Trifecta-Heart cfDNA-MMDx Study

Heart Transplant Rejection Clinical Trial

Official title:

Trifecta-Heart cfDNA-MMDX Study: Comparing the DD-cfDNA Test to MMDx Microarray Test and Central HLA Antibody Test

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04707872
• Other study ID #: ATAGC06
• Status: Recruiting
• Start date: June 1, 2021
• Est. completion date: July 2025

Study information

• Verified date: June 2024
• Source: University of Alberta
• Contact: Konrad Famulski, PhD
• Phone: 1 780 782 9463
• Email: konrad[@]ualberta.ca
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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 258 biopsies and 216 corresponding cfDNA samples. Due to a considerable interest from participation centers, this study aims to collect 400 biopsies and corresponding blood samples. This study is an extension of the INTERHEART ClinicalTrials.gov Identifier: NCT02670408

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 300
• Est. completion date: July 2025
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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.

Related Conditions & MeSH terms

• Heart Transplant Rejection

Intervention

Diagnostic Test:
• MMDx diagnostic test
Microarray test of gene expression in heart biopsies
• Prospera
Donor derived cell-free DNA in patient blood
• HLA antibody
Centralized measurement of HLA antibodies in patient blood

Locations

Country	Name	City	State
Australia	Cardiac Transplantation Laboratory, The Victor Chang Cardiac Research Institute	Darlinghurst
Austria	Department of Cardiac Surgery, Medical University of Vienna	Vienna
Canada	Division of Cardiology, University of Alberta	Edmonton	Alberta
Czechia	Institute for Clinical and Experimental Medicine - IKEM Videnska 1958/9	Prague
Italy	Heart Failure and Heart Transplant Unit, University of Bologna	Bologna
Poland	Silesian Center for Heart Diseases (S!askie Centrum Chorób Serca w Zabrzu	Zabrze
Spain	Advanced Heart Failure Transplant Unit	La Coruna
United States	Montefiore Medical Center, 3319 Rochambeau Avenue, 2nd FL	Bronx	New York
United States	Annette C. and Harold C. Simmons Transplant Institute, BaylorScott&White Research Institute	Dallas	Texas
United States	Baptist Health Institute for Research and Innovation	Little Rock	Arkansas
United States	Cedars-Sinai Heart Institute	Los Angeles	California
United States	UCLA Medical Centre	Los Angeles	California
United States	Cardiovascular Medicine, University of Utah Health	Salt Lake City	Utah
United States	Columbia University Medical Center, Columbia Interventional Cardiovascular Care	W. New York	New Jersey

Sponsors (3)

Lead Sponsor	Collaborator
University of Alberta	Natera, Inc., One Lambda

Countries where clinical trial is conducted

United States,  Australia,  Austria,  Canada,  Czechia,  Italy,  Poland,  Spain, 

References & Publications (2)

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. Transplan — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Calibration of Prospera test for T cell-mediated rejection	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.	18 months
Primary	Calibration of Prospera test for antibody-mediated rejection	Set DD-cfDNA test cut-off values against the probability of antibody-mediated rejection in the biopsy as reported by MMDx.	18 months
Primary	Calibration of Prospera test for heart injury	Set DD-cfDNA test cut-off values against the probability of acute and chronic heart injury in the biopsy as reported by MMDx.	18 month
Primary	Report calibrated Prospera test results for rejection	Obtain clinicians feedback	6 months
Primary	Report calibrated Prospera test results for heart injury	Obtain clinicians feedback	6 month
Secondary	Determine if Prospera blood test can replace heart biopsy test	Obtain clinicians feedback	6 month
Secondary	Determine if Prospera blood test can replace follow up heart biopsy	Determine whether resolution of DD-cfDNA after treatment can monitor response to therapy and avoid follow-up biopsies	6 month
Secondary	Assessment of donor-specific antibody status	Report and compare the DSA status based on centralized and local HLA antibody measurement.	6 months