Clinical trial NCT02670408: Diagnostic and Therapeutic Applications of Microarrays in Heart Transplantation
Official title: Diagnostic and Therapeutic Applications of Microarrays in Heart Transplantation, a Multicenter Study (INTERHEART)
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Cardiac Transplant Disorder
Keywords: Heart transplant
global gene expression
molecular diagnostics
Lead sponsor: University of Alberta
Sponsor class: OTHER
First posted: 2016-02-01
Enrollment: 900
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 1200 biopsies from heart transplant patients for clinical indications and the standard of care biopsies.

Brief summary: Demonstrate the impact of the Molecular Microscope Diagnostic System as the standard of care for heart transplant patients.

Detailed description: The current standard for biopsy-based diagnoses of rejection of heart transplants is the ISHLT classification from 2004, which represents a widely-used international consensus, based on morphological criteria of the cellular infiltrate within the myocardial specimen system with certainties and some arbitrary and blurred parameters. Recent data-driven approaches using molecular and conventional technologies indicate that this system produces incorrect diagnoses with potential 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 heart transplant endomyocardial biopsies (EMBs). The present study will develop a Reference Set of EMB, adapt the MMDx system to assess and report EMBs; and validate and refine this system in 900 unselected prospectively collected for clinical indications and a standard of care EMBs 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. We refine now our MMDx system using a new type of analysis (see primary outcome) and the resulting MMDx report. Currently, INTERHEART recruited 1912 biopsies from 1279 patients.

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 heart transplant biopsies, in a reference set of 200 biopsies
timeFrame: 2 years
Secondary outcomes:
measure: Assign in real time (three working days upon biopsy receipt) molecular scores (probability) of T cell mediated rejection and antibody mediated rejection.
timeFrame: 1 year
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA Medical Centre
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Heart Institute
state: California
city: Dallas
country: United States
facility: Annette C. and Harold C. Simmons Transplant Institute, BaylorScott&amp;White Research Institute
state: Texas
city: Salt Lake City
country: United States
facility: Cardiovascular Medicine, University of Utah Health
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University, Division of Cardiology
state: Virginia
city: Darlinghurst
country: Australia
facility: Cardiac Transplantation Laboratory, The Victor Chang Cardiac Research Institute
city: Vienna
country: Austria
facility: Department of Cardiac Surgery, Medical University of Vienna
city: Edmonton
country: Canada
facility: Alberta Transplant Applied Genomics Center, University of Alberta
state: Alberta
city: Edmonton
country: Canada
facility: Division of Cardiology, University of Alberta
state: Alberta
city: Prague
country: Czechia
facility: Institute for Clinical and Experimental Medicine - IKEM
city: Paris
country: France
facility: Service de Néphrologie-Dialyse Adultes , Hôpital Necker-Enfants Malades
city: Bologna
country: Italy
facility: Heart Failure and Heart Transplant Unit, University of Bologna
city: La Coruna
country: Spain
facility: Advanced Heart Failure Transplant Unit
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: Loupy A, Duong Van Huyen JP, Hidalgo L, Reeve J, Racape M, Aubert O, Venner JM, Falmuski K, Bories MC, Beuscart T, Guillemain R, Francois A, Pattier S, Toquet C, Gay A, Rouvier P, Varnous S, Leprince P, Empana JP, Lefaucheur C, Bruneval P, Jouven X, Halloran PF. Gene Expression Profiling for the Identification and Classification of Antibody-Mediated Heart Rejection. Circulation. 2017 Mar 7;135(10):917-935. doi: 10.1161/CIRCULATIONAHA.116.022907. Epub 2017 Feb 1.
citation: Halloran PF, Potena L, Van Huyen JD, Bruneval P, Leone O, Kim DH, Jouven X, Reeve J, Loupy A. Building a tissue-based molecular diagnostic system in heart transplant rejection: The heart Molecular Microscope Diagnostic (MMDx) System. J Heart Lung Transplant. 2017 Nov;36(11):1192-1200. doi: 10.1016/j.healun.2017.05.029. Epub 2017 May 29.
citation: Halloran PF, Reeve J, Aliabadi AZ, Cadeiras M, Crespo-Leiro MG, Deng M, Depasquale EC, Goekler J, Jouven X, Kim DH, Kobashigawa J, Loupy A, Macdonald P, Potena L, Zuckermann A, Parkes MD. Exploring the cardiac response to injury in heart transplant biopsies. JCI Insight. 2018 Oct 18;3(20):e123674. doi: 10.1172/jci.insight.123674.
citation: Parkes MD, Aliabadi AZ, Cadeiras M, Crespo-Leiro MG, Deng M, Depasquale EC, Goekler J, Kim DH, Kobashigawa J, Loupy A, Macdonald P, Potena L, Zuckermann A, Halloran PF. An integrated molecular diagnostic report for heart transplant biopsies using an ensemble of diagnostic algorithms. J Heart Lung Transplant. 2019 Jun;38(6):636-646. doi: 10.1016/j.healun.2019.01.1318. Epub 2019 Feb 6.
citation: Halloran PF, Madill-Thomsen KS. The Molecular Microscope Diagnostic System: Assessment of Rejection and Injury in Heart Transplant Biopsies. Transplantation. 2023 Jan 1;107(1):27-44. doi: 10.1097/TP.0000000000004323. Epub 2022 Dec 8.
citation: Halloran PF, Madill-Thomsen K, Mackova M, Aliabadi-Zuckermann AZ, Cadeiras M, Crespo-Leiro MG, Depasquale EC, Deng M, Gokler J, Hall SA, Kim DH, Kobashigawa J, Macdonald P, Potena L, Shah K, Stehlik J, Zuckermann A, Reeve J. Molecular states associated with dysfunction and graft loss in heart transplants. J Heart Lung Transplant. 2024 Mar;43(3):508-518. doi: 10.1016/j.healun.2023.11.013. Epub 2023 Nov 30.
citation: Halloran PF, Madill-Thomsen K, Aliabadi-Zuckermann AZ, Cadeiras M, Crespo-Leiro MG, Depasquale EC, Deng M, Gokler J, Kim DH, Kobashigawa J, Macdonald P, Potena L, Shah K, Stehlik J, Zuckermann A. Many heart transplant biopsies currently diagnosed as no rejection have mild molecular antibody-mediated rejection-related changes. J Heart Lung Transplant. 2022 Mar;41(3):334-344. doi: 10.1016/j.healun.2021.08.004. Epub 2021 Aug 26.
citation: Halloran PF, Madill-Thomsen K, Aliabadi-Zuckermann AZ, Cadeiras M, Crespo-Leiro MG, Depasquale EC, Deng M, Gokler J, Hall S, Jamil A, Kim DH, Kobashigawa J, Macdonald P, Melenovsky V, Patel J, Potena L, Shah K, Stehlik J, Zuckermann A. Redefining the molecular rejection states in 3230 heart transplant biopsies: Relationships to parenchymal injury and graft survival. Am J Transplant. 2024 Aug;24(8):1414-1426. doi: 10.1016/j.ajt.2024.03.031. Epub 2024 Mar 26.
citation: Madill-Thomsen KS, Reeve J, Aliabadi-Zuckermann A, Cadeiras M, Crespo-Leiro MG, Depasquale EC, Deng M, Goekler J, Kim DH, Kobashigawa J, Macdonald P, Potena L, Shah K, Stehlik J, Zuckermann A, Halloran PF. Assessing the Relationship Between Molecular Rejection and Parenchymal Injury in Heart Transplant Biopsies. Transplantation. 2022 Nov 1;106(11):2205-2216. doi: 10.1097/TP.0000000000004231. Epub 2022 Oct 21.
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.