Diagnostic and Therapeutic Applications of Microarrays in Heart Transplantation

Официальное название

Diagnostic and Therapeutic Applications of Microarrays in Heart Transplantation, a Multicenter Study (INTERHEART)

Обзор

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

Подробное описание

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.

Вмешательства

• Процедура Endomyocardial biopsy
  One of several endomyocardial biopsy bites taken as the standard of care. We are asking now for two endomyocardial biopsy bites, to determine tissue sampling variability.

Первичные конечные точки

• Assign molecular scores (probability) of T cell mediated rejection, antibody mediated rejection in heart transplant biopsies, in a reference set of 200 biopsies [Срок оценки: 2 years]

Вторичные конечные точки (1)

• Assign in real time (three working days upon biopsy receipt) molecular scores (probability) of T cell mediated rejection and antibody mediated rejection. [Срок оценки: 1 year]

Критерии участия

Критерии включения

• biopsy for clinical indications

Критерии исключения

• no consent
• pregnant women

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Модель наблюдения

Когортное

Центры проведения

США · 5 центров

• UCLA Medical Centre — Los Angeles
• Cedars-Sinai Heart Institute — Los Angeles
• Annette C. and Harold C. Simmons Transplant Institute, BaylorScott&White Research Inst — Dallas
• Cardiovascular Medicine, University of Utah Health — Salt Lake City
• Virginia Commonwealth University, Division of Cardiology — Richmond

Канада · 2 центра

• Alberta Transplant Applied Genomics Center, University of Alberta — Edmonton
• Division of Cardiology, University of Alberta — Edmonton

Австралия · 1 центр

• Cardiac Transplantation Laboratory, The Victor Chang Cardiac Research Institute — Darlinghurst

Австрия · 1 центр

• Department of Cardiac Surgery, Medical University of Vienna — Vienna

Чехия · 1 центр

• Institute for Clinical and Experimental Medicine - IKEM — Prague

Франция · 1 центр

• Service de Néphrologie-Dialyse Adultes , Hôpital Necker-Enfants Malades — Paris

Италия · 1 центр

• Heart Failure and Heart Transplant Unit, University of Bologna — Bologna

Испания · 1 центр

• Advanced Heart Failure Transplant Unit — A Coruña

Публикации

• 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. PMID 38819301
• 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) PMID 28148598
• 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. PMID 28662985
• 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. PMID 30333303
• 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. PMID 30795962
• 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. PMID 36508644
• 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 PMID 38042442
• 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.2 PMID 34548198

Идентификаторы

NCT: NCT02670408 · ATAGC 002

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗