INTERHEART Donor-Derived Cell Free DNA Study

Overview

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

Full Title of Study: “INTERHEART cfDNA-MMDX Study: Comparing the DD-cfDNA Test to MMDx Microarray Test”

Study Type

  • Study Type: Observational
  • Study Design
    • Time Perspective: Prospective
  • Study Primary Completion Date: July 2022

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 PCR 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. This study is an extension of the INTERHEART ClinicalTrials.gov Identifier: NCT02670408

Interventions

  • Diagnostic Test: MMDx diagnostic test
    • Molecular diagnostic tests

Arms, Groups and 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.

Clinical Trial Outcome Measures

Primary Measures

  • 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

Secondary Measures

  • 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

Participating in This Clinical Trial

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, regardless of time post-transplant. Patients are enrolled based on standard of care biopsies, including surveillance biopsies in high-risk patients (according to the Center definition), with informed consent. Exclusion Criteria:

  • Patients will be excluded from the study if they decline participation or are unable to give informed consent.

Gender Eligibility: All

Minimum Age: N/A

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • University of Alberta
  • Collaborator
    • Natera, Inc.
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Philip F Halloran, MD PhD, Principal Investigator, Alberta Transplant Applied Genomics Center, University of Alberta
  • Overall Contact(s)
    • Konrad Famulski, PhD, 1 780 782 9463, konrad@ualberta.ca

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