eprintid: 123023 rev_number: 37 eprint_status: archive userid: 15745 dir: disk0/00/12/30/23 datestamp: 2016-08-19 08:09:39 lastmod: 2021-10-06 09:55:45 status_changed: 2016-12-14 12:50:17 type: article metadata_visibility: show creators_name: Teerlink, John R. creators_name: Felker, G. Michael creators_name: McMurray, John J.V. creators_name: Solomon, Scott D. creators_name: Adams, Jr., Kirkwood F. creators_name: Cleland, John G.F. creators_name: Ezekowitz, Justin A. creators_name: Goudev, Assen creators_name: Macdonald, Peter creators_name: Metra, Marco creators_name: Mitrovic, Veselin creators_name: Ponikowski, Piotr creators_name: Serpytis, Pranas creators_name: Spinar, Jindrich creators_name: Tomcsányi, János creators_name: Vandekerckhove, Hans J. creators_name: Voors, Adriaan A. creators_name: Monsalvo, Maria Laura creators_name: Johnston, James creators_name: Malik, Fady I. creators_name: Honarpour, Narimon creators_orcid: 0000-0002-6317-3975 creators_orcid: 0000-0002-1471-7016 title: Chronic oral study of myosin activation to increase contractility in heart failure (COSMIC-HF): a phase 2, pharmacokinetic, randomised, placebo-controlled trial ispublished: pub divisions: 25200000 divisions: 25606000 full_text_status: public abstract: 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. date: 2016-12-10 date_type: published publication: Lancet volume: 388 number: 10062 publisher: Elsevier pagerange: 2895-2903 id_number: 10.1016/S0140-6736(16)32049-9 refereed: TRUE issn: 0140-6736 copyright_holders: Copyright © 2016 Elsevier prior: First published in Lancet 388(10062):2895-2903 repro: Reproduced in accordance with the copyright policy of the publisher uniqueid: glaseprints:2016-123023 issn_online: 1474-547X hoa_compliant: 511 hoa_emb_len: 6 hoa_ref_pan: AB hoa_date_acc: 2016-08-18 hoa_date_pub: 2016-12-01 hoa_date_foa: 2017-06-07 hoa_version_fcd: AM hoa_exclude: FALSE hoa_gold: FALSE oa_research_materials_ack: No rioxx2_apc_input: not required citation: Teerlink, J. R. et al. (2016) Chronic oral study of myosin activation to increase contractility in heart failure (COSMIC-HF): a phase 2, pharmacokinetic, randomised, placebo-controlled trial. Lancet , 388(10062), pp. 2895-2903. (doi: 10.1016/S0140-6736(16)32049-9 ) document_url: https://eprints.gla.ac.uk/123023/7/123023.pdf