Efficacy and safety of nebulized formoterol as add-on therapy in COPD patients receiving maintenance tiotropium bromide: Results from a 6-week, randomized, placebo-controlled, clinical trial.

Current guidelines for the treatment of chronic obstructive pulmonary disease (COPD) recommend the use of long-acting bronchodilators in the maintenance management of COPD. Combining bronchodilators that work through different mechanisms is recommended in patients with continuous symptoms. We conducted this study to confirm and further investigate the efficacy and safety of nebulized formoterol as an add-on therapy to maintenance tiotropium in patients with COPD. This randomized, double-blind, placebo-controlled, parallel-group study (NCT00507234) was conducted at 24 US sites from March to October 2007 in 155 patients aged > or =40 years with post-bronchodilator forced expiratory volume in 1 second (FEV(1)) > or =25% to <65% predicted normal. COPD patients receiving open-label tiotropium bromide 18 microg once daily during a 1- to 2-week run-in period were randomized to receive either formoterol fumarate inhalation solution 20 microg or placebo by nebulization twice daily for 6 weeks while continuing treatment with tiotropium. Outcomes included serial spirometry, inspiratory capacity (IC), baseline dyspnoea index/transition dyspnoea index (BDI/TDI), daily symptom scores, salbutamol (albuterol) use and health status measured by the St George's Respiratory Questionnaire (SGRQ). The primary efficacy endpoint was standardized absolute FEV(1) area under the curve over 3 hours (AUC(0-3)) at week 6. Treatment groups (formoterol plus tiotropium, n = 78; placebo plus tiotropium, n = 77) were comparable at baseline. At 6 weeks, FEV(1) AUC(0-3) was significantly greater in the formoterol group compared with the placebo group (1.57 vs 1.38 L [p < 0.0001]). Similarly, formoterol plus tiotropium improved other lung function measures, including FEV(1), forced vital capacity and post-dose IC at day 1, and maintained efficacy through week 6. Formoterol plus tiotropium decreased rescue albuterol use throughout the study (p < 0.05). Mean TDI, SGRQ and most symptom scores did not differ between the two treatment groups. Overall, 37% of formoterol plus tiotropium recipients experienced adverse events versus 51% of those receiving placebo plus tiotropium. The addition of nebulized formoterol to tiotropium in maintenance treatment of COPD provided clinically meaningful, statistically significant and sustained improvements in pulmonary function without additional adverse effects.