Reduction in the Risk of Rejection by Mycophenolate Mofetil Dose Adjustment in Liver Transplant Patients With Side Effects Caused by the Calcineurine Inhibitors

Study Overview
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Brief Summary
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The aim of this project is to determine whether, in liver transplant patients with side effects due to ICN, the use of MMF in monotherapy can be optimised by dose adjustment based on the area under the curve (AUC) of mycophenolic acid (MPA). It involves a multicentre phase IV trial with direct individual benefit. A population of 130 liver transplant patients at 2 to 10 years post-transplant, showing significant clinical ICN side effects and being given bitherapy by ICN +MMF will be included and randomised 1:1 in two arms: Arm 1: progressive interruption of ICN after obtaining an AUC of MPA of 50 mg.h/l, followed by MMF monotherapy with dose adjustment based on the AUC of MPA, Arm 2: continuation of the ICN+MMF bitherapy without MMF therapeutic drug monitoring. The main judgement criterion will be the incidence of acute rejection in the 2 groups at 6 months. The secondary judgment criterion will be the evaluation of the benefit of stopping ICN on the side effects caused by these drugs.

Official Title
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Interruption of the Calcineurine Inhibitors (ICN) and Introduction of Mycophenolate Mofetil (MMF) in Liver Transplant Patients With Side Effects Due to ICN: Study of the Reduction of the Risks of Rejection by Mycophenolate Mofetil Therapeutic Drug Monitoring

Conditions
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Liver Transplantation

Intervention / Treatment
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* Drug: Mycophénolate Mofétil
* Drug: Ciclosporine A
* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient with first liver transplantion or retransplantation since more than 6 months: with a post-transplant lapse of time of 2 to 10 years and showing one of the following adverse effects of ICN: Renal insufficiency defined by a creatinine clearance <50ml/mn (calculated or estimated according to the Cockcroft formula) Arterial hypertension not controlled by an anti-hypertensive bitherapy Diabetes mellitus (fasting glycaemia >7.0mmol/l), whether treated or not Neuromuscular toxicity Immunosuppression by cyclosporine or tacrolimus and MMF Hepatic biopsy performed within the 6 months preceding the inclusion for the patients with a post-transplant period of <5 years and in the 12 months preceding the inclusion for patients with a post transplant period of >5 years. Exclusion Criteria: Acute rejection within the 6 months preceding the screening Previous history of cortico-resistant rejection Chronic rejection Significant ductopenia (absence of inter-lobule biliary canals in more than 30% of the portal tracts) on the pre-screening biopsy. Existence of a pre-transplantation diabetes mellitus. Liver transplantation for auto-immune hepatitis or primary sclerosing cholangitis Patients transplanted for viral C cirrhosis with reinfection lesions of the transplanted organ, rendering treatment by ribarivine + interferon conceivable in the year following inclusion. Counter-indications to MMF (anaemia, leucopenia) Immunosuppression by sirolimus, everolimus, azathioprine or corticoids

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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 |
| --- | --- |
| Experimental: adjument MMF<br>adjusting the dose according to the MMF AUC of mycophenolic acid | Drug: Mycophénolate Mofétil<br> <br> Drug: Ciclosporine A<br> <br> Drug: Tacrolimus<br> <br> |
| Active Comparator: continued treatment<br>Continued treatment empirically usual | Drug: Mycophénolate Mofétil<br> <br> Drug: Ciclosporine A<br> <br> Drug: Tacrolimus<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of biopsy proven acute rejection treated | Incidence of biopsy proven acute rejection treated with corticoids or requiring a re-introduction of ICN in arm 1 -- or an increase of ICN in arm 2 -- 6 months after the interruption of ICN (arm 1) or after randomization (arm 2). | 6 months |