Trifecta-Heart cfDNA-MMDx Study
Study Details
Study Description
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 | Phase |
|---|---|---|
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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
Study Design
Arms and Interventions
| Arm | 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
|
Outcome Measures
Primary Outcome Measures
- Calibration of Prospera test for T cell-mediated rejection [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.
- Calibration of Prospera test for antibody-mediated rejection [18 months]
Set DD-cfDNA test cut-off values against the probability of antibody-mediated rejection in the biopsy as reported by MMDx.
- Calibration of Prospera test for heart injury [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.
- Report calibrated Prospera test results for rejection [6 months]
Obtain clinicians feedback
- Report calibrated Prospera test results for heart injury [6 month]
Obtain clinicians feedback
Secondary Outcome Measures
- Determine if Prospera blood test can replace heart biopsy test [6 month]
Obtain clinicians feedback
- Determine if Prospera blood test can replace follow up heart biopsy [6 month]
Determine whether resolution of DD-cfDNA after treatment can monitor response to therapy and avoid follow-up biopsies
- Assessment of donor-specific antibody status [6 months]
Report and compare the DSA status based on centralized and local HLA antibody measurement.
Eligibility Criteria
Criteria
Inclusion Criteria:
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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.
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Patients are enrolled based on standard of care biopsies, including surveillance biopsies in high-risk patients, with informed consent.
Exclusion Criteria:
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Patients will be excluded from the study if they decline participation
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Are unable to give informed consent.
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Recipients of multiple organs.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | UCLA Medical Centre | Los Angeles | California | United States | 90024 |
| 2 | Cedars-Sinai Heart Institute | Los Angeles | California | United States | 90048 |
| 3 | Annette C. and Harold C. Simmons Transplant Institute, BaylorScott&White Research Institute | Dallas | Texas | United States | 75246 |
| 4 | Cardiovascular Medicine, University of Utah Health | Salt Lake City | Utah | United States | 84132 |
| 5 | Cardiac Transplantation Laboratory, The Victor Chang Cardiac Research Institute | Darlinghurst | Australia | NSW 2010 | |
| 6 | Department of Cardiac Surgery, Medical University of Vienna | Vienna | Austria | A-1090 | |
| 7 | Division of Cardiology, University of Alberta | Edmonton | Alberta | Canada | T6G 2R7 |
| 8 | Institute for Clinical and Experimental Medicine - IKEM Videnska 1958/9 | Prague | Czechia | 140 21 | |
| 9 | Heart Failure and Heart Transplant Unit, University of Bologna | Bologna | Italy | 40138 | |
| 10 | Advanced Heart Failure Transplant Unit | La Coruna | Spain |
Sponsors and Collaborators
- University of Alberta
- Natera, Inc.
- One Lambda
Investigators
- Principal Investigator: Philip F Halloran, MD PhD, Alberta Transplant Applied Genomics Center, University of Alberta
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- ATAGC06