Assessment Of the Safety and Benefit of Prospective Immunosuppressive Drug Withdrawal in Liver Transplantation and Prediction of Operational Tolerance

NCT00647283 | Unknown Phase 2 DMC

• 2 other identifiers: V-2005-CE512090-ORISET
• Study Type: interventional
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

In liver transplantation up to 20% of recipients can completely discontinue immunosuppressive therapy maintaining normal graft function, and are conventionally considered as operationally tolerant. Discontinuation of immunosuppressive drugs in operationally tolerant recipients could lessen the side effects of chronic immunosuppressive therapy. However, this strategy results in the development of rejection in a high proportion of recipients who require lifelong immunosuppression. Thus, there is a need to identify predictive factors of successful drug withdrawal and to define the clinical and histological outcomes of operationally tolerant liver recipients. The main objective of this study is to establish the safety of attempting immunosuppressive (IS) drug withdrawal in stable liver transplant recipients, using standard clinical, biological and histopathological methods, to screen and follow-up patients, and to confirm the benefit of maintaining immunosuppressive drug interruption in patients who are tolerant to their liver transplant. The secondary objective of this study is to identify predictive factors of operational tolerance and to attempt to develop a multi-parameter "decision rule" to predict patient tolerance or non-tolerance in order to improve patient screening and follow-up. In a diagnostic observational sub-study, peripheral blood and liver tissue samples collected before immunosuppressive drug withdrawal will be employed to validate the diagnostic accuracy of a previously identified set of tolerance biomarkers and to identify potential new biomarkers capable of predicting the outcome of the immunosuppressive withdrawal protocol.

Conditions

Liver Transplantation

Keywords

Liver Transplantation; Tolerance; Allograft tolerance; Immunosuppression minimization; Immunosuppression weaning; Immunological tolerance

Outcome Measures

Primary Outcomes (1)

• Operational tolerance defined as liver transplant survival with immunosuppressive drug interruption and without liver transplant rejection after starting drug dose reduction and following 12 months of complete drug discontinuation.

  18 months

Secondary Outcomes (2)

• Prevalence of patients developing permanent graft dysfunction as a consequence of immunosuppressive drug withdrawal.

  48 months

• Effects of the immunosuppression weaning procedure on immunosuppression-related side effects (hypertension, diabetes, nephrotoxicity, hyperlipidemia)

  48 months

Study Arms (1)

1

EXPERIMENTAL

Stable liver transplant recipients fulfilling inclusion criteria.

Procedure: Gradual immunosuppression drug withdrawal

Interventions

Gradual immunosuppression drug withdrawal PROCEDURE

After the obtention of biological samples (peripheral blood, liver tissue), enrolled patients undergo gradual weaning of all immunosuppressive therapy over a 6-9 month period under close medical supervision.

1

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Liver transplantation performed for non-autoimmune liver disease performed at least 3 years before IS weaning.
• Absence of acute and/or chronic rejection episodes during the 12 months before weaning.
• Basal liver biopsy without signs of acute and/or chronic rejection.
• No evidences of autoimmune liver disease.
• Absence of acute and/or chronic rejection episodes during the 12 months before weaning.
• Basal liver biopsy without signs of acute and/or chronic rejection.
• Low dose immunosuppression (monotherapy with calcineurin inhibitors, mTOR inhibitors or mycophenolate mofetil, or combined therapy with 2 drugs at very low doses).
• Absence of medical or psychological disturbances that preclude the safe performance of the trial.
• Stability of liver graft function, defined as: normal liver function tests (AST, ALT, ALP, GGT) during at least 6 months, or, alternatively, minor alterations in liver function tests that have not changed over the previous 6 months (AST/ALT \< 2 fold normal levels; ALP \< 1.5 fold normal levels; GGT \< 2 fold normal levels; bilirubin \< 2 mg/dL).
• Patients exhibiting at least one of the following characteristics: a) severe side effects of immunosuppressive drugs (diabetes, renal failure, hyperlipidemia, hypertension); b) risk of neoplasm development defined by history of previous non-hepatocarcinoma neoplasms or history of any of the following risk factors: tobacco or alcohol consumption, age greater than 60 years; c) chronic liver disease due to hepatitis C virus infection in patients not receiving anti-viral treatment.
• Signature of informed consent.

Sponsors & Collaborators

• Hospital Clinic of Barcelona: lead
• Fondo de Investigacion Sanitaria: collaborator
• European Commission: collaborator
• TcLand Expression S.A.: collaborator

Study Sites (1)

Hospital Clinic Barcelona, University of Barcelona

Barcelona, Barcelona, 08036, Spain

Location

Related Publications (1)

• Martinez-Llordella M, Puig-Pey I, Orlando G, Ramoni M, Tisone G, Rimola A, Lerut J, Latinne D, Margarit C, Bilbao I, Brouard S, Hernandez-Fuentes M, Soulillou JP, Sanchez-Fueyo A. Multiparameter immune profiling of operational tolerance in liver transplantation. Am J Transplant. 2007 Feb;7(2):309-19. doi: 10.1111/j.1600-6143.2006.01621.x.

  PMID: 17241111 BACKGROUND

Study Officials

• Alberto Sanchez-Fueyo, MD

  Hospital Clinic Barcelona / IDIBAPS, Barcelona, Spain

  PRINCIPAL INVESTIGATOR

• Giuseppe Tisone, MD

  University Tor Vergata, Rome, Italy

  STUDY CHAIR

• Jacques Pirenne, MD

  Abdominal Transplant Surgery Department, University Hospitals Leuven, Belgium

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: March 26, 2008
• First Posted: March 31, 2008
• Study Start: November 1, 2005
• Primary Completion: September 1, 2010
• Study Completion: December 1, 2012
• Last Updated: April 20, 2011

Record last verified: 2011-04

Locations

ES (1)