Evaluation of the Added Clinical Value of Donor-derived Cell-free DNA for the Monitoring of Cardiac Allograft Rejection.

Completed

• Conditions: Heart Transplantation; Rejection Heart Transplant

• Registration Number: NCT06740578
• Lead Sponsor: Paris Translational Research Center for Organ Transplantation

Brief Summary

The goal of this observational study is to assess the clinical added value of donor-derived cell-free DNA (dd-cfDNA) to monitor cardiac allograft rejection. The main question it aims to answer is whether dd-cfDNA is independently associated with rejection and if it allows a significant improvement in individual risk stratification of rejection on top of a robust predictive model based on standard clinical and biological predictive variables.

Detailed Description

Despite major advances in immunosuppression, allograft rejection remains an important complication after heart transplantation. International guidelines recommend performing routine endomyocardial biopsies (EMB) to detect allograft rejection with the goal of identifying rejection at a subclinical state. However, this invasive strategy suffers from major limitations, making an improvement in individual risk stratification of rejection highly needed. Major advances in the field of non-invasive biomarkers of cardiac rejection have been made. Strong associations between donor-derived cell-free DNA (dd-cfDNA) and cardiac rejection have been reported, including in properly designed prospective observational studies with a longitudinal follow-up. However, the independent nature of this association and the improvement in individual risk stratification with dd-cfDNA on top of routine parameters have not yet been demonstrated. The aim of our study is to challenge, in a large observational prospective cohort, the clinical added value of dd-cfDNA with a previously published robust rejection predictive model including the following variables: time post-transplant, pre-transplant sensitizing event, circulating anti-HLA donor-specific antibodies (DSA) with mean fluorescence intensity ≥ 3,000, acute graft dysfunction and prior history of rejection.

Study Timeline

• Study Start: 2021-10-01
• Primary Completion: 2023-10-31
• Study Completion: 2023-10-31
• Status Verified: 2024-12
• Study First Submitted: 2024-12-13
• Study First Submitted QC: 2024-12-13
• Study First Posted: 2024-12-18
• Last Update Submitted: 2025-01-02
• Last Update Posted: 2025-01-03

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 320

Inclusion Criteria

• heart transplant recipients,
• heart transplantation performed for more than 30 days,
• clinical indication of an endomyocardial biopsy, either protocol or for cause,
• informed consent

Exclusion Criteria

• multiorgan transplantation
• refusal to participate

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Number of patients with biopsy proven rejection and / or acute allograft dysfunction	12 months	* acute cellular rejection ≥ 2R according to the international society for heart and lung transplantation working formulation; * antibody-mediated rejection ≥ pAMR1 according to the international society for heart and lung transplantation working formulation; * acute allograft dysfunction defined as an unknown left ventricular ejection fraction - LVEF \< 0.50 and/or acute drop in LVEF ≥ 0.15 compared to baseline evaluation.

Secondary Outcome Measures

Name	Time	Method
Independent association between donor-derived cell-free DNA and allograft ejection	12 months	- test the independent association between dd-cfDNA and rejection after adjustment for important clinical and biological predictive variables or rejection that were included in a previously published predictive model (time post-transplant, pre-transplant sensitizing event, circulating anti-HLA donor-specific antibodies (DSA) with mean fluorescence intensity ≥ 3000, acute graft dysfunction and prior history of rejection).; The association between %dd-cfDNA and rejection was tested using a three-level mixed-effect logistic regression with a random intercept (random effects: "subject-level" nested in the "center-level", integration method = adaptive Gauss-Hermite quadrature, number of integration points = seven) to account for the clustering of patients within a center and the clustering of samples from the same subject.
Individual risk stratification	12 months	- test the improvement of individual risk stratification of rejection with dd-cfDNA on top of the baseline risk model: discrimination (area under the ROC curve), calibration (graphical evaluation), reclassification indices (net reclassification index - NRI, integrated discrimination index - IDI).

Trial Locations

Locations (2)

Pitié-Salpêtrière Hospital; 🇫🇷 Paris, France

Georges Pompidou European Hospital; 🇫🇷 Paris, France