Molecular Diagnosis of Heart Allograft Rejection Using Intra-Graft Targeted Gene Expression Profiling. (Nano-Heart)

May 28, 2024 updated by: Paris Translational Research Center for Organ Transplantation

The goal of this observational study is to develop and validate a molecular heart rejection diagnostic system based on targeted transcriptome as a novel monitoring companion tool for heart allograft precision diagnostics applicable to formalin-fixed paraffin-embedded endomyocardial biopsies.

The primary outcome will be the biopsy-proven rejection, that will be predicted with molecular classifiers (cellular and antibody-mediated rejection scores).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Heart transplantation (HTx) remains the most valuable therapeutic option for patients with end-stage heart failure refractory to optimal medical therapy. Despite major improvements in immunosuppression and transplant care, acute and chronic rejection-induced allograft injuries remain one of the leading causes of mortality and morbidity after heart transplantation, thus limiting recipients' life expectancy. An improvement in the overall management of rejection remains an unmet medical need. As a first step, a precise diagnosis of rejection is crucial to guide patient care and optimize management.

Nowadays, the diagnosis of cardiac rejection relies exclusively on the pathological assessment of endomyocardial biopsies (EMBs) by identifying and grading cellular infiltrates and myocardial damage. While important advances have been made in the standardization of the rejection diagnosis, pathology remains an imperfect gold-standard, particularly due to the inter-observer variability, sample bias and the use of qualitative or semi-quantitative scales that oversimplify complex phenotypes. Additionally, disease severity, degree of myocardial injury and progression stage are crucial pieces of information poorly captured by the current working formulations. All these limits represent major barriers to achieve a precise and reliable diagnosis of rejection.

In this context, gene expression profiling analysis of fresh myocardial samples retrieved during an extra-core biopsy and using a whole transcriptome approach arose as a potential objective companion tool of pathology to refine the diagnosis of rejection. However, important drawbacks have limited the routine clinical applicability of whole-transcriptome based molecular diagnosis including extra-core sampling bias, low reproducibility, technical and analytical heaviness, with costs and sample turn-around that is not compatible with a clinical setting.

Recent technologies may overcome this limitation by allowing analysis of the same tissue used for histology assessment. Targeted molecular profiling applicable to formalin-fixed paraffin-embedded (FFPE) endomyocardial biopsies may allow the implementation of molecular diagnosis into the clinical routine. Recently, we have shown that the Banff Human Organ Transplant Panel (B-HOT) panel, a consortium-approved consensual targeted panel including 770 genes, developed by the Banff Molecular Diagnostics Working Group, accurately captured key molecular patterns of antibody-mediated rejection (AMR) in heart allograft biopsies and may serve as a proxy to whole transcriptome-based analysis.

The aim of the present study is therefore to identify gene expression signatures for AMR and acute cellular rejection in heart transplantation and to develop and validate a molecular heart rejection diagnostic system based on targeted transcriptome as a novel monitoring companion tool for heart allograft precision diagnostics applicable to FFPE-EMB.

Study Type

Observational

Enrollment (Actual)

496

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Paris, France
        • Paris Translational Research Center for Organ Transplantation
  • Italy
      • Padova, Italy
        • Center Gallucci of the University General Hospital of Padova
  • United States
    • California
      • Los Angeles, California, United States, 90048
        • Cedars Sinai Medical Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Probability Sample

Study Population

We designed an international multicenter study, building a deep phenotyped cohort of heart transplant recipients recruited at 4 referral centers (Pitié-Salpêtrière and Georges Pompidou hospitals in Paris, Center Gallucci of the University General Hospital of Padova and the Cedars Sinai Medical Center in Los Angeles, USA).

Description

Inclusion Criteria:

  • heart transplant recipients ≥ 18 years old
  • at least one endomyocardial biopsy performed as part of routine clinical care
  • biopsy performed at least ≥ 1 month post transplant and less that 10-year post-transplant
  • written informed consent

Exclusion Criteria:

  • age below 18 years old

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Development cohort
Random selection of 80% of the overall cohort.
Diagnostic test: Nano-Heart tool: Intra-Graft Targeted Gene Expression Profiling
Targeted molecular profiling will be performed on formalin-fixed paraffin-embedded (FFPE) endomyocardial biopsies using the NanoString nCounter technology. A consortium-approved consensual targeted panel including 770 genes, developed by the Banff Molecular Diagnostics Working Group (MDWG) will be used.
Validation cohort
Random selection of 20% of the overall cohort.
Diagnostic test: Nano-Heart tool: Intra-Graft Targeted Gene Expression Profiling
Targeted molecular profiling will be performed on formalin-fixed paraffin-embedded (FFPE) endomyocardial biopsies using the NanoString nCounter technology. A consortium-approved consensual targeted panel including 770 genes, developed by the Banff Molecular Diagnostics Working Group (MDWG) will be used.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Biopsy-proven rejection: acute cellular-rejection and antibody-mediated rejection.
Time Frame: 1 month
Prediction performances of the molecular classifiers (cellular and antibody-mediated rejection scores) to predict biopsy-proven rejection: diagnostic accuracy, Receiver Operating Characteristic - area under the curve, Precision Recall - area under the curve, Brier score, F1 score.
1 month

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Discrepancies between molecular and pathology diagnosis of rejection.
Time Frame: 1-month
Confusion matrix, detailed review of the cases.
1-month

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Paris Translational Research Center for Organ Transplantation

Collaborators

University of Padova
Cedars Sinai Medical Center, Los Angeles, USA

Investigators

  • Study Director: Alexandre Loupy, MD, PhD, Paris Translational Research Center for Organ Transplantation
  • Principal Investigator: Guillaume Coutance, MD, PhD, Paris Translational Research Center for Organ Transplantation

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 10, 2021

Primary Completion (Actual)

December 15, 2023

Study Completion (Actual)

December 15, 2023

Study Registration Dates

First Submitted

May 14, 2024

First Submitted That Met QC Criteria

May 28, 2024

First Posted (Actual)

May 30, 2024

Study Record Updates

Last Update Posted (Actual)

May 30, 2024

Last Update Submitted That Met QC Criteria

May 28, 2024

Last Verified

May 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NANOHEART

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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