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

This study is currently recruiting participants. (see Contacts and Locations)
Verified March 2017 by Medical College of Wisconsin
National Heart, Lung, and Blood Institute (NHLBI)
Columbia University
Duke University
University of Arkansas
Emory University
Children's Healthcare of Atlanta
Vanderbilt University
TAI Diagnostics, Inc.
Information provided by (Responsible Party):
Michael Mitchell, Medical College of Wisconsin Identifier:
First received: February 10, 2014
Last updated: March 23, 2017
Last verified: March 2017

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.

Condition Intervention
Cardiovascular Disease
Acute Rejection of Cardiac Transplant
Cardiac Transplant Rejection
Heart Transplant Failure and Rejection
Diagnostic Test: Blood Draw of up to 10 ml

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Prospective
Official Title: Quantitative Detection of Circulating Donor-Specific DNA in Organ Transplant Recipients (DTRT-Multi-Center Study)

Resource links provided by NLM:

Further study details as provided by Medical College of Wisconsin:

Primary Outcome Measures:
  • Assay and laboratory protocol development and optimization. [ Time Frame: Year 1-5 ]
    To develop and optimize an assay and protocol to detect donor-specific cell free DNA from recipient plasma.

Secondary Outcome Measures:
  • Biomarker Development [ Time Frame: Year 1-3 ]
    To determine the threshold of elevation of circulating donor specific cell free DNA (cfDNA)

Other Outcome Measures:
  • Validation [ Time Frame: Years 4-5 ]
    To validate the threshold and predictive model to evaluate sensitivity and specificity.

Biospecimen Retention:   Samples With DNA
Whole Blood

Estimated Enrollment: 480
Study Start Date: September 2013
Estimated Study Completion Date: May 2018
Estimated Primary Completion Date: May 2018 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
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.

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.


Ages Eligible for Study:   Child, Adult, Senior
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT02109575

Contact: Anne L Laulederkind, BSN, BA (414) 805-8932

United States, Arkansas
Arkansas Children's Hospital Recruiting
Little Rock, Arkansas, United States, 72202
Contact: Ginger Gilmore, MCSc, APN    501-364-4292   
Contact: Denise Graves    501-364-2237   
Principal Investigator: Kenneth R Knecht, MD         
United States, Georgia
Emory University Recruiting
Atlanta, Georgia, United States, 30322
Contact: Susie Gentry, BSN, BBA, BS    404-785-6953   
Contact: Allison Wellons, BS, RN    404-785-6459   
Principal Investigator: Shriprasad Deshpande, MD         
United States, Illinois
Lurie Children's Hospital Not yet recruiting
Chicago, Illinois, United States, 60611
Contact: Kathleen Van't Hof    312-227-1549   
Principal Investigator: Elfrieda Pahl, MD         
United States, New York
Columbia University Recruiting
New York, New York, United States, 10032
Contact: Cristina Falo, PhD    212-305-3839   
Principal Investigator: Marc Richmond, MD         
United States, North Carolina
Duke University Recruiting
Durham, North Carolina, United States, 27711
Contact: Sarah Casalinova    919-613-5621   
Principal Investigator: Jacob N Schroder, MD         
United States, Tennessee
Vanderbilt University Recruiting
Nashville, Tennessee, United States, 37212
Contact: Karen Trochez    615-343-6021    karen.m.trochez@Vanderbilt.Edu   
Principal Investigator: David Bichell, MD         
Principal Investigator: Mark Wigger, MD         
United States, Wisconsin
Children's Hospital of Wisconsin Recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: Gail Stendahl, NP    414-266-5775   
Contact: Julie Schmidt, NP    414-266-5740   
Principal Investigator: Steven Kindel, MD         
Froedtert Hospital Recruiting
Milwaukee, Wisconsin, United States, 53226
Contact: Susan K Mauermann, RN, CRCC    414-955-6749   
Contact: Janet Gosset, RN    414-955-6784   
Principal Investigator: Nunzio Gaglianello, MD         
Sponsors and Collaborators
Medical College of Wisconsin
National Heart, Lung, and Blood Institute (NHLBI)
Columbia University
Duke University
University of Arkansas
Emory University
Children's Healthcare of Atlanta
Vanderbilt University
TAI Diagnostics, Inc.
Principal Investigator: Michael Mitchell, MD Medical College of Wisconsin
Principal Investigator: Aoy Tomita-Mitchell, PhD Medical College of Wisconsin
  More Information

Responsible Party: Michael Mitchell, Professor Cardiovascular Surgery, Medical College of Wisconsin Identifier: NCT02109575     History of Changes
Other Study ID Numbers: CHW 10/83
R01HL119747 ( US NIH Grant/Contract Award Number )
Study First Received: February 10, 2014
Last Updated: March 23, 2017

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: Yes
Device Product Not Approved or Cleared by U.S. FDA: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Medical College of Wisconsin:
Acute Rejection
Cardiac Biomarkers
Cardiac Catheterization
Cell-Free DNA
Congenital Heart Defect
Congenital Heart Disease
Coronary Angiogram
Donor Specific DNA
Donor Specific Cell-Free DNA
Endomyocardial Biopsy
Heart Failure
Heart Transplant Failure
Heart Transplant
Heart Transplant Rejection

Additional relevant MeSH terms:
Cardiovascular Diseases processed this record on April 21, 2017