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

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ClinicalTrials.gov Identifier: NCT00135694
Recruitment Status : Completed
First Posted : August 26, 2005
Results First Posted : December 8, 2016
Last Update Posted : February 4, 2019
Sponsor:
Collaborator:
Immune Tolerance Network (ITN)
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Tracking Information
First Submitted Date  ICMJE August 25, 2005
First Posted Date  ICMJE August 26, 2005
Results First Submitted Date  ICMJE October 13, 2016
Results First Posted Date  ICMJE December 8, 2016
Last Update Posted Date February 4, 2019
Study Start Date  ICMJE October 2005
Actual Primary Completion Date September 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 13, 2016)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: August 25, 2005)
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
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 8, 2016)
  • 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.).
Original Secondary Outcome Measures  ICMJE
 (submitted: August 25, 2005)
  • Tolerance induction
  • Laboratory tests indicative of successful withdrawal
  • Hepatitis C immune response and graft injury
  • Definition of rejection profiles from laboratory tests
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Gradual Withdrawal of Immune System Suppressing Drugs in Patients Receiving a Liver Transplant
Official Title  ICMJE A Phase II Trial to Assess the Safety of Immunosuppression Withdrawal in Liver Transplant Recipients
Brief Summary 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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Hepatitis C
  • Hepatitis C, Chronic
  • Nonimmune Nonviral Causes of Liver Failure
Intervention  ICMJE
  • 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.
Study Arms  ICMJE
  • 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
Publications * Shaked A, DesMarais MR, Kopetskie H, Feng S, Punch JD, Levitsky J, Reyes J, Klintmalm GB, Demetris AJ, Burrell BE, Priore A, Bridges ND, Sayre PH. Outcomes of immunosuppression minimization and withdrawal early after liver transplantation. Am J Transplant. 2019 May;19(5):1397-1409. doi: 10.1111/ajt.15205. Epub 2018 Dec 31. Erratum in: Am J Transplant. 2019 Aug;19(8):2393.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 7, 2007)
275
Original Enrollment  ICMJE
 (submitted: August 25, 2005)
157
Actual Study Completion Date  ICMJE September 2015
Actual Primary Completion Date September 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00135694
Other Study ID Numbers  ICMJE DAIT ITN030ST
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institute of Allergy and Infectious Diseases (NIAID)
Study Sponsor  ICMJE National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators  ICMJE Immune Tolerance Network (ITN)
Investigators  ICMJE
Study Chair: Abraham Shaked, MD, PhD University of Pennsylvania
PRS Account National Institute of Allergy and Infectious Diseases (NIAID)
Verification Date January 2019

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