Mycophenolate Mofetil Immunosuppression Without/With Reduced Dose Calcineurin Inhibitor Long After Liver Transplantation

• biopsy proven rejection incidence at 12 months [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  

• patient and graft survival at 12 months [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  
• adverse events including infections at 12 months [ Time Frame: 12 months ] [ Designated as safety issue: Yes ]
  
• hepatic profile (ALT, total bilirubin) - change from baseline over 12 months [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  
• blood pressure profile - change from baseline over 12 months [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  
• renal function (serum creatinine) - change from baseline over 12 months [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  
• diabetes profile - change from baseline over 12 months [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  
• lipid profile (low-density lipoprotein [LDL], high-density lipoprotein [HDL], HDL/LDL ratio, total cholesterol, triglycerides) - change from baseline over 12 months [ Time Frame: 12 months ] [ Designated as safety issue: No ]
  

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, 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).

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).

Eligible patients will be randomized to receive either mycophenolate mofetil monotherapy, or mycophenolate mofetil and half their baseline dose of calcineurin inhibitor. 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.