Clinical trial NCT05837663: Trifecta-Lung cfDNA-MMDx Study
Official title: Trifecta-Lung cfDNA-MMDx Study: Comparing the Dd-cfDNA Test to MMDx Microarray Test and Central HLA Antibody Test
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Lung Transplantation
Keywords: Donor derived cfDNA
Gene expression
Lung transplant biopsy
Blood
Lead sponsor: University of Alberta
Sponsor class: OTHER
Collaborators: name: Natera, Inc.
name: One Lambda
First posted: 2023-05-01
Enrollment: 600
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: All adult lung transplant recipients undergoing indication biopsy for suspected graft dysfunction will be eligible.

Brief summary: Demonstrate the relationship between dd-cfDNA levels and HLA antibodies in blood transplant recipient and Demonstrate the Molecular Microscope® (MMDx) Diagnostic System results in indication and protocol biopsies from lung transplants.

Detailed description: The current standard for assessment of rejection in lung transplants is a transbronchial biopsy (TBB) interpreted by histology according to International Society of Heart and Lung Transplantation (ISHLT) guidelines. This has considerable error rates, many due to the high disagreement among pathologists. There is a need for new methods of assessing TBBs. Furthermore, by analyzing different types of biopsies (TBBs and endobronchial - 3BMBs), we hope to improve the safety of the biopsy procedure, while maintaining its accuracy. The emergence of blood donor-derived cell-free DNA (dd-cfDNA) measurement offers a new opportunity for screening for rejection. 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 genome-wide gene expression and interpret lung transplant rejection and injury ((chronic lung allograft dysfunction (CLAD) related changes)). Now a new screening test is being introduced: the monitoring of 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 lung transplant recipients. dd-cf-DNA test for lung 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-like) and tissue injury. The present study will compare dd-cfDNA and MMDx in 600 prospectively collected TBBs and 3BMBs for clinical indications and protocol, and accompanying 1800 blood samples, to calibrate the dd-cfDNA (Natera Inc.) levels against the MMDx biopsy diagnoses of TCMR, ABMR-like (and its stages), and injury, as well as central assessment of Human Leukocyte Antibody (HLA) antibody (One Lambda), interpreted centrally as donor specific antibody (DSA) based on the tissue typing results. This study is an extension of the INTERLUNG ClinicalTrials.gov identifier: NCT02812290.

Currently the study accrued 108 paired TBBs and 3BMBs, 9 TBBs, and 64 corresponding blood samples for dd-cfDNA test.

Eligibility criteria: Inclusion Criteria:

Adult, Older adult

Exclusion Criteria:

Patients will be excluded from the study if they decline participation Are unable to give informed consent. Recipients of multiple organs, cancer patients and pregnant women

Primary outcomes:
measure: Calibration of Prospera® test for T cell mediated rejection
timeFrame: 18 months
measure: Calibration of Prospera® test for antibody-mediated rejection
timeFrame: 18 months
measure: Calibration of Prospera® test for lung injury
timeFrame: 18 months
measure: Report calibrated Prospera® test results for rejection
timeFrame: 6 months
measure: Report calibrated Prospera® test results for lung injury
timeFrame: 6 months
Secondary outcomes:
measure: Assessment of donor-specific antibody status
timeFrame: 6 months
measure: .Estimate the false positive rate of dd-cfDNA for MMDx and histology in indication and protocol biopsies
timeFrame: 6 months
measure: Determine whether calibrated dd-cfDNA blood test will replace biopsies
timeFrame: 6 months
measure: Determine whether calibrated dd-cfDNA blood test predicts the effect of treatment
timeFrame: 6 months
Other outcomes:
Locations:
city: Gainesville
country: United States
facility: Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida, College of Medicine
state: Florida
city: Tampa
country: United States
facility: USF Health, Morsani College of Medicine, 12901 Bruce B. Downs Blvd. MDC40
state: Florida
city: New York
country: United States
facility: Division of Pulmonary, Allergy & Critical Care Medicine Columbia University Irving Medical Center
state: New York
city: Dallas
country: United States
facility: BAYLOR SCOTT & WHITE RESEARCH INSTITUTE , 3409 Worth Street
state: Texas
city: Melbourne
country: Australia
facility: The Alfred Hospital, Monash University
city: Vienna
country: Austria
facility: Department of Thoracic Surgery, Medical University of Vienna
city: Edmonton
country: Canada
facility: Department of Medicine, University of Alberta
state: Alberta
city: Edmonton
country: Canada
facility: Alberta Transplant Applied Genomics Centre, University of Alberta
state: Alberta
city: Toronto
country: Canada
facility: University Health Network, Toronto General Hospital
state: Ontario
city: Prague
country: Czechia
facility: Motol University Hospital, V Uvalu 84
city: Prague
country: Czechia
facility: Charles University/Hospital Motol
Study officials:
affiliation: Alberta Transplant Applied Genomics Centre, University of Alberta
name: Philip F Halloran, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: