Efficacy and safety of inhaled formoterol 4.5 and 9 μg twice daily in Japanese and European COPD patients: phase III study results

Miron A Bogdan, Hisamichi Aizawa, Yoshinosuke Fukuchi, Michiaki Mishima, Masaharu Nishimura, Masakazu Ichinose, Miron A Bogdan, Hisamichi Aizawa, Yoshinosuke Fukuchi, Michiaki Mishima, Masaharu Nishimura, Masakazu Ichinose

Abstract

Background: This study evaluated the efficacy and safety of the long-acting β₂-agonist formoterol in patients with moderate-to-severe COPD.

Methods: This double-blind, placebo-controlled, parallel-group, multinational phase III study randomized patients ≥ 40 years of age with moderate-to-severe COPD to inhaled formoterol 4.5 or 9 μg twice daily (bid) via Turbuhaler or placebo for 12 weeks. Salbutamol 100 μg/actuation via pMDI was permitted as reliever medication. The primary outcome variable was change (ratio) from baseline to treatment period in FEV1 60-min post-dose.

Results: 613 patients received treatment (formoterol 4.5 μg n = 206; 9 μg n = 199; placebo n = 208); 539 (87.9%) male; 324 (52.9%) Japanese and 289 (47.1%) European. End of study increases in FEV1 60-min post-dose were significantly greater (p < 0.001 for both) with formoterol 4.5 and 9 μg bid (113% of baseline for both) than with placebo, as were all secondary outcome measures. The proportion of patients with an improvement in St George's Respiratory Questionnaire score of ≥ 4 was 50.2% for formoterol 4.5 μg (p = 0.0682 vs. placebo), 59.2% (p = 0.0004) for 9 μg, and 41.3% for placebo. Reduction in reliever medication use was significantly greater with formoterol vs. placebo (9 μg: -0.548, p < 0.001; 4.5 μg: -0.274, p = 0.027), with 9 μg being significantly superior to 4.5 μg (-0.274, p = 0.029). Formoterol was well tolerated with the incidence and type of adverse events not being different for the three groups.

Conclusions: Formoterol 4.5 μg and 9 μg bid was effective and well tolerated in patients with COPD; there was no difference between formoterol doses for the primary endpoint; however, an added value of formoterol 9 μg over 4.5 μg bid was observed for some secondary endpoints.

Trial registration: NCT00628862 (ClinicalTrials.gov); D5122C00001 (AstraZeneca Study code).

Figures

Figure 1
Figure 1
Patients flow through the study.
Figure 2
Figure 2
FEV1 at 60-min post-dose in patients with COPD receiving formoterol or placebo; *p < 0.001 vs. placebo. FEV1 at 60-min post-dose (ratio to baseline) in patients with COPD receiving formoterol 4.5 or 9 μg twice daily or placebo. *p < 0.001 vs. placebo.
Figure 3
Figure 3
Percentage of patients with a SGRQ improvement rate > 4; *p < 0.001 vs. placebo.
Figure 4
Figure 4
Mean change from baseline in use of salbutamol over time.

References

    1. Chamberlain AM, Schabath MB, Folson AR. Associations of chronic obstructive pulmonary disease with all-cause mortality in Blacks and Whites: the atherosclerosis risk in communities (ARIC) study. Ethn Dis. 2009;19:308–314.
    1. Ekberg-Aronsson M, Pehrsson K, Nilsson JA, Nilsson PM, Löfdahl CG. Mortality in GOLD stages of COPD and its dependence on symptoms of chronic bronchitis. Respir Res. 2005;6:98. doi: 10.1186/1465-9921-6-98.
    1. Lung Health Study Research Group. Effect of inhaled triamcinolone on the decline in pulmonary function in chronic obstructive pulmonary disease. N Engl J Med. 2000;343:1902–1999.
    1. Pauwels RA, Löfdahl CG, Laitinen LA, Schouten JP, Postma DS, Pride NB, Ohlsson SV. Long-term treatment with inhaled budesonide in persons with mild chronic obstructive pulmonary disease who continue smoking. N Engl J Med. 1999;340:1948–1953. doi: 10.1056/NEJM199906243402503.
    1. Calverley PM, Boonsawat W, Cseke Z, Zhong N, Peterson S, Olsson H. Maintenance therapy with budesonide and formoterol in chronic obstructive pulmonary disease. Eur Respir J. 2003;22:912–919. doi: 10.1183/09031936.03.00027003. Erratum in: Eur Respir J 2004, 24:1075.
    1. Calverley P, Pauwels R, Vestbo J, Jones P, Pride N, Gulsvik A, Anderson J, Maden C. TRial of Inhaled STeroids ANd long-acting beta2 agonists study group. Combined salmeterol and fluticasone in the treatment of chronic obstructive pulmonary disease: a randomised controlled trial. Lancet. 2003;361:449–456. doi: 10.1016/S0140-6736(03)12459-2. Erratum in: Lancet 2003, 361:1660.
    1. Szafranski W, Cukier A, Ramirez A, Menga G, Sansores R, Nahabedian S, Peterson S, Olsson H. Efficacy and safety of budesonide/formoterol in the management of chronic obstructive pulmonary disease. Eur Respir J. 2003;21:74–81. doi: 10.1183/09031936.03.00031402. Erratum in: Eur Respir J 2003, 21:912.
    1. Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J. TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356:775–789. doi: 10.1056/NEJMoa063070.
    1. Global Initiative for Chronic Obstructive Lung Disease (GOLD) Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (updated 2010)
    1. Salpeter SR, Buckley NS, Salpeter EE. Meta-analysis: anticholinergics, but not β-agonists, reduce severe exacerbations and respiratory mortality. Int J COPD. 2006;21:1011–1019.
    1. Rodrigo GJ, Nannini LJ, Rodriguez-Roisin R. Safety of long-acting β-agonists in stable COPD: a systematic review. Chest. 2008;133:1079–1087. doi: 10.1378/chest.07-1167.
    1. Campbell M, Eliraz A, Johansson G, Tornling G, Nihlén U, Bengtsson T, Rabe K. Formoterol for maintenance and as-needed treatment of chronic obstructive pulmonary disease. Respir Med. 2005;99:1511–1520. doi: 10.1016/j.rmed.2005.08.016.
    1. Jones PW. Interpreting thresholds for a clinically significant change in health status in asthma and COPD. Eur Respir J. 2002;19:398–404. doi: 10.1183/09031936.02.00063702.
    1. Nelson HS, Weiss ST, Bleecker ET, Yancey SW, Dorinsky PM. The Salmeterol Multicenter Asthma Research Trial. Chest. 2006;129:15–26. doi: 10.1378/chest.129.1.15.
    1. 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. doi: 10.1053/rmed.2001.1161.
    1. Bouros D, Kottakis J, Le Gros V, Overend T, Della Cioppa G, Siafakas N. Effects of formoterol and salmeterol on resting inspiratory capacity in COPD patients with poor FEV(1) reversibility. Curr Med Res Opin. 2004;20:581–586. doi: 10.1185/030079904125003368.
    1. Dahl R, Greefhorst LA, Nowak D, Nonikov V, Byrne AM, Thomson MH, Till D, Della Cioppa G. Formoterol in Chronic Obstructive Pulmonary Disease I Study Group. Inhaled formoterol dry powder versus ipratropium bromide in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2001;164:778–784.
    1. Di Marco F, Verga M, Santus P, Morelli N, Cazzola M, Centanni S. Effect of formoterol, tiotropium, and their combination in patients with acute exacerbation on chronic obstructive pulmonary disease: a pilot study. Respir Med. 2006;100:1925–1932. doi: 10.1016/j.rmed.2006.03.007.
    1. Maesen BL, Westermann CJ, Duurkens VA, van den Bosch JM. Effects of formoterol in apparently poorly reversible chronic obstructive pulmonary disease. Eur Respir J. 1999;13:1103–1108. doi: 10.1034/j.1399-3003.1999.13e27.x.
    1. Rossi A, Kristufek P, Levine BE, Thomson MH, Till D, Kottakis J, Della Cioppa G. Formoterol in Chronic Obstructive Pulmonary Disease (FICOPD) II Study Group. Comparison of the efficacy, tolerability, and safety of formoterol dry powder and oral, slow-release theophylline in the treatment of COPD. Chest. 2002;121:1058–1069. doi: 10.1378/chest.121.4.1058.
    1. Kottakis J, Cioppa GD, Creemers J, Greefhorst L, Lecler V, Pistelli R, Overend T, Till D, Rapatz G, Le Gros V, Bouros D, Siafakas N. Faster onset of bronchodilation with formoterol than with salmeterol in patients with stable, moderate to severe COPD: results of a randomized, double-blind clinical study. Can Respir J. 2002;9:107–115.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться