Liver Disease, Liver Transplantation
Conditions
Keywords
transplantation, liver transplant, rejection, tolerance, antibody induction
Brief summary
Alemtuzumab is a man-made antibody used to treat certain blood disorders. Tacrolimus is a drug used to decrease immune system activity in people who have received organ transplants so that the new organ will not be rejected. This study will determine whether treatment with alemtuzumab and tacrolimus is effective in preventing organ rejection and maintaining the recipient's health after liver transplantation in patients with end-stage liver disease, and whether gradual tapering of tacrolimus treatment is safe for these patients.
Detailed description
Organ transplantation is a common procedure in hospitals, but organ rejection and serious side effects are potential problems for the patient. Alemtuzumab is a monoclonal antibody that binds to and depletes excess T cells in the bone marrow of leukemia patients. In this study, alemtuzumab will destroy the recipient's white blood cells (WBCs) at the time of transplantation. It is hoped that WBCs produced after alemtuzumab administration will recognize the transplanted liver as self and not reject the new liver. Drugs that suppress the immune system, such as tacrolimus, have contributed to increased success of transplantation. However, to prevent organ rejection, transplant recipients need to take immunosuppressive drugs for the rest of their lives, and these drugs make patients more susceptible to infection, endangering their health and survival. Regimens that are less toxic to or can eventually be withdrawn from transplant recipients are needed. This study will evaluate the effects of two in-patient doses of alemtuzumab followed by maintenance antirejection medication given to liver transplant patients post-transplant. This study will also determine if post-transplant tacrolimus therapy can be slowly and safely tapered off and withdrawn a year after transplant. Participants in this study will be patients with end-stage liver disease who will undergo liver transplantation at the start of the study. This study will last at least 2 years. Patients will undergo liver transplantation at the start of the study on Day 0. Patients will receive in-patient infusions of alemtuzumab on Days 0 and 4. Starting on Day 1, patients will receive oral cyclosporine, mycophenolate mofetil, and/or tacrolimus daily. Patients will be hospitalized for at least 1 week after transplantation. Because of suppression of patients' immune systems by alemtuzumab and these other immunosuppressants, they will also receive prophylactic medications for a minimum of 3 months after transplantation to prevent opportunistic infections. There will be at least eight study visits; they will occur at Days 4, 7, and 14 and at Months 1, 3, 6, 9, and 12. Patients will have liver biopsies at Day 0 and Months 6 and 12. At Month 12, participants will have assessments and blood tests to determine if they meet certain criteria and are eligible to undergo tacrolimus tapering. Patients eligible for tapering will undergo a 12-month gradual withdrawal of tacrolimus; they will be followed for an additional 2 years, with study visits at Months 18, 24, 30, and 36. Patients ineligible for tacrolimus tapering will continue taking their antirejection medication for the duration of the study; they will be followed for an additional year, with study visits at Months 18 and 24.
Interventions
DRUGAlemtuzumab
T-cell depleting monoclonal antibody; two doses by intravenous infusion on Days 0 and 4
DRUGCyclosporine
Oral immunosuppressant
DRUGMycophenolate mofetil
Oral immunosuppressant
DRUGTacrolimus
Oral immunosuppressant
PROCEDURELiver transplant
Occurs at study entry
PROCEDUREImmunosuppression withdrawal
Beginning no earlier than Year 1
Sponsors
Immune Tolerance Network (ITN)
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosis of nonimmune, nonviral, end-stage liver disease * Need liver transplant * Willing to use acceptable means of contraception for the duration of the study
Exclusion criteria
* Previous transplant * Multiorgan transplant or living donor transplant * Donor liver from a donor positive for antibody against hepatitis B core antigen or hepatitis C virus * Donor liver from a non-heart-beating donor * Liver failure due to autoimmune disease, such as autoimmune hepatitis, primary sclerosing cholangitis, or primary biliary cirrhosis * Hepatitis B or C virus infection * HIV infection * Stage III or higher hepatocellular cancer based on pre-transplant imaging * History of cancer. Patients with hepatocellular cancer, adequately treated in situ cervical carcinoma, or adequately treated basal or squamous cell carcinoma of skin are not excluded. * Active systemic infection at the time of transplantation * Clinically significant chronic renal, cardiovascular, or cerebrovascular disease * Any investigational drug within 6 weeks of study entry * Hypersensitivity to alemtuzumab or tacrolimus
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Who Have Graft Loss or Death | Within 1 year of post-transplantation | Proportion of participants who had liver graft loss or who died within 1 year of undergoing transplantation. Note: Participants who discontinued treatment or terminated the study prior to 1 year post transplantation are considered treatment failures and are included in this measure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants Who Had Graft Loss or Death | Within 2 years after initiation of immunosuppression withdrawal | Proportion of participants who had liver graft loss or who died or terminated from the study within 2 years of initiating immunosuppression withdrawal |
| Number of Events: Immunosuppression-related Complications | From transplantation until study completion or participant termination (participants followed up to 60 months) | Certain events are associated with immunosuppression. This measure looks at post-transplant infection, post-transplant malignancies, post-transplant diabetes, and post-transplant renal failure. Immunosuppression withdrawal is intended to reduce these type of events. However, reduction in immunosuppression can lead to complications in liver and renal function, as measured by acute rejection, chronic rejection, and post-transplant renal failure. Lower numbers for any of these events indicates greater success with transplantation and immunosuppression withdrawal (where applicable) |
| Proportion of Participants Successfully Withdrawn From Immunosuppressants | From 1 year post- transplantation until study completion or participant termination (participants followed up to 48 months post-transplant) | This measure of tolerance induction includes the proportion of participants who qualify for immunosuppression withdrawal as determined by a review of individual clinical results by a protocol withdrawal committee. Successful withdrawal definition: participants who remain off immunosuppression for at least 8 weeks. |
| Proportion of Participants Successfully Withdrawn and Remain Off Immunosuppressants | From 1 year post- transplantation until study completion or participant termination (participants followed up to 48 months post-transplant) | This measure of tolerance induction includes the proportion of participants who qualify for immunosuppression withdrawal as determined by a review of individual clinical results by a protocol withdrawal committee, were successfully withdrawn from immunosuppressants, and remained off immunosuppressants at the time the trial ended. Successful withdrawal definition: participants who remain off immunosuppression for at least 8 weeks and do not restart immunosuppressant drugs after successful withdrawal. |
Countries
Canada, United States
Participant flow
Recruitment details
Recruitment details: Eight centers in the United States and one center in Canada enrolled 27 participants with end-stage liver disease who met entry criteria between February 2005 and May 2006.
Participants by arm
| Arm | Count |
|---|---|
| Alemtuzumab Recipients of a liver allograft for end-stage liver disease received a 30 mg IV dose of alemtuzumab on study days 0 and 4 (immunosuppressive induction). Beginning on study day 1, participants received tacrolimus orally (dose adjusted to yield trough blood levels of 5-12 ng/mL) with or without mycophenolate orally (\<= 1.5g twice daily), at the discretion of the investigator. Six months post transplant, the tacrolimus dose was adjusted to yield trough blood levels of 5-10 ng/mL. Participants with significant toxicities related to tacrolimus were changed to cyclosporine (CsA), with the dose adjusted to maintain trough blood levels of 200-350 ng/mL during the first 3 months post transplant and 100-300 ng/mL from month 4 until CsA tapering was initiated. Maintenance immunosuppression was maintained for at least 12 months. At 12 months, participants were assessed for immune reconstitution and for the ability to undergo tapering and subsequent withdrawal of immunosuppression | 27 |
| Total | 27 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 4 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Alemtuzumab |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants |
| Age Continuous | 52.5 years STANDARD_DEVIATION 10.3 |
| Region of Enrollment Canada | 1 participants |
| Region of Enrollment United States | 26 participants |
| Sex: Female, Male Female | 8 Participants |
| Sex: Female, Male Male | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 26 / 27 |
| serious Total, serious adverse events | 27 / 27 |
Outcome results
Primary
Proportion of Participants Who Have Graft Loss or Death
Proportion of participants who had liver graft loss or who died within 1 year of undergoing transplantation. Note: Participants who discontinued treatment or terminated the study prior to 1 year post transplantation are considered treatment failures and are included in this measure.
Time frame: Within 1 year of post-transplantation
Population: Safety Sample
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alemtuzumab | Proportion of Participants Who Have Graft Loss or Death | 0.22 Proportion of Participants |
95% CI: [0.086, 0.423]Exact Binomial Confidence Interval
Secondary
Number of Events: Immunosuppression-related Complications
Certain events are associated with immunosuppression. This measure looks at post-transplant infection, post-transplant malignancies, post-transplant diabetes, and post-transplant renal failure. Immunosuppression withdrawal is intended to reduce these type of events. However, reduction in immunosuppression can lead to complications in liver and renal function, as measured by acute rejection, chronic rejection, and post-transplant renal failure. Lower numbers for any of these events indicates greater success with transplantation and immunosuppression withdrawal (where applicable)
Time frame: From transplantation until study completion or participant termination (participants followed up to 60 months)
Population: Safety Sample
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Alemtuzumab | Number of Events: Immunosuppression-related Complications | Chronic Rejection | 1 Events |
| Alemtuzumab | Number of Events: Immunosuppression-related Complications | Post-transplant Diabetes | 0 Events |
| Alemtuzumab | Number of Events: Immunosuppression-related Complications | Acute Rejection | 6 Events |
| Alemtuzumab | Number of Events: Immunosuppression-related Complications | Post-transplant Malignancies | 1 Events |
| Alemtuzumab | Number of Events: Immunosuppression-related Complications | Post-transplant Infection | 76 Events |
| Alemtuzumab | Number of Events: Immunosuppression-related Complications | Post-transplant Renal Failure | 11 Events |
| Completed Withdrawal and Remains Off Immunosuppression | Number of Events: Immunosuppression-related Complications | Post-transplant Infection | 2 Events |
| Completed Withdrawal and Remains Off Immunosuppression | Number of Events: Immunosuppression-related Complications | Acute Rejection | 0 Events |
| Completed Withdrawal and Remains Off Immunosuppression | Number of Events: Immunosuppression-related Complications | Post-transplant Malignancies | 0 Events |
| Completed Withdrawal and Remains Off Immunosuppression | Number of Events: Immunosuppression-related Complications | Chronic Rejection | 0 Events |
| Completed Withdrawal and Remains Off Immunosuppression | Number of Events: Immunosuppression-related Complications | Post-transplant Diabetes | 0 Events |
| Completed Withdrawal and Remains Off Immunosuppression | Number of Events: Immunosuppression-related Complications | Post-transplant Renal Failure | 0 Events |
| Completed Withdrawal and Restarted Immunosuppression | Number of Events: Immunosuppression-related Complications | Post-transplant Infection | 10 Events |
| Completed Withdrawal and Restarted Immunosuppression | Number of Events: Immunosuppression-related Complications | Acute Rejection | 0 Events |
| Completed Withdrawal and Restarted Immunosuppression | Number of Events: Immunosuppression-related Complications | Chronic Rejection | 0 Events |
| Completed Withdrawal and Restarted Immunosuppression | Number of Events: Immunosuppression-related Complications | Post-transplant Malignancies | 0 Events |
| Completed Withdrawal and Restarted Immunosuppression | Number of Events: Immunosuppression-related Complications | Post-transplant Diabetes | 0 Events |
| Completed Withdrawal and Restarted Immunosuppression | Number of Events: Immunosuppression-related Complications | Post-transplant Renal Failure | 2 Events |
| Discontinued Immunosuppression Withdrawal | Number of Events: Immunosuppression-related Complications | Chronic Rejection | 0 Events |
| Discontinued Immunosuppression Withdrawal | Number of Events: Immunosuppression-related Complications | Post-transplant Renal Failure | 1 Events |
| Discontinued Immunosuppression Withdrawal | Number of Events: Immunosuppression-related Complications | Post-transplant Diabetes | 1 Events |
| Discontinued Immunosuppression Withdrawal | Number of Events: Immunosuppression-related Complications | Acute Rejection | 0 Events |
| Discontinued Immunosuppression Withdrawal | Number of Events: Immunosuppression-related Complications | Post-transplant Malignancies | 0 Events |
| Discontinued Immunosuppression Withdrawal | Number of Events: Immunosuppression-related Complications | Post-transplant Infection | 11 Events |
Secondary
Proportion of Participants Successfully Withdrawn and Remain Off Immunosuppressants
This measure of tolerance induction includes the proportion of participants who qualify for immunosuppression withdrawal as determined by a review of individual clinical results by a protocol withdrawal committee, were successfully withdrawn from immunosuppressants, and remained off immunosuppressants at the time the trial ended. Successful withdrawal definition: participants who remain off immunosuppression for at least 8 weeks and do not restart immunosuppressant drugs after successful withdrawal.
Time frame: From 1 year post- transplantation until study completion or participant termination (participants followed up to 48 months post-transplant)
Population: Intent-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alemtuzumab | Proportion of Participants Successfully Withdrawn and Remain Off Immunosuppressants | 0.1 Proportion of Participants |
95% CI: [0.01, 0.2]Exact Binomial Confidence Interval
Secondary
Proportion of Participants Successfully Withdrawn From Immunosuppressants
This measure of tolerance induction includes the proportion of participants who qualify for immunosuppression withdrawal as determined by a review of individual clinical results by a protocol withdrawal committee. Successful withdrawal definition: participants who remain off immunosuppression for at least 8 weeks.
Time frame: From 1 year post- transplantation until study completion or participant termination (participants followed up to 48 months post-transplant)
Population: Intent-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alemtuzumab | Proportion of Participants Successfully Withdrawn From Immunosuppressants | 0.2 Proportion of Participants |
95% CI: [0.04, 0.3]Exact Binomial Confidence Interval
Secondary
Proportion of Participants Who Had Graft Loss or Death
Proportion of participants who had liver graft loss or who died or terminated from the study within 2 years of initiating immunosuppression withdrawal
Time frame: Within 2 years after initiation of immunosuppression withdrawal
Population: Participants who initiated immunosuppression withdrawal
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Alemtuzumab | Proportion of Participants Who Had Graft Loss or Death | 0 Proportion of Participants |
95% CI: [0, 0.3]Exact Binomial Confidence Interval