title: A randomized, placebo- and moxifloxacin-controlled thorough QT study of umeclidinium monotherapy and umeclidinium/vilanterol combination in healthy subjects.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  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%)..
  
  
  CONCLUSIONS
  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..
authors.affiliation: Respiratory Medicines Development Center, GlaxoSmithKline, Research Triangle Park, USA. Electronic address: dennis.l.kelleher@gsk.com.
authors.forename: Dennis
authors.initials: D
authors.lastname: Kelleher
authors.affiliation: Synergy, Statistics and Programming, Slough, Berkshire, UK.
authors.forename: Lee
authors.initials: L
authors.lastname: Tombs
authors.affiliation: Respiratory Medicines Development Centre, GlaxoSmithKline, Stockley Park, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Preece
authors.affiliation: Respiratory Medicines Development Centre, GlaxoSmithKline, Stockley Park, UK.
authors.forename: Noushin
authors.initials: N
authors.lastname: Brealey
authors.affiliation: Respiratory Medicines Development Center, GlaxoSmithKline, Research Triangle Park, USA.
authors.forename: Rashmi
authors.initials: R
authors.lastname: Mehta
mesh_terms: D000280:Administration, Inhalation; D058666:Adrenergic beta-2 Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects*; D000328:Adult; D001592:Benzyl Alcohols / Q000008:administration & dosage / Q000009:adverse effects*; D002722:Chlorobenzenes / Q000008:administration & dosage / Q000009:adverse effects*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004338:Drug Combinations; D058995:Dry Powder Inhalers; D005260:Female; D024841:Fluoroquinolones / Q000009:adverse effects; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000009:adverse effects*; D011812:Quinuclidines / Q000008:administration & dosage / Q000009:adverse effects*; D016037:Single-Blind Method; D055815:Young Adult
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D001592:Benzyl Alcohols; D002722:Chlorobenzenes; D004338:Drug Combinations; D024841:Fluoroquinolones; C573971:GSK573719; D018727:Muscarinic Antagonists; D011812:Quinuclidines; C550468:vilanterol; D000077266:Moxifloxacin
keywords: Chronic obstructive pulmonary disease; GSK573719; QT interval; Umeclidinium; Vilanterol