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

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.