Trifecta-Kidney cfDNA-MMDx Study

Kidney Transplant Rejection Clinical Trial

Official title:

Trifecta-Kidney cfDNA-MMDx Study: Comparing the DD-cfDNA Test to MMDx Microarray Test, Central HLA Antibody Test, and Histology.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04239703
• Other study ID #: ATAGC05
• Status: Recruiting
• Start date: December 1, 2019
• Est. completion date: December 2025

Study information

• Verified date: June 2024
• Source: University of Alberta
• Contact: Konrad S Famulski, PhD
• Phone: 1 780 492 1725
• 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, and the Molecular Microscope® (MMDx) Diagnostic System results in indication biopsies.

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 1014 kidney biopsies and corresponding blood samples. Due to considerable interest from participating centers, we extend this study to the total of 1300 biopsies and 3900 blood samples.

Recruitment information / eligibility

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

Eligibility

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.

Related Conditions & MeSH terms

• Kidney Transplant Rejection

Intervention

Diagnostic Test:
• MMDx
Portion of kidney transplant indication biopsy
• Prospera
Transplant patient blood sample
• HLA antibody
Transplant patient blood sample

Locations

Country	Name	City	State
Australia	Department of Nephrology, The Royal Melbourne Hospital 1 South East	Melbourne
Canada	University of Alberta, Department of Medicine	Edmonton	Alberta
Canada	ST. Paul's Hospital, 6A Providence Building, 1081 Burrard Street	Vancouver	British Columbia
Croatia	University Hospital Merkur Renal Division	Zagreb
Czechia	Institute for Clinical and Experimental Medicine (IKEM)	Prague
Germany	Charite-Medical University of Berlin Department of Nephrology	Berlin
Lithuania	Centre of Nephrology, Vilnius University Hospital Santaros Klinikos	Vilnius
Poland	Department of Nephrology and Transplantation Medical University in Bialystok	Bialystok
Poland	University Hospital nr1 Bydgoszcz, Klinika Transplantologii	Bydgoszcz
Poland	Medical University of Gdansk Klinika Nefrologii Transplantologii i Chorób Wewnetrznych	Gdansk
Poland	Medical University of Silesia	Katowice
Poland	Department of Transplantation and General Surgery, Wojewodzki Hospital	Poznan
Poland	Department of Nephrology, Transplantation and Internal Medicine, University Hospital n.2	Szczecin
Poland	Pomeranian Medical University, Samodzielny Publiczny Woj. Szpital Zespolony, Oddzial Nefrologii i Transplantacji Nerek	Szczecin
Poland	Medical University of Warsaw, Department of Transplantation Medicine, Nephrology and Internal Diseases	Warsaw
Poland	The Children's Memorial Health Institute, Department of Nephrology, Kidney Transplantation and Hypertension	Warsaw
Poland	Transplant Medicine & Nephrology Clinic, Medical University of Warsaw	Warsaw
Poland	Wroclaw Medical University, Department of Nephrology and Transplantation Medicine	Wroclaw
Slovenia	Department of Nephrology, University Medical Centre	Ljubljana
Switzerland	University Hospital Zurich	Zürich
United States	The Johns Hopkins University, School of Medicine	Baltimore	Maryland
United States	University of Maryland School of Medicine	Baltimore	Maryland
United States	Cleveland Clinic	Cleveland	Ohio
United States	University Hospitals Cleveland Medical Ctr.	Cleveland	Ohio
United States	Detroit Medical Center, Harper University Hospital of Wayne State University	Detroit	Michigan
United States	Henry Ford Hospital	Detroit	Michigan
United States	Intermountain Transplant Services	Murray	Utah
United States	Virginia Commonwealth University Medical Center	Richmond	Virginia
United States	Barnes-Jewish Hospital, Washington University at St. Louis	Saint Louis	Missouri
United States	Division of Nephrology & UW Organ Transplant Center University of Washington	Seattle	Washington
United States	Tampa General Hospital	Tampa	Florida

Sponsors (3)

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

Countries where clinical trial is conducted

United States,  Australia,  Canada,  Croatia,  Czechia,  Germany,  Lithuania,  Poland,  Slovenia,  Switzerland, 

References & Publications (6)

Gauthier PT, Madill-Thomsen KS, Demko Z, Prewett A, Gauthier P, Halloran PF; Trifecta-Kidney Investigators. Distinct Molecular Processes Mediate Donor-derived Cell-free DNA Release From Kidney Transplants in Different Disease States. Transplantation. 2024 — View Citation

Halloran PF, Madill-Thomsen KS, Reeve J. The Molecular Phenotype of Kidney Transplants: Insights From the MMDx Project. Transplantation. 2024 Jan 1;108(1):45-71. doi: 10.1097/TP.0000000000004624. Epub 2023 Dec 13. — View Citation

Halloran PF, Reeve J, Madill-Thomsen KS, Demko Z, Prewett A, Billings P; Trifecta Investigators. The Trifecta Study: Comparing Plasma Levels of Donor-derived Cell-Free DNA with the Molecular Phenotype of Kidney Transplant Biopsies. J Am Soc Nephrol. 2022 — View Citation

Halloran PF, Reeve J, Madill-Thomsen KS, Demko Z, Prewett A, Gauthier P, Billings P, Lawrence C, Lowe D, Hidalgo LG; the Trifecta Investigators. Antibody-mediated Rejection Without Detectable Donor-specific Antibody Releases Donor-derived Cell-free DNA: R — View Citation

Halloran PF, Reeve J, Madill-Thomsen KS, Kaur N, Ahmed E, Cantos C, Al Haj Baddar N, Demko Z, Liang N, Swenerton RK, Zimmermann BG, Van Hummelen P, Prewett A, Rabinowitz M, Tabriziani H, Gauthier P, Billings P; Trifecta Investigators*. Combining Donor-der — 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	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	Calibration of 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 kidney injury	Calibration of DD-cfDNA test cut-off values against the probability of acute and chronic kidney injury in the biopsy as reported by MMDx.	18 months
Primary	Report calibrated Prospera test results for rejection	Report new DD-cfDNA test cut-off values for rejection	6 months
Primary	Report calibrated Prospera test results for kidney injury	Report new DD-cfDNA test cut-off values for acute and chronic kidney injury	6 month
Secondary	Determine if Prospera blood test can replace kidney biopsy test	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.	6 months
Secondary	Assessment of donor-specific antibody status	Report and compare the DSA status based on centralized and local HLA antibody measurement.	6 months