Sirolimus-based Immunosuppression Treatment Regimen for Liver Transplantation

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Liver Transplantation
• Intervention / Treatment: Drug: Tacrolimus; Drug: MMF and/or steroids; Drug: Tacrolimus (Tacrolimus elimination); Drug: Sirolimus

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 130
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Peihua Cao, Ph.D; Phone Number: 86-020-62783685; Email: cphcc@smu.edu.cn

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510515
      • Nanfang Hospital of Southern Medical University
      • Contact: Chongyang Duan, M.D; Phone Number: 86-020-61649462; Email: donyduang@126.com
      • Principal Investigator: Dinghua Yang, M.D
    • Guangzhou, Guangdong, China, 510282
      • ZhuJiang Hospital of Southern Medical University
      • Contact: Peihua Cao, Ph.D; Phone Number: 86-020-62783685; Email: cphcc@smu.edu.cn
      • Principal Investigator: Kebo Zhong, M.D
    • Guanzhou, Guangdong, China, 510080
      • First Affiliated Hospital, Sun Yat-Sen University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Tacrolimus-based group; Tacrolimus-based immunosuppression regimen: Tacrolimus+MMF and/or steroids	Drug: Tacrolimus; 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.; Other Names: Prograf; Fujimycin; Protopic; FK-506; Advagraf; Drug: MMF and/or steroids; 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.; Other Names: Mycophenolate mofetil
Experimental: Sirolimus-based group; Sirolimus-based immunosuppression regimen: Tacrolimus (Tacrolimus elimination 30 (± 5) days post LT)+Sirolimus+MMF and/or steroids	Drug: MMF and/or steroids; 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.; Other Names: Mycophenolate mofetil; Drug: Tacrolimus (Tacrolimus elimination); 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.; Other Names: Prograf; Fujimycin; Protopic; FK-506; Advagraf; Drug: Sirolimus; 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.; Other Names: Rapamune

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Southern Medical University, China
• Collaborators: First Affiliated Hospital, Sun Yat-Sen University; Nanfang Hospital of Southern Medical University
• Investigators: Principal Investigator: Kebo Zhong, M.D, Department of Heptobiliary Surgery II, Zhujiang Hospital, Southern Medical University, China

Study record dates

Study Major Dates

• Study Start (Anticipated): May 1, 2018
• Primary Completion (Anticipated): May 31, 2023
• Study Completion (Anticipated): May 31, 2023

Study Registration Dates

• First Submitted: March 29, 2018
• First Submitted That Met QC Criteria: April 16, 2018
• First Posted (Actual): April 18, 2018

Study Record Updates

• Last Update Posted (Actual): April 18, 2018
• Last Update Submitted That Met QC Criteria: April 16, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Keywords: Liver transplantation; Tacrolimus; Sirolimus; HCC recurrence free survival
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Tacrolimus; Mycophenolic Acid; Sirolimus
• Other Study ID Numbers: 2017-GDEK-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No