Cardiac safety of indacaterol in healthy subjects: a randomized, multidose, placebo- and positive-controlled, parallel-group thorough QT study

Background: Indacaterol is a novel once-daily ultra long-acting beta(2)-agonist for the treatment of chronic obstructive pulmonary disease. It is known that beta(2)-agonists, like other adrenergic compounds, can prolong the QT-interval. This thorough QT/QTc study (as per ICH E14 guideline) evaluated the effect of indacaterol on the QT interval in healthy subjects. Methods: In this randomized, double-blind, parallel-group, placebo-and positive-controlled (open-label moxifloxacin) study, non-smoking healthy subjects (18-55 years, body mass index:18.5-32.0 kg/m(2)) were randomized (4:4:2:4:1) to 14-day treatment with once-daily indacaterol (150 mu g, 300 mu g, or 600 mu g), placebo, or placebo/moxifloxacin (double-blind 14-day treatment with placebo and a single open-label dose of 400 mg moxifloxacin on Day 14). The primary endpoint was the change from baseline on Day 14 in QTcF (QT interval corrected for heart rate using Fridericia's formula). Results: In total, 404 subjects were randomized to receive indacaterol (150 [n = 108], 300 [n = 108], 600 mu g [n = 54]), placebo (n = 107), or placebo/moxifloxacin (n = 27); 388 subjects completed the study. Maximal time-matched mean (90% confidence intervals) treatment differences from placebo in QTcF change from baseline on Day 14 were 2.66 (0.55, 4.77), 2.98 (1.02, 4.93) and 3.34 (0.86, 5.82) ms for indacaterol 150 mu g, 300 mu g and 600 mu g, respectively. Study sensitivity was confirmed with moxifloxacin demonstrating a significant maximal time-matched QTcF prolongation of 13.90 (10.58, 17.22) ms compared to placebo. All indacaterol doses were well tolerated. Conclusion: Indacaterol, at doses up to 600 mu g once daily (2-4 times the therapeutic dose) does not have any clinically relevant effect on the QT interval.