Reduction of Tacrolimus Dose in Association With Mycophenolate Mofetil After Liver Transplantation

NCT ID: NCT00151632

Last Updated: 2012-07-04

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 195 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2003-05-31
• Study Completion Date: 2009-05-31

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.

Conditions

Evidence of Liver Transplantation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

MMF+FK

Low doses of tacrolimus in association with mycophenolate mofetil

Group Type: EXPERIMENTAL

Mycophenolate mofetil

Intervention Type: DRUG

Mycophenolate mofetil is administered at a dose of 1,5 g x 2 / day for the 6 first weeks, then 1g x 2 / day until M12.

Tacrolimus

Intervention Type: DRUG

In arm 1: Tacrolimus is administered at half recommended dose: 0,040 mg/Kg x 2 , in order to maintain plasma levels between 6 and 10 ng/ml for the 6 first weeks, between 5 and 8 ng/ml from week 7 to M6 and between 4 and 6 ng/ml between M6 and M12.

In arm 2: Tacrolimus is administered at the recommended dose: 0,075 mg/Kg x 2 , in order to maintain plasma levels between 12 and 20 ng/ml for the 6 first weeks, between 10 and 15 ng/ml from week 7 to week 12, between 8 and 12 ng/ml between M4 and M6 and between 6 and 10 ng/ml between M6 and M12.

FK

Full recommended doses of tacrolimus

Group Type: ACTIVE_COMPARATOR

Tacrolimus

Intervention Type: DRUG

In arm 1: Tacrolimus is administered at half recommended dose: 0,040 mg/Kg x 2 , in order to maintain plasma levels between 6 and 10 ng/ml for the 6 first weeks, between 5 and 8 ng/ml from week 7 to M6 and between 4 and 6 ng/ml between M6 and M12.

In arm 2: Tacrolimus is administered at the recommended dose: 0,075 mg/Kg x 2 , in order to maintain plasma levels between 12 and 20 ng/ml for the 6 first weeks, between 10 and 15 ng/ml from week 7 to week 12, between 8 and 12 ng/ml between M4 and M6 and between 6 and 10 ng/ml between M6 and M12.

Interventions

Mycophenolate mofetil

Mycophenolate mofetil is administered at a dose of 1,5 g x 2 / day for the 6 first weeks, then 1g x 2 / day until M12.

Intervention Type: DRUG

Tacrolimus

In arm 1: Tacrolimus is administered at half recommended dose: 0,040 mg/Kg x 2 , in order to maintain plasma levels between 6 and 10 ng/ml for the 6 first weeks, between 5 and 8 ng/ml from week 7 to M6 and between 4 and 6 ng/ml between M6 and M12.

In arm 2: Tacrolimus is administered at the recommended dose: 0,075 mg/Kg x 2 , in order to maintain plasma levels between 12 and 20 ng/ml for the 6 first weeks, between 10 and 15 ng/ml from week 7 to week 12, between 8 and 12 ng/ml between M4 and M6 and between 6 and 10 ng/ml between M6 and M12.

Intervention Type: DRUG

Other Intervention Names

MMF; CELLCEPT; FK; PROGRAF

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

• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ministry of Health, France

OTHER_GOV

Sponsor Role: collaborator

Rennes University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Karim Boudjema, MD, PhD

Role: STUDY_DIRECTOR

CHU Rennes

Eric Bellissant, MD, PhD

Role: STUDY_CHAIR

CHU Rennes

Locations

Service de Chirurgie Digestive - Hôpital de la Côte de Nacre

Caen, , France

Service d'Hépatogastroentérologie - Hôpital Beaujon

Clichy, , France

Service d'Hépatogastroentérologie - Hôpital Henri Mondor

Créteil, , France

Chirurgie Générale et Digestive - Hôpital de La Croix Rousse

Lyon, , France

Service d'Hépaogastroentérologie - Hôpital Saint Eloi

Montpellier, , France

Service de Chirurgie Générale - Hôpital Cochin

Paris, , France

Département de Chirurgie Viscérale - Hôpital Pontchaillou

Rennes, , France

Centre Hépato-biliaire - Hôpital Paul Brousse

Villejuif, , France

Countries

France

References

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.

Reference Type: BACKGROUND

PMID: 9846530 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 10083497 (View on PubMed)

Other Identifiers

PHRC/01-01

Identifier Type: OTHER

Identifier Source: secondary_id

CIC0203/011

Identifier Type: -

Identifier Source: secondary_id

AFSSAPS 030200

Identifier Type: -

Identifier Source: org_study_id