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Trifecta-Heart cfDNA-MMDx Study

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04707872
Recruitment Status : Recruiting
First Posted : January 13, 2021
Last Update Posted : May 3, 2024
Sponsor:
Collaborators:
Natera, Inc.
One Lambda
Information provided by (Responsible Party):
University of Alberta

Tracking Information
First Submitted Date January 11, 2021
First Posted Date January 13, 2021
Last Update Posted Date May 3, 2024
Actual Study Start Date June 1, 2021
Estimated Primary Completion Date December 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: April 7, 2021)
  • 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.
  • 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.
  • 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.
  • Report calibrated Prospera test results for rejection [ Time Frame: 6 months ]
    Obtain clinicians feedback
  • Report calibrated Prospera test results for heart injury [ Time Frame: 6 month ]
    Obtain clinicians feedback
Original Primary Outcome Measures
 (submitted: January 11, 2021)
  • Calibration of Prospera test for T cell-mediated rejection [ Time Frame: 18 months ]
    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 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 [ Time Frame: 18 months ]
    Calibration of 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 [ Time Frame: 18 month ]
    Calibration of 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 [ Time Frame: 6 mnoths ]
    Report new DD-cfDNA test cut-off values for rejection
  • Report calibrated Prospera test results for heart injury [ Time Frame: 6 month ]
    Report new DD-cfDNA test cut-off values for acute and chronic heart injury
Change History
Current Secondary Outcome Measures
 (submitted: May 6, 2021)
  • Determine if Prospera blood test can replace heart biopsy test [ Time Frame: 6 month ]
    Obtain clinicians feedback
  • 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
  • Assessment of donor-specific antibody status [ Time Frame: 6 months ]
    Report and compare the DSA status based on centralized and local HLA antibody measurement.
Original Secondary Outcome Measures
 (submitted: January 11, 2021)
  • Determine if Prospera blood test can replace heart biopsy test [ Time Frame: 6 month ]
    Determine if Prospera test, as calibrated by this DD-cfDNA-MMDx study, will avoid need for indication biopsy when heart transplant function deteriorates. This will be based on the consensus between participating clinicians.
  • 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
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title 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
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 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
Study Type Observational
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples Without DNA
Description:
RNA isolated from patient biopsy.
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.
Condition Heart Transplant Rejection
Intervention
  • 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
Study Groups/Cohorts 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.
Interventions:
  • Diagnostic Test: MMDx diagnostic test
  • Diagnostic Test: Prospera
  • Diagnostic Test: HLA antibody
Publications * 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 Mar 28. doi: 10.1097/TP.0000000000004986. Online ahead of print.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: January 11, 2021)		 300
Original Estimated Enrollment Same as current
Estimated Study Completion Date July 2025
Estimated Primary Completion Date December 2024   (Final data collection date for primary outcome measure)
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.
Sex/Gender
Sexes Eligible for Study: All
Ages Child, Adult, Older Adult
Accepts Healthy Volunteers No
Contacts
Contact: Konrad Famulski, PhD 1 780 782 9463 konrad@ualberta.ca
Contact: Robert Polakowski, PhD 1 780 492 5091 polakows@ualberta.ca
Listed Location Countries Australia,   Austria,   Canada,   Czechia,   Italy,   Poland,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number NCT04707872
Other Study ID Numbers ATAGC06
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement
Plan to Share IPD: No
Plan Description: Only IPD data will be shared within a participating center.
Current Responsible Party University of Alberta
Original Responsible Party Same as current
Current Study Sponsor University of Alberta
Original Study Sponsor Same as current
Collaborators
  • Natera, Inc.
  • One Lambda
Investigators
Principal Investigator: Philip F Halloran, MD PhD Alberta Transplant Applied Genomics Center, University of Alberta
PRS Account University of Alberta
Verification Date May 2024