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

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.

Study Overview

• Status: Completed
• Conditions: Heart Transplant Rejection
• Intervention / Treatment: Diagnostic test: donor-derived cell-free DNA (dd-cfDNA)

Detailed Description

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.

• Study Type: Observational
• Enrollment (Actual): 134

Contacts and Locations

Study Locations

• Sweden
  • Gothenburg, Sweden, 41234
    • Transplantation Center, Sahlgrenska University Hospital
  • Gothenburg, Sweden, 41685
    • Pediatric Heart Center, The Queen Silvia Children's Hospital, Sahlgrenska University Hospital
  • Lund, Sweden, 22241
    • Pediatric Heart Center, Skåne University Hospital
  • Stockholm, Sweden, 17176
    • Pediatric Heart Center, Karolinska University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

All patients on waiting list for heart transplantion at the participating centers

Description

Inclusion Criteria:

1. Patient on waiting list for heart transplantation
2. Signed informed consent

Exclusion Criteria:

1. Follow-up outside Sweden

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Adult patients; Adult patients (18 years or older) undergoing heart transplantation	Diagnostic test: donor-derived cell-free DNA (dd-cfDNA); Measurement of dd-cfDNA and comparison against grade of rejection as measured by endomyocardial biopsy, taken simultaneously
Pediatric patients; Pediatric patients (0-17 years) undergoing heart transplantation	Diagnostic test: donor-derived cell-free DNA (dd-cfDNA); Measurement of dd-cfDNA and comparison against grade of rejection as measured by endomyocardial biopsy, taken simultaneously

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Vastra Gotaland Region
• Collaborators: Karolinska University Hospital; Lund University Hospital
• Investigators: Principal Investigator: Jan Sunnegårdh, MD, PhD, Pediatric Heart Center, The Queen Silvia Children's Hospital, Sahlgrenska University Hospital

Publications and helpful links

Helpful Links

• Homepage of the Study

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2016
• Primary Completion (Actual): December 31, 2021
• Study Completion (Actual): December 31, 2021

Study Registration Dates

• First Submitted: March 15, 2018
• First Submitted That Met QC Criteria: March 23, 2018
• First Posted (Actual): March 26, 2018

Study Record Updates

• Last Update Posted (Actual): May 2, 2022
• Last Update Submitted That Met QC Criteria: April 29, 2022
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: heart failure; diagnosis; cell-free DNA; economics; digital droplet PCR
• Additional Relevant MeSH Terms: Pathologic Processes; Disease
• Other Study ID Numbers: ver 1.0; 014-16 (Other Identifier: Regional ethical review board in Gothenburg)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided
• IPD Plan Description: Not decided yet.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No