TRU-IMMUNO: Optimizing Liver Immunosuppression

A Clinical Pilot Study to Test the Acceptability and Feasibility of TruGraf Liver and TRAC Liver Testing as Part of Standard of Care: Optimizing Liver ImmunoSuppression (TRU-IMMUNO)

This is a prospective, multi-center, randomized study. The primary objective is to evaluate the feasibility and utility of TruGraf/TRAC Liver testing used in addition to standard of care measures of liver dysfunction to guide immunosuppression management.

Study Overview

• Status: Not yet recruiting
• Conditions: Liver Transplant Rejection
• Intervention / Treatment: Diagnostic test: Patients monitored with TruGraf and TRAC Liver testing

Detailed Description

This study will provide TruGraf Liver and TRAC liver tests to one group of transplant providers early after liver transplantation to clarify if the Trugraf Liver and TRAC Liver results can complement their immunosuppression minimization strategies to avoid complications and reduce the occurrence of acute rejection. The ability to decrease IS will be compared to the group that does not receive the test results.

Subjects will be randomized into 2 groups: one will receive Trugraf/TRAC Liver testing and the other will not. Subjects in the biomarker arm will have TruGraf Liver and TRAC Liver testing at study enrollment (1-2 months post-liver transplant) and thereafter every month for 6 months. Subjects will also have Trugraf Liver and TRAC Liver testing at months 9 and 12 following transplantation (7-8 and 10-11 months post baseline). The TruGraf and TRAC Liver results will be used in the biomarker arm in conjunction with all other clinical parameters available to guide decisions related to immunosuppression changes. There are no protocol mandated immunosuppression changes. Subjects in the standard of care arm will not have biomarkers available for decisions related to immunosuppression changes.

• Study Type: Observational
• Enrollment (Anticipated): 130

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

-This study is an observational study in adult (age ≥ 18 years), liver transplant patients who are 1-2 months post-transplantation. Approximately 130 subjects will be enrolled.

Description

Inclusion Criteria:

• At least 18 years of age.
• Recipient of a primary or subsequent deceased-donor or living donor liver transplantation.
• Normal liver function tests at the time of or within 2 weeks of the baseline visit, defined by Total Bilirubin (TB) ≤1.5 mg/dL and Direct Bilirubin (DB) <0.5 mg/dL, Alkaline Phosphatase (AP) ≤200 U/L, and Alanine Transaminase (ALT) ≤60 U/L (males) ≤36 U/L (females).
• Between 1-2 months post-liver transplantation

Exclusion Criteria:

• Inability or unwillingness to provide informed consent.
• Recipients of previous hepatic or non-hepatic solid organ transplantation
• History of ≥2 mild or moderate rejections or 1 severe rejection prior to enrollment defined by BANFF 2016 criteria
• History of autoimmune liver disease
• Listed for repeat liver transplantation
• Infection with HIV
• Active HBV or HCV viremia (patients with undetectable virus can be included)

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Patients monitored with TruGraf/TRAC Liver testing; Subjects in the biomarker arm will have TruGraf Liver and TRAC Liver testing at study enrollment (1-2 months post-liver transplant) and thereafter every month for 6 months. Subjects will also have Trugraf Liver and TRAC Liver testing at months 9 and 12 following transplantation (7-8 and 10-11 months postbaseline) The TruGraf and TRAC Liver results will be used in the biomarker arm in conjunction with all other clinical parameters available to guide decisions of the Principal Investigator and Sub-Investigators related to immunosuppression management. changes.	Diagnostic test: Patients monitored with TruGraf and TRAC Liver testing; This is an observational study there are no protocol mandated interventions. TruGraf and TRAC Liver results will be utilized in conjunction with standard of care assessments to determine patient management in the study arm.
Patients not monitored with TruGraf/TRAC Liver testing; Patients in control/ stamdard of care arm will have immusuppresion reduction based on the clinical judgement and management of the Principal Investigator and Sub-Investigators.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunosuppression reduction	Percent of subjects in each arm achieving at least 50% reduction from baseline total immunosuppressant (non-corticosteroid) dose at 6 months	6-months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Immunosuppressant trough	Immunosuppressant trough levels at 6 months post transplant	6-months
Median and mean IS trough	Median and mean change in IS trough levels from baseline to 6 months	6-months
monotherapy immunosuppression	Percent of patients achieving monotherapy immunosuppression	1 year
clinical utility	Percent and total number of TruGraf Liver and TRAC Liver results that the PI identified as having clinical utility (Utility).	1 year
Liver testing workflow	Percent and total number of eligible patients for whom the PI was able to complete the entire TruGraf Liver and TRAC Liver testing workflow (Feasibility).	1 year
CKD score	Progression of CKD score managed by the KDIGO (Kidney Disease: Improving Global Outcomes) criteria from a scale of GI (normal kidney) to G5 (kidney failure)	1 year
BPAR for-cause biopsy	Incidence of biopsy proven acute rejection on a for cause biopsy at months 6 and 12	1 year
Acute rejection	Incidence of clinically treated acute rejection at months 6 and 12	1 year
eGFR timepoints	eGFR at months 6 and 12	1 year
eGFR timepoint range	eGFR change from baseline to months 6 and 12	1 year
Slope of eGFR	Slope of eGFR from baseline to months 6 and 12	1 year
eGFR decline or progression of CKD	Risk factors for eGFR decline or progression of CKD score	1 year
Infections	Incidence of grade 3 or greater infections at months 6 and 12	1 year
SF-36 scores	Change in SF-36 scores from baseline to 6 months and end of study (SF 36 is a 36-item patient-reported questionnaire that covers eight health domains: physical functioning (10 items), bodily pain (2 items), role limitations due to physical health problems (4 items), role limitations due to personal or emotional problems (4 items), emotional well-being (5 items), social functioning (2 items), energy/fatigue (4 items), and general health perceptions (5 items). Scores for each domain range from 0 to 100, with a higher score defining a more favorable health state.	1 year

Collaborators and Investigators

• Sponsor: Transplant Genomics, Inc.
• Investigators: Principal Investigator: Patty West-Thielke, PharmD, Transplant Genomics

Publications and helpful links

General Publications

• Gielis EM, Ledeganck KJ, De Winter BY, Del Favero J, Bosmans JL, Claas FH, Abramowicz D, Eikmans M. Cell-Free DNA: An Upcoming Biomarker in Transplantation. Am J Transplant. 2015 Oct;15(10):2541-51. doi: 10.1111/ajt.13387. Epub 2015 Jul 16.
• Sharon E, Shi H, Kharbanda S, Koh W, Martin LR, Khush KK, Valantine H, Pritchard JK, De Vlaminck I. Quantification of transplant-derived circulating cell-free DNA in absence of a donor genotype. PLoS Comput Biol. 2017 Aug 3;13(8):e1005629. doi: 10.1371/journal.pcbi.1005629. eCollection 2017 Aug.
• Shaked A, DesMarais MR, Kopetskie H, Feng S, Punch JD, Levitsky J, Reyes J, Klintmalm GB, Demetris AJ, Burrell BE, Priore A, Bridges ND, Sayre PH. Outcomes of immunosuppression minimization and withdrawal early after liver transplantation. Am J Transplant. 2019 May;19(5):1397-1409. doi: 10.1111/ajt.15205. Epub 2018 Dec 31. Erratum In: Am J Transplant. 2019 Aug;19(8):2393.
• Fischer L, Klempnauer J, Beckebaum S, Metselaar HJ, Neuhaus P, Schemmer P, Settmacher U, Heyne N, Clavien PA, Muehlbacher F, Morard I, Wolters H, Vogel W, Becker T, Sterneck M, Lehner F, Klein C, Kazemier G, Pascher A, Schmidt J, Rauchfuss F, Schnitzbauer A, Nadalin S, Hack M, Ladenburger S, Schlitt HJ. A randomized, controlled study to assess the conversion from calcineurin-inhibitors to everolimus after liver transplantation--PROTECT. Am J Transplant. 2012 Jul;12(7):1855-65. doi: 10.1111/j.1600-6143.2012.04049.x. Epub 2012 Apr 11.
• Sterneck M, Kaiser GM, Heyne N, Richter N, Rauchfuss F, Pascher A, Schemmer P, Fischer L, Klein CG, Nadalin S, Lehner F, Settmacher U, Neuhaus P, Gotthardt D, Loss M, Ladenburger S, Paulus EM, Mertens M, Schlitt HJ. Everolimus and early calcineurin inhibitor withdrawal: 3-year results from a randomized trial in liver transplantation. Am J Transplant. 2014 Mar;14(3):701-10. doi: 10.1111/ajt.12615. Epub 2014 Feb 6.
• Levitsky J, Asrani SK, Schiano T, Moss A, Chavin K, Miller C, Guo K, Zhao L, Kandpal M, Bridges N, Brown M, Armstrong B, Kurian S, Demetris AJ, Abecassis M; Clinical Trials in Organ Transplantation - 14 Consortium. Discovery and validation of a novel blood-based molecular biomarker of rejection following liver transplantation. Am J Transplant. 2020 Aug;20(8):2173-2183. doi: 10.1111/ajt.15953. Epub 2020 May 25.
• Levitsky J, Kandpal M, Guo K, Zhao L, Kurian S, Whisenant T, Abecassis M. Prediction of Liver Transplant Rejection With a Biologically Relevant Gene Expression Signature. Transplantation. 2022 May 1;106(5):1004-1011. doi: 10.1097/TP.0000000000003895. Epub 2021 Jul 22.
• Levitsky J, Kandpal M, Guo K, Kleiboeker S, Sinha R, Abecassis M. Donor-derived cell-free DNA levels predict graft injury in liver transplant recipients. Am J Transplant. 2022 Feb;22(2):532-540. doi: 10.1111/ajt.16835. Epub 2021 Sep 24.
• Charlton M, Levitsky J, Aqel B, O'Grady J, Hemibach J, Rinella M, Fung J, Ghabril M, Thomason R, Burra P, Little EC, Berenguer M, Shaked A, Trotter J, Roberts J, Rodriguez-Davalos M, Rela M, Pomfret E, Heyrend C, Gallegos-Orozco J, Saliba F. International Liver Transplantation Society Consensus Statement on Immunosuppression in Liver Transplant Recipients. Transplantation. 2018 May;102(5):727-743. doi: 10.1097/TP.0000000000002147. Erratum In: Transplantation. 2019 Jan;103(1):e37.
• Levitsky J, O'Leary JG, Asrani S, Sharma P, Fung J, Wiseman A, Niemann CU. Protecting the Kidney in Liver Transplant Recipients: Practice-Based Recommendations From the American Society of Transplantation Liver and Intestine Community of Practice. Am J Transplant. 2016 Sep;16(9):2532-44. doi: 10.1111/ajt.13765. Epub 2016 Apr 22.

Study record dates

Study Major Dates

• Study Start (Anticipated): May 1, 2022
• Primary Completion (Anticipated): May 1, 2023
• Study Completion (Anticipated): May 1, 2023

Study Registration Dates

• First Submitted: April 12, 2022
• First Submitted That Met QC Criteria: April 12, 2022
• First Posted (Actual): April 19, 2022

Study Record Updates

• Last Update Posted (Actual): May 2, 2022
• Last Update Submitted That Met QC Criteria: April 26, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Keywords: Immunosuppression; Biomarkers; Subclinical Rejection
• Other Study ID Numbers: TGRP09

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No