Clinical trial NCT04707872: Trifecta-Heart cfDNA-MMDx Study
Official title: Trifecta-Heart cfDNA-MMDX Study: Comparing the DD-cfDNA Test to MMDx Microarray Test and Central HLA Antibody Test
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Heart Transplant Rejection
Keywords: Donor derived cfDNA
gene expression
heart transplant biopsy
Lead sponsor: University of Alberta
Sponsor class: OTHER
Collaborators: name: Natera, Inc.
name: One Lambda
First posted: 2021-01-13
Enrollment: 300
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: The study population includes patients with a functioning heart transplant undergoing a biopsy for clinical indications or surveillance (protocol) biopsy.

Brief summary: Demonstrate the relationship between DD-cfDNA levels and HLA antibodies in blood transplant recipient and the Molecular Microscope® (MMDx) Diagnostic System results in indication and protocol biopsies from heart transplants.

Detailed description: The current standard for assessment of rejection in heart transplants is an endomyocardial biopsy (EMB) interpreted by histology according to ISHLT guidelines. This has considerable error rates, many due to the high disagreement among pathologists in assessing lesions and diagnoses. To address the unmet need for precision and accuracy, the Alberta Transplant Applied Genomics Centre (ATAGC, University of Alberta) has developed a new diagnostic system - the Molecular Microscope® Diagnostic System (MMDx), which uses microarrays to define the global gene expression features of rejection and injury. Now a new screening test is being introduced: the monitoring of donor-derived cell-free DNA (DD-cfDNA) released in the blood by the heart during rejection. The Natera Inc DD-cfDNA Prospera® test is based on the massively multiplex polymerase chain reaction that targets 13,392 single nucleotide polymorphisms and targeted sequences are quantified by Next Generation Sequencing. The Prospera® test has been done on kidney transplant recipients and detected "active rejection" and differentiated it from borderline rejection and no rejection. However, Prospera® test was not examined (the DD-cfDNA results) in heart transplant recipients. DD-cf-DNA test for heart transplants must now be calibrated against MMDx that is based on global gene expression, the new standard for biopsy interpretation. The present study will calibrate centrally measured (Natera Inc) DD-cfDNA levels obtained at the time of an indication or protocol biopsy against the MMDx measurements of T cell-mediated rejection (TCMR), antibody-mediated rejection (ABMR) and early and late tissue injury. The present study will compare DD-cfDNA and MMDx in 300 prospectively collected biopsies for clinical indications and protocol, and accompanying 600 blood samples, to calibrate the DD-cfDNA (Natera Inc.) levels against the MMDx biopsy diagnoses of TCMR, ABMR (and its stages), and acute (early) and chronic (late) injury, , as well as central assessment of HLA antibody (One Lambda) in 300 blood samples, interpreted centrally as donor specific antibody (DSA) based on the tissue typing results. Trifecta-Heart collected 575 biopsies and 573 cfDNA samples, and 573 One Lambda samples so far. Due to a considerable interest from participation centers, this study aims to collect 300 more biopsies and corresponding blood samples. This study is an extension of the INTERHEART ClinicalTrials.gov Identifier: NCT02670408

Eligibility criteria: Inclusion Criteria:

* All heart transplant recipients undergoing a biopsy for clinical indications and protocol biopsies, as determined by their physician or surgeon, will be eligible to enroll in the study.
* Patients are enrolled based on standard of care biopsies, including surveillance biopsies in high-risk patients, with informed consent.

Exclusion Criteria:

* Patients will be excluded from the study if they decline participation
* Are unable to give informed consent.
* Recipients of multiple organs.

Primary outcomes:
measure: Calibration of Prospera test for T cell-mediated rejection
timeFrame: 18 months
measure: Calibration of Prospera test for antibody-mediated rejection
timeFrame: 18 months
measure: Calibration of Prospera test for heart injury
timeFrame: 18 month
measure: Report calibrated Prospera test results for rejection
timeFrame: 6 months
measure: Report calibrated Prospera test results for heart injury
timeFrame: 6 month
Secondary outcomes:
measure: Determine if Prospera blood test can replace heart biopsy test
timeFrame: 6 month
measure: Determine if Prospera blood test can replace follow up heart biopsy
timeFrame: 6 month
measure: Assessment of donor-specific antibody status
timeFrame: 6 months
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: Baptist Health Institute for Research and Innovation
state: Arkansas
city: W. New York
country: United States
facility: Columbia University Medical Center, Columbia Interventional Cardiovascular Care
state: New Jersey
city: Bronx
country: United States
facility: Montefiore Medical Center, 3319 Rochambeau Avenue, 2nd FL
state: New York
city: Dallas
country: United States
facility: Annette C. and Harold C. Simmons Transplant Institute, BaylorScott&White Research Institute
state: Texas
city: Salt Lake City
country: United States
facility: Cardiovascular Medicine, University of Utah Health
state: Utah
city: Darlinghurst
country: Australia
facility: Cardiac Transplantation Laboratory, The Victor Chang Cardiac Research Institute
city: Edmonton
country: Canada
facility: Division of Cardiology, University of Alberta
state: Alberta
city: Prague
country: Czechia
facility: Institute for Clinical and Experimental Medicine - IKEM Videnska 1958/9
city: Bologna
country: Italy
facility: Heart Failure and Heart Transplant Unit, University of Bologna
city: Zabrze
country: Poland
facility: Silesian Center for Heart Diseases (Ś!ąskie Centrum Chorób Serca w Zabrzu
city: La Coruna
country: Spain
facility: Advanced Heart Failure Transplant Unit
Study officials:
affiliation: Alberta Transplant Applied Genomics Center, University of Alberta
name: Philip F Halloran, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Madill-Thomsen KS, Halloran PF. Precision diagnostics in transplanted organs using microarray-assessed gene expression: concepts and technical methods of the Molecular Microscope(R) Diagnostic System (MMDx). Clin Sci (Lond). 2024 Jun 5;138(11):663-685. doi: 10.1042/CS20220530.
citation: Halloran PF, Madill-Thomsen KS. Donor-derived Cell-free DNA: A Step Forward in the Quest for Transplant Truth. Transplantation. 2025 Jun 1;109(6):910-914. doi: 10.1097/TP.0000000000005332. Epub 2025 Jan 28. No abstract available.
citation: Halloran PF, Reeve J, Mackova M, Madill-Thomsen KS, Demko Z, Olymbios M, Campbell P, Melenovsky V, Gong T, Hall S, Stehlik J. Comparing Plasma Donor-derived Cell-free DNA to Gene Expression in Endomyocardial Biopsies in the Trifecta-Heart Study. Transplantation. 2024 Sep 1;108(9):1931-1942. doi: 10.1097/TP.0000000000004986. Epub 2024 Aug 20.