Effects of mometasone furoate/formoterol fumarate fixed-dose combination formulation on chronic obstructive pulmonary disease (COPD): results from a 52-week Phase III trial in subjects with moderate-to-very severe COPD

Dennis E Doherty, Donald P Tashkin, Edward Kerwin, Barbara A Knorr, Tulin Shekar, Sibabrata Banerjee, Heribert Staudinger, Dennis E Doherty, Donald P Tashkin, Edward Kerwin, Barbara A Knorr, Tulin Shekar, Sibabrata Banerjee, Heribert Staudinger

Abstract

Rationale: The purpose of this study was to investigate the clinical efficacy and safety of a fixed-dose combination of mometasone furoate/formoterol fumarate (MF/F) administered via a metered-dose inhaler in subjects with moderate-to-very severe chronic obstructive pulmonary disease (COPD).

Methods: This multicenter, double-blind, placebo-controlled trial had a 26-week treatment period and a 26-week safety extension. Subjects (n = 1196), at least 40 years old, were current or ex-smokers randomized to twice-daily inhaled MF/F 400/10 μg, MF/F 200/10 μg, MF 400 μg, F 10 μg, or placebo. The trial's co-primary endpoints were mean changes from baseline, as area under the curve (AUC), in forced expiratory volume (FEV(1)) over 0-12 hours (AUC(0-12 h) FEV(1)) with MF/F versus MF, and in morning (AM) pre-dose (trough) FEV(1) with MF/F versus F after 13 weeks of treatment. Key secondary endpoints were the effects of MF/F on respiratory health status using the Saint George's Respiratory Questionnaire (SGRQ), symptom-free nights, partly stable COPD at 26 weeks, and time to first COPD exacerbation.

Results: The largest improvements in AUC(0-12 h) FEV(1) were observed with MF/F 400/10 μg and MF/F 200/10 μg. Serial spirometry results demonstrated that bronchodilator effects with MF/F occurred rapidly (within 5 minutes), persisted for 12 hours after dosing, and were sustained over the 26-week treatment period. Similar findings were observed for AM pre-dose FEV(1), for which effects were further investigated, excluding subjects whose AM FEV(1) data were incorrectly collected after 2 days from the last dose of study treatment. Improvements in SGRQ scores surpassed the minimum clinically important difference of more than four units with both MF/F treatments. At 26 weeks, no notable between-treatment differences in the occurrence and nature of adverse events (AEs) were reported. No unexpected AEs were observed. Overall, 90 subjects reported AEs considered to be treatment-related, the most common of which were lenticular opacities, dysphonia, and oral candidiasis.

Discussion: In conclusion, MF/F treatments improved lung function and respiratory health status, reduced exacerbations, and were well tolerated in subjects with moderate-to-very severe COPD.

Trial registration: ClinicalTrials.gov NCT00383721.

Keywords: COPD; FEV1; bronchodilator; exacerbation; inhaled corticosteroid; spirometry.

Figures

Figure 1
Figure 1
Subject disposition. Notes: Total doses were delivered after two inhalations BID of the following actuated doses: MF/F 200/5 μg, MF/F 100/5 μg, MF 200 μg, F 5 μg, or placebo. Abbreviations: AE, adverse event; BID, twice daily; F, formoterol; MF, mometasone furoate; MF/F, mometasone furoate/formoterol fixed-dose combination formulation.
Figure 2
Figure 2
FEV1 AUC0–12 h at week 13 endpoint (LOCF). Abbreviations: AUC0–12 h, area under the curve from 0 to 12 hours post-dose; BID, twice daily; FEV1, forced expiratory volume in 1 second; LOCF, last observation carried forward; F, formoterol; MF, mometasone furoate; MF/F, mometasone furoate/formoterol fixed-dose combination formulation.
Figure 3
Figure 3
Serial FEV1 post-dose at day 1 (A) and week 26 (B). Notes: Significantly greater increases in FEV1 occurred with both MF/F treatments compared with MF at all time points on day 1 (P < 0.001), as well as week 26 (P ≤ 0.035). Compared with F 10 μg, MF/F 400/10 μg had significantly greater increases in FEV1 at all time points on week 26 (P ≤ 0.016), whereas MF/F 200/10 μg had significantly greater increases versus F only at the 4 and 8 hour post-dose time points (P ≤ 0.022). Abbreviations: BID, twice daily; FEV1, forced expiratory volume in 1 second; F, formoterol; MF, mometasone furoate; MF/F, mometasone furoate/formoterol fixed-dose combination formulation.
Figure 4
Figure 4
AM pre-dose (trough) FEV1 at week 13 endpoint. Abbreviations: AM, morning; BID, twice daily; FEV1, forced expiratory volume in 1 second; F, formoterol; MF, mometasone furoate; MF/F, mometasone furoate/formoterol fixed-dose combination formulation.
Figure 5
Figure 5
SGRQ total score change from baseline at week 26 endpoint. Notes: Compared with placebo, significantly greater improvements in SGRQ total scores occurred with MF/F 400/10 μg (P = 0.020) and MF 400 μg (P = 0.023), as well as with MF/F 200/10 μg. The difference between MF/F 200/10 μg and F 10 μg was also significant (P = 0.020) at the week 26 endpoint. Abbreviations: BID, twice daily; SGRQ, St George’s Respiratory Questionnaire; FEV1, forced expiratory volume in 1 second; F, formoterol; MF, mometasone furoate; MF/F, mometasone furoate/formoterol fixed-dose combination formulation.
Figure 6
Figure 6
Time to first moderate or severe exacerbation over the 26-week treatment period. Notes: *P < 0.001 versus placebo; †P = 0.027 versus placebo; ‡P = 0.003 versus placebo. Abbreviations: F, formoterol; MF, mometasone furoate; MF/F, mometasone furoate/formoterol fixed-dose combination formulation.

References

    1. Buist S. COPD: a common disease that is preventable and treatable. Prim Care Respir J. 2006;15:7–9.
    1. American College of Physicians. Four physician organizations issue new clinical recommendations for diagnosing and treating COPD. [Accessed August 4, 2011]. Available at: .
    1. Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004;23:932–946.
    1. Global Initiative for Chronic Obstructive Lung Disease (GOLD) Global strategy for the diagnosis, management and prevention of COPD. [Accessed July 21, 2011]. Available at:
    1. Donohue JF. Therapeutic responses in asthma and COPD. Bronchodilators. Chest. 2004;126:125S–137S. discussion 159S–161S.
    1. Tashkin DP, Celli B, Decramer M, et al. Bronchodilator responsiveness in patients with COPD. Eur Respir J. 2008;31:742–750.
    1. Qaseem A, Wilt TJ, Weinberger SE, et al. Diagnosis and management of stable chronic obstructive pulmonary disease: a clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med. 2011;155:179–191.
    1. Mahler DA, Wire P, Horstman D, et al. Effectiveness of fluticasone propionate and salmeterol combination delivered via the Diskus device in the treatment of chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2002;166:1084–1091.
    1. Hanania NA, Darken P, Horstman D, et al. The efficacy and safety of fluticasone propionate (250 microg)/salmeterol (50 microg) combined in the Diskus inhaler for the treatment of COPD. Chest. 2003;124:834–843.
    1. Szafranski W, Cukier A, Ramirez A, et al. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur Respir J. 2003;21:74–81.
    1. Rennard SI, Tashkin DP, McElhattan J, et al. 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.
    1. Vestbo J, Pauwels R, Anderson JA, Jones P, Calverley P. Early onset of effect of salmeterol and fluticasone propionate in chronic obstructive pulmonary disease. Thorax. 2005;60:301–304.
    1. Bourbeau J, Christodoulopoulos P, Maltais F, et al. Effect of salmeterol/fluticasone propionate on airway inflammation in COPD: a randomised controlled trial. Thorax. 2007;62:938–943.
    1. Tashkin DP, Rennard SI, Martin P, et al. Efficacy and safety of budesonide and formoterol in one pressurized metered-dose inhaler in patients with moderate to very severe chronic obstructive pulmonary disease: results of a 6-month randomized clinical trial. Drugs. 2008;68:1975–2000.
    1. Cote C, Pearle JL, Sharafkhaneh A, Spangenthal S. Faster onset of action of formoterol versus salmeterol in patients with chronic obstructive pulmonary disease: a multicenter, randomized study. Pulm Pharmacol Ther. 2009;22:44–49.
    1. Hubner M, Hochhaus G, Derendorf H. Comparative pharmacology, bioavailability, pharmacokinetics, and pharmacodynamics of inhaled glucocorticosteroids. Immunol Allergy Clin North Am. 2005;25:469–488.
    1. Smith C, Kreutner W. In vitro glucocorticoid receptor binding and transcriptional activation by topically active glucocorticoids. Arzneim-Forsch. 1998;48:956–960.
    1. Affrime MB, Cuss F, Padhi D, et al. Bioavailability and metabolism of mometasone furoate following administration by metered-dose and dry-powder inhalers in healthy human volunteers. J Clin Pharmacol. 2000;40:1227–1236.
    1. Anderson GP. Long acting inhaled beta-adrenoceptor agonists the comparative pharmacology of formoterol and salmeterol. Agents Actions Suppl. 1993;43:253–269.
    1. Calverley PM, Rennard S, Nelson HS, et al. One-year treatment with mometasone furoate in chronic obstructive pulmonary disease. Respir Res. 2008;9:73.
    1. Cazzola M, Centanni S, Regorda C, et al. Onset of action of single doses of formoterol administered via Turbuhaler in patients with stable COPD. Pulm Pharmacol Ther. 2001;14:41–45.
    1. Aalbers R, Ayres J, Backer V, et al. Formoterol in patients with chronic obstructive pulmonary disease: a randomized, controlled, 3-month trial. Eur Respir J. 2002;19:936–943.
    1. Meltzer EO, Kuna P, Nolte H, Nayak AS, Laforce C on behalf of the P04073 Study Investigators. Mometasone furoate/formoterol reduces asthma deteriorations and improves lung function. Eur Respir J. 2011. Epub ahead of print at ERJ Express.
    1. Nathan RA, Nolte H, Pearlman DS. Twenty-six-week efficacy and safety study of mometasone furoate/formoterol 200/10 microg combination treatment in patients with persistent asthma previously receiving medium-dose inhaled corticosteroids. Allergy Asthma Proc. 2010;31:269–279.
    1. Weinstein SF, Corren J, Murphy K, Nolte H, White M. Twelve-week efficacy and safety study of mometasone furoate/formoterol 200/10 microg and 400/10 microg combination treatments in patients with persistent asthma previously receiving high-dose inhaled corticosteroids. Allergy Asthma Proc. 2010;31:280–289.
    1. Maspero JF, Nolte H, Cherrez-Ojeda I. Long-term safety of mometasone furoate/formoterol combination for treatment of patients with persistent asthma. J Asthma. 2010;47:1106–1115.
    1. Jones PW, Quirk FH, Baveystock CM, Littlejohns P. A self-complete measure of health status for chronic airflow limitation. The St George’s Respiratory Questionnaire. Am Rev Respir Dis. 1992;145:1321–1327.
    1. Jones PW. St George’s Respiratory Questionnaire: MCID. COPD. 2005;2:75–79.
    1. Jones PW. Interpreting thresholds for a clinically significant change in health status in asthma and COPD. Eur Respir J. 2002;19:398–404.
    1. Celli BR, Tashkin DP, Rennard SI, McElhattan J, Martin UJ. Bronchodilator responsiveness and onset of effect with budesonide/formoterol pMDI in COPD. Respir Med. 2011;105:1176–1188.
    1. Dolovich MB, Ahrens RC, Hess DR, et al. Device selection and outcomes of aerosol therapy: evidence-based guidelines: American College of Chest Physicians/American College of Asthma, Allergy, and Immunology. Chest. 2005;127:335–371.
    1. Barrons R, Pegram A, Borries A. Inhaler device selection: special considerations in elderly patients with chronic obstructive pulmonary disease. Am J Health Syst Pharm. 2011;68:1221–1232.
    1. Melani AS. Inhalatory therapy training: a priority challenge for the physician. Acta Biomed. 2007;78:233–245.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe