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Trifecta-Kidney cfDNA-MMDx Study

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ClinicalTrials.gov Identifier: NCT04239703
Recruitment Status : Recruiting
First Posted : January 27, 2020
Last Update Posted : November 26, 2021
Sponsor:
Collaborators:
Natera, Inc.
One Lambda
Information provided by (Responsible Party):
Philip Halloran, University of Alberta

Brief Summary:
Demonstrate the relationship between DD-cfDNA levels and HLA antibodies in blood, and the Molecular Microscope® (MMDx) Diagnostic System results in indication biopsies.

Condition or disease Intervention/treatment
Kidney Transplant Rejection Diagnostic Test: MMDx Diagnostic Test: Prospera Diagnostic Test: HLA antibody

Detailed Description:
There is a need for better screening of kidney transplant patients for rejection. Patients with kidney transplants are routinely tested (creatinine, urine protein, histology and donor specific antibody (DSA) as standard of care to detect rejection, but these tests are not adequate. Rejection is often missed by these tests (false negatives) and other processes such as acute kidney injury can produce false-positive results. Moreover, histology has a high interobserver disagreement diagnosing rejection, and cannot accurately assess acute injury. A definitive molecular assessment of rejection and injury in kidney biopsies has emerged - the Molecular Microscope® Diagnostic System (MMDx) - developed by the Alberta Transplant Applied Genomics Centre, University of Alberta. Now a new screening test is being introduced: the monitoring of donor-derived cell-free DNA (DD-cfDNA) released in the blood by the kidney 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 done on kidney transplant recipients detected "active rejection" and differentiated it from borderline rejection and no rejection. It is likely, however, that DD-cfDNA test may miss some T cell-mediated rejection (TCMR) cases and the distinction between early and fully developed antibody-mediated rejection (ABMR) was not tested. No study has actually examined the DD-cfDNA results in kidney transplants with acute or chronic kidney disease (AKI and CKD). DD-cfDNA measurements have only been correlated with histology, a flawed standard. DD-cf-DNA test 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 biopsy against the MMDx measurements of TCMR, and ABMR (early-stage, fully-developed, and late-stage), AK, and atrophy-fibrosis. We will compare blood DD-cfDNA measurements in 600 samples at the time of 300 indication biopsies to the MMDx results, as well as central assessment of HLA antibody (One Lambda) in 300 blood samples, interpreted centrally as DSA based on the tissue typing results. This study is an extension of the INTERCOMEX ClinicalTrials.gov Identifier: NCT01299168. We have collected 300 kidney biopsies and corresponding blood samples. Due to considerable interest from participating centers, we extend this study to the total of 700 biopsies and 2,100 blood samples.

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Study Type : Observational
Estimated Enrollment : 300 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Trifecta-Kidney cfDNA-MMDx Study: Comparing the DD-cfDNA Test to MMDx Microarray Test, Central HLA Antibody Test, and Histology.
Actual Study Start Date : December 1, 2019
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2023

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
Kidney transplant biopsies for cause
The study population includes patients with a functioning kidney transplant undergoing a biopsy for clinical indications as standard of care.
Diagnostic Test: MMDx
Portion of kidney transplant indication biopsy

Diagnostic Test: Prospera
Transplant patient blood sample
Other Name: transplant patient blood sample

Diagnostic Test: HLA antibody
Transplant patient blood sample
Other Name: transplant patient blood sample




Primary Outcome Measures :
  1. 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.

  2. 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.

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

  4. Report calibrated Prospera test results for rejection [ Time Frame: 6 months ]
    Report new DD-cfDNA test cut-off values for rejection

  5. Report calibrated Prospera test results for kidney injury [ Time Frame: 6 month ]
    Report new DD-cfDNA test cut-off values for acute and chronic kidney injury


Secondary Outcome Measures :
  1. Determine if Prospera blood test can replace kidney biopsy test [ Time Frame: 6 months ]
    Determine if Prospera test, as calibrated by this DD-cfDNA-HLA-MMDx study, will avoid need for indication biopsy when kidney transplant function deteriorates. This will be based on the consensus between participating clinicians.

  2. 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 kidney biopsies


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 kidney transplant undergoing a biopsy for clinical indications as standard of care to determine the cause of their graft dysfunction (deterioration in graft function, delayed graft function, proteinuria).
Criteria

Inclusion Criteria:

  • All kidney transplant recipients undergoing a kidney biopsy for clinical indications, as determined by their physician or surgeon, will be eligible to enroll in the study.

Exclusion Criteria:

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

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): NCT04239703


Contacts
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Contact: Konrad S Famulski, PhD 1 780 492 1725 konrad@ualberta.ca
Contact: Robert Polakowski, PhD 1 780 492 5091 polakows@ualberta.ca

Locations
Show Show 31 study locations
Sponsors and Collaborators
University of Alberta
Natera, Inc.
One Lambda
Investigators
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Principal Investigator: Philip F Halloran, MD, PhD University of Alberta
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Responsible Party: Philip Halloran, Distinguished Professor, University of Alberta
ClinicalTrials.gov Identifier: NCT04239703    
Other Study ID Numbers: ATAGC05
First Posted: January 27, 2020    Key Record Dates
Last Update Posted: November 26, 2021
Last Verified: November 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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 Philip Halloran, University of Alberta:
donor derived cell-free DNA
blood
kidney biopsy
Additional relevant MeSH terms:
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Antibodies
Immunologic Factors
Physiological Effects of Drugs