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Gradual Withdrawal of Immune System Suppressing Drugs in Patients Receiving a Liver Transplant (A-WISH)

Primary Purpose

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

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
calcineurin inhibitor-based immunosuppression
liver transplant
corticosteroids
immunosuppression withdrawal
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hepatitis C focused on measuring hepatitis, hepatitis C, HCV, liver, liver disease, liver transplant, liver transplantation, transplant, hepatic, hepatic transplantation, immunosuppression, rejection

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • University of California, San Francisco
  • University of Colorado
  • Northwestern University
  • University of Michigan
  • Cleveland Clinic
  • University of Pennsylvania
  • Baylor University
  • University of Washington

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Immunosuppression Withdrawal

Immunosuppression Maintenance

Arm Description

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.

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Number of Participants Who Qualify for Random Assignment
Number of Participants Who Successfully Stop Taking Immunosuppression for at Least 6 Months
Immunosuppression-free Duration
Time (in days) from withdrawing off of all immunosuppressive drugs to re-starting immunosuppression or study termination/completion.
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.
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.
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.)
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.).

Full Information

First Posted
August 25, 2005
Last Updated
January 15, 2019
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators
Immune Tolerance Network (ITN)
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1. Study Identification

Unique Protocol Identification Number
NCT00135694
Brief Title
Gradual Withdrawal of Immune System Suppressing Drugs in Patients Receiving a Liver Transplant
Acronym
A-WISH
Official Title
A Phase II Trial to Assess the Safety of Immunosuppression Withdrawal in Liver Transplant Recipients
Study Type
Interventional

2. Study Status

Record Verification Date
January 2019
Overall Recruitment Status
Completed
Study Start Date
October 2005 (undefined)
Primary Completion Date
September 2015 (Actual)
Study Completion Date
September 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators
Immune Tolerance Network (ITN)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
275 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Immunosuppression Withdrawal
Arm Type
Experimental
Arm Description
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.
Arm Title
Immunosuppression Maintenance
Arm Type
Active Comparator
Arm Description
Liver transplant, followed by maintenance doses of continuous calcineurin inhibitor-based immunosuppression therapy.
Intervention Type
Drug
Intervention Name(s)
calcineurin inhibitor-based immunosuppression
Intervention Description
May be cyclosporine, mycophenolate mofetil, or tacrolimus
Intervention Type
Procedure
Intervention Name(s)
liver transplant
Other Intervention Name(s)
liver transplantation
Intervention Description
Occurs at study entry
Intervention Type
Drug
Intervention Name(s)
corticosteroids
Other Intervention Name(s)
prednisone
Intervention Description
3-month course of corticosteroids
Intervention Type
Other
Intervention Name(s)
immunosuppression withdrawal
Intervention Description
One year after transplantation, participants eligible for withdrawal are randomly assigned in a 4 to 1 ratio to immunosuppression withdrawal or to maintenance.
Primary Outcome Measure Information:
Title
Number of Participants With Clinical Complications Usually Attributed to Immunosuppression
Description
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.
Time Frame
Randomization to 2 years post-randomization
Secondary Outcome Measure Information:
Title
Number of Participants Who Qualify for Random Assignment
Time Frame
One to two years post-transplantation
Title
Number of Participants Who Successfully Stop Taking Immunosuppression for at Least 6 Months
Time Frame
Randomization until study completion or participant termination (up to six years post-transplant)
Title
Immunosuppression-free Duration
Description
Time (in days) from withdrawing off of all immunosuppressive drugs to re-starting immunosuppression or study termination/completion.
Time Frame
Discontinuation of all immunosuppression to end of trial participation or to time of restarting immunosuppression, whichever came first, assessed up to two years
Title
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
Description
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.
Time Frame
Randomization to 2 years post-randomization.
Title
Number of Participants Experiencing Graft Loss or Death
Description
Number of participants with graft loss or death. Graft loss is defined as subject death or re-transplantation.
Time Frame
Randomization to 2 years post-randomization.
Title
Total Immunosuppression From Month 21 to Month 24 Post-randomization
Description
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.)
Time Frame
Month 21 to Month 24 post-randomization
Title
Total Burden of Immunosuppression From Random Assignment to Month 24
Description
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.).
Time Frame
Randomization to Month 24 post-randomization

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Abraham Shaked, MD, PhD
Organizational Affiliation
University of Pennsylvania
Official's Role
Study Chair
Facility Information:
Facility Name
University of California, San Francisco
City
San Francisco
State/Province
California
ZIP/Postal Code
94143
Country
United States
Facility Name
University of Colorado
City
Denver
State/Province
Colorado
ZIP/Postal Code
80262
Country
United States
Facility Name
Northwestern University
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60208
Country
United States
Facility Name
University of Michigan
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Cleveland Clinic
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44195
Country
United States
Facility Name
University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Baylor University
City
Dallas
State/Province
Texas
ZIP/Postal Code
76798
Country
United States
Facility Name
University of Washington
City
Seattle
State/Province
Washington
ZIP/Postal Code
98195
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
30506630
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. Erratum In: Am J Transplant. 2019 Aug;19(8):2393.
Results Reference
result
PubMed Identifier
33979314
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.
Results Reference
derived
Links:
URL
https://www.niaid.nih.gov/
Description
National Institute of Allergy and Infectious Diseases website
URL
http://www.immunetolerance.org
Description
Click here for the Immune Tolerance Network website

Learn more about this trial

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

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