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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:
ClinicalTrials.gov Identifier:
NCT00135694
First Posted: August 26, 2005
Last Update Posted: February 2, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
Immune Tolerance Network (ITN)
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
August 25, 2005
August 26, 2005
October 13, 2016
December 8, 2016
February 2, 2017
October 2005
September 2015   (Final data collection date for primary outcome measure)
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.
Proportion of participants with progression of hepatitis C-related liver disease, defined as Stage 4 or higher fibrosis on the Ishak scale, in the 2 years following random assignment
Complete list of historical versions of study NCT00135694 on ClinicalTrials.gov Archive Site
  • 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.).
  • Tolerance induction
  • Laboratory tests indicative of successful withdrawal
  • Hepatitis C immune response and graft injury
  • Definition of rejection profiles from laboratory tests
Not Provided
Not Provided
 
Gradual Withdrawal of Immune System Suppressing Drugs in Patients Receiving a Liver Transplant
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.
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.
Interventional
Phase 2
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
  • Hepatitis C
  • Hepatitis C, Chronic
  • Nonimmune Nonviral Causes of Liver Failure
  • 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.
  • 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.
    Interventions:
    • Drug: calcineurin inhibitor-based immunosuppression
    • Procedure: liver transplant
    • Drug: corticosteroids
    • Other: immunosuppression withdrawal
  • Active Comparator: Immunosuppression Maintenance
    Liver transplant, followed by maintenance doses of continuous calcineurin inhibitor-based immunosuppression therapy.
    Interventions:
    • Drug: calcineurin inhibitor-based immunosuppression
    • Procedure: liver transplant
    • Drug: corticosteroids
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
275
September 2015
September 2015   (Final data collection date for primary outcome measure)

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.
Sexes Eligible for Study: All
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
 
NCT00135694
DAIT ITN030ST
Yes
Not Provided
Not Provided
National Institute of Allergy and Infectious Diseases (NIAID)
National Institute of Allergy and Infectious Diseases (NIAID)
Immune Tolerance Network (ITN)
Study Chair: Abraham Shaked, MD, PhD University of Pennsylvania
National Institute of Allergy and Infectious Diseases (NIAID)
December 2016

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