Clinical trial NCT00151632: Reduction of Tacrolimus Dose in Association With Mycophenolate Mofetil After Liver Transplantation
Official title: Evaluation of the Benefit/Risk Ratio of a Reduction of Tacrolimus Dose in Association With Mycophenolate Mofetil on the Prevention of Complications in Adult Liver Transplantation
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Evidence of Liver Transplantation
Keywords: Immunosuppression
Liver transplantation
Acute graft rejection
Treatment combination
Lead sponsor: Rennes University Hospital
Sponsor class: OTHER
Collaborators: name: Ministry of Health, France
First posted: 2005-09-09
Enrollment: 195
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The prevention of graft rejection after liver transplantation benefits nowadays from a variety of newly developed immunosuppressive agents. This allows more flexible and individualized immunoprophylaxis and gives an opportunity to reduce the long-term side effects (hypertension, renal failure, diabetes, etc.) of immunosuppression. The purpose of this study is to evaluate, in liver transplanted patients, if low doses of tacrolimus, given in combination with mycophenolate mofetil, can result in a lower rate of long-term side effects without increasing the rate of graft rejection.

Detailed description: Tacrolimus and mycophenolate mofetil are currently approved immunosuppressive agents for the prevention of acute and chronic rejection in liver transplantation. Adverse effects of tacrolimus are dose-dependent and appear early after the onset of treatment. To prevent side effects, we propose to combine reduced doses of tacrolimus with another immunosuppressant, i.e. mycophenolate mofetil, administered at usual doses. This study evaluates the interest of this combination and, subsequently, the pharmacokinetics of mycophenolate mofetil in this therapeutic context. Patients undergoing liver transplantation will be randomized to tacrolimus at normal doses or to the combination of tacrolimus at half doses and mycophenolate mofetil. A corticotherapy will be associated in both groups. The safety will be evaluated on the number of graft rejections between day 1 after transplantation and week 48; the onset of complications (hypertension, renal failure, diabetes, etc.) will allow to evaluate the efficacy of both treatment schedules.

Eligibility criteria: Inclusion Criteria:

* Adults over 18 years of age
* Primary liver transplantation
* Immunosuppressive treatment associating tacrolimus and steroids at low doses (\< 20 mg/d)
* Written informed consent

Non-Inclusion Criteria:

* Pregnancy or ineffective contraception
* Immunosuppressive treatment
* Blood group incompatibility with the donor
* Autoimmune hepatitis
* Fulminant hepatitis
* Primary sclerosing cholangitis
* Combined transplantations
* Reduced liver
* Living donor
* Treated hypertension and/or diastolic pressure ≥ 90 mmHg and/or systolic pressure ≥ 140 mmHg,
* Acute or chronic renal failure(creatininemia ≥ 130 μmol/L) before transplantation
* Treated diabetes and/or fasting glycemia ≥ 7 mmol/L
* Treated hypercholesterolemia and/or cholesterolemia ≥ 7 mmol/L
* post-operative creatininemia ≥ 200 μmol/L

Primary outcomes:
measure: Onset of acute rejection (criterion evaluating the risk)
timeFrame: between Day 1 and Week 48
measure: Onset of at least one complication (hypertension, renal failure, diabetes) requiring a specific treatment (criterion evaluating the benefit)
timeFrame: between Week 9 and Week 48
Secondary outcomes:
measure: Onset of hypertension, renal failure, diabetes, hypercholesterolemia, or of a serious adverse effect of mycophenolate mofetil
timeFrame: between Day 1 and Week 48
Other outcomes:
Locations:
city: Caen
country: France
facility: Service de Chirurgie Digestive - Hôpital de la Côte de Nacre
city: Clichy
country: France
facility: Service d'Hépatogastroentérologie - Hôpital Beaujon
city: Créteil
country: France
facility: Service d'Hépatogastroentérologie - Hôpital Henri Mondor
city: Lyon
country: France
facility: Chirurgie Générale et Digestive - Hôpital de La Croix Rousse
city: Montpellier
country: France
facility: Service d'Hépaogastroentérologie - Hôpital Saint Eloi
city: Paris
country: France
facility: Service de Chirurgie Générale - Hôpital Cochin
city: Rennes
country: France
facility: Département de Chirurgie Viscérale - Hôpital Pontchaillou
city: Villejuif
country: France
facility: Centre Hépato-biliaire - Hôpital Paul Brousse
Study officials:
affiliation: CHU Rennes
name: Karim Boudjema, MD, PhD
role: STUDY_DIRECTOR
affiliation: CHU Rennes
name: Eric Bellissant, MD, PhD
role: STUDY_CHAIR
References:
citation: Jain AB, Hamad I, Rakela J, Dodson F, Kramer D, Demetris J, McMichael J, Starzl TE, Fung JJ. A prospective randomized trial of tacrolimus and prednisone versus tacrolimus, prednisone, and mycophenolate mofetil in primary adult liver transplant recipients: an interim report. Transplantation. 1998 Nov 27;66(10):1395-8. doi: 10.1097/00007890-199811270-00024.
citation: Klupp J, Glanemann M, Bechstein WO, Platz KP, Langrehr JM, Keck H, Settmacher U, Radtke C, Neuhaus R, Neuhaus P. Mycophenolate mofetil in combination with tacrolimus versus Neoral after liver transplantation. Transplant Proc. 1999 Feb-Mar;31(1-2):1113-4. doi: 10.1016/s0041-1345(98)01925-3. No abstract available.