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

Abstract

BackgroundIndacaterol is a novel once-daily ultra long-acting β2-agonist for the treatment of chronic obstructive pulmonary disease. It is known that β2-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.MethodsIn 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/m2) were randomized (4:4:2:4:1) to 14-day treatment with once-daily indacaterol (150 μg, 300 μg, or 600 μg), 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).ResultsIn total, 404 subjects were randomized to receive indacaterol (150 [n = 108], 300 [n = 108], 600 μg [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 μg, 300 μg and 600 μg, 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.ConclusionIndacaterol, at doses up to 600 μg once daily (2-4 times the therapeutic dose) does not have any clinically relevant effect on the QT interval.Trial RegistrationClinicalTrials.gov: NCT01263808

Single- and multiple-dose pharmacokinetics of inhaled indacaterol in healthy Chinese volunteers

“…There were no serious or unexpected AEs. Cough was the most commonly observed treatment-related adverse event, consistent with previous clinical studies (Kinoshita et al 2012 ; Dahl et al 2010 ; Kornmann et al 2011 ) as well as observations in healthy subjects from other Asian ethnic populations (Khindri et al 2011 ).…”

“…While the pharmacokinetics of indacaterol have been previously extensively studied in Caucasian and Japanese patients (Hosoe et al 2011 ; EU SMPC) and healthy volunteers (Khindri et al 2011 ), this is the first study to evaluate the pharmacokinetics of indacaterol following administration of single and repeated once-daily doses of 150 and 300 µg in healthy Chinese volunteers. Following single (Day 1) and repeated (Day 14) inhalation, indacaterol was rapidly absorbed into the systemic circulation with the median time to maximum serum concentrations ( T max ) occurring 15 min post inhalation for both doses.…”

“…The finding that systemic concentrations of indacaterol rapidly decline to very low levels may be advantageous for the drug’s safety profile, since there is little risk of sustained high systemic concentrations and/or significant drug accumulation during chronic dosing. The dissociation between the short residence time in the systemic circulation and the long duration of action of indacaterol (Hosoe et al 2011 ; Khindri et al 2011 ; Moen 2010 ) might be related to the fact that local drug load in the lung is required for maintenance of bronchodilation effect in the lung whilst systemic drug concentrations have little or no relevant contribution to the bronchodilator effect.…”

Orally administered moxifloxacin prolongs QTc in healthy Chinese volunteers: a randomized, single-blind, crossover study

“…However, some studies involving Caucasian subjects showed larger QTcF effects [15][16][17] . Therefore, further studies are required to determine ethnicity-specific effects, especially prospectively designed direct comparisons of moxifloxacininduced QT prolongation in Asians versus Caucasians.…”

Role of indacaterol and the newer very long-acting β2-agonists in patients with stable COPD: a review

“…β2-agonists, like other adrenergic compounds, can prolong the QT interval. In one randomized, double-blind, parallel-group, placebo-controlled, and positive-controlled study in healthy subjects, 404 individuals were randomized to receive indacaterol (at doses of 150, 300 or 600 μg), placebo, or placebo/moxifloxacin 22. The primary endpoint was the change in QTcF (QT interval corrected for heart rate using Fridericia’s formula) from baseline on day 14.…”