Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF): a phase 2, pharmacokinetic, randomised, placebo-controlled trial

John R. Teerlink*, G. Michael Felker, John J. V. McMurray, Scott D. Solomon, Kirkwood F. Adams, John G. F. Cleland, Justin A. Ezekowitz, Assen Goudev, Peter Macdonald, Marco Metra, Veselin Mitrovic, Piotr Ponikowski, Pranas Serpytis, Jindrich Spinar, Janos Tomcsanyi, Hans J. Vandekerckhove, Adriaan A. Voors, Maria Laura Monsalvo, James Johnston, Fady I. MalikNarimon Honarpour, COSMIC-HFf Investigators

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Background Impaired contractility is a feature of heart failure with reduced ejection fraction. We assessed the pharmacokinetics and eff ects on cardiac function and structure of the cardiac myosin activator, omecamtiv mecarbil.

Methods 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.

Findings From March 17, 2014, to March 5, 2015, we enrolled 150 patients in the fi xed-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 fi xed-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 diff erences 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 diff er between groups.

Interpretation Omecamtiv mecarbil dosing guided by pharmacokinetics achieved plasma concentrations associated with improved cardiac function and decreased ventricular diameter.

Original languageEnglish
Pages (from-to)2895-2903
Number of pages9
JournalThe Lancet
Volume388
Issue number10062
DOIs
Publication statusPublished - 10-Dec-2016

Keywords

  • CARDIAC RESYNCHRONIZATION THERAPY
  • OMECAMTIV MECARBIL
  • TIME
  • MECHANISMS
  • PREDICTION
  • MORTALITY
  • EXERCISE
  • SAFETY

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