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Effect of Immunosuppression Drug Weaning on Hepatitis C Virus (HCV)-Induced Liver Damage After Liver Transplantation

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ClinicalTrials.gov Identifier: NCT00668369
Recruitment Status : Completed
First Posted : April 29, 2008
Last Update Posted : December 20, 2013
Sponsor:
Information provided by (Responsible Party):
Alberto Sanchez-Fueyo, Hospital Clinic of Barcelona

Tracking Information
First Submitted Date  ICMJE April 24, 2008
First Posted Date  ICMJE April 29, 2008
Last Update Posted Date December 20, 2013
Study Start Date  ICMJE April 2008
Actual Primary Completion Date September 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 28, 2008)
Proportion of hepatitis C virus positive liver recipients successfully withdrawing immunosuppressive drugs. [ Time Frame: 18 months ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 28, 2008)
  • Effects of immunosuppression withdrawal on hepatitis C virus induced liver damage. [ Time Frame: 18 months ]
  • Influence of HCV-induced immune responses on the feasibility of successfully withdrawing immunosuppressive drugs in liver transplant recipients. [ Time Frame: 18 months ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effect of Immunosuppression Drug Weaning on Hepatitis C Virus (HCV)-Induced Liver Damage After Liver Transplantation
Official Title  ICMJE Effect of Immunosuppression Drug Weaning on Hepatitis C Virus Induced Liver Damage After Liver Transplantation.
Brief Summary

Viral infections can profoundly influence alloimmune responses and hamper allograft tolerance induction. Persistent hepatitis C virus (HCV) infection occurs in 50% of liver and 20% of kidney transplant recipients, but the impact of HCV on the acquisition of allograft tolerance has not been elucidated. Liver transplantation constitutes a unique clinical model to address this question, given that up to 20% of liver recipients can completely discontinue immunosuppressive drugs and attain operational tolerance.

The goal of our study is to determine the influence of HCV-driven immune responses on the acquisition of operational tolerance in liver transplant recipients following drug weaning, and to assess whether immunosuppression withdrawal ameliorates HCV-induced liver damage.

This is a prospective trial in which immunosuppressive drug weaning will be offered to HCV-positive liver recipients (selected on the basis of a high likelihood of tolerance) as a strategy to improve HCV-mediated liver disease.

Detailed Description

Objective: To determine the influence of hepatitis C virus (HCV)-driven immune responses on the acquisition of operational tolerance in liver transplant recipients following drug weaning, and to assess whether immunosuppression withdrawal ameliorates HCV-induced liver damage.

Background: Viral infections can profoundly influence alloimmune responses and hamper allograft tolerance induction. Persistent HCV infection occurs in 50% of liver and 20% of kidney transplant recipients, but the impact of HCV on the acquisition of allograft tolerance has not been elucidated. Liver transplantation constitutes a unique clinical model to address this question, given that up to 20% of liver recipients can completely discontinue immunosuppressive drugs and attain operational tolerance.

Hypothesis/Specific Aims: We hypothesize that HCV positive patients failing to attain operational tolerance will exhibit both decreased anti-HCV specific T cell responses and exacerbated non-specific immunoactivation. Furthermore, we anticipate that successful immunosuppression withdrawal will decrease the progression of HCV-induced liver damage. Thus our aims are:

  1. To test whether the magnitude of HCV-mediated inflammatory responses influence the acquisition of operational tolerance following liver transplantation.
  2. To establish the impact of anti-HCV specific CD4+ and CD8+ T cell immune responses on the capacity of liver recipients to successfully withdraw immunosuppression.
  3. To determine how the immunophenotypic traits and functional properties of T cells, NK cells and antigen presenting cells affect the development of operational tolerance in HCV-positive liver recipients.
  4. To assess the effect of immunosuppression weaning on the histological progression of HCV-induced liver damage.

Proposed methods: On the basis of a previously identified immunophenotypic signature of tolerance (high ratio of delta 1 to delta 2 gammadelta T cell in peripheral blood), drug weaning will be offered to HCV-positive liver recipients as a strategy to improve HCV-mediated liver disease. We estimate that patients selected on the basis of this biomarker will have a likelihood of successful weaning greater than 50%. Both peripheral blood and liver tissue samples will be collected for diagnostic purposes before the initiation of drug weaning in order to perform the following assays: measurement of anti-HCV CD4+ and CD8+ T cell immunity, peripheral blood and liver tissue gene expression profiling, peripheral blood cell phenotyping and functional assays and, in a subset of patients, measurement of anti-donor T cell responses. Immunosuppression drugs will be weaned over a period of 6 months, and thereafter patients will be followed for 12 additional months. Patients not undergoing rejection during this 18 month period will be considered tolerant. Liver biopsies will be obtained before the beginning of the study and at the end. Progression of HCV-induced liver diseased will be compared to that of patients with a low delta1/delta2 ratio, in whom no changes in immunosuppressive drugs will be conducted and liver biopsies will be obtained yearly (according to our clinical guidelines).

Expected results: We expect to precisely define how HCV influences the acquisition of operational tolerance after liver transplantation, and confirm the beneficial effect of immunosuppression withdrawal in these patients.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Hepatitis C Virus Infection
  • Liver Transplantation
Intervention  ICMJE Procedure: Gradual immunosuppression drug withdrawal.
Ater obtention of biological samples (peripheral blood, liver tissue) enrolled patients undergo gradual decrease in the doses of immunosuppression drugs (tacrolimus, cyclosporine A and/or mofetil mycophenolate) until complete discontinuation or appearance of rejection.
Study Arms  ICMJE Experimental: 1
Liver transplant recipients with HCV infection fulfilling inclusion criteria.
Intervention: Procedure: Gradual immunosuppression drug withdrawal.
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: December 19, 2013)
34
Original Estimated Enrollment  ICMJE
 (submitted: April 28, 2008)
53
Actual Study Completion Date  ICMJE September 2011
Actual Primary Completion Date September 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Liver transplantation for HCV-related liver disease performed at least 3 years before weaning;
  • Peripheral blood Vgd1+/Vgd2+ T cell ratio >2.33 and/or increased expression of KLRF1 and SLAMF7 genes in peripheral blood (measured by qPCR).
  • No indication for treatment with pegylated a-interferon plus ribavirin during the weaning procedure;
  • Stability of liver function tests for at least 6 months;
  • 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.
  • Absence of decompensated chronic liver disease.

Exclusion Criteria:

  • HIV infection
  • Double liver-kidney transplantation
  • HCV cholestatic fibrosing hepatitis
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Spain
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00668369
Other Study ID Numbers  ICMJE Weaning_HCV
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Alberto Sanchez-Fueyo, Hospital Clinic of Barcelona
Study Sponsor  ICMJE Hospital Clinic of Barcelona
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Alberto Sanchez-Fueyo, MD Hospital Clinic Barcelona / IDIBAPS, Barcelona, Spain
Study Chair: Giuseppe Tisone, MD University Tor Vergata, Rome, Italy
Study Chair: Marina Berenguer, MD HOSPITAL LA FE VALENCIA
PRS Account Hospital Clinic of Barcelona
Verification Date December 2013

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP