Clinical trial NCT03652402: Precision Risk Stratification in Kidney Transplant Patients - EU-TRAIN
Official title: The EUropean TRAnsplantation and INnovation Consortium for Risk Stratification in Kidney Transplant Patients
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Kidney Transplant Rejection
Kidney Transplantation
Risk Stratification
Prognosis
Keywords: Kidney
Allogenic transplantation
Cohort study
Rejection
Biomarkers
Response to treatment
Integrative medicine
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2018-08-29
Enrollment: 558
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: New kidney transplants patients

Brief summary: Main objective: To design a precision risk stratification system that predicts individual risk of rejection

Detailed description: Allograft rejection is still a major threat to allografts with thousands of allografts failing every year worldwide due to organ rejection, with immediate consequences for the patients in terms of mortality and morbidity. With a prevalence around 20% in the first-year post transplant, rejection also carries high economic impact representing a 72% increase in transplantation price and downstream cost because of return on dialysis (60,000€ health care increase per patient). The rough estimates from 200,000 kidney allograft failures per year equals to 12 billion extra cost for the health care system per year.

Various explanations may be involved: 1) The current stratification system relies on various elements of the follow up of standard of care after kidney transplantation (histology, immunology) taken separately and, 2) Current therapeutic strategy is a "one fit for all" approach. Literature data show that therapeutics are not individualized, with 98% of patients having the same immunosuppressive regimens without analysis of response to therapy; 3) Lack of integration of omics in the stratification process. Today, the only approaches used to monitor the advent of immune-mediated allograft damage are nonspecific markers such as serum creatinine level and proteinuria which are not integrated in a dynamic approach. Some kidney transplant programs have implemented surveillance allograft biopsies, but they lack specificity and sensitivity and do not provide etiopathology of the underlying process. This impairs the risk stratification process.

In this project, leading European scientific teams, which have created relevant population cohorts and expertise, have joined forces to allow for large-scale (\>5,000 patients) risk prediction studies in the field of kidney transplantation. The overall goal of the EUropean TRAnsplantation and INnovation consortium (EU-TRAIN) is to prevent kidney allograft failure and improve allograft survival by informing clinical decision and delivering optimised interventions to patients at individual level. The project aims to improve the current gold standard for risk stratification and prognosis among kidney transplant recipients.

The members of the EU-TRAIN consortium have invested heavily in the last decade to create large highly detailed European kidney transplant cohorts and to achieve best level scientific expertise in the assessment of innovative biomarkers and rejection reclassification on the basis of disease mechanism using gene expression. Ground-breaking concrete results have already been obtained that have changed patient care and transplant medicine guidelines: This is underlined by highly cited publications in the leading specialised journals and also in journals aimed at a popular audience that underlines the systemic nature of this approach, (NEJM (n=10), Lancet (n=2), BMJ (n=1), JASN (n=18)). Using this approach, the investigators have recently identified new forms of allograft rejection, resulting in changes in the most recent international allograft Banff classification and reclassifying rejection diagnosis and disease stage. This research strategy also led to recently demonstrate the clinical relevance of new non-invasive biomarkers for defining the pathogenicity of anti-HLA antibodies and allograft loss risk assessment and incorporate gene expression measurements in allograft rejection risk stratification.

The EU-TRAIN project will further elevate these cohorts synergistically by adding data on novel biomarkers, so far underdeveloped in kidney transplant research, in particular genomics and immunological data. A comprehensive integration strategy of these exceptionally large and complete cohorts constitutes a quantum leap in transplant research, and offers a unique opportunity, out of reach so far, to design strategies for truly personalised medicine.

The expected benefit for participants and society will be to reduce the financial burden of graft rejection for society.

500 new transplanted patients in the 7 clinical transplant sites will be included in the prospective multicentre EU-TRAIN cohort with centralised analysis of samples in CHUN (blood mRNA), ICS (blood cellular assays), Charité (non-HLA antibodies and blood endothelial targets), AP-HP (blood anti-HLA DSA), and INSERM (Biopsy mRNA).

Vulnerable participants excluded.

Schedule for the study:

* inclusion period: 12 months
* participation period (treatment - follow-up): 12 months
* total duration of the study: 24 months

Exclusion period for participation in other studies, and justification: the participation to other minimal risks and constraints studies and observational non-interventional studies is allowed during this study. There is no exclusion period at the end of study. The participation to other interventional and observational non-interventional studies is allowed after the end of the study.

Number of enrolments expected per site and per month :

* Necker Hospital, Paris: 10 patients / month
* Saint-Louis Hospital, Paris: 6 patients / month
* CHU Nantes: 10 patients / month
* Charité-Universitätsmedizin, Campus Virchow Klinikum, Berlin: 4 patients / month
* Charité-Universitätsmedizin, Campus Mitte, Berlin: 3 patients / month
* Bellvitge University Hospital, Barcelona: 7 patients / month
* Geneva University Hospitals, Geneva: 2 patients / month
* Vall d'Hebron Hospital, Barcelona : 6 patients / month
* Kremlin Bicêtre Hospital, Paris : 4 patients / month

Eligibility criteria: Inclusion Criteria:

* Men and women, Age ≥ 18 years old at the time of transplantation.
* Patients receiving a living or deceased donor kidney allograft.
* Patients who signed the informed consent form and willing to comply with study procedures.
* Female patients of child-bearing potential must have a negative pregnancy test (serum beta-hCG) and must be practicing an effective, reliable and medically approved contraceptive regimen

Exclusion Criteria:

* History of multi-organ transplant (interference with rejection natural history).
* Participant is unable or unwilling to comply with study procedures (including foreign language speakers who are not assisted by a native language speaker).
* Vulnerable participants (minors, protected adults, legally detained)

Primary outcomes:
measure: Capacity of non-invasive biomarkers and intragraft gene expression profiles combined to standard of care data (HLA system, clinical and biological data)
timeFrame: Day 0, Month 3, Month 12, clinical indication over 12 months
Secondary outcomes:
measure: Correlation of blood biomarkers concentration with allograft rejection (rejection assessed by histopathology)
timeFrame: Day 0, Month 3, Month12, clinical indication over 12 months
measure: Correlation of blood biomarker concentrations with allograft function (function measured by the Glomerular Filtration Rate (GFR)).
timeFrame: Day 0, Month 3, Month12, clinical indication over 12 months
measure: Assessment of changes in biomarker levels in serial measurements and association with allograft function (function measured by the GFR)
timeFrame: Day 0, Month 3, Month12, clinical indication over 12 months
measure: Correlation of gene expression in kidney allografts with allograft rejection (rejection assessed by histopathology)
timeFrame: Day 0, Month 3, Month 12, clinical indication over 12 months
measure: Gene expression related risk stratification of response to treatment in kidney allograft rejection (rejection assessed by histopathology)
timeFrame: Day 0, Month 3, Month12, clinical indication over 12 months
measure: Assessment of the changes of patient's well-being across time and centres
timeFrame: Day 0, Month 3, Month12, clinical indication over 12 months
Other outcomes:
Locations:
city: Paris
country: France
facility: Hopital Saint Louis
state: Ile De France
city: Le Kremlin-Bicêtre
country: France
facility: Hôpital du Kremlin Bicêtre
state: Paris
city: Nantes
country: France
facility: CHU Nantes
city: Paris
country: France
facility: Hôpital Necker
city: Berlin-Mitte
country: Germany
facility: Hospital La Charité
state: Berlin
city: Berlin
country: Germany
facility: Hospital La Charité Campus Virchow
city: Barcelona
country: Spain
facility: Hospital Bellvitge
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Geneva
country: Switzerland
facility: Hôpitaux Universitaires de Genève
Study officials:
affiliation: Institut National de la Santé Et de la Recherche Médicale, France
name: Alexandre Loupy, Pr
role: STUDY_DIRECTOR
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