Cytokinetics, Incorporated announced the publication of a manuscript relating to the design of GALACTIC-HFIII3 event driven cardiovascular outcomes clinical trial of omecamtiv mecarbil in the Journal of American College of Cardiology: Heart Failure (JACC: HF). Omecamtiv mecarbil, a selective cardiac myosin activator, is being developed for the potential treatment of heart failure with reduced ejection fraction under a collaboration between Amgen and Cytokinetics, with funding and strategic support from Servier.
GALACTIC-HF : Designed to Enroll High Risk Patients from Inpatient and Outpatient Settings : GALACTIC-HF is designed to evaluate whether treatment with omecamtiv mecarbil, dosed twice-daily in accordance with a pharmacokinetic-guided dose selection regimen, when added to standard of care, reduces the risk of heart failure events (heart failure hospitalization or other urgent, unscheduled treatment for heart failure) and cardiovascular (CV) death in patients with chronic heart failure and reduced ejection fraction. GALACTIC-HF opened to enrollment in late 2016 and was designed to enroll approximately 8,000 heart failure patients with reduced ejection fraction at over 1,000 sites in 35 countries who are either currently hospitalized for a primary reason of heart failure or have had a hospitalization or admission to an emergency room for a primary reason of heart failure within one year prior to screening. Patients were also required to have a left ventricular ejection fraction (LVEF) less than 35% and elevated natriuretic peptides.
GALACTIC-HF completed enrollment in 2019, having enrolled 8,256 patients in 35 countries. Approximately 25% of patients in GALACTIC-HF were hospitalized at the time of randomization.
GALACTIC-HF: Designed to Provide 90% Statistical Power to Assess Risk of Cardiovascular Death :The primary efficacy endpoint in GALACTIC-HF is the composite of time to CV death or first heart failure event, whichever occurs first. However, the trial is statistically powered based on a hypothesis relating to the first secondary endpoint, time to CV death. An accrual of 1,590 CV deaths provides 90% power to detect a hazard ratio of 0.8 for CV death. A sample size of 8,000 patients was chosen assuming the following: an annualized rate of CV death of 10% in the first year and 7% thereafter, a 24-month enrollment period, total study duration set to 48 months, a 3-month treatment lag with a treatment effect hazard ratio of 0.8 thereafter, 10% annual rate of study drug discontinuation, and 10% of subjects lost to endpoint determination either through non-CV death or study discontinuation over the course of the trial. The overall type I error is 0.05 for 2-sided testing. Assuming the rates for experiencing either a heart failure event or CV death are double those for CV death alone, and the same other assumptions as for CV death alone, the primary composite endpoint is expected to have greater than 99% statistical power.
GALACTIC-HF: Second Interim Analysis Expected to Occur in Q1 2020 : According to protocol, the first and second interim analyses in GALACTIC-HF are to be conducted by the Data Monitoring Committee (DMC) following the accrual of approximately one-third and two-thirds respectively of the targeted 1,590 CV deaths. In March 2019, the DMC completed the first planned interim analysis which could have provided for the early stopping of the trial for futility. The DMC reviewed data from the trial and recommended that the trial continue without changes to its conduct. The second interim analysis is expected to occur in Q1 2020 and the DMC will assess for both futility and superiority. The statistical analysis plan provides guidance for the DMC to recommend stopping the trial for superiority if the primary composite endpoint and the secondary endpoint of time to CV death are both highly statistically significant. The DMC may also stop the trial for futility if there is a low likelihood of the trial demonstrating a statistically significant benefit on the primary endpoint.
About Omecamtiv Mecarbil and the Phase III Clinical Trials Program :Omecamtiv mecarbil is a novel investigational selective cardiac myosin activat or that binds to the catalytic domain of myosin. Preclinical research has shown that cardiac myosin activators increase cardiac contractility without affecting intracellular myocyte calcium concentrations or myocardial oxygen consumption. Cardiac myosin is the cytoskeletal motor protein in the cardiac muscle cell that is directly responsible for converting chemical energy into the mechanical force resulting in cardiac contraction. Omecamtiv mecarbil is being developed for the potential treatment of heart failure with reduced ejection fraction (HFrEF) under a collaboration between Amgen and Cytokinetics, with funding and strategic support from Servier. Omecamtiv mecarbil is the subject of a comprehensive Phase III clinical trials program comprised of GALACTIC-HF (Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure), a large, Phase III global event driven cardiovascular outcomes study, and METEORIC-HF (Multicenter Exercise Tolerance Evaluation of Omecamtiv Mecarbil Related to Increased Contractility in Heart Failure), a Phase III clinical trial designed to evaluate the effect of treatment with omecamtiv mecarbil compared to placebo on exercise capacity.
See- "Omecamtiv Mecarbil in Chronic Heart Failure With Reduced Ejection Fraction Rationale and Design of GALACTIC-HF"-
John R. Teerlink, Rafael Diaz, G. Michael Felker, John J.V. McMurray, Marco Metra, Scott D. Solomon, Jason C. Legg, Gustavo Büchele, Claire Varin, Christopher E. Kurtz, Fady I. Malik, Narimon Honarpour
JACC: Heart Failure February 05, 2020, 1205; DOI: 10.1016/j.jchf.2019.12.001.