Clinical trial NCT00135694: Gradual Withdrawal of Immune System Suppressing Drugs in Patients Receiving a Liver Transplant
Official title: A Phase II Trial to Assess the Safety of Immunosuppression Withdrawal in Liver Transplant Recipients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Hepatitis C
Hepatitis C, Chronic
Nonimmune Nonviral Causes of Liver Failure
Keywords: hepatitis
hepatitis C
HCV
liver
liver disease
liver transplant
liver transplantation
transplant
hepatic
hepatic transplantation
immunosuppression
rejection
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Immune Tolerance Network (ITN)
First posted: 2005-08-26
Enrollment: 275
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With Clinical Complications Usually Attributed to Immunosuppression
timeFrame: Randomization to 2 years post-randomization
Secondary outcomes:
measure: Number of Participants Who Qualify for Random Assignment
timeFrame: One to two years post-transplantation
measure: Number of Participants Who Successfully Stop Taking Immunosuppression for at Least 6 Months
timeFrame: Randomization until study completion or participant termination (up to six years post-transplant)
measure: Immunosuppression-free Duration
timeFrame: Discontinuation of all immunosuppression to end of trial participation or to time of restarting immunosuppression, whichever came first, assessed up to two years
measure: 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
timeFrame: Randomization to 2 years post-randomization.
measure: Number of Participants Experiencing Graft Loss or Death
timeFrame: Randomization to 2 years post-randomization.
measure: Total Immunosuppression From Month 21 to Month 24 Post-randomization
timeFrame: Month 21 to Month 24 post-randomization
measure: Total Burden of Immunosuppression From Random Assignment to Month 24
timeFrame: Randomization to Month 24 post-randomization
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California, San Francisco
state: California
city: Denver
country: United States
facility: University of Colorado
state: Colorado
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Dallas
country: United States
facility: Baylor University
state: Texas
city: Seattle
country: United States
facility: University of Washington
state: Washington
Study officials:
affiliation: University of Pennsylvania
name: Abraham Shaked, MD, PhD
role: STUDY_CHAIR
References:
citation: 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.
citation: Muthukumar T, Akat KM, Yang H, Schwartz JE, Li C, Bang H, Ben-Dov IZ, Lee JR, Ikle D, Demetris AJ, Tuschl T, Suthanthiran M. Serum MicroRNA Transcriptomics and Acute Rejection or Recurrent Hepatitis C Virus in Human Liver Allograft Recipients: A Pilot Study. Transplantation. 2022 Apr 1;106(4):806-820. doi: 10.1097/TP.0000000000003815.