Gradual Withdrawal of Immune System Suppressing Drugs in Patients Receiving a Liver Transplant (A-WISH)

January 15, 2019 updated by: National Institute of Allergy and Infectious Diseases (NIAID)

A Phase II Trial to Assess the Safety of Immunosuppression Withdrawal in Liver Transplant Recipients

In order to prevent organ rejection, patients receiving liver transplants currently require life-long treatment with immune system-suppressing medications to prevent the rejection of the transplanted liver. However, these medications can cause long-term side effects, such as infection, kidney problems, diabetes, and cancer. In patients infected with hepatitis C virus (HCV), these medications may increase the risk of HCV infection in the transplanted liver. The purpose of this study is to determine whether a slow withdrawal of immune system-suppressing medications is safe in two groups of subjects: those who receive a liver transplant due to HCV, and those who receive a liver transplant due to non-immune, non-viral causes of liver failure. The study will also look at whether slow withdrawal will help reduce the long-term side effects of immune system-suppressing medications and decrease the chance for HCV infection of the new liver in transplant patients with HCV.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

This is a prospective multicenter, open-label, randomized trial in which individuals with liver failure due to hepatitis C or to nonimmune nonviral causes undergo liver transplantation and receive immunosuppression with a calcineurin inhibitor and corticosteroids. Corticosteroids are tapered in the 3 months after transplantation and the calcineurin inhibitor is continued. Participants are regularly assessed for evidence of allograft rejection. One year after transplantation, participants eligible for withdrawal are randomly assigned in a 4 to 1 ratio to immunosuppression withdrawal or to maintenance. Participants assigned to withdrawal undergo a scheduled taper over approximately 1 year.

Study Type

Interventional

Enrollment (Actual)

275

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

  • United States
    • California
      • San Francisco, California, United States, 94143
        • University of California, San Francisco
    • Colorado
      • Denver, Colorado, United States, 80262
        • University of Colorado
    • Illinois
      • Chicago, Illinois, United States, 60208
        • Northwestern University
    • Michigan
      • Ann Arbor, Michigan, United States, 48109
        • University of Michigan
    • Ohio
      • Cleveland, Ohio, United States, 44195
        • Cleveland Clinic
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • University of Pennsylvania
    • Texas
      • Dallas, Texas, United States, 76798
        • Baylor University
    • Washington
      • Seattle, Washington, United States, 98195
        • University of Washington

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

16 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Male or female 18 years of age or older.
  2. Necessity for liver transplant.
  3. For females of childbearing potential: a negative pregnancy test at study entry and agreement to use approved methods of birth control for the duration of their participation.
  4. Ability to provide informed consent.
  5. Availability of donor specimen(s).
  6. For individuals with hepatitis C infection, presence of hepatitis genomes in blood.

Exclusion Criteria:

  1. Previous transplant.
  2. Multiorgan or split liver transplant other than with a right trisegment.
  3. Living donor transplant.
  4. Donor liver from a donor positive for antibody against hepatitis C.
  5. Donor liver from a non-heart-beating donor.
  6. Liver failure due to autoimmune disease.
  7. Fulminant liver failure.
  8. Hepatitis B infection as defined by the presence of HbSAg or hepatitis-C infection with a genome other than genome 1.
  9. Stage III or higher hepatocellular cancer.
  10. History of malignancy except hepatocellular cancer, adequately treated in situ cervical carcinoma,adequately treated basal or squamous cell carcinoma of skin, or other cancer judged to have a 5-year risk of recurrence less than 10%.
  11. Active systemic infection at the time of transplantation.
  12. Clinically significant chronic renal disease.
  13. Clinically significant cardiovascular or cerebrovascular disease.
  14. Infection with human immunodeficiency virus.
  15. Any investigational drug received within 6 weeks of study entry or any investigational vaccine received at any time.
  16. Hypersensitivity to tacrolimus.
  17. Unwillingness or inability to comply with study requirements.

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)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Immunosuppression Withdrawal
Subjects may randomize to this group at 12 to 24 months after transplantation. This is followed by tapered withdrawal of calcineurin inhibitor-based immunosuppression therapy over the course of 1 year.
Drug: calcineurin inhibitor-based immunosuppression
May be cyclosporine, mycophenolate mofetil, or tacrolimus
Procedure: liver transplant
Occurs at study entry
Other Names:
  • liver transplantation
Drug: corticosteroids
3-month course of corticosteroids
Other Names:
  • prednisone
Other: immunosuppression withdrawal
One year after transplantation, participants eligible for withdrawal are randomly assigned in a 4 to 1 ratio to immunosuppression withdrawal or to maintenance.
Active Comparator: Immunosuppression Maintenance
Liver transplant, followed by maintenance doses of continuous calcineurin inhibitor-based immunosuppression therapy.
Drug: calcineurin inhibitor-based immunosuppression
May be cyclosporine, mycophenolate mofetil, or tacrolimus
Procedure: liver transplant
Occurs at study entry
Other Names:
  • liver transplantation
Drug: corticosteroids
3-month course of corticosteroids
Other Names:
  • prednisone

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants With Clinical Complications Usually Attributed to Immunosuppression
Time Frame: Randomization to 2 years post-randomization
This is a composite endpoint comprising clinical complications related to immunosuppression and is defined as the occurrence of any of the following: death or graft loss, grade 4 secondary malignancy (graded by Common Terminology Criteria for Adverse Events [CTCAE] version 3.0), grade 4 opportunistic infection (graded by CTCAE version 3.0), stage 3 or higher fibrosis, or decrease in renal function. Decrease in renal function is defined as: a) the estimated glomerular filtration rate (eGFR) using creatinine obtained prior to and closest to randomization will be considered the baseline and will be compared to the eGFR using creatinine obtained at 24 months +/- 3 months after randomization; b) for those with a baseline eGFR 30-90 ml per min per 1.73 meter-squared, a 25% decrease in eGFR; c) for those with a baseline eGFR greater than 90 ml per min per 1.73 meter-squared, a 25% decrease in eGFR and a decrease in eGFR to less than 90 ml per min per 1.73 meter-squared.
Randomization to 2 years post-randomization

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of Participants Who Qualify for Random Assignment
Time Frame: One to two years post-transplantation
One to two years post-transplantation
Number of Participants Who Successfully Stop Taking Immunosuppression for at Least 6 Months
Time Frame: Randomization until study completion or participant termination (up to six years post-transplant)
Randomization until study completion or participant termination (up to six years post-transplant)
Immunosuppression-free Duration
Time Frame: Discontinuation of all immunosuppression to end of trial participation or to time of restarting immunosuppression, whichever came first, assessed up to two years
Time (in days) from withdrawing off of all immunosuppressive drugs to re-starting immunosuppression or study termination/completion.
Discontinuation of all immunosuppression to end of trial participation or to time of restarting immunosuppression, whichever came first, assessed up to two years
Number of Hepatitis C Infected Participants With Progression of Hepatitis C Related Liver Disease, Defined as Stage 4 or Higher Fibrosis on the Ishak Scale
Time Frame: Randomization to 2 years post-randomization.
Number of subjects with a biopsy showing stage 4 fibrosis or higher on the Ishak scale. Stage 4 represents at least 13.7% fibrosis measurement with a description of fibrous expansion of portal areas with marked bridging (P-P) as well as portal to central (P-C). Stage 5 is marked bridging (P-P and/or P-C), with occasional nodules (incomplete cirrhosis) and stage 6 is cirrhosis, probable or definite.
Randomization to 2 years post-randomization.
Number of Participants Experiencing Graft Loss or Death
Time Frame: Randomization to 2 years post-randomization.
Number of participants with graft loss or death. Graft loss is defined as subject death or re-transplantation.
Randomization to 2 years post-randomization.
Total Immunosuppression From Month 21 to Month 24 Post-randomization
Time Frame: Month 21 to Month 24 post-randomization
Daily immunosuppression score in units per day averaged over the 3-month period from Month 21 to Month 24 post-randomization. Daily doses were assigned a score of 1 unit as follows: tacrolimus 1 mg, cyclosporine 100 mg, Sirolimus 1 mg, mycophenolate mofetil 1000 mg, Mycophenolic acid 720 mg, azathioprine 50 mg, and prednisone 5 mg. Any antibody use equaled 20 units. Unit scores based on Vasudev (Vasudev B, Hariharan S, Hussain SA, Zhu YR, Bresnahan BA et al. BK virus nephritis: risk factors, timing, and outcome in renal transplant recipients. Kidney Int. 2005; 8(4):1834-1839.)
Month 21 to Month 24 post-randomization
Total Burden of Immunosuppression From Random Assignment to Month 24
Time Frame: Randomization to Month 24 post-randomization
Total immunosuppression score in units taken as the sum of units per day over the 2-year period from randomization to Month 24 post-randomization. Daily doses were assigned a score of 1 unit as follows: tacrolimus 1 mg, cyclosporine 100 mg, Sirolimus 1 mg, mycophenolate mofetil 1000 mg, Mycophenolic acid 720 mg, azathioprine 50 mg, and prednisone 5 mg. Any antibody use equaled 20 units. Unit scores based on Vasudev (Vasudev B, Hariharan S, Hussain SA, Zhu YR, Bresnahan BA et al. BK virus nephritis: risk factors, timing, and outcome in renal transplant recipients. Kidney Int. 2005; 8(4):1834-1839.).
Randomization to Month 24 post-randomization

Collaborators and Investigators

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

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

Collaborators

Immune Tolerance Network (ITN)

Investigators

  • Study Chair: Abraham Shaked, MD, PhD, University of Pennsylvania

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

Helpful Links

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

October 1, 2005

Primary Completion (Actual)

September 1, 2015

Study Completion (Actual)

September 1, 2015

Study Registration Dates

First Submitted

August 25, 2005

First Submitted That Met QC Criteria

August 25, 2005

First Posted (Estimate)

August 26, 2005

Study Record Updates

Last Update Posted (Actual)

February 4, 2019

Last Update Submitted That Met QC Criteria

January 15, 2019

Last Verified

January 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DAIT ITN030ST

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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