Gradual Withdrawal of Immune System Suppressing Drugs in Patients Receiving a Liver Transplant (AWISH)

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Immune Tolerance Network (ITN)
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT00135694
First received: August 25, 2005
Last updated: March 26, 2014
Last verified: March 2014
  Purpose

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.


Condition Intervention Phase
Hepatitis C
Hepatitis C, Chronic
Nonimmune Nonviral Causes of Liver Failure
Drug: calcineurin inhibitor-based immunosuppression
Procedure: liver transplant
Drug: corticosteroids
Other: immunosuppression withdrawal
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase II Trial to Assess the Safety of Immunosuppression Withdrawal in Liver Transplant Recipients

Resource links provided by NLM:


Further study details as provided by National Institute of Allergy and Infectious Diseases (NIAID):

Primary Outcome Measures:
  • Proportion of participants with progression of hepatitis C-related liver disease, [ Time Frame: Randomization to Year 2 ] [ Designated as safety issue: Yes ]

    This is a composite endpoint comprising specific clinical complications related to immunosuppression and is defined as the occurrence anytime in the 24 months after random assignment of any one of the following:

    • death or graft loss,
    • grade 4 secondary malignancy, (graded by CTCAE 3.0),
    • grade 4 opportunistic infection, (graded by CTCAE 3.0),
    • gradestage 3 or higher fibrosis, or
    • grade 2 or higher decrease in renal function defined as follows:

      1. the 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, in the absence of intercurrent illness, after randomization;
      2. for those with a baseline GFR 30-90 ml per min per 1.73 metersquared, a 25% decrease in GFR;
      3. for those with a baseline GFR greater than 90 ml per min per 1.73 meter-squared, a 25% decrease in GFR and a decrease


Secondary Outcome Measures:
  • The proportion of participants who qualify for random assignment [ Time Frame: 1 to 2 years post-transplantation ] [ Designated as safety issue: No ]
  • The proportion of subjects who are successfully stop taking immunosuppression for at least 6 months [ Time Frame: throughout study ] [ Designated as safety issue: No ]
  • Immunosuppression-free duration [ Time Frame: discontinuation of immunosuppression to end of trial participation or to time of restarting immunosuppression ] [ Designated as safety issue: No ]
  • Laboratory tests, mechanistic assays, or clinical assessments indicative of successful withdrawal [ Time Frame: immediately before and after immunosuppression withdrawal ] [ Designated as safety issue: No ]
  • Hepatitis C viral load [ Time Frame: immediately before and after immunosuppression withdrawal ] [ Designated as safety issue: Yes ]
  • In-vitro T-cell anti-hepatitis-C responses [ Time Frame: throughout study ] [ Designated as safety issue: No ]
  • Histopathologic assessment for hepatitis in the allograft [ Time Frame: throughout study ] [ Designated as safety issue: No ]
  • Definition of rejection profiles from laboratory tests, mechanistic studies, or clinical assessments [ Time Frame: after immunosuppression withdrawal ] [ Designated as safety issue: No ]
  • The proportion 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 ] [ Designated as safety issue: Yes ]
  • The proportion of graft loss or death [ Time Frame: randomization to 2 years ] [ Designated as safety issue: Yes ]
  • Total immunosuppression, defined as the daily immunosuppression score in units per day averaged over the 3-month period [ Time Frame: from month 21 after randomization to year 2 ] [ Designated as safety issue: No ]
  • Total burden of immunosuppression from random assignment [ Time Frame: randomization to 2 years ] [ Designated as safety issue: No ]
  • Long-term Renal Function [ Time Frame: randomization to 2 years ] [ Designated as safety issue: No ]

Enrollment: 275
Study Start Date: October 2005
Estimated Study Completion Date: November 2015
Estimated Primary Completion Date: November 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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
Drug: corticosteroids
3-month course of corticosteroids.
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
Drug: corticosteroids
3-month course of corticosteroids.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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. [deleted criterion 4]
  5. Donor liver from a donor positive for antibody against hepatitis C.
  6. Donor liver from a non-heart-beating donor.
  7. Liver failure due to autoimmune disease.
  8. Fulminant liver failure.
  9. Hepatitis B infection as defined by the presence of HbSAg or hepatitis-C infection with a genome other than genome 1.
  10. Stage III or higher hepatocellular cancer.
  11. 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%.
  12. Active systemic infection at the time of transplantation.
  13. Clinically significant chronic renal disease.
  14. Clinically significant cardiovascular or cerebrovascular disease.
  15. Infection with human immunodeficiency virus.
  16. Any investigational drug received within 6 weeks of study entry or any investigational vaccine received at any time.
  17. Hypersensitivity to tacrolimus.
  18. Unwillingness or inability to comply with study requirements.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00135694

Locations
United States, California
University of California, San Francisco
San Francisco, California, United States, 94143
United States, Colorado
University of Colorado
Denver, Colorado, United States, 80262
United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60208
United States, Michigan
University of Michigan
Ann Arbor, Michigan, United States, 48109
United States, Ohio
Cleveland Clinic
Cleveland, Ohio, United States, 44195
United States, Pennsylvania
University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
United States, Texas
Baylor University
Dallas, Texas, United States, 76798
United States, Washington
University of Washington
Seattle, Washington, United States, 98195
Sponsors and Collaborators
Immune Tolerance Network (ITN)
Investigators
Study Chair: Abraham Shaked, MD, PhD University of Pennsylvania
  More Information

Additional Information:
No publications provided

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT00135694     History of Changes
Other Study ID Numbers: DAIT ITN030ST
Study First Received: August 25, 2005
Last Updated: March 26, 2014
Health Authority: United States: Federal Government
United States: Institutional Review Board

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):
hepatitis
hepatitis C
HCV
liver
liver disease
liver transplant
liver transplantation
transplant
hepatic
hepatic transplantation
immunosuppression
rejection

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis C
Liver Failure
Hepatitis C, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections
Hepatic Insufficiency
Hepatitis, Chronic

ClinicalTrials.gov processed this record on July 23, 2014