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

Evidence of Liver Transplantation Clinical Trial

— MMF-FK  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00151632
• Other study ID #: AFSSAPS 030200
• Secondary ID: PHRC/01-01CIC020
• Status: Terminated
• Phase: Phase 3
• First received: September 8, 2005
• Last updated: July 3, 2012
• Start date: May 2003
• Est. completion date: May 2009

Study information

• Verified date: July 2012
• Source: Rennes University Hospital
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 195
• Est. completion date: May 2009
• Est. primary completion date: December 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Related Conditions & MeSH terms

• Evidence of Liver Transplantation

Intervention

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.
• 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.

Locations

Country	Name	City	State
France	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

Sponsors (2)

Lead Sponsor	Collaborator
Rennes University Hospital	Ministry of Health, France

Country where clinical trial is conducted

France, 

References & Publications (2)

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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Onset of acute rejection (criterion evaluating the risk)		between Day 1 and Week 48	No
Primary	Onset of at least one complication (hypertension, renal failure, diabetes) requiring a specific treatment (criterion evaluating the benefit)		between Week 9 and Week 48	Yes
Secondary	Onset of hypertension, renal failure, diabetes, hypercholesterolemia, or of a serious adverse effect of mycophenolate mofetil		between Day 1 and Week 48	Yes