A New Biomarker for the Non-invasive Diagnosis of Rejection After Heart Transplantation

Study Overview
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Brief Summary
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This study is a prospective, observational multi-center cohort study. The study will consist of patients undergoing heart transplantation. The main purpose is to test a new biomarker for rejection against the gold-standard, the endomyocardial biopsy (EMB). 80 patients will be included, both children and adults.

Detailed Description
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The primary objective is a comparison of an the established, invasive diagnostic test, the endomyocardial biopsy (EMB) against a new, non-invasive test. The new test is the measurement of donor-derived cell-free DNA (dd-cfDNA) circulating in the blood stream of the recipient, quantified by droplet digital PCR (polymerase-chain reaction) after targeted multiplex preamplification. Sensitivity is calculated with EMB as the gold standard. The patients will be followed during one year post-transplantation with simultaneous blood samples and EMB. The patients will further be followed clinically for 5 years. A suitable cut-off for the ratio of dd-cfDNA will be calculated using receiver operating characteristic (ROC) analysis. Secondary objectives are description of patient outcomes with respect to organ function, quality of life and adverse events. Secondary objectives are the calculation of the costs related to the transplantation process as well as to the follow-up with EMB. A simulation will be done with respect to possible savings achieved if the new biomarker could be implemented. The study consists of two cohorts: all adult recipients of heart transplantation at Sahlgrenska University Hospital (one of two center conducting heart transplantation in Sweden): regional study. The other cohort consists of all children undergoing heart transplantation in Sweden:national study. Patients will undergo transplantation at Sahlgrenska University Hospital in Gothenburg as well as at Skåne University Hospital in Lund. Follow-up with blood samples and EMB of these patients will be in Gothenburg, Lund and at Karolinska University Hospital in Stockholm.

Official Title
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A New Biomarker for the Non-invasive Diagnosis of Rejection After Heart Transplantation

Conditions
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Heart Transplant Rejection

Intervention / Treatment
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* Diagnostic Test: donor-derived cell-free DNA (dd-cfDNA)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient on waiting list for heart transplantation Signed informed consent Exclusion Criteria: 1. Follow-up outside Sweden
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Adult patients<br>Adult patients (18 years or older) undergoing heart transplantation | Diagnostic Test: donor-derived cell-free DNA (dd-cfDNA)<br>* Measurement of dd-cfDNA and comparison against grade of rejection as measured by endomyocardial biopsy, taken simultaneously<br>|
| Pediatric patients<br>Pediatric patients (0-17 years) undergoing heart transplantation | Diagnostic Test: donor-derived cell-free DNA (dd-cfDNA)<br>* Measurement of dd-cfDNA and comparison against grade of rejection as measured by endomyocardial biopsy, taken simultaneously<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of donor-derived cell-free DNA and endomyocardial biopsy with respect to rejection | Measurement of both fraction of donor-derived cell-free DNA of all cell-free DNA (derived from recipient and donor) as well as the absolute number of copies per ml plasma derived from the donor. Comparison is made with simultaneously obtained endomyocardial biopsies that are graded with respect to rejection, according to the official guidelines provided by the International Society of Heart and Lung Transplantation. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cost analysis 1 | Costs of heart transplantation during the first year post-transplantation | 5 years | 
| Rejection | Cumulative incidence of rejection (according to the biopsy grading system provided by the International Society of Heart and Lung Transplantation) | 5 years | 
| Graft-vasculopathy | Cumulative incidence of graft-vasculopathy | 5 years | 
| Overweight | Prevalence of overweight (BMI >25) and obesity (BMI>30) | 5 years | 
| Quality of life | Health-related quality of life as measured by EQ5D | 5 years | 
| Survival | Survival | 5 years | 
| Re-transplantation | Proportion of patients who have undergone re-transplantation | 5 years | 
| GFR (glomerular filtration rate) | Renal function evaluated by calculated and measured GFR (Iohexol or Cr-Clearance) | 1 year | 
| GFR (glomerular filtration rate) | Renal function evaluated by calculated and measured GFR (Iohexol or Cr-Clearance) | 3 years | 
| GFR (glomerular filtration rate) | Renal function evaluated by calculated and measured GFR (Iohexol or Cr-Clearance) | 5 years | 
| Infections | Cumulative incidence of infections requiring hospital admission | 5 years | 
| Circulatory support to transplantation | Proportion of patients undergoing heart transplantation from a ventricular assist device or extra-corporeal membrane oxygenation (ECMO) or from mechanical ventilation. | 5 years | 
| Immunization status | Impact of pre-transplantation immunization status on primary and secondary outcomes | 5 years | 
| Malignancy | Cumulative incidence of malignancy (post-transplantation lymphoproliferative disorder PTLD and others) | 3 years | 
| Malignancy | Cumulative incidence of malignancy (PTLD and others) | 5 years | 
| Prior cardiac surgery | Impact of prior cardiac surgery on other outcomes | 5 years | 
| Neonatal cardiac surgery | Impact of neonatal (first 4 weeks of life) cardiac surgery on other outcomes | 5 years | 
| Donor cardiac arrest | Correlation between circulatory arrest in the donor and cardiac function | 5 years | 
| Donor cardiopulmonary resuscitation (CPR) impact | Impact of CPR of the donor on the incidence of assumed early rejection | 3 years | 
| Initial immunosuppression | Correlation between initial immunosuppression and the incidence of rejection | 5 years | 
| Initial immunosuppression and malignancy | Correlation between type of initial immunosuppression and incidence of malignancy | 5 years | 
| Immunosuppression and adverse effects | Correlation of time points with over- or under-immunosuppression (as measured by blood levels of immunosuppressive drugs and comparison with desired levels) and the incidence of severe infection, renal function decline and malignancy | 5 years | 
| Immunosuppression and rejection | Correlation of time points with over- or under-immunosuppression (as measured by blood levels of immunosuppressive drugs and comparison with desired levels) with rejection events | 5 years | 
| Ischemia time | Correlation between ischemic graft time and cardiac function as measured by echocardiography | 5 years | 
| Blood products and adverse events | Correlation between the number of blood products (red blood cells, thrombocytes, plasma) given after transplantation and the incidence of adverse effects | 5 years | 
| Survival | Survival | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diagnosis, economics, cell-free DNA, digital droplet PCR, heart failure