Induction Treatment Followed by Immunosuppression Withdrawal in Liver Transplantation: A Comparative Trial (ATEGE-LIVER)

May 19, 2009 updated by: Hospital Clinic of Barcelona

Study of ATEGE-Fresenius Induction in Liver Transplantation Followed by Tacrolimus Weaning.

This is a randomized, controlled trial in liver transplantation in which conventional immunosuppressive treatment will be compared with a therapeutic strategy consisting in pre-transplant antibody-mediated T cell depletion followed by reduced calcineurin inhibitor usage. The working hypothesis is that antibody induction followed by calcineurin inhibitor minimization may promote development of tolerogenic mechanisms allowing the eventual withdrawal of all immunosuppressive therapy.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

This is an open-label randomised controlled study in which patients will be randomised according to a 1:1 ratio to receive conventional immunosuppressive treatment or induction treatment plus reduced tacrolimus dosage. All transplanted patients enrolled in the study will be followed during 12 months and evaluated according to an intention-to-treat approach.

  • Specific Aim 1: To determine the proportion of liver recipients in whom tacrolimus usage can be significantly reduced 1 year after transplantation. Patients will be considered as successfully receiving a reduced tacrolimus regimen if this drug is given as a single dose every other day, or at the most administered as a single dose daily with trough levels < 5ng/mL.
  • Specific Aim 2: To determine the effect of induction treatment plus minimized immunosuppression on graft and patient survival.
  • Specific Aim 3: To determine the impact of induction treatment plus minimized immunosuppression on the development of: acute and chronic allograft rejection, hepatitis C virus graft recurrence, opportunistic infections, bone fractures, kidney failure, tacrolimus-related neurotoxicity, dyslipidemia and arterial hypertension.
  • Specific Aim 4: To establish whether the use of ATG induction followed by reduced doses of tacrolimus differentially affects anti-donor immune responses and/or promotes the development of T cell dependent immunoregulatory networks.

  • Conventional immunosuppressive protocol:

    1. Methylprednisolone iv 500 mg before laparotomy, and 500 mg at the time of reperfusion.
    2. Methylprednisolone iv according to the following schedule: postoperative day 1 200 mg, day 2 160mg, day 3 120 mg, day 4 80 mg, day 5 40 mg, and thereafter 20 mg oral prednisone.
    3. Oral tacrolimus q12h starting on postoperative day 1 in order to reach trough drug levels between 10 and 15 ng/mL. These levels will be maintained in this range during the first month after transplantation. Subsequently, tacrolimus levels will be gradually reduced as follows: : month 1-3: 8-15 ng/ml; month 4-12: 7-12 ng/ml; afterwards: 5-10 ng/ml.
    4. Progressive prednisone withdrawal between month 6 and 9 after transplantation.
    5. Treatment of acute rejection episodes: according to our conventional clinical protocol. All efforts must be done in order to histologically document the rejection episode. Hence, empirical treatment should be avoided if possible.

  • Induction protocol:

    1. ATG-Fresenius 9mg/kg pre-transplantation, preceded by administration of 500 mg iv methylprednisolone. Infusion of ATG-F will be started whenever the surgeon confirms the suitability of the graft, and will take place during 6 hours.
    2. Oral tacrolimus q12h, starting on postoperative day 1 at the required dosages in order to reach through drug levels between 5 and 12 ng/mL

    3. Reduction of tacrolimus dosages starting 3 months after transplantation in stable patients with no evidences of graft rejection in the previous 60 days, and according to the following protocol:

      • posttransplant month 3: 1 dose per day
      • posttransplant month 6: 1 dose every 48 hours
      • posttransplant month 9: ½ dose every 48 hours
      • posttransplant month 12: evaluate the possibility of complete drug withdrawal or alternatively establish the optimal maintenance dose.
    4. Treatment of acute rejection episodes: mild to moderate acute rejection episodes: re-start 1-2 daily doses of tacrolimus. Severe acute rejection episodes or those mild to moderate episodes that do not improve after 10 days of treatment: 1-2 daily doses of tacrolimus plus methylprednisolone 0.5-1 g for 3 days. Resolution of the rejection episode will be followed by resumption of the above mentioned protocol. If a new rejection episode takes place, after treatment of the acute episode no further attempts to reduce tacrolimus dosages will be attempted. In all cases rejection will be confirmed by liver biopsy.
    5. Patients suffering from hepatitis C virus infection will be treated as above, unless alpha-interferon treatment is considered. In this case, daily tacrolimus will be administered.
    6. All patients will receive CMV prophylaxis with iv ganciclovir for 14 days and oral valganciclovir to complete 3 months after transplantation.
  • Sample collection during the study period

In addition to routine diagnostic tests, all enrolled patients will undergo the following procedures:

  • Cryopreservation of donor spleen cells to measure anti-donor immune responses.
  • HCV viral load quantification pre-transplantation and at post-transplant months 1, 6 and 12.
  • All patients will undergo liver biopsy 1 year after transplantation and yearly thereafter. In addition, HCV positive patients will be undergo liver biopsy 3 months after transplantation. A portion of all liver biopsies will be cryopreserved for gene expression studies.
  • Anti-donor and anti-HCV T cell immune responses will be quantified before transplantation, and 6 and 12 months after transplantation by gamma-interferon ELISpot assay.
  • Peripheral blood mononuclear cells will be harvested and cryopreserved before transplantation, 6 months and 12 months after transplantation to perform gene expression and flow cytometry studies.
  • A sample of recipient DNA will be cryopreserved to perform DNA polymorphism studies.

Study Type

Interventional

Enrollment (Anticipated)

72

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Spain
      • Barcelona, Spain, 08036
        • Hospital Clinic Barcelona, University of Barcelona

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age > 18 years
  • Recipient of a primary liver graft
  • Absence of any of our exclusion criteria

Exclusion Criteria:

  • Pretransplant renal failure, defined as serum creatinine > 1.5 mg/dL
  • Severe pretransplant thrombopenia, defined as platelets < 50000/mL
  • Combined liver-kidney transplantation
  • Autoimmune hepatitis, primary biliary cirrhosis or primary sclerosing cholangitis as causes of liver transplantation
  • Chronic hepatic encephalopathy
  • Living donor liver transplantation
  • Recipient with human immunodeficiency virus infection
  • Severe pretransplant leukopenia, defined as < 1500 leukocytes/mL

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Proportion of patients who can significantly decrease the doses of tacrolimus 1 year after transplantation (as defined by: tacrolimus administered on alternate days, or daily with trough levels below 5 ng/mL.
Time Frame: 1 year
1 year

Secondary Outcome Measures

Outcome Measure
Time Frame
Patient survival
Time Frame: 1 year
1 year
Graft survival
Time Frame: 1 year
1 year
Incidence of opportunistic infections
Time Frame: 1 year
1 year
Incidence of acute/chronic rejection
Time Frame: 1 year
1 year
Incidence of hypertension, renal failure, diabetes, hyperlipidemia
Time Frame: 1 year
1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Hospital Clinic of Barcelona

Collaborators

Astellas Pharma Inc
Fresenius AG

Investigators

  • Principal Investigator: Alberto Sanchez-Fueyo, Hospital Clinic Barcelona, Barcelona, Spain

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2006

Primary Completion (Anticipated)

July 1, 2009

Study Registration Dates

First Submitted

February 16, 2007

First Submitted That Met QC Criteria

February 16, 2007

First Posted (Estimate)

February 19, 2007

Study Record Updates

Last Update Posted (Estimate)

May 20, 2009

Last Update Submitted That Met QC Criteria

May 19, 2009

Last Verified

May 1, 2009

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EudraCT 2005-005635-10

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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