Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF): a phase 2, pharmacokinetic, randomised, placebo-controlled trial
Language English Country Great Britain, England Media print-electronic
Document type Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't
PubMed
27914656
DOI
10.1016/s0140-6736(16)32049-9
PII: S0140-6736(16)32049-9
Knihovny.cz E-resources
- MeSH
- Administration, Oral * MeSH
- Ventricular Function, Left drug effects MeSH
- Humans MeSH
- Urea administration & dosage analogs & derivatives pharmacokinetics MeSH
- Natriuretic Peptide, Brain MeSH
- Peptide Fragments MeSH
- Ventricular Remodeling drug effects MeSH
- Cardiac Myosins metabolism pharmacokinetics MeSH
- Heart Failure drug therapy physiopathology MeSH
- Systole MeSH
- Stroke Volume drug effects MeSH
- Dose-Response Relationship, Drug MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Clinical Trial, Phase II MeSH
- Multicenter Study MeSH
- Research Support, Non-U.S. Gov't MeSH
- Randomized Controlled Trial MeSH
- Names of Substances
- Urea MeSH
- Natriuretic Peptide, Brain MeSH
- omecamtiv mecarbil MeSH Browser
- Peptide Fragments MeSH
- pro-brain natriuretic peptide (1-76) MeSH Browser
- Cardiac Myosins MeSH
BACKGROUND: 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. 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 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. INTERPRETATION: Omecamtiv mecarbil dosing guided by pharmacokinetics achieved plasma concentrations associated with improved cardiac function and decreased ventricular diameter. FUNDING: Amgen.
British Heart Foundation Cardiovascular Research Centre University of Glasgow Glasgow UK
Cardiology Department St John of God Hospital Budapest Hungary
Cytokinetics South San Francisco CA USA
Department of Cardiology AZ St Lucas Ghent Belgium
Department of Medicine University of Alberta Edmonton AB Canada
Division of Cardiology Duke University School of Medicine Durham NC USA
Division of Cardiology University of Brescia Brescia Italy
Division of Cardiology University of North Carolina at Chapel Hill Chapel Hill NC USA
University Hospital Brno and Medical Faculty of Masaryk University Brno Czech Republic
University of Groningen University Medical Centre Groningen Groningen Netherlands
References provided by Crossref.org
ClinicalTrials.gov
NCT01786512
