Melissa A Daubert1, Eric Yow2, Gary Dunn2, Sotir Marchev2, Huiman Barnhart2, Pamela S Douglas2, Christopher O'Connor2, Sidney Goldstein2, James E Udelson2, Hani N Sabbah2. 1. From the Duke University Medical Center, Duke Clinical Research Institute, Durham, NC (M.A.D., E.Y., G.D., H.B., P.S.D.); Medical University of Pleven, Bulgaria (S.M.); Inova Heart and Vascular Institute, Falls Church, VA (C.O.); Henry Ford Hospital, Detroit, MI (S.G., H.N.S.); and Tufts Medical Center, Boston, MA (J.E.U.). melissa.daubert@duke.edu. 2. From the Duke University Medical Center, Duke Clinical Research Institute, Durham, NC (M.A.D., E.Y., G.D., H.B., P.S.D.); Medical University of Pleven, Bulgaria (S.M.); Inova Heart and Vascular Institute, Falls Church, VA (C.O.); Henry Ford Hospital, Detroit, MI (S.G., H.N.S.); and Tufts Medical Center, Boston, MA (J.E.U.).
Abstract
BACKGROUND: Mitochondrial dysfunction and energy depletion in the failing heart are innovative therapeutic targets in heart failure management. Elamipretide is a novel tetrapeptide that increases mitochondrial energy; however, its safety, tolerability, and therapeutic effect on cardiac structure and function have not been studied in heart failure with reduced ejection fraction. METHODS AND RESULTS: In this double-blind, placebo-controlled, ascending-dose trial, patients with heart failure with reduced ejection fraction (ejection fraction, ≤35%) were randomized to either a single 4-hour infusion of elamipretide (cohort 1 [n=8], 0.005; cohort 2 [n=8], 0.05; and cohort 3 [n=8], 0.25 mg·kg-1·h-1) or placebo control (n=12). Safety and efficacy were assessed by clinical, laboratory, and echocardiographic assessments performed at pre-, mid- and end-infusion and 6-, 8-, 12- and 24-hours postinfusion start. Peak plasma concentrations of elamipretide occurred at end-infusion and were undetectable by 24 hours postinfusion. There were no serious adverse events. Blood pressure and heart rate remained stable in all cohorts. Compared with placebo, a significant decrease in left ventricular end-diastolic volume (-18 mL; P=0.009) and end-systolic volume (-14 mL; P=0.005) occurred at end infusion in the highest dose cohort. CONCLUSIONS: This is the first study to evaluate elamipretide in heart failure with reduced ejection fraction and demonstrates that a single infusion of elamipretide is safe and well tolerated. High-dose elamipretide resulted in favorable changes in left ventricular volumes that correlated with peak plasma concentrations, supporting a temporal association and dose-effect relationship. Further study of elamipretide is needed to determine long-term safety and efficacy. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02388464.
RCT Entities:
BACKGROUND:Mitochondrial dysfunction and energy depletion in the failing heart are innovative therapeutic targets in heart failure management. Elamipretide is a novel tetrapeptide that increases mitochondrial energy; however, its safety, tolerability, and therapeutic effect on cardiac structure and function have not been studied in heart failure with reduced ejection fraction. METHODS AND RESULTS: In this double-blind, placebo-controlled, ascending-dose trial, patients with heart failure with reduced ejection fraction (ejection fraction, ≤35%) were randomized to either a single 4-hour infusion of elamipretide (cohort 1 [n=8], 0.005; cohort 2 [n=8], 0.05; and cohort 3 [n=8], 0.25 mg·kg-1·h-1) or placebo control (n=12). Safety and efficacy were assessed by clinical, laboratory, and echocardiographic assessments performed at pre-, mid- and end-infusion and 6-, 8-, 12- and 24-hours postinfusion start. Peak plasma concentrations of elamipretide occurred at end-infusion and were undetectable by 24 hours postinfusion. There were no serious adverse events. Blood pressure and heart rate remained stable in all cohorts. Compared with placebo, a significant decrease in left ventricular end-diastolic volume (-18 mL; P=0.009) and end-systolic volume (-14 mL; P=0.005) occurred at end infusion in the highest dose cohort. CONCLUSIONS: This is the first study to evaluate elamipretide in heart failure with reduced ejection fraction and demonstrates that a single infusion of elamipretide is safe and well tolerated. High-dose elamipretide resulted in favorable changes in left ventricular volumes that correlated with peak plasma concentrations, supporting a temporal association and dose-effect relationship. Further study of elamipretide is needed to determine long-term safety and efficacy. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02388464.
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