Benefit of Immunoprophylaxis on Fibrosis to Reduce Viral Load After Liver Transplantation

Study Overview
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Brief Summary
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An open-label randomized multicenter clinical study comparing three regimes of immunosuppression : (A) tacrolimus and steroids, (B) antithymocyte induction therapy and full dose of tacrolimus, (C) antithymocyte induction therapy with mycophenolate mofetil and a reduced dose of tacrolimus.

Official Title
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Evaluation of the Benefit of Antithymocyte Induction Therapy on Hepatic Fibrosis in de Novo Hepatitis C Virus Liver Transplant Patients.

Conditions
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Liver Transplantation

Intervention / Treatment
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* Drug: tacrolimus
* Drug: tacrolimus, ATG
* Drug: ATG+mycophénolate mofétil+tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients who received a first liver transplantation, presenting with a qualitative or quantitative PCR positive for hepatitis C virus at time of transplantation, whatever the transaminase activity, Women of childbearing potential with a negative pregnancy test, Male or female patients who agree to use an effective method of contraception, patients who signed a written informed consent form to participate in the study, patients who are compliant and likely to follow the visits specified by the study protocol Exclusion Criteria: • Preoperative serious renal impairment (serum creatinine levels > 200 µmol/l), repeat transplantation, multiple organ transplantation, transplantation performed with an organ transplant obtained from a living donor or a reduced or shared organ grafts, serious concomitant disorder, positive serology for HBs antigen or HIV positive at time of enrollment, previous history of nonhepatic cancer (except for localized skin cancer), presence of a hepatocellular carcinoma, for which the primary lesion exceeds 5 cm or is complicated by portal thrombosis or metastatic disease, an investigational product or therapy administered less than one month before entry into the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: A<br>tacrolimus + steroids | Drug: tacrolimus<br>* Tacrolimus started at 0.50 mg/kg b.i.d. starting at D0, by nasogastric tube and then 1 to 2 hours before meals. The dose of tacrolimus will be adjusted as soon as possible to obtain trough concentrations of the product between 10 and 20 µg/L between D0 and 6 months and then between 8 and 15 µg/L after 6 months<br>* Other names: PROGRAF;|
| Experimental: B<br>ATG+ tacrolimus without steroids in maintenance therapy | Drug: tacrolimus, ATG<br>* immunoprophylaxis allowing sparing of steroids in maintenance therapy combining induction therapy with 3 injections of antithymocyte globulins (ATG) (1.5 mg/kg/d at D0, D2 and D4) and tacrolimus at usual dosage. In this group of patients, the first injection of ATG will be infused over a period of at least 6 hours and will be started as soon as vascular anastomosis has been completed. It will be preceded by an injection of 3 mg/kg/d methylprednisolone. The second injection of ATG at D2, post transplantation will also be infused over 6 hours and will be preceded by an injection of 1 mg/kg methylprednisolone, and then subsequently steroids will be excluded from the treatment. The third and last injection at D4 post transplantation will be administered over a 6-hour period but will not be preceded by steroids. In this study arm, tacrolimus will be administered as in arm (A)<br>* Other names: Thymoglobuline;|
| Experimental: C<br>ATG+ Mycophenolate Mofetil + tacrolimus a reduced dosage without steroids in maintenance therapy | Drug: ATG+mycophénolate mofétil+tacrolimus<br>* immunoprophylaxis allowing sparing of steroids in maintenance therapy combined with mycophenolate mofetil, at an initial dosage of 2 grams a day, and then adjusted to safety and tolerability in such a way so as to maintain PMN ≥ 750/mm3, and platelet counts ≥ 30000/mm3. In this study arm, the patients will receive the same doses of ATG and steroids (and according to the same methods) as in arm B. Tacrolimus started at 0.05 mg/kg b.i.d. starting at D0 by nasogastric tube and then 1 to 2 hours before meals. In this study arm, the tacrolimus dose will be reduced: targeted trough concentrations will be between 7 and 12 µg/L between D0 and 6 months and then between 3 et 7 µg/L after 6 months.<br>* Other names: Mycophénolate mofétil = Cellcept;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary endpoint will be degree of fibrosis = Ishak's histological score of hepatic biopsy at 1 year |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| • Ishak's degree of activity |  | 1 year | 
| Ishak's degree of fibrosis |  | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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liver transplantation, hepatitis C virus, immunoprophylaxis