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

University of Limoges (UL)

Status and phase: Completed; Phase 4

Conditions: Liver Transplantation

Treatments: Drug: Tacrolimus; Drug: Mycophénolate Mofétil; Drug: Ciclosporine A

Study type: Interventional

Funder types: Other

Identifiers

NCT00456235

I06024

Details and patient eligibility

About

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.

Enrollment: 92 patients

Sex: All

Ages: 18 to 80 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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92 participants in 2 patient groups

adjument MMF

Experimental group

Description:

adjusting the dose according to the MMF AUC of mycophenolic acid

Treatment:

Drug: Tacrolimus

Drug: Ciclosporine A

Drug: Mycophénolate Mofétil

continued treatment

Active Comparator group

Description:

Continued treatment empirically usual

Treatment:

Drug: Tacrolimus

Drug: Ciclosporine A

Drug: Mycophénolate Mofétil