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

• ClinicalTrials.gov Identifier: NCT00135694
• Recruitment Status: Completed
• First Posted: August 26, 2005
• Results First Posted: December 8, 2016
• Last Update Posted: February 4, 2019
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborator: Immune Tolerance Network (ITN)
• Information provided by (Responsible Party): National Institute of Allergy and Infectious Diseases (NIAID)

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.

Condition or disease	Intervention/treatment	Phase
Hepatitis C; Hepatitis C, Chronic; Nonimmune Nonviral Causes of Liver Failure	Drug: calcineurin inhibitor-based immunosuppression; Procedure: liver transplant; Drug: corticosteroids; Other: immunosuppression withdrawal	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 275 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial to Assess the Safety of Immunosuppression Withdrawal in Liver Transplant Recipients
• Study Start Date: October 2005
• Actual Primary Completion Date: September 2015
• Actual Study Completion Date: September 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: Immunosuppression Withdrawal; 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; May be cyclosporine, mycophenolate mofetil, or tacrolimus; Procedure: liver transplant; Occurs at study entry; Other Name: liver transplantation; Drug: corticosteroids; 3-month course of corticosteroids; Other Name: prednisone; Other: immunosuppression withdrawal; One year after transplantation, participants eligible for withdrawal are randomly assigned in a 4 to 1 ratio to immunosuppression withdrawal or to maintenance.
Active Comparator: Immunosuppression Maintenance; Liver transplant, followed by maintenance doses of continuous calcineurin inhibitor-based immunosuppression therapy.	Drug: calcineurin inhibitor-based immunosuppression; May be cyclosporine, mycophenolate mofetil, or tacrolimus; Procedure: liver transplant; Occurs at study entry; Other Name: liver transplantation; Drug: corticosteroids; 3-month course of corticosteroids; Other Name: prednisone

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Clinical Complications Usually Attributed to Immunosuppression [ Time Frame: Randomization to 2 years post-randomization ]
   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 :

1. Number of Participants Who Qualify for Random Assignment [ Time Frame: One to two years post-transplantation ]
2. 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) ]
3. Immunosuppression-free Duration [ 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 ]
   Time (in days) from withdrawing off of all immunosuppressive drugs to re-starting immunosuppression or study termination/completion.
4. 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 [ Time Frame: Randomization to 2 years post-randomization. ]
   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.
5. Number of Participants Experiencing Graft Loss or Death [ Time Frame: Randomization to 2 years post-randomization. ]
   Number of participants with graft loss or death. Graft loss is defined as subject death or re-transplantation.
6. Total Immunosuppression From Month 21 to Month 24 Post-randomization [ Time Frame: 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.)
7. Total Burden of Immunosuppression From Random Assignment to Month 24 [ Time Frame: Randomization to Month 24 post-randomization ]
   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.).

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, California

University of California, San Francisco

San Francisco, California, United States, 94143

United States, Colorado

University of Colorado

Denver, Colorado, United States, 80262

United States, Illinois

Northwestern University

Chicago, Illinois, United States, 60208

United States, Michigan

University of Michigan

Ann Arbor, Michigan, United States, 48109

United States, Ohio

Cleveland Clinic

Cleveland, Ohio, United States, 44195

United States, Pennsylvania

University of Pennsylvania

Philadelphia, Pennsylvania, United States, 19104

United States, Texas

Baylor University

Dallas, Texas, United States, 76798

United States, Washington

University of Washington

Seattle, Washington, United States, 98195

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Immune Tolerance Network (ITN)

Investigators

• Study Chair: Abraham Shaked, MD, PhD; University of Pennsylvania

More Information

Additional Information:

National Institute of Allergy and Infectious Diseases website 

Click here for the Immune Tolerance Network website 

Publications of Results:

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT00135694
• Other Study ID Numbers: DAIT ITN030ST
• First Posted: August 26, 2005
• Results First Posted: December 8, 2016
• Last Update Posted: February 4, 2019
• Last Verified: January 2019

Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID):

hepatitis; hepatitis C; HCV; liver; liver disease; liver transplant; liver transplantation; transplant; hepatic; hepatic transplantation; immunosuppression; rejection

Additional relevant MeSH terms:

Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Hepatitis; Liver Failure; Liver Diseases; Digestive System Diseases; Hepatitis, Viral, Human; Virus Diseases; Infections; Enterovirus Infections; Picornaviridae Infections; RNA Virus Infections; Blood-Borne Infections; Communicable Diseases; Flaviviridae Infections; Hepatic Insufficiency; Hepatitis, Chronic; Chronic Disease; Disease Attributes; Pathologic Processes; Prednisone; Calcineurin Inhibitors; Anti-Inflammatory Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs; Antineoplastic Agents, Hormonal; Antineoplastic Agents