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AzTrials

Heart TransplantationHEART-FREENCT06740578

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

An observational study of Heart Transplantation and Rejection Heart Transplant, run by Paris Translational Research Center for Organ Transplantation at 2 sites in France.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
How many people
320 participants
Where
2 sitesFrance
Study dates
1 Oct 2021to 31 Oct 2023
How long will I take part?
12 Months
Phase
Observational
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Study population: Prospective cohort of heart transplant recipients (> 30 days post-transplant)

Who may be able to join

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

Who cannot join

  • multiorgan transplantation
  • refusal to participate

Trial locations and contacts

2 sites in 1 country.

France2 sites

  • Pitié-Salpêtrière Hospital

    Paris, 75013

  • Georges Pompidou European Hospital

    Paris, 75015

Other trials in France

About this study

Official 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.

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.

Read the 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.

Keywords
heart transplantation, donor-derived cell-free DNA, non-invasive biomarker, allograft rejection, risk stratification

What is being measured

The primary outcome is the main question the study is designed to answer.

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

    • 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.

    Measured: 12 months

Secondary outcomes (2)

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

    • 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.

    Measured: 12 months

  2. Individual risk stratification

    • 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).

    Measured: 12 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted18 Dec 2024
  2. Study start1 Oct 2021
  3. Primary completion31 Oct 2023
  4. Study completion31 Oct 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Observational
Observational model
Cohort
Time perspective
Prospective
Enrolment
320 participants (actual)
Target duration
12 Months
IDs, dates and publications
ClinicalTrials.gov ID
NCT06740578
Sponsor's protocol ID
HEART-FREE
Acronym
HEART-FREE
Status last verified
Dec 2024
First submitted
13 Dec 2024
Last updated
3 Jan 2025
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
No: Data used to conduct the research are available from the corresponding author upon reasonable request.

Publications

  • Kobashigawa J, Hall S, Shah P, Fine B, Halloran P, Jackson AM, Khush KK, Margulies KB, Sani MM, Patel JK, Patel N, Peyster E; conference participants. The evolving use of biomarkers in heart transplantation: Consensus of an expert panel. Am J Transplant. 2023 Jun;23(6):727-735. doi: 10.1016/j.ajt.2023.02.025. Epub 2023 Mar 3.

    PubMed 36870390

  • Stewart S, Winters GL, Fishbein MC, Tazelaar HD, Kobashigawa J, Abrams J, Andersen CB, Angelini A, Berry GJ, Burke MM, Demetris AJ, Hammond E, Itescu S, Marboe CC, McManus B, Reed EF, Reinsmoen NL, Rodriguez ER, Rose AG, Rose M, Suciu-Focia N, Zeevi A, Billingham ME. Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant. 2005 Nov;24(11):1710-20. doi: 10.1016/j.healun.2005.03.019. Epub 2005 Jun 20.

    PubMed 16297770

  • Teszak T, Bodor C, Hegyi L, Levay L, Nagy B, Fintha A, Merkely B, Sax B. Local laboratory-run donor-derived cell-free DNA assay for rejection surveillance in heart transplantation-first six months of clinical experience. Clin Transplant. 2023 Sep;37(9):e15078. doi: 10.1111/ctr.15078. Epub 2023 Jul 25.

    PubMed 37489087

  • Berry GJ, Angelini A, Burke MM, Bruneval P, Fishbein MC, Hammond E, Miller D, Neil D, Revelo MP, Rodriguez ER, Stewart S, Tan CD, Winters GL, Kobashigawa J, Mehra MR. The ISHLT working formulation for pathologic diagnosis of antibody-mediated rejection in heart transplantation: evolution and current status (2005-2011). J Heart Lung Transplant. 2011 Jun;30(6):601-11. doi: 10.1016/j.healun.2011.02.015. No abstract available.

    PubMed 21555100

  • Coutance G, Kransdorf E, Aubert O, Bonnet G, Yoo D, Rouvier P, Duong Van Huyen JP, Bruneval P, Taupin JL, Leprince P, Varnous S, Kobashigawa J, Jouven X, Patel J, Loupy A. Clinical Prediction Model for Antibody-Mediated Rejection: A Strategy to Minimize Surveillance Endomyocardial Biopsies After Heart Transplantation. Circ Heart Fail. 2022 Oct;15(10):e009923. doi: 10.1161/CIRCHEARTFAILURE.122.009923. Epub 2022 Oct 6.

    PubMed 36200456

  • Agbor-Enoh S, Shah P, Tunc I, Hsu S, Russell S, Feller E, Shah K, Rodrigo ME, Najjar SS, Kong H, Pirooznia M, Fideli U, Bikineyeva A, Marishta A, Bhatti K, Yang Y, Mutebi C, Yu K, Kyoo Jang M, Marboe C, Berry GJ, Valantine HA; GRAfT Investigators. Cell-Free DNA to Detect Heart Allograft Acute Rejection. Circulation. 2021 Mar 23;143(12):1184-1197. doi: 10.1161/CIRCULATIONAHA.120.049098. Epub 2021 Jan 13.

    PubMed 33435695

  • Velleca A, Shullo MA, Dhital K, Azeka E, Colvin M, DePasquale E, Farrero M, Garcia-Guereta L, Jamero G, Khush K, Lavee J, Pouch S, Patel J, Michaud CJ, Shullo MA, Schubert S, Angelini A, Carlos L, Mirabet S, Patel J, Pham M, Urschel S, Kim KH, Miyamoto S, Chih S, Daly K, Grossi P, Jennings DL, Kim IC, Lim HS, Miller T, Potena L, Velleca A, Eisen H, Bellumkonda L, Danziger-Isakov L, Dobbels F, Harkess M, Kim D, Lyster H, Peled Y, Reinhardt Z. The International Society for Heart and Lung Transplantation (ISHLT) guidelines for the care of heart transplant recipients. J Heart Lung Transplant. 2023 May;42(5):e1-e141. doi: 10.1016/j.healun.2022.10.015. Epub 2022 Dec 20. No abstract available.

    PubMed 37080658

Questions about this trial

What is this clinical trial studying?

An observational study of Heart Transplantation and Rejection Heart Transplant, run by Paris Translational Research Center for Organ Transplantation at 2 sites in France.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 3 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of patients with biopsy proven rejection and / or acute allograft dysfunction (time frame: 12 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT06740578, which also lists 7 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 Jan 2025.

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