Liver Immune Tolerance Marker Utilization Study (LITMUS)

The purpose of this study is to validate and test a tolerance gene expression profile for the identification of operationally tolerant liver transplant recipients, allowing for the successful withdrawal of immunosuppression without rejection in these patients.

Study Overview

• Status: Completed
• Conditions: Immunosuppression; Immune Tolerance
• Intervention / Treatment: Other: Controlled weaning of immunosuppression

Detailed Description

Previous pre-clinical work in the Levy Lab identified a novel biomarker gene set for the identification of tolerance in murine models of rapamycin-induced cardiac tolerance and spontaneous hepatic tolerance. Validation of this gene expression tolerance biomarker in operationally tolerant patients is now required for its implementation in the clinical setting. This proposal intends to validate and test our pre-clinically established tolerance gene expression biomarker in the clinical setting in order to translate our findings into improving the length and quality of life of transplant patients in the clinic.

The investigators hypothesize that a distinct gene expression profile expressed in the peripheral blood will identify operationally tolerant liver transplant recipients, allowing for the successful withdrawal of immunosuppression in these patients. Our study aims are: (I) To validate the pre-clinical gene expression profile for the identification of operationally tolerant liver recipients in plasma peripheral blood mononuclear cells (PBMCs) (2) To determine that the gene expression profile in the PBMCs is the same as the intra-graft gene expression profile (3) To demonstrate that liver transplant recipients with the tolerant gene expression profile can be safely weaned off of immunosuppression.

This proof of principle study will be conducted in two phases at the Toronto General Hospital (TGH) Phase 1 will address study aims 1 and 2, and phase 2 will address study aim 3. Potential participants will be screened and selected following predefined eligibility criteria. Eligible participants will undergo an informed consent process. The primary goal of this study is to validate the pre-clinical tolerant gene expression profile that will allow for the identification of tolerant liver recipients and for the monitored weaning off immunosuppression in these tolerant patients.

• Study Type: Interventional
• Enrollment (Actual): 69
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 2C4
      • Toronto General Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• To be eligible to participate in this study, patients must:

  1. Be between 18 and 65 years of age.
  2. Be recipients of a hepatic allograft.
  3. Be less than 3 months post-transplant and be experiencing rejection, or be a minimum of 3 months post-transplant with or without presently experiencing rejection.
  4. Be healthy live liver donors

Exclusion Criteria:

• Patients with the following conditions may not participate in the study:

  1. Patients under the age of 18 and over the age of 65.
  2. Patients who are positive for Human Immunodeficiency Virus (HIV),
  3. Patients who have detectable levels of HCV RNA, and HBV DNA, at the time of enrollment.
  4. Patients who have a combined transplant and/or have been re-transplanted.
  5. Patients taking immunosuppression for other diseases besides their liver transplant.
  6. Patients unable to give written informed consent in accordance with research ethics board guidelines.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Controlled weaning of immunosuppression; Participants who are found to have the tolerance gene expression profile during phase 1 of the study will undergo closely monitored immunosuppression weaning during phase 2.

Other: Controlled weaning of immunosuppression; At week 0 patients have liver biopsy and liver functional tests (LFTs). Week 1-4 medication reduction to 1.5mg Tacrolimus (Tac) daily or 150mg Cyclosporine A (CsA). At week 4 LFTs. Week 5-8 medication reduction to 1mg Tac / 100mg CsA. Week 8 LFTs. Week 9-12 reduction to 0.5mg Tac/ 50mg CsA. Week 12 LFTs. Week 13-16 reduction to 0mg. Week 16 liver biopsy & LFTs. Weekly LFTs performed Week 17-20. Monthly LFTs for the next 3 months. LFTs every 3 months for monitoring.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Validation of Tolerance Gene Expression Profile	The primary endpoint of this study is the identification and validation of a unique tolerance gene expression profile, consisting of a 6 gene profile, in 3-6 operationally tolerant patients compared to 25 rejecting and 25 healthy controls.	Enrollment to one year post cessation of immunosuppression

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tolerance gene expression profile in graft versus peripheral blood mononuclear cells (PBMCs)	This endpoint will be defined as the ratio of patients (n=55) that will express the tolerance gene expression profile in the liver graft versus in the peripheral blood mononuclear cells.	Enrollment to one year post cessation of immunosuppression
Test of tolerance gene expression profile	This endpoint will assess whether the tolerance gene expression profile can be successfully used to select immunosuppressed patients for the successful weaning off immunosuppression. This endpoint will be evaluated using the number of successful immunosuppression-weaned patients from a 7-10 patient cohort. Successful immunosuppression-weaned patients are defined as patients who achieve an immunosuppression free state without any histological or clinical evidence of rejection for a minimum of 1 year.	Enrollment to one year post cessation of immunosuppression

Collaborators and Investigators

• Sponsor: University of Toronto
• Investigators: Principal Investigator: Gary Levy, M.D., University Health Network, University of Toronto; Study Chair: Leslie Lilly, M.D., University Health Network, Toronto; Study Chair: Nazia Selzner, M.D. PhD., University Health Network, Toronto; Study Director: Meaghan MacArthur, M.Ed, University Health Network, Toronto

Publications and helpful links

General Publications

• Chruscinski A, Rojas-Luengas V, Moshkelgosha S, Issachar A, Luo J, Yowanto H, Lilly L, Smith R, Renner E, Zhang J, Epstein M, Grant D, McEvoy CM, Konvalinka A, Humar A, Adeyi O, Fischer S, Volmer FH, Taubert R, Jaeckel E, Juvet S, Selzner N, Levy GA. Evaluation of a gene expression biomarker to identify operationally tolerant liver transplant recipients: the LITMUS trial. Clin Exp Immunol. 2022 Jan 28;207(1):123-139. doi: 10.1093/cei/uxab011.

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2015
• Primary Completion (Actual): May 31, 2021
• Study Completion (Actual): May 31, 2021

Study Registration Dates

• First Submitted: September 2, 2015
• First Submitted That Met QC Criteria: September 3, 2015
• First Posted (Estimate): September 4, 2015

Study Record Updates

• Last Update Posted (Actual): September 30, 2021
• Last Update Submitted That Met QC Criteria: September 29, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Keywords: Immunosuppression; Immunology; Transplantation; Gene Expression; Biological Markers; Liver Transplantation; Immune Tolerance; Real-Time Polymerase Chain Reaction; Transplantation Tolerance; Multiplex Polymerase Chain Reaction
• Other Study ID Numbers: Tol002