Hepatitis C, Hepatitis C, Chronic, Nonimmune Nonviral Causes of Liver Failure
Conditions
Keywords
hepatitis, hepatitis C, HCV, liver, liver disease, liver transplant, liver transplantation, transplant, hepatic, hepatic transplantation, immunosuppression, rejection
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.
Interventions
DRUGcalcineurin inhibitor-based immunosuppression
May be cyclosporine, mycophenolate mofetil, or tacrolimus
PROCEDUREliver transplant
Occurs at study entry
DRUGcorticosteroids
3-month course of corticosteroids
One year after transplantation, participants eligible for withdrawal are randomly assigned in a 4 to 1 ratio to immunosuppression withdrawal or to maintenance.
Sponsors
Immune Tolerance Network (ITN)
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Clinical Complications Usually Attributed to Immunosuppression | 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
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Qualify for Random Assignment | One to two years post-transplantation | — |
| 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 | 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 | 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. |
| 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) | — |
| Total Immunosuppression From Month 21 to Month 24 Post-randomization | 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 | 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.). |
| Number of Participants Experiencing Graft Loss or Death | Randomization to 2 years post-randomization. | Number of participants with graft loss or death. Graft loss is defined as subject death or re-transplantation. |
Countries
United States
Participant flow
Recruitment details
Participants with liver failure due to hepatitis C infection or non-immune, non-viral causes were enrolled between October 2005 and April 2011.
Pre-assignment details
Participants 12-24 months post-transplant, stable on immunosuppression monotherapy for at least 3 months prior to random assignment, with stage 2 or less fibrosis on the Ishak scale, adequate hepatic and renal function, and no biopsy-proven rejection were randomized between November 2006 and December 2012.
Participants by arm
| Arm | Count |
|---|---|
| Terminated Prior to Randomization Subjects enrolled and transplanted into the trial but not eligible for randomization. | 180 |
| Randomized to Immunosuppression Withdrawal Subjects enrolled and transplanted into the trial and followed for at least one year and eligible for random assignment and randomized to immunosuppression withdrawal. | 77 |
| Randomized to Immunosuppression Maintenance Subjects enrolled and transplanted into the trial and followed for at least one year and eligible for random assignment and randomized to immunosuppression maintenance. | 18 |
| Total | 275 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 17 | 4 | 0 |
| Overall Study | Death | 14 | 1 | 2 |
| Overall Study | Hepatitis C related reasons | 39 | 1 | 0 |
| Overall Study | Ineligible for Random assignment | 42 | 0 | 0 |
| Overall Study | Lost to Follow-up | 8 | 7 | 1 |
| Overall Study | Protocol Violation | 19 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 41 | 7 | 4 |
Baseline characteristics
| Characteristic | Terminated Prior to Randomization | Randomized to Immunosuppression Withdrawal | Randomized to Immunosuppression Maintenance | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 19 Participants | 9 Participants | 5 Participants | 33 Participants |
| Age, Categorical Between 18 and 65 years | 161 Participants | 68 Participants | 13 Participants | 242 Participants |
| Age, Continuous | 55.5 years STANDARD_DEVIATION 7.83 | 54.3 years STANDARD_DEVIATION 9.92 | 57.4 years STANDARD_DEVIATION 7.7 | 55.3 years STANDARD_DEVIATION 8.47 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 10 Participants | 11 Participants | 3 Participants | 24 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 167 Participants | 66 Participants | 15 Participants | 248 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 1 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Black or African American | 22 Participants | 7 Participants | 0 Participants | 29 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) White | 153 Participants | 66 Participants | 17 Participants | 236 Participants |
| Region of Enrollment United States | 180 participants | 77 participants | 18 participants | 275 participants |
| Serum Creatinine | 1.5 mg/dL STANDARD_DEVIATION 1.18 | 1.3 mg/dL STANDARD_DEVIATION 0.65 | 1.1 mg/dL STANDARD_DEVIATION 0.68 | 1.4 mg/dL STANDARD_DEVIATION 1.04 |
| Sex: Female, Male Female | 53 Participants | 14 Participants | 5 Participants | 72 Participants |
| Sex: Female, Male Male | 127 Participants | 63 Participants | 13 Participants | 203 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 155 / 180 | 18 / 18 | 76 / 77 |
| serious Total, serious adverse events | 89 / 180 | 9 / 18 | 54 / 77 |
Outcome results
Primary
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.
Time frame: Randomization to 2 years post-randomization
Population: Evaluable randomized subjects having a targeted event and/or having available data for calculation of eGFR
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized to Immunosuppression Withdrawal | Number of Participants With Clinical Complications Usually Attributed to Immunosuppression | 12 participants |
| Randomized to Immunosuppression Maintenance | Number of Participants With Clinical Complications Usually Attributed to Immunosuppression | 4 participants |
90% CI: [-35, 10]
Secondary
Immunosuppression-free Duration
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
Population: Participants randomized to immunosuppression withdrawal who completed withdrawal and discontinued all immunosuppression
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Randomized to Immunosuppression Withdrawal | Immunosuppression-free Duration | 555.2 Days |
Secondary
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.
Time frame: Randomization to 2 years post-randomization.
Population: Hepatitis C infected participants randomized.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized to Immunosuppression Withdrawal | 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 | 0 participants |
| Randomized to Immunosuppression Maintenance | 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 | 0 participants |
Secondary
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.
Time frame: Randomization to 2 years post-randomization.
Population: Randomized participants (intent-to-treat sample)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized to Immunosuppression Withdrawal | Number of Participants Experiencing Graft Loss or Death | 1 participants |
| Randomized to Immunosuppression Maintenance | Number of Participants Experiencing Graft Loss or Death | 0 participants |
Secondary
Number of Participants Who Qualify for Random Assignment
Time frame: One to two years post-transplantation
Population: All subjects transplanted
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized to Immunosuppression Withdrawal | Number of Participants Who Qualify for Random Assignment | 95 participants |
Secondary
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)
Population: Participants randomized to immunosuppression withdrawal
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Randomized to Immunosuppression Withdrawal | Number of Participants Who Successfully Stop Taking Immunosuppression for at Least 6 Months | 12 participants |
Secondary
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.).
Time frame: Randomization to Month 24 post-randomization
Population: Randomized participants still being followed 24 months post-randomization.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Randomized to Immunosuppression Withdrawal | Total Burden of Immunosuppression From Random Assignment to Month 24 | 2198.5 units |
| Randomized to Immunosuppression Maintenance | Total Burden of Immunosuppression From Random Assignment to Month 24 | 2708.4 units |
p-value: <0.0001ANCOVA
Secondary
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.)
Time frame: Month 21 to Month 24 post-randomization
Population: Randomized participants still being followed 24 months post-randomization.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Randomized to Immunosuppression Withdrawal | Total Immunosuppression From Month 21 to Month 24 Post-randomization | 2.8 units per day |
| Randomized to Immunosuppression Maintenance | Total Immunosuppression From Month 21 to Month 24 Post-randomization | 3.7 units per day |
p-value: 0.0183ANCOVA