title: Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF): a phase 2, pharmacokinetic, randomised, placebo-controlled trial.
abstract: Impaired contractility is a feature of heart failure with reduced ejection fraction. We assessed the pharmacokinetics and effects on cardiac function and structure of the cardiac myosin activator, omecamtiv mecarbil.
  
  
  
  In this randomised, double-blind study, done at 87 sites in 13 countries, we recruited patients with stable, symptomatic chronic heart failure and left ventricular ejection fraction 40% or lower. Patients were randomly assigned equally, via an interactive web response system, to receive 25 mg oral omecamtiv mecarbil twice daily (fixed-dose group), 25 mg twice daily titrated to 50 mg twice daily guided by pharmacokinetics (pharmacokinetic-titration group), or placebo for 20 weeks. We assessed the maximum concentration of omecamtiv mecarbil in plasma (primary endpoint) and changes in cardiac function and ventricular diameters. This trial is registered with ClinicalTrials.gov, number NCT01786512.
  
  
  
  From March 17, 2014, to March 5, 2015, we enrolled 150 patients in the fixed-dose omecamtiv mecarbil group and 149 in the pharmacokinetic-titration and placebo groups. Mean maximum concentration of omecamtiv mecarbil at 12 weeks was 200 (SD 71) ng/mL in the fixed-dose group and 318 (129) ng/mL in the pharmacokinetic-titration group. For the pharmacokinetic-titration group versus placebo group at 20 weeks, least square mean differences were as follows: systolic ejection time 25 ms (95% CI 18-32, p<0·0001), stroke volume 3·6 mL (0·5-6·7, p=0·0217), left ventricular end-systolic diameter -1·8 mm (-2·9 to -0·6, p=0·0027), left ventricular end-diastolic diameter -1·3 mm, (-2·3 to 0·3, p=0·0128), heart rate -3·0 beats per min (-5·1 to -0·8, p=0·0070), and N-terminal pro B-type natriuretic peptide concentration in plasma -970 pg/mL (-1672 to -268, p=0·0069). The frequency of adverse clinical events did not differ between groups.
  
  
  
  Omecamtiv mecarbil dosing guided by pharmacokinetics achieved plasma concentrations associated with improved cardiac function and decreased ventricular diameter.
  
  
  
  Amgen.
authors.affiliation: School of Medicine, University of California San Francisco, San Francisco, CA, USA; Section of Cardiology, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA. Electronic address: john.teerlink@ucsf.edu.
authors.forename: John R
authors.initials: JR
authors.lastname: Teerlink
authors.affiliation: Division of Cardiology, Duke University School of Medicine, Durham, NC, USA.
authors.forename: G Michael
authors.initials: GM
authors.lastname: Felker
authors.affiliation: British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
authors.forename: John J V
authors.initials: JJ
authors.lastname: McMurray
authors.affiliation: Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Solomon
authors.affiliation: Division of Cardiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Kirkwood F
authors.initials: KF
authors.lastname: Adams
authors.affiliation: National Heart and Lung Institute, Royal Brompton and Harefield Hospitals, Imperial College, London, UK; Robertson Centre for Biostatistics and Clinical Trials, University of Glasgow, Glasgow, UK.
authors.forename: John G F
authors.initials: JG
authors.lastname: Cleland
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, AB, Canada.
authors.forename: Justin A
authors.initials: JA
authors.lastname: Ezekowitz
authors.affiliation: Department of Cardiology, Queen Giovanna University Hospital and Medical University-Sofia, Sofia, Bulgaria.
authors.forename: Assen
authors.initials: A
authors.lastname: Goudev
authors.affiliation: Heart Transplant Unit, St Vincent's Hospital and Transplantation Research Laboratory, Victor Chang Cardiac Research Institute and University of New South Wales, Sydney, NSW, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Macdonald
authors.affiliation: Division of Cardiology, University of Brescia, Brescia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Metra
authors.affiliation: Kerckhoff-Klinik Forschungsgesellschaft, Frankfurt, Germany; Johann-Wolfgang Goethe University, Main, Germany.
authors.forename: Veselin
authors.initials: V
authors.lastname: Mitrovic
authors.affiliation: Department of Heart Diseases, Medical University and Centre for Heart Diseases, Military Hospital, Wrocław, Poland.
authors.forename: Piotr
authors.initials: P
authors.lastname: Ponikowski
authors.affiliation: Emergency Centre, Vilnius University Hospital Santariskiu Klinikos and Vilnius University, Vilnius, Lithuania.
authors.forename: Pranas
authors.initials: P
authors.lastname: Serpytis
authors.affiliation: University Hospital Brno and Medical Faculty of Masaryk University, Brno, Czech Republic.
authors.forename: Jindrich
authors.initials: J
authors.lastname: Spinar
authors.affiliation: Cardiology Department, St John of God Hospital, Budapest, Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Tomcsányi
authors.affiliation: Department of Cardiology, AZ-St-Lucas, Ghent, Belgium.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Vandekerckhove
authors.affiliation: University of Groningen, University Medical Centre Groningen, Groningen, Netherlands.
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Voors
authors.affiliation: Amgen, Thousand Oaks, CA, USA.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Monsalvo
authors.affiliation: Amgen, Thousand Oaks, CA, USA.
authors.forename: James
authors.initials: J
authors.lastname: Johnston
authors.affiliation: Cytokinetics, South San Francisco, CA, USA.
authors.forename: Fady I
authors.initials: FI
authors.lastname: Malik
authors.affiliation: Amgen, Thousand Oaks, CA, USA.
authors.forename: Narimon
authors.initials: N
authors.lastname: Honarpour
mesh_terms: D000284:Administration, Oral; D024722:Cardiac Myosins / Q000378:metabolism / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D020097:Natriuretic Peptide, Brain; D010446:Peptide Fragments; D013318:Stroke Volume / Q000187:drug effects; D013599:Systole; D014508:Urea / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects
chemical_list: D010446:Peptide Fragments; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; C547293:omecamtiv mecarbil; D014508:Urea; D024722:Cardiac Myosins