Clinical trial NCT00456235: Reduction in the Risk of Rejection by Mycophenolate Mofetil Dose Adjustment in Liver Transplant Patients With Side Effects Caused by the Calcineurine Inhibitors
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Liver Transplantation
Lead sponsor: University Hospital, Limoges
Sponsor class: OTHER
First posted: 2007-04-04
Enrollment: 92
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Incidence of biopsy proven acute rejection treated
timeFrame: 6 months
Secondary outcomes:
Other outcomes:
Locations:
city: Besancon
country: France
facility: CHU de Besançon
city: Bordeaux
country: France
facility: CHU de Bordeaux
city: Caen
country: France
facility: CHU de Caen
city: Clichy
country: France
facility: Hôpital Beaujon
city: Creteil
country: France
facility: Hôpital Henri Mondor
city: Grenoble
country: France
facility: CHU de Grenoble
city: Lille
country: France
facility: CHU de Lille
city: Lyon
country: France
facility: Hôpital Edouard Herriot
city: Marseille
country: France
facility: CHU de Marseille
city: Montpellier
country: France
facility: CHU de Montpellier
city: Nice
country: France
facility: CHU de Nice
city: Paris
country: France
facility: Hôpital Saint Antoine
city: Paris
country: France
facility: Hôpital Cochin
city: Rennes
country: France
facility: CHU de Rennes
city: Strasbourg
country: France
facility: CHU de Strasbourg
city: Toulouse
country: France
facility: CHU de Toulouse
city: Villejuif
country: France
facility: Hôpital Paul Brousse
Study officials:
affiliation: CHU Limoges
name: Pierre MARQUET, MD
role: PRINCIPAL_INVESTIGATOR
References: