Clinical trial NCT00296244: Steroid Free Immunosuppression in Liver Transplantation
Official title: Steroid Free Immunosuppression in Liver Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Liver Cirrhosis
Liver Transplant Disorder
Keywords: steroid-free immunosuppression
liver transplantation
Lead sponsor: Thomas Jefferson University
Sponsor class: OTHER
Collaborators: name: Novartis Pharmaceuticals
First posted: 2006-02-24
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 72
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: 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

Primary outcomes:
measure: Graft Survival Rate
timeFrame: 1 and 2 years
measure: Patient Survival Rate
timeFrame: 1 and 2 years
measure: Acute Rejection Rate
timeFrame: 6 months post-transplant
Secondary outcomes:
measure: Infection as an Adverse Effect of Steroids
timeFrame: 3 months post-transplant
measure: Incidence and Severity of HCV Recurrence Post-OLT
timeFrame: 6 months post-transplant
measure: New-onset Diabetes Mellitus (NODM) as Secondary Outcome
timeFrame: 6 months
Other outcomes:
Locations:
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
Study officials:
affiliation: Thomas Jefferson University
name: Carlo Gerardo B Ramirez, M.D.
role: PRINCIPAL_INVESTIGATOR
References: