Nebulized arformoterol in patients with COPD: A 12-week, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled trial

Objective: The aim of this study was to assess the efficacy and tolerability of nebulized arformoterol tartrate (a selective, long-acting beta(2)-adrenergic agonist that is the [R,R] isomer of formoterol) and salmeterol xinafoate versus placebo in patients with chronic obstructive pulmonary disease (COPD). Methods: This 12-week, multicenter, randomized, double-blind, double-dummy, placebo- and active-controlled trial was conducted at 60 centers across the United States. Male and female patients aged >= 35 years with physician-diagnosed COPD received arformoterol (15 mu g BID, 25 mu g BID, or 50 mu g QD via nebulizer), salmeterol (42 mu g BID via metered dose inhaler), or placebo. Pulmonary function was assessed by spirometry; dyspnea, by the Transitional Dyspnea Index (TDI); and health status, by the St. George's Respiratory Questionnaire (SGRQ). Adverse events (AEs) were assessed by site personnel at all clinic visits (screening, first dose at week 0, and at weeks 3, 6, 9, 12, and follow-up). COPD exacerbations were defined as worsening respiratory status requiring a change in medication or an unscheduled provider visit. Results: A total of 717 patients received study medication. The demographic composition of all treatment arms was similar. The mean age was 62.9 years, 58% were men, and mean baseline forced expiratory volume in 1 second (FEV1) was 1.2 L (41% predicted). Mean improvement in trough FEV1 over 12 weeks was significantly greater with all 3 arformoterol doses (15 mu g BID, +16.9%; 25 mu g BID, +18.9%; 50 mu g QD, +14.9%) and for salmeterol (+17.4%) relative to placebo (+6.0%; P < 0.001). There were significantly greater improvements in the mean percentage change in FEV1 AUC(0-12 h) from the predose value over 12 weeks (15 mu g BID, 12.7%; 25 mu g BID, 13.9%; 50 mu g QD, 18.9%; salmeterol, 9.8%) versus placebo (2.7%; P <= 0.001); all doses of arformoterol were statistically different from salmeterol for this end point (P <= 0.024). At week 12, TDI focal scores were significantly greater with all arformoterol doses compared with placebo (mean [95% CI]: 15 mu g BID, 0.97 [0.25-1.69]; 25 mu g BID, 1.08 [0.3-1.86]; 50 mu g QD, 1.04 [0.32-1.77]), suggesting treatment-associated improvement in dyspnea; however, the difference between salmeterol and placebo was not statistically significant (0.36 [-0.40 to 1.12]). Improvements in health status, as measured using SGRQ total scores, were -2.6 to -3.6 U in the arformoterol groups, -4.4 U for salmeterol, and -1.2 U for placebo; 95% CI of differences versus placebo suggested signiflcant improvement for the arformoterol 25 mu g BID and salmeterol groups. There was a similar frequency of AEs and COPD exacerbations across all groups, including placebo. Conclusions: In this trial, patients with moderate to severe COPD administered nebulized arformoterol over 12 weeks were observed to have significant and sustained improvements in airway function and dyspnea compared with placebo. The results also suggest that all doses of arformoterol, including the lowest dose (15 mu g BID), were effective. Overall, nebulized arformoterol was well tolerated.