التفاصيل البيبلوغرافية
| العنوان: |
A randomized, placebo- and moxifloxacin-controlled thorough QT study of umeclidinium monotherapy and umeclidinium/vilanterol combination in healthy subjects. |
| المؤلفون: |
Kelleher, Dennis1 dennis.l.kelleher@gsk.com, Tombs, Lee2, Preece, Andrew3, Brealey, Noushin3, Mehta, Rashmi1 |
| المصدر: |
Pulmonary Pharmacology & Therapeutics. Oct2014, Vol. 29 Issue 1, p49-57. 9p. |
| مصطلحات موضوعية: |
*OBSTRUCTIVE lung disease treatment, *PLACEBOS, *MOXIFLOXACIN, *RANDOMIZED controlled trials, *ADVERSE health care events, *ELECTROCARDIOGRAPHY, *THERAPEUTICS |
| مستخلص: |
Introduction: The long-acting muscarinic antagonist umeclidinium (UMEC) and the combination of UMEC with the long-acting beta2 agonist vilanterol (VI) are approved maintenance treatments for chronic obstructive pulmonary disease in the US and EU. Objectives: This study investigated the effect of UMEC and UMEC/VI on the QT interval corrected using Fridericia's correction (QTcF) following a 10-day treatment period. Methods: Randomized, placebo- and moxifloxacin-controlled, 4-period incomplete block crossover study of healthy non-smokers (n = 103). All treatments were double blind, except for moxifloxacin/moxifloxacin placebo controls which were single blinded. Subjects were randomized to a treatment sequence which consisted of 4 of 5 regimens. Each regimen consisted of once-daily doses on Days 1-10 via the ELLIPTA™ dry powder inhaler and a single tablet on Day 10 of the following: placebo + placebo; placebo + moxifloxacin; UMEC 500 µg + placebo; UMEC/VI 125/25 µg (delivered dose: 113/22 µg) + placebo; UMEC/VI 500/100 µg + placebo. QT interval, additional cardiac parameters, pharmacokinetics, pharmacodynamics and safety were assessed. Results: No clinically significant changes from baseline in QTcF occurred with UMEC 500 µg and UMEC/VI 125/25 µg compared with placebo, however, there was a change in QTcF from baseline of 6.4 ms (90% confidence interval [CI]: 4.3, 8.5) at 10 min and 8.2 ms (90%: 6.2, 10.2) at 30 min post dose following UMEC/VI 500/100 µg compared with placebo. On Day 10, categorical analysis demonstrated absolute QTcF values >450-480 ms for UMEC/VI 125/25 µg (1 subject) and moxifloxacin (3 subjects), and a change from baseline QTcF of >30-60 ms for UMEC/VI 125/25 µg, UMEC 500/100 µg and placebo (1 subject each) and moxifloxacin (2 subjects). On Day 10, the mean change from baseline in heart rate was increased with UMEC/VI 125/25 µg and UMEC 500/100 µg compared with placebo with the maximum increase occurring at 10 min post dose (8.4 bpm [90% CI: 7.0, 9.8] for UMEC/VI 125/25 µg; 20.3 bpm [90% CI: 18.9, 21.7] for UMEC/VI 500/100 µg); after this timepoint, heart rate rapidly returned to normal levels. UMEC and VI systemic exposures following UMEC/VI 500/100 µg were >4-fold higher than those following UMEC/VI 125/25 µg. All treatments were generally well tolerated in terms of adverse events, laboratory, vital signs and electrocardiogram data; the proportion of subjects with any adverse event was similar across treatments arms (39-59%). Conclusion: There was no clinically significant effect on QTcF observed following 10-days' treatment with inhaled UMEC/VI 125/25 µg or UMEC 500 µg compared with placebo. The supratherapeutic dose of UMEC/VI 500/100 µg prolonged QTcF by 6.4 ms (90% CI: 4.3, 8.5) at 10 min and 8.2 ms (90% CI: 6.2, 10.2) at 30 min compared with placebo, following which QTcF interval difference from placebo declined rapidly. [ABSTRACT FROM AUTHOR] |
| قاعدة البيانات: |
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