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

Khindri S, Sabo R, Harris S, Woessner R, Jennings S, Drollmann AF - BMC Pulm Med (2011)

Bottom Line: 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.Indacaterol, 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Novartis Horsham Research Centre, Horsham, West Sussex RH12 5AB, UK. sanjeev.khindri@novartis.com

ABSTRACT

Background: Indacaterol 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.

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/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).

Results: In 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.

Conclusion: Indacaterol, 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.

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Related in: MedlinePlus

Difference from placebo in mean change from baseline in QTcF on Day 14. Data presented are mean and 90% confidence interval. Dotted horizontal line corresponds to the 10 ms threshold.
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Figure 1: Difference from placebo in mean change from baseline in QTcF on Day 14. Data presented are mean and 90% confidence interval. Dotted horizontal line corresponds to the 10 ms threshold.

Mentions: The mean differences in time-matched changes from (time-averaged) baseline in QTcF interval between all indacaterol doses and placebo on Day 14 were well below 5 ms (the threshold of regulatory concern) at each time point (Table 2, Figure 1), with no discernible dose-relationship. The maximal time-matched mean differences from placebo in QTcF change from baseline for indacaterol 150 μg (2.66 ms) and 300 μg (2.98 ms) doses were observed at 2 h post-dose (Table 2). The corresponding maximal difference between indacaterol 600 μg and placebo (3.34 ms) was observed at 6 h post-dose (Table 2). For all three indacaterol doses, the corresponding upper bounds of the two-sided 90% CIs (equivalent to the upper bound of a one-sided 95% CI) excluded 10 ms indicating a negative thorough QT study.


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

Khindri S, Sabo R, Harris S, Woessner R, Jennings S, Drollmann AF - BMC Pulm Med (2011)

Difference from placebo in mean change from baseline in QTcF on Day 14. Data presented are mean and 90% confidence interval. Dotted horizontal line corresponds to the 10 ms threshold.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3116479&req=5

Figure 1: Difference from placebo in mean change from baseline in QTcF on Day 14. Data presented are mean and 90% confidence interval. Dotted horizontal line corresponds to the 10 ms threshold.
Mentions: The mean differences in time-matched changes from (time-averaged) baseline in QTcF interval between all indacaterol doses and placebo on Day 14 were well below 5 ms (the threshold of regulatory concern) at each time point (Table 2, Figure 1), with no discernible dose-relationship. The maximal time-matched mean differences from placebo in QTcF change from baseline for indacaterol 150 μg (2.66 ms) and 300 μg (2.98 ms) doses were observed at 2 h post-dose (Table 2). The corresponding maximal difference between indacaterol 600 μg and placebo (3.34 ms) was observed at 6 h post-dose (Table 2). For all three indacaterol doses, the corresponding upper bounds of the two-sided 90% CIs (equivalent to the upper bound of a one-sided 95% CI) excluded 10 ms indicating a negative thorough QT study.

Bottom Line: 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.Indacaterol, 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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Novartis Horsham Research Centre, Horsham, West Sussex RH12 5AB, UK. sanjeev.khindri@novartis.com

ABSTRACT

Background: Indacaterol 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.

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/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).

Results: In 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.

Conclusion: Indacaterol, 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.

Show MeSH
Related in: MedlinePlus