Donor Derived Cell Free DNA (Dd-cfDNA) as a Biomarker for Allograft Rejection in Heart Transplant Recipients

NCT07886489 — Enrolling by invitation, 100 participants, University of Aarhus

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Registry	NCT07886489, acronym TRANSCEND
Status	Enrolling by invitation
Study type	Observational
Enrollment	100 (Estimated)
Sponsor	University of Aarhus (Other); collaborators: Aarhus University Hospital, Copenhagen University Hospital, Rigshospitalet, Oslo University Hospital
Conditions	Heart Transplantation
Interventions	Donor-derived cell free DNA (Diagnostic test)
Dates	start 2026-09-01, primary completion 2029-08-31 (estimated), completion 2038-08-31 (estimated), first posted 2026-10-21, last updated 2026-10-21
Locations	3 sites in Denmark, Norway

-Summary

Following heart transplantation (HTx), lifelong immunosuppressive treatment is required to prevent the immune system from attacking, damaging, and rejecting the donor hear (allograft). Currently, diagnosis of allograft rejection is based on evaluation of endomyocardial biopsies (EMB), which remains the gold standard for rejection diagnostics. However, previous research have highlighted limitations of EMBs, including interrater variation, sampling error and risks of complications.

Donor-derived cell-free DNA (dd-cfDNA) has emerged as a promising post-transplant biomarker of allograft rejection. Nevertheless, evidence suggests that dd-cfDNA demonstrates greater diagnostic performance for antibody-mediated rejection (AMR) than for cellular rejection (TCR) and that the specificity exceeds its sensitivity in predicting rejection, highlighting limitations in its clinical application.

The primary objective of this observational project are to investigate if measurement of dd-cfDNA can be utilized as a biomarker for acute rejection in the management of heart transplant recipients during the first year after transplantation in a Danish-Norwegian patient cohort.

Secondary objectives include:

* to correlate dd-cfDNA levels with markers of allograft dysfunction and rejection, i.e., EMBs, ejection fraction, left ventricular global longitudinal strain, troponin T, natriuretic peptide test (proBNP) and score of cardiac allograft vasculopathy (CAV)
* to examine post-transplant dd-cfDNA kinetics during the first 6 six weeks after HTx
* to explore clinical meaningful change in dd-cfDNA associated with acute allograft rejection
* to investigate the association between dd-cfDNA, chronic allograft rejection, allograft dysfunction and patients' long-term survival

To study the objectives, this project will include 100 HTx patients prior to transplantation over a 2-3 year period and conduct a long-time follow up 10 years after transplantation. Patients entering the waiting list for HTx at Rigshospitalet Copenhagen, Denmark, Oslo University Hospital, Rikshospitalet Oslo, Norway, or Aarhus University Hospital, Denmark, are invited to participate in the project. Patients are invited to participate in the current project if fulfilling the pre-defined inclusion criteria and no exclusion criteria.

A comprehensive collection of clinical, pathological and immunological data is conducted from up to 15 visits during the first year after transplantation. Thereafter, from all annual visits and upon admission if allograft rejection is suspected.

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+Arms and interventions

Arm	Type	Interventions	Description
Heart transplant recipients		Diagnostic Test: Donor-derived cell free DNA

Donor-derived cell free DNA (Diagnostic test): Blood samples from months 1, 3, 6 and 12, and upon suspected allograft rejection, will be analysed to quantify dd-cfDNA studying the primary objective. To study additional objectives dd-cfDNA is further analyzed yearly after year 1 in all included patients. In a subgroup of patients without allograft rejection, dd-cfDNA will be analyed weekly within the first 6 weeks after transplantation to study normal dd-cfDNA kinetics after transplantation.

+Outcome measures

Primary outcomes

Association between dd-cfDNA level and acute allograft rejection (TCR and AMR) in the first year after transplantation, which will be evaluated using a linear mixed model and reported as the model estimate for the fixed effect (allograft rejection) [From baseline to one year follow up]

Secondary outcomes

Association between dd-cfDNA level and acute allograft rejection in the 3rd, 5th and 10th year after transplantation implementing linear mixed models and reported as the model estimate for the fixed effect (allograft rejection) [From baseline to 10 year follow up]
The area under the ROC curve (AUROC) depicting the performance of dd-cfDNA to distinguish between acute allograft rejection or no rejection in the 1st, 3rd, 5th and 10th year after transplantation. [From baseline to 10 ten year follow up]
The sensitivity and positive predictive value (PPV) of dd-cfDNA as a biomarker of allograft rejection, i.e., the proportion of positive results (increased dd-cfDNA) that are true positive (developed rejection) after 1, 3, 5 and 10 years [Baseline to 10 year follow up]
The specificity and negative predictive value (NPV) of dd-cfDNA as a biomarker of acute allograft rejection, i.e., the proportion of negative results (decreased/no change in dd-cfDNA) that are true negative (no rejection) after 1, 3, 5 and 10 years [Baseline to 10 year follow up]
Change in the fraction of dd-cfDNA (dd-cfDNA kinetics) in patients without allograft rejection in the first six weeks after transplantation [Baseline to 6 weeks afters transplantation]
Correlation between dd-cfDNA level, clinical findings (GLS, biopsy results, etc.) and patient characteristics [Baseline to 1, 3, 5, and 10 year follow up]

Other outcomes

AUROC depicting the performance of current available biomarkers, including TnT to distinguish between acute allograft rejection or no rejection, and compare with AUROC statistics of dd-cfDNA [Baseline to 1, 3, 5, and 10 year follow up]
Allograft dysfunction, i.e., frequency of patients developing moderate to severe CAV (CAV score ≥2) after year 1, 2, 5 and 10 of transplantation stratified by the number and type of rejection [Baseline to 1, 3, 5, and 10 year follow up]
Correlation between dd-cfDNA levels, CAV progression and overall mortality during the 10-year project period [Baseline to 10 year follow up]
The frequency of patients developing HLA antibodies over the 10-year project and the correlation to overall mortality stratified by type of donor-specific HLA antibodies and strengths [Baseline to 1, 3, 5, and 10 year follow up]
Correlation between HLA antibodies (type and strength), dd-cfDNA level and overall mortality [Baseline to 1, 3, 5, and 10 year follow up]
Patient survival 10 years after heart transplantation [Baseline to 5 and 10 year follow up]

+Eligibility

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Patients entering the waiting list for their first heart transplantation (HTX1) at Rigshospitalet Copenhagen, Denmark, Rikshospitalet Oslo, Norway, or Aarhus University Hospital, Denmark
* Patients ≥18 years old
* Patients signing informed consent

Exclusion Criteria:

* Patients who are withdrawn from the heart transplant waiting list after informed consent has been provided
* Patients who have previously received a solid organ transplantation
* Patients unable to receive and understand the oral and written project information

+Locations (3)

Facility	City	Country
Aarhus University Hospital	Aarhus	Denmark
Rigshospitalet Copenhagen	Copenhagen	Denmark
Oslo University Hospital	Oslo	Norway