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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02109575
Recruitment Status : Active, not recruiting
First Posted : April 10, 2014
Last Update Posted : January 22, 2020
National Heart, Lung, and Blood Institute (NHLBI)
Columbia University
Duke University
Arkansas Children's Hospital Research Institute
Emory University
Children's Healthcare of Atlanta
Vanderbilt University
TAI Diagnostics, Inc.
Ann & Robert H. Lurie Children's Hospital Chicago
Children's Hospital and Health System Foundation, Wisconsin
Information provided by (Responsible Party):
Michael Mitchell, Medical College of Wisconsin

Brief Summary:

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 or disease Intervention/treatment
Cardiovascular Disease Acute Rejection of Cardiac Transplant Cardiac Transplant Rejection Heart Transplant Failure and Rejection 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.

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Study Type : Observational
Estimated Enrollment : 480 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Quantitative Detection of Circulating Donor-Specific DNA in Organ Transplant Recipients (DTRT-Multi-Center Study)
Actual Study Start Date : March 1, 2014
Estimated Primary Completion Date : May 27, 2020
Estimated Study Completion Date : October 1, 2020

Resource links provided by the National Library of Medicine

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.

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

Other Outcome Measures:
  1. 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

Information from the National Library of Medicine

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, Learn About Clinical Studies.

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Ages Eligible for Study:   Child, Adult, Older Adult
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02109575

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United States, Arkansas
Arkansas Children's Hosoptial Research Institute
Little Rock, Arkansas, United States, 72202
United States, Georgia
Emory University
Atlanta, Georgia, United States, 30322
United States, Illinois
Ann & Robert H. Lurie Children's Hospital Chicago
Chicago, Illinois, United States, 60611
United States, New York
Columbia University
New York, New York, United States, 10032
United States, North Carolina
Duke University
Durham, North Carolina, United States, 27711
United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States, 37212
United States, Wisconsin
Children's Hospital of Wisconsin
Milwaukee, Wisconsin, United States, 53226
Froedtert Hospital
Milwaukee, Wisconsin, United States, 53226
Sponsors and Collaborators
Medical College of Wisconsin
National Heart, Lung, and Blood Institute (NHLBI)
Columbia University
Duke University
Arkansas Children's Hospital Research Institute
Emory University
Children's Healthcare of Atlanta
Vanderbilt University
TAI Diagnostics, Inc.
Ann & Robert H. Lurie Children's Hospital Chicago
Children's Hospital and Health System Foundation, Wisconsin
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Principal Investigator: Michael Mitchell, MD Medical College of Wisconsin
Principal Investigator: Aoy Tomita-Mitchell, PhD Medical College of Wisconsin
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Responsible Party: Michael Mitchell, Professor Cardiovascular Surgery, Medical College of Wisconsin Identifier: NCT02109575    
Other Study ID Numbers: CHW 10/83
R01HL119747 ( U.S. NIH Grant/Contract )
First Posted: April 10, 2014    Key Record Dates
Last Update Posted: January 22, 2020
Last Verified: January 2020

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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
Keywords provided by Michael Mitchell, 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:
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Cardiovascular Diseases