Eliminating the Need for Pancreas Biopsy Using Peripheral Blood Cell-free DNA (PancDX)

• ClinicalTrials.gov Identifier: NCT04166149
• Recruitment Status: Recruiting
• First Posted: November 18, 2019
• Last Update Posted: February 24, 2022
• Sponsor: University of Maryland, Baltimore
• Collaborators: University of Wisconsin, Madison; Georgetown University
• Information provided by (Responsible Party): Jonathan Bromberg, University of Maryland, Baltimore

Study Description

Brief Summary:

Donor-derived cell-free DNA (dd-cfDNA) has shown promise as an early marker for cellular injury caused by rejection. dd-cfDNA changes may also indicate other injuries that lead to progressive decline in transplant organ function associated with, in the case of kidney transplantation, the presence of interstitial fibrosis (IF) and tubular atrophy (TA) seen in biopsy specimens. Here, we will study the utility of dd-cfDNA to predict rejection in pancreas and pancreas-kidney recipients.

Condition or disease	Intervention/treatment
Transplant;Failure,Kidney; Transplant; Failure, Pancreas; Rejection Acute Renal; Rejection Acute Pancreas	Diagnostic Test: dd-cfDNA Blood Test

Detailed Description:

+Objective The objective of this prospective observational study is to correlate circulating dd-cfDNA to clinical and sub-clinical acute rejection in pancreas transplant alone (PTA), pancreas after kidney (PAK), and simultaneous pancreas kidney (SPK) allograft recipients. The secondary objective study is to correlate circulating dd-cfDNA to pancreas and kidney function, using Hgb1c, C-peptide and insulin requirement to assess pancreas function, and using serum creatinine and estimated glomerular filtration rate (eGFR) to assess kidney function.

The clinical data and specimen collection will also enable future biomarker research.

+Study endpoints Serial dd-cfDNA in individuals over time will be correlated with clinical status and outcomes, such as events of allograft dysfunction or biopsy proven rejection.

The primary endpoints of the study are:

1. Clinical T cell as well as antibody mediated acute rejection
2. Sub-clinical T cell as well as antibody mediated acute rejection
3. Composite of clinical and sub-clinical T cell as well as antibody mediated acute rejection.

The secondary endpoints for the study are:

1. eGFR (estimated Glomerular Filtration Rate [mL/min]): will be derived from serum creatinine level, corrected for variables, using the CKD-RPI (Chronic Kidney Disease Epidemiology Collaboration) equation.
2. Renal allograft injury from BKV (Polyomaviridae polyomavirus) nephritis, CNI (calcineurin inhibitor) toxicity, acute pyelonephritis and recurrent disease confirmed by renal histology.
3. Pancreas allograft function derived from hemoglobin A1c, insulin requirement, and serum c-peptide per SOC
4. Pancreas allograft injury from pancreatitis (all causes, including gastrointestinal dysmotility or viral).
5. Correlate cfDNA levels with presence or absence of delayed graft function (DGF) and subsequent outcomes in a subset of enrolled patients.

Study Design

• Study Type: Observational
• Estimated Enrollment: 400 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: Non-invasive Blood Test to Diagnose Acute Rejection After Pancreas and Kidney Transplantation: Pancreas and Renal Rejection Diagnosis Using Circulating Donor-derived Cell-free DNA in Peripheral Blood
• Actual Study Start Date: September 1, 2019
• Estimated Primary Completion Date: July 31, 2022
• Estimated Study Completion Date: July 31, 2022

Groups and Cohorts

Group/Cohort	Intervention/treatment
University of Maryland; Pancreas and pancreas kidney patients enrolled at University of Maryland. Determine if dd-cfDNA exists in PTA, SPK, and PAK transplant recipient's blood by taking blood specimens at months 1-4, 6, 9, and 12 in the first year post transplant, and quarterly (month 15, 18, 21, 24) in the second year post transplant.	Diagnostic Test: dd-cfDNA Blood Test; The cfDNA measurement isolated from the peripheral blood contains small amounts from the graft. The blood sample is collected in Cell-Free DNA BCT (blood collection) tubes. These are measured by their difference in SNP (single nucleotide polymorphisms) genotype to determine the ratio of donor to recipient through shotgun sequencing. Higher levels of dd-cfDNA in a patient experiencing rejection is measured as a higher percentage of the total cf-DNA.
University of Wisconsin; Pancreas and pancreas kidney patients enrolled at University of Wisconsin. Determine if dd-cfDNA exists in PTA, SPK, and PAK transplant recipient's blood by taking blood specimens at months 1-4, 6, 9, and 12 in the first year post transplant, and quarterly (month 15, 18, 21, 24) in the second year post transplant.	Diagnostic Test: dd-cfDNA Blood Test; The cfDNA measurement isolated from the peripheral blood contains small amounts from the graft. The blood sample is collected in Cell-Free DNA BCT (blood collection) tubes. These are measured by their difference in SNP (single nucleotide polymorphisms) genotype to determine the ratio of donor to recipient through shotgun sequencing. Higher levels of dd-cfDNA in a patient experiencing rejection is measured as a higher percentage of the total cf-DNA.
Georgetown University; Pancreas and pancreas kidney patients enrolled at Georgetown University. Determine if dd-cfDNA exists in PTA, SPK, and PAK transplant recipient's blood by taking blood specimens at months 1-4, 6, 9, and 12 in the first year post transplant, and quarterly (month 15, 18, 21, 24) in the second year post transplant.	Diagnostic Test: dd-cfDNA Blood Test; The cfDNA measurement isolated from the peripheral blood contains small amounts from the graft. The blood sample is collected in Cell-Free DNA BCT (blood collection) tubes. These are measured by their difference in SNP (single nucleotide polymorphisms) genotype to determine the ratio of donor to recipient through shotgun sequencing. Higher levels of dd-cfDNA in a patient experiencing rejection is measured as a higher percentage of the total cf-DNA.

Outcome Measures

Primary Outcome Measures :

1. dd-cfDNA correlation to acute rejection [ Time Frame: August 1, 2019 to July 31, 2022 ]

   To correlate circulating dd-cfDNA to clinical and sub-clinical acute rejection in PTA, PAK, and SPK allograft recipients.

   1. Clinical T cell as well as antibody mediated acute rejection.
   2. Sub-clinical T cell as well as antibody mediated acute rejection.
   3. Composite of clinical and sub-clinical T cell as well as antibody mediated acute rejection.

Secondary Outcome Measures :

1. dd-cfDNA correlation to pancreas and kidney function [ Time Frame: August 1, 2019 to July 31, 2022 ]

   To correlate circulating dd-cfDNA to pancreas and kidney function, using Hgb1c, C-peptide and insulin requirement to assess pancreas function, and using serum creatinine and estimated glomerular filtration rate [eGFR] to assess kidney function.

   1. eGFR (estimated Glomerular Filtration Rate [mL/min]): will be derived from serum creatinine level, corrected for variables, using the CKD-RPI (Chronic Kidney Disease Epidemiology Collaboration) equation.
   2. Renal allograft injury from BKV (Polyomaviridae polyomavirus) nephritis, CNI (calcineurin inhibitor) toxicity, acute pyelonephritis and recurrent disease confirmed by renal histology.
   3. Pancreas allograft function derived from hemoglobin A1c, insulin requirement, and serum C-peptide per SOC 4. Pancreas allograft injury from pancreatitis (all causes, including gastrointestinal dysmotility or viral).

Biospecimen Retention:   Samples With DNA

Blood samples from recipients are taken in order to determine if peripheral blood has presence of donor-derived DNA.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No
• Sampling Method: Non-Probability Sample

Study Population

Participants with PTA, PAK, and SPK transplants. The data will compared to data obtained from the kidney transplant populations already investigated by CareDx in the DART and KOAR studies will be used as controls.

Criteria

Inclusion Criteria:

1. Adult recipients (Age > 18 years )
2. All genders and all racial and ethnic groups
3. Pancreas transplant alone (PTA)
4. Simultaneous kidney-pancreas transplantation (SPK)
5. Pancreas-after-kidney (PAK) 6. Simultaneous pancreas and living donor kidney (SPLK)

7. Primary or re-transplants 8. Ability to come for follow-up and undergo biopsy (Performed in accordance to SOC) 9. Provided consent

Exclusion Criteria:

1. Pediatric recipients (Age < 18 years)
2. Pregnant women
3. Patients undergoing multi-organ transplants not otherwise specified (e.g., pancreas-liver, multi-visceral, or pancreas-heart)
4. Patients receiving donor kidney from an identical twin, as part of an SPLK (see above)
5. Did not provide consent

Contacts and Locations

Contacts

Contact: Jonathan S Bromberg, MD; 4103280008; Jbromberg@som.umaryland.edu

Contact: Amanda Bartosic, MBA; 4107061376; ABartosic@som.umaryland.edu

Locations

United States, District of Columbia

Georgetown University; Recruiting

Washington, District of Columbia, United States, 20007

Contact: Naomi Kalume naomi.kalume@medstar.net

Principal Investigator: Matthew Cooper, MD

United States, Maryland

University of Maryland; Recruiting

Baltimore, Maryland, United States, 21201

Contact: Mariela Pinedo 410-706-1375 mpinedo@som.umaryland.edu

United States, Wisconsin

UW Health University Hospital; Recruiting

Madison, Wisconsin, United States, 53792

Contact: Kaelin Grant 608-576-0788 SurgeryResearch@surgery.wisc.edu

Principal Investigator: John Odorico

Sponsors and Collaborators

University of Maryland, Baltimore

University of Wisconsin, Madison

Georgetown University

More Information

Publications:

Haas M, Sis B, Racusen LC, Solez K, Glotz D, Colvin RB, Castro MC, David DS, David-Neto E, Bagnasco SM, Cendales LC, Cornell LD, Demetris AJ, Drachenberg CB, Farver CF, Farris AB 3rd, Gibson IW, Kraus E, Liapis H, Loupy A, Nickeleit V, Randhawa P, Rodriguez ER, Rush D, Smith RN, Tan CD, Wallace WD, Mengel M; Banff meeting report writing committee. Banff 2013 meeting report: inclusion of c4d-negative antibody-mediated rejection and antibody-associated arterial lesions. Am J Transplant. 2014 Feb;14(2):272-83. doi: 10.1111/ajt.12590. Erratum in: Am J Transplant. 2015 Oct;15(10):2784. Rangel, Erika [corrected to Rangel, Erika B].

Lo YM. Transplantation monitoring by plasma DNA sequencing. Clin Chem. 2011 Jul;57(7):941-2. doi: 10.1373/clinchem.2011.166686.

Snyder TM, Khush KK, Valantine HA, Quake SR. Universal noninvasive detection of solid organ transplant rejection. Proc Natl Acad Sci U S A. 2011 Apr 12;108(15):6229-34. doi: 10.1073/pnas.1013924108. Epub 2011 Mar 28.

Code of Federal Regulations, Title 42 - Public Health, Part 493 - Laboratory Requirements, Subpart A - General Provisions, Sections 1, 2 & 3.

Streck, Cell-Free DNA BCT Instructions for Use: EXT-REF-Q-00002

Hidestrand M, Tomita-Mitchell A, Hidestrand PM, Oliphant A, Goetsch M, Stamm K, Liang HL, Castleberry C, Benson DW, Stendahl G, Simpson PM, Berger S, Tweddell JS, Zangwill S, Mitchell ME. Highly sensitive noninvasive cardiac transplant rejection monitoring using targeted quantification of donor-specific cell-free deoxyribonucleic acid. J Am Coll Cardiol. 2014 Apr 1;63(12):1224-1226. doi: 10.1016/j.jacc.2013.09.029. Epub 2013 Oct 16.

Sigdel TK, Vitalone MJ, Tran TQ, Dai H, Hsieh SC, Salvatierra O, Sarwal MM. A rapid noninvasive assay for the detection of renal transplant injury. Transplantation. 2013 Jul 15;96(1):97-101. doi: 10.1097/TP.0b013e318295ee5a.

De Vlaminck I, Valantine HA, Snyder TM, Strehl C, Cohen G, Luikart H, Neff NF, Okamoto J, Bernstein D, Weisshaar D, Quake SR, Khush KK. Circulating cell-free DNA enables noninvasive diagnosis of heart transplant rejection. Sci Transl Med. 2014 Jun 18;6(241):241ra77. doi: 10.1126/scitranslmed.3007803.

• Responsible Party: Jonathan Bromberg, Principal Investigator, University of Maryland, Baltimore
• ClinicalTrials.gov Identifier: NCT04166149
• Other Study ID Numbers: Panc-DX
• First Posted: November 18, 2019
• Last Update Posted: February 24, 2022
• Last Verified: February 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: As described in complete protocol.
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: 2-3 years from study start.

• 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

Additional relevant MeSH terms:

Renal Insufficiency; Kidney Diseases; Urologic Diseases