Sirolimus-based Immunosuppression Treatment Regimen for Liver Transplantation

Study Overview
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Brief Summary
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This is a multicenter, open-label, randomized, controlled clinical trial, in order to compare sirolimus-based (tacrolimus-free) versus tacrolimus-based (sirolimus-free) immunosuppression regimen for Hepatocellular Carcinoma (HCC) patients after liver transplantation.

Detailed Description
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This 5-year study consisted of a 2-year enrolment period and a 3-year follow-up period. Patients will be screened for eligibility prior to liver transplantation. Patients who have undergone successful liver transplantation will be initiated on a tacrolimus-based regimen that includes MMF and/or Steroids and enter the baseline period (between 3 and 7 days post-transplantation). At 30 (± 5) days post-transplantation, patients who meet additional randomization inclusion/exclusion criteria will be randomized into 2 groups of this study. In the first group, patients will be maintained on a tacrolimus-based (sirolimus-free) immunosuppression regimen. The second group will be treated with sirolimus-based (tacrolimus-free) immunosuppression regimen. For patients in both groups, mycophenolic acid prodrugs like mycophenolate mofetil (MMF) and steroids are initiated at the time of liver transplantation according to local practice. Steroids reduction is encouraged by 3 months post liver transplantation. In the first year after randomization all patients will be followed up after month 1, 2, 3, 4, 5, 6, 8, 10 and 12. After that, patients are followed every 3 months. Tacrolimus and sirolimus trough levels in patients of both groups will be tested and adjusted if need be at each follow-up date to achieve the desired steady-state trough levels. The primary endpoint is defined as HCC recurrence-free time interval between the date of liver transplantation and the date of HCC recurrence or death; patients who are alive and recurrence-free at the end of month 36 will be censored at the time of their last follow-up date. HCC recurrence can be determined during the entire follow-up period.

Official Title
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Sirolimus-based Immunosuppression Treatment Regimen for Liver Transplantation: A Multicenter, Open-label, Randomized, Controlled Clinical Trial in Liver Transplant Recipients With Hepatocellular Carcinoma

Conditions
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Liver Transplantation

Intervention / Treatment
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* Drug: Tacrolimus
* Drug: Tacrolimus (Tacrolimus elimination)
* Drug: Sirolimus
* Drug: MMF and/or steroids


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Recipients who are 18-65 years of age Histologically proven HCC before randomization Recipients who have been initiated on an immunosuppressive regimen that contains tacrolimus, 3-7 days post-transplantation Allograft is functioning at an acceptable level by the time of randomization as defined by protocol specific laboratory values Ability and willingness to provide written informed consent and adhere to study regimen Exclusion Criteria: Patients with non-HCC malignancies within the past 5 years Patients who are multiple-organ recipients Patients who are known HIV-positive patients Patients who have received mTOR inhibitors prior to day 30 after liver transplantation Patients with a known hypersensitivity to the drugs used on study or their class, or to any of the excipients Patients who have any surgical or medical condition, which in the opinion of the investigator, might significantly alter the absorption, distribution, metabolism and excretion of study drug Patients with a psychologic, familial, sociologic or geographic condition potentially hampering compliance with the study protocol and follow-up schedule

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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 |
| --- | --- |
| Active Comparator: Tacrolimus-based group<br>Tacrolimus-based immunosuppression regimen: Tacrolimus+MMF and/or steroids | Drug: Tacrolimus<br>* Tacrolimus will be started between 3 and 7 days post-transplantation and continued after randomization at a dose of 1.0 mg twice a day (bid, 2 mg daily dose). The tacrolimus trough level is measured twice a week for 1 month, followed by trough level once a month thereafter. Tacrolimus trough levels are targeted to be maintained at 8-15ng/ml until Month 6. After Month 6, the dose will be adjusted over time to maintain steady-state tacrolimus trough blood levels of approximately 5-10 ng/mL.<br>* Other names: Advagraf;Drug: MMF and/or steroids<br>* For patients in both groups, MMF and/or steroids are initiated at or prior to the time of liver transplantation according to local practice. Steroids reduction is encouraged by 3 months post liver transplantation.<br>* Other names: Mycophenolate mofetil;|
| Experimental: Sirolimus-based group<br>Sirolimus-based immunosuppression regimen: Tacrolimus (Tacrolimus elimination 30 (± 5) days post LT)+Sirolimus+MMF and/or steroids | Drug: Tacrolimus (Tacrolimus elimination)<br>* Tacrolimus will be started between 3 and 7 days post-transplantation at a dose of 1.0 mg twice a day (bid, 2 mg daily dose) for 30 (± 5) days and eliminated when randomization is done.<br>* Other names: Advagraf;Drug: Sirolimus<br>* Within 24 hours of randomization, sirolimus will be started at a dose of 2.0 mg once a day. The sirolimus trough level is measured twice a week for 1 month, followed by trough level once a month thereafter. The dose will be adjusted over time to maintain steady-state sirolimus trough blood levels of approximately 4-10 ng/mL.<br>* Other names: Rapamune;Drug: MMF and/or steroids<br>* For patients in both groups, MMF and/or steroids are initiated at or prior to the time of liver transplantation according to local practice. Steroids reduction is encouraged by 3 months post liver transplantation.<br>* Other names: Mycophenolate mofetil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HCC recurrence free survival | The primary endpoint is defined as HCC recurrence-free time interval between the date of liver transplantation and the date of HCC recurrence or death; patients who are alive and recurrence-free at the end of month 36 will be censored at the time of their last follow-up date. HCC recurrence can be determined during the entire follow-up period. | Randomization to Month 36 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival was defined as the time from date of randomization to date of death from any cause. If a patient was not known to have died, patient overall survival was censored as the date of last contact. | Randomization to Month 36 | 
| Incidence of acute rejection | Incidence of acute rejection will be assessed in both groups. | Randomization to Month 36 | 
| Treatment failures defined as introduction of Tacrolimus to experimental group | Treatment failures defined as introduction of Tacrolimus to experimental group | Randomization to Month 36 | 
| Graft survival | Graft survival was defined as the time from the date of randomization to the date of graft loss. If a patient was not known to suffer from a graft loss or died without graft loss, time to graft loss was censored with date of last contact or date of death, respectively. | Randomization to Month 36 | 
| Incidence of adverse events | Evaluation of common post Liver Transplantation Adverse Events: wound healing, bone marrow depression, hyperlipidemia, proteinuria, diabetes mellitus, diagnosed hypertension, infections. | Randomization to Month 36 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Liver transplantation, Sirolimus, Tacrolimus, HCC recurrence free survival