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

This study has been completed.
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: December 8, 2016
Last verified: December 2016
  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
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:
  • 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.


Secondary Outcome Measures:
  • Number of Participants Who Qualify for Random Assignment [ Time Frame: 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) ]
  • 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.

  • 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.

  • 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.

  • 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.)

  • 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.).


Enrollment: 275
Study Start Date: October 2005
Study Completion Date: September 2015
Primary Completion Date: September 2015 (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
Other Name: liver transplantation
Drug: corticosteroids
3-month course of corticosteroids
Other Name: 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 Name: liver transplantation
Drug: corticosteroids
3-month course of corticosteroids
Other Name: prednisone

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.
  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
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. 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.
  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
National Institute of Allergy and Infectious Diseases (NIAID)
Immune Tolerance Network (ITN)
Investigators
Study Chair: Abraham Shaked, MD, PhD University of Pennsylvania
  More Information

Additional Information:
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
Results First Received: October 13, 2016
Last Updated: December 8, 2016

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
Hepatitis C, Chronic
Liver Failure
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections
Hepatitis, Chronic
Hepatic Insufficiency
Liver Extracts
Calcineurin Inhibitors
Hematinics
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on March 23, 2017