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

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.

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Key information

Conditions

Heart Transplantation Rejection Heart Transplant

Age range

18 year and older

Sex eligibility

All sexes

Study type

Observational

Primary location

Georges Pompidou European Hospital, Paris, France

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

Primary outcomes

Number of patients with biopsy proven rejection and / or acute allograft dysfunction

Time frame: 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 outcomes

Independent association between donor-derived cell-free DNA and allograft ejection

Time frame: 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

Time frame: 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).

Sponsors and collaborators

Lead sponsor

Paris Translational Research Center for Organ Transplantation

Other

Registry information

Official study title

Evaluation of the Added Clinical Value of Donor-derived Cell-free DNA for the Monitoring of Cardiac Allograft Rejection: an Observational Prospective Longitudinal Multicenter Study.

Acronym: HEART-FREE

Important dates

Study start: 2021
Primary completion: 2023
Study completion: 2023
First posted: Dec 18, 2024
Registry last updated: Jan 3, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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