Clinical trial NCT01299168: Diagnostic and Therapeutic Applications in Microarrays in Organ Transplantation
Official title: Multi-centric Observational Study to Analyse the Diagnostic Molecular Features in the Clinical Setting of Kidney Allograft Biopsies
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Validation Study of Molecular Diagnostic System
Development of Reporting System for Molecular Diagnosis
Incorporate Molecular Diagnosis Into Diagnostic Standards
Keywords: global gene expression
molecular diagnostic classifiers
Lead sponsor: University of Alberta
Sponsor class: OTHER
First posted: 2011-02-18
Enrollment: 500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: The study population includes patients with a functioning kidney transplant undergoing a biopsy for clinicalindications as standard of care to determine the cause of their graft dysfunction (deterioration in graft function, delayed graft function, proteinuria).

Brief summary: The current standard for biopsy-based diagnoses of dysfunction of kidney transplants is the Banff Classification which represents arbitrary international consensus. Recent data-driven approaches using molecular and conventional technologies indicate that mere consensus produces frequently 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) has developed a new diagnostic system that combines the molecular and histopathological features of transplant biopsies, plus clinical and laboratory parameters, to create the first Integrated Diagnostic System. The present study will validate and refine this system in 500 prospectively unselected biopsies for clinical indications from American, Canadian and European centres in addition to 300 biopsies already collected. Due to a considerable interest and support from participating Centers, the study is further extended to 1500 prospective biopsies. Thus this is the extension of the INTERCOM study (INTERCOMEX). In addition to demonstrating the feasibility and value of this System in routine patient care and clinical trials, the study will develop and optimize a transparent and user-friendly reporting format to communicate this information to clinicians and obtain detailed feedback on how this system can best improve patient care.

Detailed description: The study has enrolled so far 3012 biopsies from 2313 participants and the results are analyzed for these biopsies. Follow-up data is, and will be collected.

Eligibility criteria: Inclusion Criteria:

* All kidney transplant recipients ≥18yrs of age undergoing a kidney biopsy for clinical indications, as determined by their physician or surgeon, will be eligible to enrol in the study.

Exclusion Criteria:

* Patients will be excluded from the study if they decline participation or are unable to give informed consent.

Primary outcomes:
measure: Validate the Integrated Diagnostic System in the International Collaborative Microarray (INTERCOM) Study
timeFrame: 2013-2016
Secondary outcomes:
measure: Demonstrate the feasibility of molecular phenotyping of 300 + 500 kidney transplant biopsies for clinical indications.
timeFrame: 2014-2016
measure: Demonstrate the feasibility of molecular phenotyping of 500 biopsies in real time i.e. returning the molecular phenotyping report in two working days upon sample arrival.
timeFrame: 2015-2016
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Baltimore
country: United States
facility: University of Maryland School of Medicine
state: Maryland
city: Ann Arbor
country: United States
facility: University of Michigan Health System
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
city: Saint Louis
country: United States
facility: Barnes-Jewish Hospital
state: Missouri
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Harrisburg
country: United States
facility: Pinnacle Transplant Associates
state: Pennsylvania
city: San Antonio
country: United States
facility: Texas Transplant Institute - Methodist Healthcare System
state: Texas
city: Richmond
country: United States
facility: Virginia Commonwealth University School of Medicine
state: Virginia
city: Madison
country: United States
facility: University of Wisconsin School of Medicine and Public Health
state: Wisconsin
city: Vienna
country: Austria
facility: Medical University of Vienna
city: Edmonton
country: Canada
facility: Department of Medicine, University of Alberta
state: Alberta
city: Vancouver
country: Canada
facility: University of British Columbia, St. Paul's Hospital
state: British Columbia
city: Zagreb
country: Croatia
facility: University Hospital Merkur
city: Prague
country: Czechia
facility: Institute for Experimental and Clinical Medicine (IKEM)
city: Paris
country: France
facility: Hopital Necker
city: Paris
country: France
facility: Hopital St. Louis
city: Berlin
country: Germany
facility: Charité - Universitätmedizin Berlin
city: Hannover
country: Germany
facility: Medizinische Hochschule
city: Dublin
country: Ireland
facility: Beaumont Hospital
city: Seoul
country: Korea, Republic of
facility: Department of Surgery, University of Usan, College of Medicine
city: Szczecin
country: Poland
facility: Pomeranian Medical University in Szczecin
city: Ljubljana
country: Slovenia
facility: University of Ljubljana
city: Barcelona
country: Spain
facility: Vall d'Hebron Hospital
city: Zürich
country: Switzerland
facility: University Hospital Zurich
city: Manchester
country: United Kingdom
facility: Manchester Royal Infirmary
Study officials:
affiliation: University of Alberta
name: Philip F Halloran, MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Halloran PF, Famulski KS, Reeve J. Molecular assessment of disease states in kidney transplant biopsy samples. Nat Rev Nephrol. 2016 Sep;12(9):534-48. doi: 10.1038/nrneph.2016.85. Epub 2016 Jun 27.
citation: Halloran PF, Venner JM, Famulski KS. Comprehensive Analysis of Transcript Changes Associated With Allograft Rejection: Combining Universal and Selective Features. Am J Transplant. 2017 Jul;17(7):1754-1769. doi: 10.1111/ajt.14200. Epub 2017 Feb 25.
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.
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: Halloran PF, Chang J, Mackova M, Madill-Thomsen KS, Akalin E, Alhamad T, Anand S, Arnol M, Baliga R, Banasik M, Blosser CD, Bohmig G, Brennan D, Bromberg J, Budde K, Chamienia A, Chow K, Ciszek M, de Freitas D, Deborska-Materkowska D, Debska-Slizien A, Djamali A, Domanski L, Durlik M, Einecke G, Eskandary F, Fatica R, Francis I, Fryc J, Gill J, Gill J, Glyda M, Gourishankar S, Gryczman M, Gupta G, Hruba P, Hughes P, Jittirat A, Jurekovic Z, Kamal L, Kamel M, Kant S, Kojc N, Konopa J, Lan J, Mannon RB, Matas A, Mazurkiewicz J, Miglinas M, Mueller T, Myslak M, Narins S, Naumnik B, Patel A, Perkowska-Ptasinska A, Picton M, Piecha G, Poggio E, Rajnochova Bloudickova S, Schachtner T, Shojai S, Sikosana ML, Slatinska J, Smykal-Jankowiak K, Solanki A, Veceric Haler Z, Viklicky O, Vucur K, Weir MR, Wiecek A, Wlodarczyk Z, Yang H, Zaky Z, Gauthier PT, Hinze C. A cross-sectional study of the role of epithelial cell injury in kidney transplant outcomes. JCI Insight. 2025 Apr 15;10(10):e188658. doi: 10.1172/jci.insight.188658. eCollection 2025 May 22.
citation: Diebold M, Gauthier PT, Mayer KA, Mackova M, Hinze C, Chang J, Patel UD, Schutz E, Jilma B, Schrezenmeier E, Budde K, Bohmig GA, Halloran PF. Effect of felzartamab on the molecular phenotype of antibody-mediated rejection in kidney transplant biopsies. Nat Med. 2025 May;31(5):1668-1676. doi: 10.1038/s41591-025-03653-3. Epub 2025 Apr 29.
citation: Halloran PF, Pereira AB, Chang J, Matas A, Picton M, De Freitas D, Bromberg J, Seron D, Sellares J, Einecke G, Reeve J. Potential impact of microarray diagnosis of T cell-mediated rejection in kidney transplants: The INTERCOM study. Am J Transplant. 2013 Sep;13(9):2352-63. doi: 10.1111/ajt.12387. Epub 2013 Aug 5.
citation: Halloran PF, Pereira AB, Chang J, Matas A, Picton M, De Freitas D, Bromberg J, Seron D, Sellares J, Einecke G, Reeve J. Microarray diagnosis of antibody-mediated rejection in kidney transplant biopsies: an international prospective study (INTERCOM). Am J Transplant. 2013 Nov;13(11):2865-74. doi: 10.1111/ajt.12465. Epub 2013 Oct 3.
citation: Loupy A, Lefaucheur C, Vernerey D, Chang J, Hidalgo LG, Beuscart T, Verine J, Aubert O, Dubleumortier S, Duong van Huyen JP, Jouven X, Glotz D, Legendre C, Halloran PF. Molecular microscope strategy to improve risk stratification in early antibody-mediated kidney allograft rejection. J Am Soc Nephrol. 2014 Oct;25(10):2267-77. doi: 10.1681/ASN.2013111149. Epub 2014 Apr 3.
citation: Halloran PF, Chang J, Famulski K, Hidalgo LG, Salazar ID, Merino Lopez M, Matas A, Picton M, de Freitas D, Bromberg J, Seron D, Sellares J, Einecke G, Reeve J. Disappearance of T Cell-Mediated Rejection Despite Continued Antibody-Mediated Rejection in Late Kidney Transplant Recipients. J Am Soc Nephrol. 2015 Jul;26(7):1711-20. doi: 10.1681/ASN.2014060588. Epub 2014 Nov 6.
citation: Halloran PF, Merino Lopez M, Barreto Pereira A. Identifying Subphenotypes of Antibody-Mediated Rejection in Kidney Transplants. Am J Transplant. 2016 Mar;16(3):908-20. doi: 10.1111/ajt.13551. Epub 2016 Jan 6.
citation: Reeve J, Chang J, Salazar ID, Lopez MM, Halloran PF. Using Molecular Phenotyping to Guide Improvements in the Histologic Diagnosis of T Cell-Mediated Rejection. Am J Transplant. 2016 Apr;16(4):1183-92. doi: 10.1111/ajt.13572. Epub 2016 Jan 5.
citation: Eskandary F, Bond G, Kozakowski N, Regele H, Marinova L, Wahrmann M, Kikic Z, Haslacher H, Rasoul-Rockenschaub S, Kaltenecker CC, Konig F, Hidalgo LG, Oberbauer R, Halloran PF, Bohmig GA. Diagnostic Contribution of Donor-Specific Antibody Characteristics to Uncover Late Silent Antibody-Mediated Rejection-Results of a Cross-Sectional Screening Study. Transplantation. 2017 Mar;101(3):631-641. doi: 10.1097/TP.0000000000001195.
citation: Aubert O, Loupy A, Hidalgo L, Duong van Huyen JP, Higgins S, Viglietti D, Jouven X, Glotz D, Legendre C, Lefaucheur C, Halloran PF. Antibody-Mediated Rejection Due to Preexisting versus De Novo Donor-Specific Antibodies in Kidney Allograft Recipients. J Am Soc Nephrol. 2017 Jun;28(6):1912-1923. doi: 10.1681/ASN.2016070797. Epub 2017 Mar 2.
citation: Halloran PF, Reeve J, Akalin E, Aubert O, Bohmig GA, Brennan D, Bromberg J, Einecke G, Eskandary F, Gosset C, Duong Van Huyen JP, Gupta G, Lefaucheur C, Malone A, Mannon RB, Seron D, Sellares J, Weir M, Loupy A. Real Time Central Assessment of Kidney Transplant Indication Biopsies by Microarrays: The INTERCOMEX Study. Am J Transplant. 2017 Nov;17(11):2851-2862. doi: 10.1111/ajt.14329. Epub 2017 May 30.
citation: Reeve J, Bohmig GA, Eskandary F, Einecke G, Lefaucheur C, Loupy A, Halloran PF; MMDx-Kidney study group. Assessing rejection-related disease in kidney transplant biopsies based on archetypal analysis of molecular phenotypes. JCI Insight. 2017 Jun 15;2(12):e94197. doi: 10.1172/jci.insight.94197. eCollection 2017 Jun 15.
citation: Madill-Thomsen KS, Wiggins RC, Eskandary F, Bohmig GA, Halloran PF. The Effect of Cortex/Medulla Proportions on Molecular Diagnoses in Kidney Transplant Biopsies: Rejection and Injury Can Be Assessed in Medulla. Am J Transplant. 2017 Aug;17(8):2117-2128. doi: 10.1111/ajt.14233. Epub 2017 Mar 23.
citation: Halloran PF, Matas A, Kasiske BL, Madill-Thomsen KS, Mackova M, Famulski KS. Molecular phenotype of kidney transplant indication biopsies with inflammation in scarred areas. Am J Transplant. 2019 May;19(5):1356-1370. doi: 10.1111/ajt.15178. Epub 2018 Dec 13.
citation: Reeve J, Bohmig GA, Eskandary F, Einecke G, Gupta G, Madill-Thomsen K, Mackova M, Halloran PF; INTERCOMEX MMDx-Kidney Study Group. Generating automated kidney transplant biopsy reports combining molecular measurements with ensembles of machine learning classifiers. Am J Transplant. 2019 Oct;19(10):2719-2731. doi: 10.1111/ajt.15351. Epub 2019 Apr 10.
citation: Madill-Thomsen K, Perkowska-Ptasinska A, Bohmig GA, Eskandary F, Einecke G, Gupta G, Halloran PF; MMDx-Kidney Study Group. Discrepancy analysis comparing molecular and histology diagnoses in kidney transplant biopsies. Am J Transplant. 2020 May;20(5):1341-1350. doi: 10.1111/ajt.15752. Epub 2020 Jan 23.
citation: Einecke G, Reeve J, Gupta G, Bohmig GA, Eskandary F, Bromberg JS, Budde K, Halloran PF; INTERCOMEX investigators. Factors associated with kidney graft survival in pure antibody-mediated rejection at the time of indication biopsy: Importance of parenchymal injury but not disease activity. Am J Transplant. 2021 Apr;21(4):1391-1401. doi: 10.1111/ajt.16161. Epub 2020 Jul 31.
citation: Madill-Thomsen KS, Bohmig GA, Bromberg J, Einecke G, Eskandary F, Gupta G, Myslak M, Viklicky O, Perkowska-Ptasinska A, Solez K, Halloran PF; the INTERCOMEX Investigators. Relating Molecular T Cell-mediated Rejection Activity in Kidney Transplant Biopsies to Time and to Histologic Tubulitis and Atrophy-fibrosis. Transplantation. 2023 May 1;107(5):1102-1114. doi: 10.1097/TP.0000000000004396. Epub 2023 Apr 22.
citation: Halloran PF, Bohmig GA, Bromberg J, Einecke G, Eskandary FA, Gupta G, Myslak M, Viklicky O, Perkowska-Ptasinska A, Madill-Thomsen KS; INTERCOMEX Investigators. Archetypal Analysis of Injury in Kidney Transplant Biopsies Identifies Two Classes of Early AKI. Front Med (Lausanne). 2022 Apr 7;9:817324. doi: 10.3389/fmed.2022.817324. eCollection 2022.
citation: Sikosana MLN, Reeve J, Madill-Thomsen KS, Halloran PF; INTERCOMEX Investigators. Using Regression Equations to Enhance Interpretation of Histology Lesions of Kidney Transplant Rejection. Transplantation. 2024 Feb 1;108(2):445-454. doi: 10.1097/TP.0000000000004783. Epub 2024 Jan 19.
citation: Halloran PF, Madill-Thomsen KS, Bohmig G, Bromberg J, Budde K, Barner M, Mackova M, Chang J, Einecke G, Eskandary F, Gupta G, Myslak M, Viklicky O, Akalin E, Alhamad T, Anand S, Arnol M, Baliga R, Banasik M, Bingaman A, Blosser CD, Brennan D, Chamienia A, Chow K, Ciszek M, de Freitas D, Deborska-Materkowska D, Debska-Slizien A, Djamali A, Domanski L, Durlik M, Fatica R, Francis I, Fryc J, Gill J, Gill J, Glyda M, Gourishankar S, Grenda R, Gryczman M, Hruba P, Hughes P, Jittirat A, Jurekovic Z, Kamal L, Kamel M, Kant S, Kasiske B, Kojc N, Konopa J, Lan J, Mannon R, Matas A, Mazurkiewicz J, Miglinas M, Muller T, Narins S, Naumnik B, Patel A, Perkowska-Ptasinska A, Picton M, Piecha G, Poggio E, Bloudickova SR, Samaniego-Picota M, Schachtner T, Shin S, Shojai S, Sikosana MLN, Slatinska J, Smykal-Jankowiak K, Solanki A, Veceric Haler Z, Vucur K, Weir MR, Wiecek A, Wlodarczyk Z, Yang H, Zaky Z. Subthreshold rejection activity in many kidney transplants currently classified as having no rejection. Am J Transplant. 2025 Jan;25(1):72-87. doi: 10.1016/j.ajt.2024.07.034. Epub 2024 Aug 6.
citation: Halloran PF, Madill-Thomsen KS, Bohmig GA, Myslak M, Gupta G, Kumar D, Viklicky O, Perkowska-Ptasinska A, Famulski KS; INTERCOMEX Investigators. A 2-fold Approach to Polyoma Virus (BK) Nephropathy in Kidney Transplants: Distinguishing Direct Virus Effects From Cognate T Cell-mediated Inflammation. Transplantation. 2021 Nov 1;105(11):2374-2384. doi: 10.1097/TP.0000000000003884.
citation: Madill-Thomsen KS, Bohmig GA, Bromberg J, Einecke G, Eskandary F, Gupta G, Hidalgo LG, Myslak M, Viklicky O, Perkowska-Ptasinska A, Halloran PF; INTERCOMEX Investigators. Donor-Specific Antibody Is Associated with Increased Expression of Rejection Transcripts in Renal Transplant Biopsies Classified as No Rejection. J Am Soc Nephrol. 2021 Nov;32(11):2743-2758. doi: 10.1681/ASN.2021040433. Epub 2021 Jul 12.
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.
citation: Halloran PF, Bohmig GA, Bromberg JS, Budde K, Gupta G, Einecke G, Eskandary F, Madill-Thomsen K, Reeve J; INTERCOMEX investigators. Discovering novel injury features in kidney transplant biopsies associated with TCMR and donor aging. Am J Transplant. 2021 May;21(5):1725-1739. doi: 10.1111/ajt.16374. Epub 2020 Nov 30.
citation: Venner JM, Famulski KS, Reeve J, Chang J, Halloran PF. Relationships among injury, fibrosis, and time in human kidney transplants. JCI Insight. 2016 Jan 21;1(1):e85323. doi: 10.1172/jci.insight.85323.