Quantitative Detection of Circulating Donor-Specific DNA in Organ Transplant Recipients (DTRT-Multi-Center Study) (DTRT)

The primary goal of this Multicenter Study is to develop and to evaluate a method for measuring donor-specific cell free DNA in blood samples from transplant recipients as markers of rejection. Blood samples obtained periodically from heart transplant recipients are assessed for cell free DNA relative to clinical data in order to determine whether changes in the level of cell free DNA indicate rejection.

This research study proposes testing a blood sample obtained from the heart transplant recipient. The research seeks to establish whether this blood test will show when the patient is beginning to or already rejecting the transplanted heart.

BACKGROUND Identifying if a transplant patient is beginning to or already rejecting the heart is necessary, so that appropriate treatment can be started to halt the rejection. Heart catheterization with biopsy is the usual method used for assessing whether a patient may be rejecting the heart. There are also a number of other methods that transplant physicians will use to look for signs of rejection including other blood tests, echocardiograms, obtaining pressure readings during heart catheterization, and micro-array testing of blood obtained during biopsy. These technologies are limited in ability to consistently and accurately identify the presence of rejection.

The usual method of checking for rejection involves obtaining a sample of the heart tissue (heart biopsy); biopsy can only be accomplished through heart catheterization which is an invasive procedure that has risks associated with disturbing the heart such as puncturing the heart or causing the heart rate to change or damaging tissue in the heart. Overtime, repeating this invasive procedure can diminish the ease of the procedure because the veins can become scarred and more difficult to access. For these reasons, researchers believe that it would be good to have a blood test that gives information about the possibility of rejection so that it may not be necessary to do as many heart biopsies. Also, a blood test may be able to provide information about the heart or about rejection that is currently not available at all.

Study Overview

• Status: Completed
• Conditions: Cardiovascular Disease; Heart Transplant Failure and Rejection; Cardiac Transplant Rejection; Acute Rejection of Cardiac Transplant
• Intervention / Treatment: Diagnostic test: Blood Draw of up to 10 ml

Detailed Description

Early detection of rejection is a major focus of organ transplant care. The use of aggressive immunosuppressive therapy has been shown to alter the prognosis of heart transplant patients who have acute rejection1. There are many modalities utilized in the routine surveillance of heart transplant patients, each with limitations. Screening transthoracic echocardiography focusing on indices of systolic and diastolic dysfunction, along with regional wall abnormalities, has been shown to have poor sensitivity and does not effectively discriminate between patients with and without rejection. Newer echocardiographic parameters including myocardial performance or diastolic velocity indices may be a better means of detecting subtle changes in cardiac function in the setting of heart transplant, but these tools are most helpful after the insult caused by rejection has already occurred. Hemodynamic changes measured during heart catheterization have also been evaluated as a means of detecting rejection. Rosenthal et al found that although there were statistically significant differences between patients with higher or lower grades of rejection scores, heart catheterization did not permit effective discrimination of patients with moderate to severe rejection. Heart biomarkers, including c-reactive protein, brain natriuretic peptides, and troponin, have been studied as non-invasive measures of determining heart dysfunction or rejection. These surrogates are weakly associated with different rejection grades on biopsy and have a poor predictive capacity for biopsy-detected rejection3. Recently, microarray technology has been used to screen for genes expressed in heart allograft rejection using peripheral leukocytes from blood samples obtained at the time of endomyocardial biopsy. This technique was shown to have a high negative predictive value for the diagnosis of acute cellular rejection but it is unable to detect low grades of rejection4. Overall, these technologies are limited in the ability to consistently and accurately predict the presence of rejection and have low positive predictive values when compared to biopsy.

The current gold standard in detection of rejection is the use of endomyocardial biopsy. Attaining these samples is invasive and long term repeated central venous access can be difficult. Risk of endomyocardial biopsy includes perforation leading to cardiac tamponade, arrhythmias including atrial fibrillation, pneumothorax, hemothorax, and valvular regurgitation secondary to rupture of chordae or damage to valve leaflets themselves. There is variability in pathological interpretation of histologic grades, especially at higher grades of rejection due to the difficulty in interpretation of nodular infiltrates. The 2005 revised ISHLT grading system has simplified the grading system of cellular rejection and now includes assessment of antibody mediated rejection. This may improve the utility of endomyocardial biopsy, but much controversy still exists on the method of grading rejection and its clinical implications. Thus, the development of a noninvasive, relatively inexpensive method that accurately predicts the presence of rejection is critical.

• Study Type: Observational
• Enrollment (Actual): 540

Contacts and Locations

Study Locations

• United States
  • Arkansas
    • Little Rock, Arkansas, United States, 72202
      • Arkansas Children's Hosoptial Research Institute
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Emory University
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann & Robert H. Lurie Children's Hospital Chicago
  • New York
    • New York, New York, United States, 10032
      • Columbia University
  • North Carolina
    • Durham, North Carolina, United States, 27711
      • Duke University
  • Tennessee
    • Nashville, Tennessee, United States, 37212
      • Vanderbilt University
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Children's Hospital of Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert 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

Study population will include people of any age who have undergone heart transplant or who are "listed" to undergo heart transplant.

Description

Inclusion Criteria:

Any patient who is "listed" to undergo or has in the past undergone heart transplantation.

Exclusion Criteria:

Any patient who is not currently listed to undergo heart transplantation or has not previously received a heart transplant;

Any patient who is not anticipated to be available for follow-up of at least 1 year;

Any patient who is unable or unwilling to provide documented informed consent for self or through a legally authorized representative.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Heart Transplant Recipients; Up to 10 cc of blood will be drawn from heart transplant recipients at various time points prior to and after transplant. Blood draw is the only research activity that study participants will undergo. In addition to blood draw, data will be collected from clinical records representing the participant's transplant course such as the medical record, imaging, and biopsy slides with pathology reports.

Diagnostic test: Blood Draw of up to 10 ml; In a laboratory setting, the blood will be spun for plasma and buffy coat, DNA will be extracted for processing using the diagnostic test. The results of the test are not provided back to the clinical setting.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assay and laboratory protocol development and optimization.	To develop and optimize an assay and protocol to detect donor-specific cell free DNA from recipient plasma.	Year 1-5

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Biomarker Development	To determine the threshold of elevation of circulating donor specific cell free DNA (cfDNA)	Year 1-3

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Validation	To validate the threshold and predictive model to evaluate sensitivity and specificity.	Years 4-5

Collaborators and Investigators

• Sponsor: Medical College of Wisconsin
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); University of California, Los Angeles; Columbia University; The Cleveland Clinic; Emory University; Duke University; Vanderbilt University; Ann & Robert H Lurie Children's Hospital of Chicago; Children's Hospital Medical Center, Cincinnati; Children's Hospital and Health System Foundation, Wisconsin; Children's Healthcare of Atlanta; Phoenix Children's Hospital; Arkansas Children's Hospital Research Institute; TAI Diagnostics, Inc.
• Investigators: Principal Investigator: Michael Mitchell, MD, Medical College of Wisconsin; Principal Investigator: Aoy Tomita-Mitchell, PhD, Medical College of Wisconsin

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2014
• Primary Completion (Actual): March 30, 2020
• Study Completion (Actual): March 30, 2020

Study Registration Dates

• First Submitted: February 10, 2014
• First Submitted That Met QC Criteria: April 7, 2014
• First Posted (Estimate): April 10, 2014

Study Record Updates

• Last Update Posted (Actual): March 26, 2021
• Last Update Submitted That Met QC Criteria: March 23, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Keywords: Heart Failure; Congenital Heart Disease; Cardiomyopathy; Heart Transplant; Cardiac Catheterization; Acute Rejection; Cardiac Biomarkers; Heart Transplant Rejection; Congenital Heart Defect; Coronary Angiogram; Cell-Free DNA; Donor Specific DNA; Donor Specific Cell-Free DNA; Endomyocardial Biopsy; Heart Transplant Failure
• Additional Relevant MeSH Terms: Cardiovascular Diseases
• Other Study ID Numbers: CHW 10/83; R01HL119747 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: No