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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Hepatitis C, Hepatitis C, Chronic, Nonimmune Nonviral Causes of Liver Failure

Intervention / Treatment
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* Drug: calcineurin inhibitor-based immunosuppression
* Procedure: liver transplant
* Drug: corticosteroids
* Other: immunosuppression withdrawal


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female 18 years of age or older. Necessity for liver transplant. 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. Ability to provide informed consent. Availability of donor specimen(s). For individuals with hepatitis C infection, presence of hepatitis genomes in blood. Exclusion Criteria: Previous transplant. Multiorgan or split liver transplant other than with a right trisegment. Living donor transplant. Donor liver from a donor positive for antibody against hepatitis C. Donor liver from a non-heart-beating donor. Liver failure due to autoimmune disease. Fulminant liver failure. Hepatitis B infection as defined by the presence of HbSAg or hepatitis-C infection with a genome other than genome 1. Stage III or higher hepatocellular cancer. 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%. Active systemic infection at the time of transplantation. Clinically significant chronic renal disease. Clinically significant cardiovascular or cerebrovascular disease. Infection with human immunodeficiency virus. Any investigational drug received within 6 weeks of study entry or any investigational vaccine received at any time. Hypersensitivity to tacrolimus. Unwillingness or inability to comply with study requirements.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Immunosuppression Withdrawal<br>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<br>* May be cyclosporine, mycophenolate mofetil, or tacrolimus<br>Procedure: liver transplant<br>* Occurs at study entry<br>* Other names: liver transplantation;Drug: corticosteroids<br>* 3-month course of corticosteroids<br>* Other names: prednisone;Other: immunosuppression withdrawal<br>* One year after transplantation, participants eligible for withdrawal are randomly assigned in a 4 to 1 ratio to immunosuppression withdrawal or to maintenance.<br>|
| Active Comparator: Immunosuppression Maintenance<br>Liver transplant, followed by maintenance doses of continuous calcineurin inhibitor-based immunosuppression therapy. | Drug: calcineurin inhibitor-based immunosuppression<br>* May be cyclosporine, mycophenolate mofetil, or tacrolimus<br>Procedure: liver transplant<br>* Occurs at study entry<br>* Other names: liver transplantation;Drug: corticosteroids<br>* 3-month course of corticosteroids<br>* Other names: prednisone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinical Complications Usually Attributed to Immunosuppression | 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 |  | One to two years post-transplantation | 
| Number of Participants Who Successfully Stop Taking Immunosuppression for at Least 6 Months |  | Randomization until study completion or participant termination (up to six years post-transplant) | 
| Immunosuppression-free Duration | 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 | 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 | 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 | 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 | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hepatitis, hepatitis C, HCV, liver, liver disease, liver transplant, liver transplantation, transplant, hepatic, hepatic transplantation, immunosuppression, rejection