Clinical trial NCT03193151: Diagnostic and Therapeutic Applications of Microarrays in Liver Transplantation
Official title: Diagnostic and Therapeutic Applications of Microarrays in Liver Transplantation, a Multicenter Study
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Liver Dysfunction
Keywords: Liver transplant
global gene expression
molecular diagnostics
Lead sponsor: University of Alberta
Sponsor class: OTHER
First posted: 2017-06-20
Enrollment: 300
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: This study aims to recruit 300 biopsies from liver transplant patients for clinical indications and the standard of care biopsies.

Brief summary: INTERLIVER is a prospective observational study of the relationship of the molecular phenotype of 300 liver transplant biopsies to the histologic phenotype and the clinical features and outcomes. A segment of a biopsy performed as standard-of-care for indications, or by center protocol, will be used for gene expression study.

Detailed description: The current standard for biopsy-based diagnoses of dysfunction of liver transplants is histology (the Banff system), an arbitrary international empirical consensus based on lesions and rules, similar in principle to the kidney, heart, and lung histology systems. Recent data-driven approaches using molecular and conventional technologies indicate that such systems frequently produce incorrect diagnoses - perhaps 40-50% in abnormal kidney or heart transplant biopsies and even more in lung biopsies, with great potential for harm to patients due to inappropriate treatment.

To address this unmet need and improve diagnostics in the area of organ transplantation, the Alberta Transplant Applied Genomics Centre (ATAGC, University of Alberta) has developed a new diagnostic system - the Molecular Microscope® Diagnostic System (MMDx) that interprets biopsies in terms of their molecular phenotype, and combines the molecular and histopathological features of transplant biopsies, plus clinical and laboratory parameters, to create the first Integrated Diagnostic System. The MMDx, developed first in kidney transplant biopsies because phenotypes are well established, will now be adapted to liver transplant biopsies. The present study will develop a Reference Set of liver biopsies, adapt the MMDx system to assess and report molecular phenotype of liver biopsies; and validate and refine this system in 300 unselected prospectively collected for clinical indications and a standard of care biopsies from North American and European Centers. In addition to demonstrating the real-time feasibility and potential value of this System in patient care, the study will develop and optimize a transparent and user-friendly reporting format to communicate this information to clinicians and obtain detailed feedback to improve its utility.

Thanks to increasing interest and support from participating centers, INTERLIVER has already received 861 biopsies from 739 participants and will extend the Reference Set to 900 biopsies.

Eligibility criteria: Inclusion Criteria:

* biopsy for clinical indications

Exclusion Criteria:

* no consent, pregnant women

Primary outcomes:
measure: Assign molecular scores (probability) of T cell mediated rejection, antibody mediated rejection in liver transplant biopsies, in a reference set of 100 biopsies
timeFrame: two years
Secondary outcomes:
measure: Assign in real time (two working days upon biopsy receipt) molecular scores (probability) of T cell mediated rejection and antibody mediated rejection.
timeFrame: 1 year
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California San Francisco, Transplant Research Unit
state: California
city: Chicago
country: United States
facility: Northwestern Memorial Hospital
state: Illinois
city: Baltimore
country: United States
facility: University of Maryland School of Medicine
state: Maryland
city: Detroit
country: United States
facility: Henry Ford Transplant Institute
state: Michigan
city: Nashville
country: United States
facility: Vanderbilt University Medical Center, Vanderbilt Transplant Center
state: Tennessee
city: Dallas
country: United States
facility: Baylor University Medical Center, Annette C. and Harold C. Simmons Transplant Institute
state: Texas
city: Richmond
country: United States
facility: Transplant Surgery, VCU Medical Center
state: Virginia
city: Seattle
country: United States
facility: Division of Transplant Surgery, University of Washington
state: Washington
city: Camperdown
country: Australia
facility: Centenary Institute of Cancer Medicine & Cell Biology, Royal Prince Alfred Hospital
city: Edmonton
country: Canada
facility: University of Alberta, Laboratory Medicine and Pathology
state: Alberta
city: Katowice
country: Poland
facility: Dep. of Nephrology, Transplantation & Internal Med., Samodzielny Publiczny Szpital Kliniczny im. A. Mieleckiego
city: Szczecin
country: Poland
facility: Independent Public Composite Regional Hospital
city: Warszawa
country: Poland
facility: Warsaw Medical University, Jesus the Child Clinical Hospital
city: Warszawa
country: Poland
facility: Warsaw Medical University, Independent Public Clinical Hospital
city: London
country: United Kingdom
facility: Institute for Liver Science, King's College London
Study officials:
affiliation: University of Alberta
name: Philip F Halloran, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.
citation: Madill-Thomsen KS, Gauthier PT, Abouljoud M, Bhati C, Bruno D, Ciszek M, Durlik M, Feng S, Foroncewicz B, Grat M, Jurczyk K, Levitsky J, McCaughan G, Maluf D, Montano-Loza A, Moonka D, Mucha K, Myslak M, Perkowska-Ptasinska A, Piecha G, Reichman T, Tronina O, Wawrzynowicz-Syczewska M, Zeair S, Halloran PF. Defining an NK Cell-enriched Rejection-like Phenotype in Liver Transplant Biopsies From the INTERLIVER Study. Transplantation. 2025 Jan 9. doi: 10.1097/TP.0000000000005269. Online ahead of print.
citation: Madill-Thomsen K, Abouljoud M, Bhati C, Ciszek M, Durlik M, Feng S, Foroncewicz B, Francis I, Grat M, Jurczyk K, Klintmalm G, Krasnodebski M, McCaughan G, Miquel R, Montano-Loza A, Moonka D, Mucha K, Myslak M, Paczek L, Perkowska-Ptasinska A, Piecha G, Reichman T, Sanchez-Fueyo A, Tronina O, Wawrzynowicz-Syczewska M, Wiecek A, Zieniewicz K, Halloran PF. The molecular diagnosis of rejection in liver transplant biopsies: First results of the INTERLIVER study. Am J Transplant. 2020 Aug;20(8):2156-2172. doi: 10.1111/ajt.15828. Epub 2020 Apr 9.
citation: Madill-Thomsen KS, Abouljoud M, Bhati C, Ciszek M, Durlik M, Feng S, Foroncewicz B, Francis I, Grat M, Jurczyk K, Klintmalm G, Krasnodebski M, McCaughan G, Miquel R, Montano-Loza A, Moonka D, Mucha K, Myslak M, Paczek L, Perkowska-Ptasinska A, Piecha G, Reichman T, Sanchez-Fueyo A, Tronina O, Wawrzynowicz-Syczewska M, Wiecek A, Zieniewicz K, Halloran PF. The molecular phenotypes of injury, steatohepatitis, and fibrosis in liver transplant biopsies in the INTERLIVER study. Am J Transplant. 2022 Mar;22(3):909-926. doi: 10.1111/ajt.16890. Epub 2021 Dec 3.
citation: Halloran PF. Integrating molecular and histologic interpretation of transplant biopsies. Clin Transplant. 2021 Apr;35(4):e14244. doi: 10.1111/ctr.14244. Epub 2021 Feb 17. No abstract available.