A randomized, placebo- and moxifloxacin-controlled thorough QT study of umeclidinium monotherapy and umeclidinium/vilanterol combination in healthy subjects

• Published in: Pulmonary pharmacology & therapeutics Vol. 29; no. 1; pp. 49 - 57
• Main Authors: Kelleher, Dennis, Tombs, Lee, Preece, Andrew, Brealey, Noushin, Mehta, Rashmi
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2014
• Subjects: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists - administration & dosage; Adrenergic beta-2 Receptor Agonists - adverse effects; Adult; Benzyl Alcohols - administration & dosage; Benzyl Alcohols - adverse effects; Chlorobenzenes - administration & dosage; Chlorobenzenes - adverse effects; Chronic obstructive pulmonary disease; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Dry Powder Inhalers; Female; Fluoroquinolones - adverse effects; GSK573719; Heart Rate - drug effects; Humans; Long QT Syndrome - chemically induced; Male; Medical Education; Middle Aged; Muscarinic Antagonists - administration & dosage; Muscarinic Antagonists - adverse effects; Pulmonary/Respiratory; QT interval; Quinuclidines - administration & dosage; Quinuclidines - adverse effects; Single-Blind Method; Umeclidinium; Vilanterol; Young Adult; Vilanterol; QT interval; GSK573719; Umeclidinium; Chronic obstructive pulmonary disease
• ISSN: 1094-5539; 1522-9629; 1522-9629
• DOI: 10.1016/j.pupt.2014.07.002

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. 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. 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. 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%).. 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..