Clinical trial NCT02423070: Genome Transplant Dynamics
Official title: Genome Transplant Dynamics
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Thoracic Organ Transplantation
Keywords: Cell-free DNA
Acute Rejection
Thoracic Organ Transplantation
Non-Invasive Testing
Chronic Rejection
Natural History
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2015-04-22
Enrollment: 991
Sex: ALL
Minimum age (years): 14
Maximum age (years): 80
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Lung and heart transplant candidates. Dual organ transplants such as those that include lung or heart PLUS any other organ are also considered for enrollment. -Subjects who have undergone lung or heart transplants and are within 3 months of transplantation. -14 years and older- Able to understand and be willing to sign the informed consent form. Subjects undergoing a double transplant will sign a single consent.- Retransplant candidates will be considered as a new transplants. These subjects will be approached for enrollment and if they consent to participate, they will be assigned a different SSPIN.

Brief summary: Study Description:

Heart and lung transplants can save lives, but long-term success is often limited by organ rejection that is hard to detect early. This study is testing a new, non-invasive blood test that looks for small pieces of DNA from the donor organ in the patient s blood. We believe higher levels of this donor DNA may signal early rejection before damage becomes permanent.

Hypothesis:

We believe that measuring donor-derived DNA in the blood can help detect early signs of rejection and improve outcomes for transplant patients.

The study also collects genetic and biological samples to explore why some people are more at risk of complications after transplant. This may help guide future research and treatments.

Who Can Join the Study:

People receiving a heart or lung transplant (or both), age 14 and older

People who are within three months of their transplant

People who can understand and agree to take part in the study

Participants will be asked to provide blood and other samples, and some of these will be used in lab research to explore new ideas about how and why transplant rejection happens.

This research could lead to better ways to monitor and treat patients after a heart or lung transplant - and help improve long-term survival and quality of life.

Detailed description: Acute rejection (AR) occurs within the first 6 months after transplantation in 20 percent of heart- transplant patients and in 50 percent of lung-transplant patients. Given the often silent clinical presentation of AR, these patients require monitoring with repeated invasive and costly endomyocardial (EMB) or transbronchial biopsies (TBBx). Since organ transplantation is essentially genomic transplantation, our prior studies leveraged the use of distinctive graft and recipient genotype single-nuclear polymorphisms (SNPs) to barcode donor DNA circulating in recipient serum. We have shown that levels of donor DNA measured as the percentage of circulating donor-derived cell-free DNA (cfDNA) correlate with AR diagnosis and severity as detected by biopsy. The performance receiver operator curve (ROC) of cfDNA yielded an area under the curve (AUC) of 0.83. Using this technique, we can diagnose AR by measuring elevations in cfDNA up to 5 months before EMB-detected pathology. While these findings suggest that monitoring cfDNA may offer a high-performing, non-invasive, and early diagnostic tool of AR, further validation studies are required to determine its clinical utility. The ability to diagnose AR earlier than is possible with a biopsy offers an opportunity to investigate the pathogenesis of rejection as well as to identify potential AR biomarkers. Thus, the primary objective of this study is to validate the predictive accuracy and ROC characteristics of cfDNA for AR in a multicenter, prospective cohort study of heart and lung transplant patients, recruited through a consortium of 5 transplant centers in Washington, DC metropolitan area. The secondary objective is to determine the association between early graft injury caused by acute rejection and infection and the development of chronic rejection, i.e., chronic lung allograft dysfunction (CLAD) or chronic allograft vasculopathy (CAV). The exploratory objectives are: 1) to compare cfDNA characteristics in AMR (antibody-mediated rejection) and ACR (acute cellular rejection), 2) to study early immunological changes associated with a significant rise in cfDNA, and 3) to examine changes in microbiome architecture and other cell-free nucleic acids in rejection, 4) to determine if cfDNA trends correlate with treatment response for transplant complications, 5) to determine if the level of pre-transplant cfDNA identify patients at high risk of rejection post-transplant, 6) to determine genetic variants associated with post-transplant risk of rejection, high cfDNA levels and other complications.

Eligibility criteria: * INCLUSION CRITERIA:
* Lung and heart transplant candidates. Dual organ transplants such as those that include lung or heart PLUS any other organ are also considered for enrollment.
* Subjects who have undergone lung or heart transplants and are within 3 months of transplantation.
* 14 years and older
* Able to understand and be willing to sign the informed consent form. Subjects undergoing a double transplant will sign a single consent.
* Retransplant candidates will be considered as a new transplants. These subjects will be approached for enrollment and if they consent to participate, they will be assigned a different SSPIN.

EXCLUSION CRITERIA:

-Pregnancy

Primary outcomes:
measure: To validate the predictive accuracy and ROC characteristics of circulating cell- free donor derived DNA (cfDNA) in multicenter, prospective cohort study of heart and lung transplant patients, recruited through a consortium of 5 transplant center...
timeFrame: At the time of biopsy-proven rejection
Secondary outcomes:
measure: To determine the association between early graft injury caused by acute rejection and infection and the development of chronic rejection, ie.,chronic lung allograft dysfunction (CLAD) or chronic allograft vasculopathy (CAV).
timeFrame: End of Study
Other outcomes:
Locations:
city: Washington
country: United States
facility: MedStar Washington Hospital Center
state: District of Columbia
city: Baltimore
country: United States
facility: Johns Hopkins University
state: Maryland
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
city: Falls Church
country: United States
facility: INOVA Fairfax Medical
state: Virginia
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
Study officials:
affiliation: National Heart, Lung, and Blood Institute (NHLBI)
name: Sean T Agbor-Enoh, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Angelini A, Andersen CB, Bartoloni G, Black F, Bishop P, Doran H, Fedrigo M, Fries JW, Goddard M, Goebel H, Neil D, Leone O, Marzullo A, Ortmann M, Paraf F, Rotman S, Turhan N, Bruneval P, Frigo AC, Grigoletto F, Gasparetto A, Mencarelli R, Thiene G, Burke M. A web-based pilot study of inter-pathologist reproducibility using the ISHLT 2004 working formulation for biopsy diagnosis of cardiac allograft rejection: the European experience. J Heart Lung Transplant. 2011 Nov;30(11):1214-20. doi: 10.1016/j.healun.2011.05.011. Epub 2011 Aug 3.
citation: De Vlaminck I, Khush KK, Strehl C, Kohli B, Luikart H, Neff NF, Okamoto J, Snyder TM, Cornfield DN, Nicolls MR, Weill D, Bernstein D, Valantine HA, Quake SR. Temporal response of the human virome to immunosuppression and antiviral therapy. Cell. 2013 Nov 21;155(5):1178-87. doi: 10.1016/j.cell.2013.10.034.
citation: Pham MX, Teuteberg JJ, Kfoury AG, Starling RC, Deng MC, Cappola TP, Kao A, Anderson AS, Cotts WG, Ewald GA, Baran DA, Bogaev RC, Elashoff B, Baron H, Yee J, Valantine HA; IMAGE Study Group. Gene-expression profiling for rejection surveillance after cardiac transplantation. N Engl J Med. 2010 May 20;362(20):1890-900. doi: 10.1056/NEJMoa0912965. Epub 2010 Apr 22.
citation: Keller M, Bush E, Diamond JM, Shah P, Matthew J, Brown AW, Sun J, Timofte I, Kong H, Tunc I, Luikart H, Iacono A, Nathan SD, Khush KK, Orens J, Jang M, Agbor-Enoh S. Use of donor-derived-cell-free DNA as a marker of early allograft injury in primary graft dysfunction (PGD) to predict the risk of chronic lung allograft dysfunction (CLAD). J Heart Lung Transplant. 2021 Jun;40(6):488-493. doi: 10.1016/j.healun.2021.02.008. Epub 2021 Feb 20.
citation: Agbor-Enoh S, Shah P, Tunc I, Hsu S, Russell S, Feller E, Shah K, Rodrigo ME, Najjar SS, Kong H, Pirooznia M, Fideli U, Bikineyeva A, Marishta A, Bhatti K, Yang Y, Mutebi C, Yu K, Kyoo Jang M, Marboe C, Berry GJ, Valantine HA; GRAfT Investigators. Cell-Free DNA to Detect Heart Allograft Acute Rejection. Circulation. 2021 Mar 23;143(12):1184-1197. doi: 10.1161/CIRCULATIONAHA.120.049098. Epub 2021 Jan 13.
citation: Agbor-Enoh S, Chan JL, Singh A, Tunc I, Gorham S, Zhu J, Pirooznia M, Corcoran PC, Thomas ML, Lewis BGT, Jang MK, Ayares DL, Horvath KA, Mohiuddin MM, Valantine H. Circulating cell-free DNA as a biomarker of tissue injury: Assessment in a cardiac xenotransplantation model. J Heart Lung Transplant. 2018 Aug;37(8):967-975. doi: 10.1016/j.healun.2018.04.009. Epub 2018 Apr 26.
citation: Agbor-Enoh S, Jackson AM, Tunc I, Berry GJ, Cochrane A, Grimm D, Davis A, Shah P, Brown AW, Wang Y, Timofte I, Shah P, Gorham S, Wylie J, Goodwin N, Jang MK, Marishta A, Bhatti K, Fideli U, Yang Y, Luikart H, Cao Z, Pirooznia M, Zhu J, Marboe C, Iacono A, Nathan SD, Orens J, Valantine HA, Khush K. Late manifestation of alloantibody-associated injury and clinical pulmonary antibody-mediated rejection: Evidence from cell-free DNA analysis. J Heart Lung Transplant. 2018 Jul;37(7):925-932. doi: 10.1016/j.healun.2018.01.1305. Epub 2018 Jan 31.