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Trifecta-Heart cfDNA-MMDx Study

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ClinicalTrials.gov Identifier: NCT04707872
Recruitment Status : Recruiting
First Posted : January 13, 2021
Last Update Posted : August 19, 2022
Natera, Inc.
One Lambda
Information provided by (Responsible Party):
University of Alberta

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.

Condition or disease Intervention/treatment
Heart Transplant Rejection Diagnostic Test: MMDx diagnostic test Diagnostic Test: Prospera Diagnostic Test: HLA antibody

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. Due to a considerable interest from participation centers, we extend this study to 700 biopsies and corresponding blood samples. This study is an extension of the INTERHEART ClinicalTrials.gov Identifier: NCT02670408

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Study Type : Observational
Estimated Enrollment : 300 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Trifecta-Heart cfDNA-MMDX Study: Comparing the DD-cfDNA Test to MMDx Microarray Test and Central HLA Antibody Test
Actual Study Start Date : June 1, 2021
Estimated Primary Completion Date : December 2023
Estimated Study Completion Date : July 2024

Resource links provided by the National Library of Medicine

Group/Cohort Intervention/treatment
Heart transplant protocol and for cause biopsies
The study population includes patients with a functioning heart transplant undergoing a biopsy for clinical indications as standard of care, or protocol biopsies of heart in high-risk patients, or follow-up after treatment.
Diagnostic Test: MMDx diagnostic test
Microarray test of gene expression in heart biopsies

Diagnostic Test: Prospera
Donor derived cell-free DNA in patient blood

Diagnostic Test: HLA antibody
Centralized measurement of HLA antibodies in patient blood

Primary Outcome Measures :
  1. Calibration of Prospera test for T cell-mediated rejection [ Time Frame: 18 months ]
    Set DD-cfDNA test cut-off values against the probability of T cell-mediated rejection in the biopsy as reported by MMDx. Calibration of DD-cfDNA test cut-off values against the probability of T cell-mediated rejection in the biopsy as reported by MMDx.

  2. Calibration of Prospera test for antibody-mediated rejection [ Time Frame: 18 months ]
    Set DD-cfDNA test cut-off values against the probability of antibody-mediated rejection in the biopsy as reported by MMDx.

  3. Calibration of Prospera test for heart injury [ Time Frame: 18 month ]
    Set DD-cfDNA test cut-off values against the probability of acute and chronic heart injury in the biopsy as reported by MMDx.

  4. Report calibrated Prospera test results for rejection [ Time Frame: 6 months ]
    Obtain clinicians feedback

  5. Report calibrated Prospera test results for heart injury [ Time Frame: 6 month ]
    Obtain clinicians feedback

Secondary Outcome Measures :
  1. Determine if Prospera blood test can replace heart biopsy test [ Time Frame: 6 month ]
    Obtain clinicians feedback

  2. Determine if Prospera blood test can replace follow up heart biopsy [ Time Frame: 6 month ]
    Determine whether resolution of DD-cfDNA after treatment can monitor response to therapy and avoid follow-up biopsies

  3. Assessment of donor-specific antibody status [ Time Frame: 6 months ]
    Report and compare the DSA status based on centralized and local HLA antibody measurement.

Biospecimen Retention:   Samples Without DNA
RNA isolated from patient biopsy.

Information from the National Library of Medicine

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04707872

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Contact: Konrad Famulski, PhD 1 780 782 9463 konrad@ualberta.ca
Contact: Robert Polakowski, PhD 1 780 492 5091 polakows@ualberta.ca

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United States, California
UCLA Medical Centre Not yet recruiting
Los Angeles, California, United States, 90024
Contact: Eugene DePasquale, MD       EDepasquale@mednet.ucla.edu   
Principal Investigator: Martin Cadeiras, MD         
Sub-Investigator: Mario Deng, MD         
Cedars-Sinai Heart Institute Not yet recruiting
Los Angeles, California, United States, 90048
Contact: Brandy Starks, MBA    310-248-7141    jon.kobashigawa@cshs.org   
Contact: Kobashigawa, MD       jon.kobashigawa@cshs.org   
Principal Investigator: Jon Kobashigawa         
United States, Texas
Annette C. and Harold C. Simmons Transplant Institute, BaylorScott&White Research Institute Recruiting
Dallas, Texas, United States, 75246
Contact: Aayla K Jamil, MBBS       Aayla.Jamil@BSWHealth.org   
Principal Investigator: Shelley Hall, MD         
United States, Utah
Cardiovascular Medicine, University of Utah Health Recruiting
Salt Lake City, Utah, United States, 84132
Contact: Jennifer Hong       Jennifer.Hong@hsc.utah.edu   
Principal Investigator: Josef Stehlik, MD, PhD         
Cardiac Transplantation Laboratory, The Victor Chang Cardiac Research Institute Not yet recruiting
Darlinghurst, Australia, NSW 2010
Contact: Carmen Herrera, MD       peter.macdonal@svha.org.au   
Principal Investigator: Peter MacDonald, MD         
Department of Cardiac Surgery, Medical University of Vienna Not yet recruiting
Vienna, Austria, A-1090
Contact: Arezu Aliabadi, MD       arezu.aliabadi@meduniwien.ac.at   
Principal Investigator: Andreas Zuckerman, MD         
Sub-Investigator: Johannes Gokler, MD         
Canada, Alberta
Division of Cardiology, University of Alberta Recruiting
Edmonton, Alberta, Canada, T6G 2R7
Contact: Daniel Kim, MD       dk@ualberta.ca   
Principal Investigator: Daniel Kim, MD         
Institute for Clinical and Experimental Medicine - IKEM Videnska 1958/9 Recruiting
Prague, Czechia, 140 21
Contact: Tereza Novakowa       novt@ikem.cz   
Principal Investigator: Vojtech Melenovsky, MD PhD         
Heart Failure and Heart Transplant Unit, University of Bologna Not yet recruiting
Bologna, Italy, 40138
Contact: Laura Borgese       laura.borgese@gmail.com   
Principal Investigator: Luciano Potena, MD         
Advanced Heart Failure Transplant Unit Not yet recruiting
La Coruna, Spain
Contact: Zulaika Grille Cancela       Zulaika.grille.cancela@sergas.es   
Principal Investigator: Maria G Crespo-Leiro, MD         
Sponsors and Collaborators
University of Alberta
Natera, Inc.
One Lambda
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Principal Investigator: Philip F Halloran, MD PhD Alberta Transplant Applied Genomics Center, University of Alberta
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Responsible Party: University of Alberta
ClinicalTrials.gov Identifier: NCT04707872    
Other Study ID Numbers: ATAGC06
First Posted: January 13, 2021    Key Record Dates
Last Update Posted: August 19, 2022
Last Verified: January 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: Only IPD data will be shared within a participating center.

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by University of Alberta:
Donor derived cfDNA
gene expression
heart transplant biopsy
Additional relevant MeSH terms:
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Immunologic Factors
Physiological Effects of Drugs