Liver Disease
Conditions
Keywords
Liver transplantation, Calcineurin inhibitor withdraw, mycophenolate mofetil, Immunosuppression side effects, Graft rejection
Brief summary
The purpose of the study is to assess the safety and efficacy of mycophenolate mofetil alone, or with reduced dose cyclosporine (CsA) or tacrolimus, for immunosuppression long-term after liver transplantation, in an attempt to reduce the potential side effects from using cyclosporine or tacrolimus.
Detailed description
Most liver transplant recipients receive an immunosuppressive drug regimen that contains either cyclosporine or tacrolimus. Although these drugs have revolutionized transplantation, in many patients their long-term use is a major cause of serious side effects, including kidney failure, hypertension, diabetes mellitus, hyperlipidemia, and/or neurologic side effects. Stopping or reducing the dose of cyclosporine or tacrolimus can ameliorate the above side effects but may increase the risk of rejection. Mycophenolate mofetil (MMF), a safe and effective immunosuppressant that does not cause the above side effects, is typically used in combination with cyclosporine or tacrolimus. Attempts in liver transplant recipients at using mycophenolate mofetil alone or with reduced dose cyclosporine or tacrolimus have been successful but some patients developed rejection, and a few patients suffered liver failure. Most rejections after liver transplantation are easy to successfully treat with increased immunosuppression, but such treatment may carry risks such as increased susceptibility to infection. There have not yet been any large trials to adequately assess the safety and efficacy of using mycophenolate mofetil this way (alone or with reduced dose calcineurin inhibitor (CNI)). The purpose of this trial is to evaluate whether mycophenolate mofetil as monotherapy or with reduced dose cyclosporine or tacrolimus long-term after liver transplantation is safe and decreases side effects related to calcineurin inhibitor use. Only liver recipients expected to have a relatively low risk of developing rejection and/or liver failure are eligible for this trial. Some reasons for considering them low risk are their stable liver function, having had the transplant for over a year, having had one or fewer prior rejection episodes, having had non-autoimmune liver disease, their currently requiring low dose/level cyclosporine or tacrolimus, and the plan to use high dose mycophenolate mofetil and to exclude patients that fail to attain target values for mycophenolic acid area under the concentration-time curve (MPA AUC - MycoPhenolic Acid Area Under the Curve). Eligible patients will be randomized to receive either mycophenolate mofetil monotherapy (MMF; CNI discontinued), or mycophenolate mofetil and half their baseline dose of calcineurin inhibitor (MMF; CNI decreased). The primary outcome is biopsy proven rejection and the secondary outcomes include patient and graft survival, adverse events, hepatic profile, blood pressure, renal function, diabetes, and lipid profile. Additionally, mycophenolic acid concentrations will be measured; a mycophenolate mofetil monotherapy trial provides unique opportunity to study the implications of such monitoring. Patients will be followed for 12 months; there will be 16 visits during the trial.
Interventions
DRUGmycophenolate mofetil
mycophenolate mofetil and half their baseline dose of calcineurin inhibitor
Sponsors
Hoffmann-La Roche
Albert Einstein Healthcare Network
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
* Male or female 18 years of age or older (females who can become pregnant must use two acceptable methods of birth control while taking mycophenolate mofetil) * Orthotopic liver transplant more than one year prior to enrollment * Using calcineurin inhibitor to prevent rejection at time of screening * Patients must be willing to provide informed consent and abide by the requirements of the study
Exclusion criteria
* Liver disease may not have been secondary to an autoimmune cause, including: * autoimmune hepatitis, * primary sclerosing cholangitis, * primary biliary cirrhosis * Patients who have had: * more than one prior episode of rejection, * rejection within the past six months, * any corticosteroid resistant rejection * Patients with a tacrolimus trough level of greater than 7 ng/ml within 90 days prior to enrollment * Patients with a cyclosporine trough level greater than 225 ng/ml within 90 days prior to enrollment * Patients taking more the 5 mg per day of prednisone within 90 days prior to enrollment * Patients taking any prednisone within 30 days of enrollment * Allograft dysfunction within 6 months of enrollment, including ALT and/or total bilirubin greater than 2x normal, and/or biopsy proven hepatitis C virus (HCV) with fibrosis greater than stage II * White blood cell count less than 2,500 or platelet count less than 50,000 within 60 days of enrollment * MPA AUC threshold: Patients are not eligible for the study if they do not attain the threshold value MPA AUC (\>30 mg\*h/L if on CsA, \>40 mg\*h/L if on tacrolimus) after 50% calcineurin inhibitor reduction, measured using a 3-sample estimate (trough, 30-min, 120-min) * Patients who have had a previous transplant of organ(s) other than liver * Patients who received a liver from a hepatitis C positive donor * Patients who received a liver from a living donor * Patients with any technical complication requiring intervention within the three months prior to screening * Current infection requiring treatment * History of post transplant lymphoproliferative disorder * History of malignancy other than non-melanoma skin cancer or Stage 1-2 hepatoma * Active or unhealed duodenal ulcer * Concomitant treatment with rapamycin and/or interferon * Known allergy or sensitivity to CellCept® or any of its components * Unable or unwilling to comply with the protocol requirements or considered by the investigator(s) to be unfit for the study * Participation in a clinical trial within 30 days prior to study entry or prior enrollment in any CellCept® clinical trial * Pregnant or breastfeeding woman * Diabetes with known, clinically significant gastroparesis
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Biopsy Proven Rejections at 12 Months | 12 months | assessed by liver biopsy using Banff International Consensus Schema |
Secondary
| Measure | Time frame |
|---|---|
| Patient and Graft Survival at 12 Months | 12 months |
| Number of Participants With Adverse Events Including Infections at 12 Months | 12 months |
Countries
United States
Participant flow
Recruitment details
Participants were current patients from 3 outpatient transplant offices and recruited between July 2006 and May 2008.
Pre-assignment details
Participants were screened over a 2 week period. Three participants withdrew consent after signing the consent form. One participant failed screening (didn't attain threshold MPA level). These subjects were excluded from the trial before assignment to groups.
Participants by arm
| Arm | Count |
|---|---|
| MMF, CNI Discontinued Received Mycophenolate Mofetil (MMF); Complete withdrawal of calcineurin inhibitors (CNI) | 9 |
| MMF; CNI Decreased Received Mycophenolate Mofetil (MMF); calcineurin inhibitors (CNI) decreased to 50% of pre-enrollment dosage | 10 |
| Total | 19 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | MMF; CNI Decreased | MMF, CNI Discontinued | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 2 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 10 Participants | 7 Participants | 17 Participants |
| Age Continuous | 54.6 years STANDARD_DEVIATION 7.26 | 56.11 years STANDARD_DEVIATION 8.46 | 55.32 years STANDARD_DEVIATION 7.67 |
| Region of Enrollment United States | 10 participants | 9 participants | 19 participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 7 Participants | 7 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 9 / 9 | 7 / 10 |
| serious Total, serious adverse events | 2 / 9 | 1 / 10 |
Outcome results
Primary
Number of Biopsy Proven Rejections at 12 Months
assessed by liver biopsy using Banff International Consensus Schema
Time frame: 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MMF, CNI Discontinued | Number of Biopsy Proven Rejections at 12 Months | 0 participants |
| MMF; CNI Decreased | Number of Biopsy Proven Rejections at 12 Months | 0 participants |
Secondary
Number of Participants With Adverse Events Including Infections at 12 Months
Time frame: 12 months
Population: everyone enrolled who completed the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MMF, CNI Discontinued | Number of Participants With Adverse Events Including Infections at 12 Months | 2 participants |
| MMF; CNI Decreased | Number of Participants With Adverse Events Including Infections at 12 Months | 1 participants |
Secondary
Patient and Graft Survival at 12 Months
Time frame: 12 months
Population: everyone enrolled who completed the study
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MMF, CNI Discontinued | Patient and Graft Survival at 12 Months | 6 participants |
| MMF; CNI Decreased | Patient and Graft Survival at 12 Months | 9 participants |