Steroid Free Immunosuppression in Liver Transplantation
Condition: Liver Cirrhosis; Liver Transplant Disorder
MeSH terms: Liver Cirrhosis
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Steroids; Basiliximab; Tacrolimus; Enteric-coated Mycophenolic acid (EC-MPA)
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): Patients randomized to Control group shall be administered steroids as 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 Naso-gastric tube (NGT) on day 6. Prednisone shall be tapered slowly starting at 1 month post-OLT and weaned off completely by 6 months post-OLT.; Basiliximab shall be given as induction therapy at 20 mg IV bolus intra-operatively and on the 4th day after transplantation.; Tacrolimus shall be used as the main maintenance immuno-suppressive drug. It will be given 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.; This drug may be given in combination with calcineurin inhibitors (tacrolimus) and steroids for maintenance immuno-prophylaxis to prevent rejection. They are particularly useful in recipients with renal dysfunction and neurotoxicity, when there is a need to reduce dose or delay introduction of calcineurin inhibitors. This drug is given at 720 mg PO BID for 3 months.
Other intervention name(s): Methylprednisolone (Solumedrol); Prednisone; Simulect; Prograf; Myfortic
Intervention MeSH terms: Mycophenolic Acid; Prednisone; Methylprednisolone; Methylprednisolone Hemisuccinate; Tacrolimus; Basiliximab
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: steroid-free immunosuppression; liver transplantation