Rationale and Design of a Randomized Controlled Trial of Donor-Derived Cell-Free DNA to Detect Rejection in Cardiac Transplantation (DETECT)

Purpose Endomyocardial biopsy (EMB) for rejection surveillance in cardiac transplantation is invasive, costly, associated with complications, variable in interpretation and thus an imperfect gold standard. Donor-derived cell-free DNA (dd-cfDNA) is an emerging biomarker for detection and surveillance of cardiac allograft rejection. Elevated circulating levels of dd-cfDNA are associated with acute cellular and antibody-mediated rejection in observational studies, but a clinical strategy trial to establish its usefulness in decreasing or eliminating EMB has not been conducted. We describe the rationale and design of the randomized clinical trial, Donor-Derived Cell-free DNA to DETect REjection in Cardiac Transplantation (DETECT) to test the hypothesis that dd-cfDNA monitoring is non-inferior to standard of care (SOC) surveillance EMB during year 1 post-transplant. Methods DETECT is a prospective, multicenter, open-label, randomized controlled trial in 600 adult heart transplant recipients at 40 transplant centers, randomized 1:1 30 days post-transplant to surveillance with dd-cfDNA (Prospera, Natera, San Carlos, CA) (Intervention) versus EMB surveillance (SOC) and followed for 1 year. Rejection surveillance in both arms will be performed per the institution's SOC EMB surveillance schedule. Results The primary endpoint is the composite of treated rejection +/- graft dysfunction, any graft dysfunction, listing for or undergoing re-transplantation or death. Secondary endpoints include number of heart biopsies performed, development of de novo donor specific antibodies and cost of care. The study has 80% power to demonstrate non-inferiority if the primary endpoint rate in the experimental arm is no greater than 0.27 (non-inferiority margin of 0.15, assuming a control rate of 0.22). Sample size re-estimation will occur once 80% of subjects are enrolled or 50% reach 1 year follow-up, whichever occurs first in order to maintain 80% power. If the non-inferiority hypothesis is met, analysis for superiority of surveillance with dd-cfDNA will be performed. Conclusion The DETECT trial will establish the efficacy and safety of dd-cfDNA as a primary clinical monitoring strategy for cardiac allograft rejection in an effort to decrease or eliminate invasive surveillance biopsies in adult heart transplant recipients. Endomyocardial biopsy (EMB) for rejection surveillance in cardiac transplantation is invasive, costly, associated with complications, variable in interpretation and thus an imperfect gold standard. Donor-derived cell-free DNA (dd-cfDNA) is an emerging biomarker for detection and surveillance of cardiac allograft rejection. Elevated circulating levels of dd-cfDNA are associated with acute cellular and antibody-mediated rejection in observational studies, but a clinical strategy trial to establish its usefulness in decreasing or eliminating EMB has not been conducted. We describe the rationale and design of the randomized clinical trial, Donor-Derived Cell-free DNA to DETect REjection in Cardiac Transplantation (DETECT) to test the hypothesis that dd-cfDNA monitoring is non-inferior to standard of care (SOC) surveillance EMB during year 1 post-transplant. DETECT is a prospective, multicenter, open-label, randomized controlled trial in 600 adult heart transplant recipients at 40 transplant centers, randomized 1:1 30 days post-transplant to surveillance with dd-cfDNA (Prospera, Natera, San Carlos, CA) (Intervention) versus EMB surveillance (SOC) and followed for 1 year. Rejection surveillance in both arms will be performed per the institution's SOC EMB surveillance schedule. The primary endpoint is the composite of treated rejection +/- graft dysfunction, any graft dysfunction, listing for or undergoing re-transplantation or death. Secondary endpoints include number of heart biopsies performed, development of de novo donor specific antibodies and cost of care. The study has 80% power to demonstrate non-inferiority if the primary endpoint rate in the experimental arm is no greater than 0.27 (non-inferiority margin of 0.15, assuming a control rate of 0.22). Sample size re-estimation will occur once 80% of subjects are enrolled or 50% reach 1 year follow-up, whichever occurs first in order to maintain 80% power. If the non-inferiority hypothesis is met, analysis for superiority of surveillance with dd-cfDNA will be performed. The DETECT trial will establish the efficacy and safety of dd-cfDNA as a primary clinical monitoring strategy for cardiac allograft rejection in an effort to decrease or eliminate invasive surveillance biopsies in adult heart transplant recipients.