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

NCT00135694 | Completed Phase 2 Results DMC

• 1 other identifier: DAIT ITN030ST
• Study Type: interventional
• Target: 275
• Locations: 1 country
• Sites: 8

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.

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (7)

• 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

  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

  Randomization to 2 years post-randomization.

• Number of Participants Experiencing Graft Loss or Death

  Randomization to 2 years post-randomization.

Study Arms (2)

Immunosuppression Withdrawal

EXPERIMENTAL

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; Procedure: liver transplant; Drug: corticosteroids; Other: immunosuppression withdrawal

Immunosuppression Maintenance

ACTIVE COMPARATOR

Liver transplant, followed by maintenance doses of continuous calcineurin inhibitor-based immunosuppression therapy.

Drug: calcineurin inhibitor-based immunosuppression; Procedure: liver transplant; Drug: corticosteroids

Interventions

calcineurin inhibitor-based immunosuppression DRUG

May be cyclosporine, mycophenolate mofetil, or tacrolimus

Immunosuppression Maintenance; Immunosuppression Withdrawal

liver transplant PROCEDURE

Occurs at study entry

Also known as: liver transplantation

Immunosuppression Maintenance; Immunosuppression Withdrawal

corticosteroids DRUG

3-month course of corticosteroids

Also known as: prednisone

Immunosuppression Maintenance; Immunosuppression Withdrawal

immunosuppression withdrawal OTHER

One year after transplantation, participants eligible for withdrawal are randomly assigned in a 4 to 1 ratio to immunosuppression withdrawal or to maintenance.

Immunosuppression Withdrawal

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead
• Immune Tolerance Network (ITN): collaborator

Study Sites (8)

University of California, San Francisco

San Francisco, California, 94143, United States

Location

University of Colorado

Denver, Colorado, 80262, United States

Location

Northwestern University

Chicago, Illinois, 60208, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Baylor University

Dallas, Texas, 76798, United States

Location

University of Washington

Seattle, Washington, 98195, United States

Location

Related Publications (2)

• 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.

  PMID: 30506630 RESULT

• 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.

  PMID: 33979314 DERIVED

Related Links

• National Institute of Allergy and Infectious Diseases website
• Click here for the Immune Tolerance Network website

MeSH Terms

Conditions

Hepatitis C; Hepatitis C, Chronic; Hepatitis; Liver Diseases; Rejection, Psychology

Interventions

Liver Transplantation; Adrenal Cortex Hormones; Prednisone

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Hepatitis, Viral, Human; Virus Diseases; Flaviviridae Infections; RNA Virus Infections; Digestive System Diseases; Hepatitis, Chronic; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Social Behavior; Behavior

Intervention Hierarchy (Ancestors)

Tissue Transplantation; Cell- and Tissue-Based Therapy; Biological Therapy; Therapeutics; Digestive System Surgical Procedures; Surgical Procedures, Operative; Organ Transplantation; Transplantation; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Results Point of Contact

• Title: Director, Clinical Research Operations Program
• Organization: DAIT/NIAID

DAITClinicalTrialsGov@niaid.nih.gov

301-594-7669

Study Officials

• Abraham Shaked, MD, PhD

  University of Pennsylvania

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 25, 2005
• First Posted: August 26, 2005
• Study Start: October 1, 2005
• Primary Completion: September 1, 2015
• Study Completion: September 1, 2015
• Last Updated: February 4, 2019
• Results First Posted: December 8, 2016

Record last verified: 2019-01

Locations

US (8)