PE: Efficacy and tolerability of budesonide/formoterol in one hydrofluoroalkane pressurized metered-dose inhaler in patients with chronic obstructive pulmonary disease: results from a 1-year randomized controlled clinical trial. Drugs 2009, 69:549-565.
• [41]Anzueto A, Ferguson GT, Feldman G, Chinsky K, Seibert A, Emmett A, Knobil K, O'Dell D, Kalberg C, Crater G: Effect of fluticasone propionate/salmeterol (250/50) on COPD exacerbations and impact on patient outcomes. COPD 2009, 6:320-329.
• [42]Campbell M, Eliraz A, Johansson G, Tornling G, Nihlen U, Bengtsson T, Rabe KF: Formoterol for maintenance and as-needed treatment of chronic obstructive pulmonary disease. Respir Med 2005, 99:1511-1520.
• [43]Kerwin E, Rennard S, Gelb A, Rekeda L, Garcia Gil E, Caracta C: Twice-daily aclidinium bromide in COPD patients: nighttime symptoms and rescue medication use in ACCORD COPD I [abstract]. Am J Respir Crit Care Med 2011, 183(1):A1592.