Reduction of Tacrolimus Dose in Association With Mycophenolate Mofetil After Liver Transplantation - Full Text View

Sponsors and Collaborators:	Rennes University Hospital Ministry of Health, France
Information provided by:	Rennes University Hospital
ClinicalTrials.gov Identifier:	NCT00151632

Purpose

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.

Condition	Intervention	Phase
Liver Transplantation	Drug: Mycophenolate mofetil Drug: Tacrolimus	Phase III

MedlinePlus related topics: Diabetes High Blood Pressure Kidney Failure Liver Transplantation

Drug Information available for: Tacrolimus Mycophenolate Mofetil Mycophenolate mofetil hydrochloride Tacrolimus anhydrous Benzocaine

U.S. FDA Resources

Study Type:	Interventional
Study Design:	Prevention, Randomized, Open Label, Active Control, Parallel Assignment, Safety/Efficacy Study
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

Further study details as provided by Rennes University Hospital:

Primary Outcome Measures:

Onset of acute rejection (criterion evaluating the risk) [ Time Frame: between Day 1 and Week 48 ] [ Designated as safety issue: No ]
Onset of at least one complication (hypertension, renal failure, diabetes) requiring a specific treatment (criterion evaluating the benefit) [ Time Frame: between Week 9 and Week 48 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Onset of hypertension, renal failure, diabetes, hypercholesterolemia, or of a serious adverse effect of mycophenolate mofetil [ Time Frame: between Day 1 and Week 48 ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	240
Study Start Date:	May 2003
Estimated Study Completion Date:	December 2008
Estimated Primary Completion Date:	December 2008 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
1: Experimental Low doses of tacrolimus in association with mycophenolate mofetil	Drug: 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. 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.
2: Active Comparator Full recommended doses of tacrolimus	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.

Arms

Assigned Interventions

1: Experimental

Low doses of tacrolimus in association with mycophenolate mofetil

Drug: 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.

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.

2: Active Comparator

Full recommended doses of tacrolimus

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.

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

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Exclusion Criteria:

Pregnancy
Immunosuppressive treatment
Blood group incompatibility with the donor
Autoimmune hepatitis
Primary sclerosing cholangitis
Combined transplantations
Hypertension
Acute or chronic renal failure
Diabetes
Hypercholesterolemia

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00151632

Locations

France
Département de Chirurgie Viscérale - Hôpital Pontchaillou
Rennes, France, 35033
Service de Chirurgie Générale - Hôpital Cochin
Paris, France, 75679
Service de Chirurgie Digestive - Hôpital de la Côte de Nacre
Caen, France, 14033
Service d'Hépatogastroentérologie - Hôpital Beaujon
Clichy, France, 92110
Chirurgie Générale et Digestive - Hôpital de La Croix Rousse
Lyon, France, 69317
Service d'Hépaogastroentérologie - Hôpital Saint Eloi
Montpellier, France
Centre Hépato-biliaire - Hôpital Paul Brousse
Villejuif, France
Service d'Hépatogastroentérologie - Hôpital Henri Mondor
Créteil, France, 94010

Sponsors and Collaborators

Rennes University Hospital

Ministry of Health, France

Investigators

Study Director:	Karim Boudjema, MD, PhD	CHU Rennes
Study Chair:	Eric Bellissant, MD, PhD	CHU Rennes

More Information

Publications:

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.

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. No abstract available.

Responsible Party:	Rennes University Hospital ( Direction of Clinical Research and Strategy )
Study ID Numbers:	AFSSAPS 030200, PHRC/01-01, CIC0203/011
Study First Received:	September 8, 2005
Last Updated:	May 21, 2008
ClinicalTrials.gov Identifier:	NCT00151632
Health Authority:	France: Afssaps - French Health Products Safety Agency

Keywords provided by Rennes University Hospital:

Immunosuppression
Liver transplantation
Acute graft rejection
Treatment combination

Study placed in the following topic categories:

Mycophenolic Acid
Mycophenolate mofetil
Benzocaine
Tacrolimus

Additional relevant MeSH terms:

Molecular Mechanisms of Pharmacological Action
Immunologic Factors
Antineoplastic Agents
Therapeutic Uses
Physiological Effects of Drugs

Enzyme Inhibitors
Antibiotics, Antineoplastic
Immunosuppressive Agents
Pharmacologic Actions

ClinicalTrials.gov processed this record on January 16, 2009