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

Transplant;Failure,Kidney Clinical Trial

— PancDX  

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04166149
• Other study ID #: Panc-DX
• Status: Active, not recruiting
• Start date: September 1, 2019
• Est. completion date: October 31, 2024

Study information

• Verified date: November 2023
• Source: University of Maryland, Baltimore
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 140
• Est. completion date: October 31, 2024
• Est. primary completion date: August 31, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Rejection Acute Pancreas
• Rejection Acute Renal
• Renal Insufficiency
• Transplant; Failure, Pancreas
• Transplant;Failure,Kidney

Intervention

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.

Locations

Country	Name	City	State
United States	University of Maryland	Baltimore	Maryland
United States	UW Health University Hospital	Madison	Wisconsin
United States	Georgetown University	Washington	District of Columbia

Sponsors (3)

Lead Sponsor	Collaborator
University of Maryland, Baltimore	Georgetown University, University of Wisconsin, Madison

Country where clinical trial is conducted

United States, 

References & Publications (8)

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

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. — View Citation

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]. — View Citation

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. No abstract available. — View Citation

Lo YM. Transplantation monitoring by plasma DNA sequencing. Clin Chem. 2011 Jul;57(7):941-2. doi: 10.1373/clinchem.2011.166686. No abstract available. — View Citation

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. — View Citation

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. — View Citation

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	dd-cfDNA correlation to acute rejection	To correlate circulating dd-cfDNA to clinical and sub-clinical acute rejection in PTA, PAK, and SPK allograft recipients.; Clinical T cell as well as antibody mediated acute rejection.; Sub-clinical T cell as well as antibody mediated acute rejection.; Composite of clinical and sub-clinical T cell as well as antibody mediated acute rejection.	August 1, 2019 to July 31, 2022
Secondary	dd-cfDNA correlation to pancreas and kidney function	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.; 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.; Renal allograft injury from BKV (Polyomaviridae polyomavirus) nephritis, CNI (calcineurin inhibitor) toxicity, acute pyelonephritis and recurrent disease confirmed by renal histology.; 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).	August 1, 2019 to July 31, 2022