Steroid Free Immunosuppression in Liver Transplantation
Steroid Free Immunosuppression in Liver Transplantation
The purpose of this study is to determine whether steroid-related complications can be
 avoided by using steroid-free immuno-suppressive drug regimen after liver transplantation.
Steroids have remained a standard part of post-transplant immunosuppression, both for
 prevention and treatment of rejection. However, steroids have been shown to cause long-term
 adverse effects, such as: susceptibility to infection, obesity, hypertension, hyperlipidemia,
 diabetes, osteopenia, cataracts and growth retardation in children. They have also been
 implicated in accelerating Hepatitis C virus (HCV) re-infection post-liver transplantation.

 Several studies have shown that early steroid reduction or withdrawal could be done safely to
 alleviate many steroid-related adverse effects after liver transplantation (OLT).

 This is a prospective controlled randomized trial on adult patients who will undergo primary
 OLT at Thomas Jefferson University Hospital (TJUH).

 Forty consecutive OLT recipients shall be randomized into two groups.

 -  Control group- immuno-suppressive drug regimen consisting of basiliximab (Simulect),
 tacrolimus (Prograf), Mycophenolic acid (Myfortic), and steroids

 -  Study group- immuno-suppressive drug regimen consisting of basiliximab, tacrolimus,
 Mycophenolic acid (Myfortic) without steroids

 Basiliximab will be given at 20 mg IV bolus intra-operatively and on the 4th day after
 transplantation. Tacrolimus shall be administered at a dose of 0.15mg/ kg/ day by mouth or
 through a naso-gastric tube (NGT), starting not earlier than 24 after the transplant but
 within 48 hrs after reperfusion. The dose shall be adjusted to achieve a trough level of
 10-15 ng/ml during the first 30 days after transplantation and lowered to 5-10 ng/ml,
 thereafter. Patients randomized to the control group shall be administered methylprednisolone
 (Solumedrol) 1000 mg IV during the anhepatic phase. Methylprednisolone will be continued
 according to the following taper schedule: 50 mg IV every 6 hrs on day 1; 40 mg IV every 6hrs
 on day 2; 30 mg IV every 6 hrs on day 3; 20 mg IV every 6 hrs on day 4; 20 mg IV every 12 hrs
 on day 5; and Prednisone 20 mg by mouth or NGT on day 6. Prednisone shall be tapered slowly
 starting at 1 month post-OLT and weaned off completely by 6 months post-OLT. Enteric-coated
 mycophenolic acid or EC-MPA (Myfortic) will be added to the regimen, particularly in patients
 with renal impairment or neuro-toxicity to minimize the dose and effects of tacrolimus. It
 will be started at 720 mg P.O. 2x/ day immediately post-transplant and shall be given for a
 period of 3 months.

 Primary end points of this study at 6 months post-transplant include: graft and patient
 survival rates, and incidence of acute rejection and therapy employed to treat rejection.
 Secondary end points include: adverse effects of steroids, particularly, diabetes, obesity,
 hyperlipidemia, and hypertension; incidence and severity of HCV recurrence, and incidence of
 infectious complications.

 Blood samples of HCV recipients shall be collected on day of surgery, 2 weeks, 1 month, 3
 months, and 6 months post-OLT as per TJUH Liver Transplant Protocol. Sera shall be stored at
 -80C and will be used for quantitative HCV RNA levels by quantitative polymerase chain
 reaction.

 Protocol liver biopsy shall be performed at the time of surgery, between 7-21 days post-OLT
 and at approximately 3 months after transplantation or as clinically indicated by elevated
 liver function test results.

 Acute rejection shall be treated initially by increasing the tacrolimus dose to achieve a
 level 15-20 ng/ml for 48 hrs. If liver function test results will not show improvement by the
 3rd day after increasing tacrolimus dose, a biopsy should be performed. Only biopsy proven
 rejection shall be treated according to the following protocol. Mild to moderate rejection
 shall be treated in the study group with methylprednisolone 1 gm IV with tapering doses of
 steroid as described above. Steroids shall be discontinued after the completion of the taper.
 In the control group, methylprednisolone 1 gm IV shall be followed by tapering doses and by
 prednisone 20 mg once daily, which shall be progressively reduced accordingly. The protocol
 shall also include a repeat biopsy if there is no improvement in the liver function test at
 the end of steroid taper. Severe rejection or steroid resistant rejection shall be treated
 with OKT3 at 5mg IV/ day for 5-10 days after pre-medication.

 Recipients with HCV recurrence shall be treated according to TJUH Liver Transplant protocol
 as follows. Abnormal liver function tests should be evaluated by hepatic imaging to exclude
 anatomic abnormality. If none, liver biopsy will be done. If liver biopsy shows > grade 4
 (inflammation more than mild) or > stage 1 (fibrosis), consider antiviral treatment
 consisting of Peg-Interferon alpha-2a 180mcg subcutaneously weekly for two weeks. If patient
 tolerates peg-interferon from hematologic and neuro-psychiatric standpoint, continue
 peg-interferon, and add ribavirin. Refer to protocol for dosing. Total duration of therapy is
 48 weeks.

 Follow up period for primary analysis will be six (6) months.
Inclusion Criteria:

 -  Male and female patients between 18 and 72 years of age

 -  Male or female patients who are primary cadaveric liver transplant recipients

 -  Cold ischemia time must be <20 hours

 -  Females capable of becoming pregnant must have a negative pregnancy test at baseline
 and are required to practice an approved method of birth control for the duration of
 the study and for a period of three months following discontinuation of study
 medication

 -  Patient has given written informed consent to participate in the study

 Exclusion Criteria:

 -  Patients meeting any of the following criteria at baseline will be excluded from study
 participation

 -  Patients who have previously received an organ transplant

 -  Patients who are recipients of a multiple organ transplants

 -  Women of childbearing potential not using the contraception method(s) specified in
 this study, as well as women who are breastfeeding

 -  Known sensitivity to Simulect or class of Simulect

 -  Patients with severe medical condition(s) that in the view of the investigator
 prohibits participation in the study

 -  Use of any other investigational agent in the last 30 days