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

Pulmonary Pharmacology and Therapeutics

Volumn 29, Issue 1, 2014, Pages 49-57

  Kelleher, Dennis ^a   Tombs, Lee ^b   Preece, Andrew ^c   Brealey, Noushin ^c   Mehta, Rashmi ^a  

^a GLAXOSMITHKLINE   (United States)

^b Synergy Statistics and Programming   (United Kingdom)

^c GLAXOSMITHKLINE   (United Kingdom)

Author keywords

Chronic obstructive pulmonary disease; GSK573719; QT interval; Umeclidinium; Vilanterol

Indexed keywords

ALANINE AMINOTRANSFERASE; ELLIPTA; MOXIFLOXACIN; PLACEBO; UMECLIDINIUM; UMECLIDINIUM PLUS VILANTEROL; UNCLASSIFIED DRUG; BENZYL ALCOHOL DERIVATIVE; BETA 2 ADRENERGIC RECEPTOR STIMULATING AGENT; CHLOROBENZENE; DRUG COMBINATION; MUSCARINIC RECEPTOR BLOCKING AGENT; QUINOLONE DERIVATIVE; QUINUCLIDINE DERIVATIVE; VILANTEROL;

ADULT; AREA UNDER THE CURVE; ARTICLE; CONTROLLED STUDY; COUGHING; CROSSOVER PROCEDURE; DIZZINESS; DRUG DOSE SEQUENCE; DRUG EFFECT; DRUG HALF LIFE; DRUG INDUCED HEADACHE; DRUG SAFETY; DRUG WITHDRAWAL; DRY POWDER INHALER; DRY THROAT; DYSGEUSIA; ECG ABNORMALITY; FATIGUE; FEMALE; GASTROENTERITIS; HEART PALPITATION; HUMAN; HUMAN EXPERIMENT; MALE; MAXIMUM PLASMA CONCENTRATION; MONOTHERAPY; NAUSEA; NORMAL HUMAN; NOSE OBSTRUCTION; OROPHARYNX PAIN; PLASMA CONCENTRATION-TIME CURVE; PRIORITY JOURNAL; QT INTERVAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); RHINITIS; RISK ASSESSMENT; THORAX PAIN; TIME TO MAXIMUM PLASMA CONCENTRATION; XEROSTOMIA; CHEMICALLY INDUCED; COMPARATIVE STUDY; DOSE RESPONSE; DOUBLE BLIND PROCEDURE; DRUG COMBINATION; DRUG EFFECTS; HEART RATE; INHALATIONAL DRUG ADMINISTRATION; LONG QT SYNDROME; MIDDLE AGED; RANDOMIZED CONTROLLED TRIAL; SINGLE BLIND PROCEDURE; YOUNG ADULT;

ADMINISTRATION, INHALATION; ADRENERGIC BETA-2 RECEPTOR AGONISTS; ADULT; BENZYL ALCOHOLS; CHLOROBENZENES; CROSS-OVER STUDIES; DOSE-RESPONSE RELATIONSHIP, DRUG; DOUBLE-BLIND METHOD; DRUG COMBINATIONS; DRY POWDER INHALERS; FEMALE; FLUOROQUINOLONES; HEART RATE; HUMANS; LONG QT SYNDROME; MALE; MIDDLE AGED; MUSCARINIC ANTAGONISTS; QUINUCLIDINES; SINGLE-BLIND METHOD; YOUNG ADULT;

EID: 84906935621     PISSN: 10945539     EISSN: 15229629     Source Type: Journal    
DOI: 10.1016/j.pupt.2014.07.002     Document Type: Article

References (35)

1. De Ponti F., Poluzzi E., Montanaro N. QT-interval prolongation by non-cardiac drugs: lessons to be learned from recent experience. Eur J Clin Pharmacol 2000, 56:1-18.
2. Raschi E., Poluzzi E., Zuliani C., Muller A., Goossens H., De Ponti F. Exposure to antibacterial agents with QT liability in 14 European countries: trends over an 8-year period. Br J Clin Pharmacol 2009, 7:88-98.
3. Shah R.R. Can pharmacogenetics help rescue drugs withdrawn from the market?. Pharmacogenomics 2006, 7:889-908.
4. European Medicines Agency ICH Topic E14. The clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs 2005, Available from:, [accessed 10.04.14]. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002879.pdf.
5. US Department of Health and Human Services Food and Drug Administration Guidance for industry. E14 clinical evaluation of QT/QTc interval prolongation and proarrhythmic potential for non-antiarrhythmic drugs 2005, Available from:, [accessed 07.04.14]. http://www.fda.gov/downloads/RegulatoryInformation/Guidances/ucm129357.pdf.
6. GOLD Global strategy for the diagnosis, management, and prevention of COPD - updated 2014, Available from:, [accessed 11.04.14]. http://www.goldcopd.org.
7. Gruffydd-Jones K., Loveridge C. The 2010 NICE COPD Guidelines: how dothey compare with the GOLD guidelines?. Prim Care Respir J 2011, 20:199-204.
8. Fromer L., Cooper C.B. Areview of the GOLD guidelines for the diagnosis and treatment of patients with COPD. Int J Clin Pract 2008, 62:1219-1236.
9. Church A., Beerahee M., Brooks J., Mehta R., Shah P. Dose response of umeclidinium administered once or twice daily in patients with COPD. BMC Pulm Med 2014, 14:2. 10.1186/1471-2466-14-2.
10. Donohue J.F., Anzueto A., Brooks J., Mehta R., Kalberg C., Crater G. Arandomized, double-blind, dose-ranging study of the novel LAMA GSK573719 in patients with COPD. Respir Med 2012, 106:970-979.
11. Decramer M., Maltais F., Feldman G., Brooks J., Harris S., Mehta R., et al. Bronchodilation of umeclidinium, a new long-acting muscarinic antagonist, in COPD patients. Respir Physiol Neurobiol 2013, 185:393-399.
12. Trivedi R., Richard N., Mehta R., Church A. Umeclidinium in patients with COPD: a randomised, placebo-controlled study. Eur Respir J 2014, 43:72-81.
13. Tal-Singer R., Cahn T., Mehta R., Preece A., Crater G., Kelleher D., et al. Initial assessment of single and repeat doses of inhaled umeclidinium in patients with chronic obstructive pulmonary disease: two randomised studies. Eur J Pharmacol 2013, 701:40-48.
14. Feldman G., Walker R.R., Brooks J., Mehta R., Crater G. 28-day safety and tolerability of umeclidinium in combination with vilanterol in COPD: a randomized placebo-controlled trial. Pulm Pharmacol Ther 2012, 25:465-471.
15. Kelleher D.L., Mehta R.S., Jean-Francois B.M., Preece A.F., Blowers J., Crater G.D., et al. Safety, tolerability, pharmacodynamics and pharmacokinetics of umeclidinium and vilanterol alone and in combination: a randomized crossover trial. PLoS One 2012, 7:e50716.
16. BREO ELLIPTA prescribing information 2013, GlaxoSmithKline, Research Triangle Park, NC, Available from:, [accessed 11.04.14]. http://us.gsk.com/products/assets/us_breo_ellipta.pdf.
17. Kempsford R., Allen A., Kelly K., Saggu P., Crim C. Arepeat-dose thorough QT study of inhaled fluticasone furoate (FF)/vilanterol (VI) combination in healthy subjects. Br J Clin Pharmacol 2014, 77:466-479.
18. Salmon M., Luttmann M.A., Foley J.J., Buckley P.T., Schmidt D.B., Burman M., et al. Pharmacological characterization of GSK573719 (umeclidinium): a novel, long-acting, inhaled antagonist of the muscarinic cholinergic receptors for treatment of pulmonary diseases. JPharmacol Exp Ther 2013, 345:260-270.
19. Goyal N., Beerahee M., Kalberg C., Church A., Kilbride S., Mehta R. Population pharmacokinetics of inhaled umeclidinium and vilanterol in patients with COPD. Clin Pharmacokinet 2014, 53(7):637-648.
20. Malik M., Hnatkova K., Schmidt A., Smetana P. Electrocardiographic QTc changes due to moxifloxacin infusion. JClin Pharmacol 2009, 49:674-683.
21. Kelleher D., Tombs L., Crater G., Preece A., Brealey N., Mehta R. Aplacebo- and moxifloxacin-controlled thorough QT study of umeclidinium monotherapy and umeclidinium/vilanterol combination in healthy subjects. Am J Respir Crit Care Med 2013, 187:A1487. [abstract].
22. WMA declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects. Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and amended (latest) by the 59th WMA General Assembly, Seoul, Korea, October 2008. Available from: [accessed 15.04.14]. http://www.wma.net/en/30publications/10policies/b3/index.html.
23. International Conference on Harmonisation Tripartite Guideline: Guidance for Good Clinical Practice E6 (R1) 1996, Available from:, [accessed: 15.04.14]. http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6_R1/Step4/E6_R1__Guideline.pdf.
24. 2-agonist olodaterol on the QT and QTc interval in healthy subjects. Am J Respir Crit Care Med 2013, 187:A2603. [abstract].
25. Decramer M., Anzueto A., Kerwin E., Kaelin T., Richard N., Crater G., et al. Efficacy and safety of umeclidinium plus vilanterol versus tiotropium, vilanterol, or umeclidinium monotherapies over 24 weeks in patients with chronic obstructive pulmonary disease: results from two multicentre, blinded, randomized controlled trials. Lancet Respir Med 2014, 2(6):472-486.
26. Hanania N.A., Feldman G., Zachgo W., Shim J.J., Crim C., Sanford L., et al. The efficacy and safety of the novel long-acting β2 agonist vilanterol in patientswith COPD: a randomized placebo-controlled trial. Chest 2012, 142:119-127.
27. Lötvall J., Bateman E.D., Bleecker E.R., Busse W.W., Woodcock A., Follows R., et al. 24-h duration of the novel LABA vilanterol trifenatate in asthma patients treated with inhaled corticosteroids. Eur Respir J 2012, 40:570-579.
28. Khindri S., Sabo R., Harris S., Woessner R., Jennings S., Drollmann A.F. Cardiac safety of indacaterol in healthy subjects: a randomized, multidose, placebo- and positive-controlled, parallel-group thorough QT study. BMC Pulm Med 2011, 11:31.
29. Maconochie J.G., Forster J.K. Dose-response study with high-dose inhaled salmeterol in healthy subjects. Br J Clin Pharmacol 1992, 33:342-345.
30. Serevent diskus prescribing information. GlaxoSmithKline, Research Triangle Park, NC, USA. Available from: [accessed 11.04.14]. http://us.gsk.com/products/assets/us_serevent_diskus.pdf.
31. Foradil aerolizer prescribing information. Merck & Co., Inc. Whitehouse Station, NJ, USA. Available from: [accessed 11.04.14]. http://www.merck.com/product/usa/pi_circulars/f/foradil/foradil_pi.pdf.
32. Spiriva Handihaler prescribing information. Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA. Available from: [accessed 11.04.14]. http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt%26folderPath=/Prescribing+Information/PIs/Spiriva/Spiriva.pdf.
33. Tudorza Pressair. Forest Pharmaceuticals, Inc., St. Louis, MO, USA. Available from: [accessed 11.04.14]. http://www.frx.com/pi/tudorza_pi.pdf.
34. Worth H., Chung K.F., Felser JM, Hu H., Rueegg P. Cardio- and cerebrovascular safety of indacaterol vs formoterol, salmeterol, tiotropium and placebo in COPD. Resp Med 2011, 105:571-579.
35. Cahn A., Tal-Singer R., Pouliquen I.J., Mehta R., Preece A., Hardes K., et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of single and repeat inhaled doses of umeclidinium in healthy subjects: two randomized studies. Clin Drug Invest 2013, 33:477-488.