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Reduction of Tacrolimus Dose in Association With Mycophenolate Mofetil After Liver Transplantation (MMF-FK)

This study has been terminated.
(insufficient enrollment)
Sponsor:
Collaborator:
Ministry of Health, France
Information provided by (Responsible Party):
Rennes University Hospital
ClinicalTrials.gov Identifier:
NCT00151632
First received: September 8, 2005
Last updated: July 3, 2012
Last verified: July 2012
History of Changes
  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
Evidence of Liver Transplantation
 Drug: Mycophenolate mofetil
Drug: Tacrolimus
 Phase 3

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

Resource links provided by NLM:

U.S. FDA Resources

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 ]

Enrollment: 195
Study Start Date: May 2003
Study Completion Date: May 2009
Primary Completion Date: December 2008 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: MMF+FK
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.
Other Names:
  • MMF
  • CELLCEPT
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.

Other Names:
  • FK
  • PROGRAF
Active Comparator: FK
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.

Other Names:
  • FK
  • PROGRAF

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

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

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

Responsible Party: Rennes University Hospital
ClinicalTrials.gov Identifier: NCT00151632     History of Changes
Other Study ID Numbers: AFSSAPS 030200, PHRC/01-01, CIC0203/011
Study First Received: September 8, 2005
Last Updated: July 3, 2012
Health Authority: France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Keywords provided by Rennes University Hospital:
Immunosuppression
Liver transplantation
Acute graft rejection
Treatment combination

Additional relevant MeSH terms:
Mycophenolate mofetil
Tacrolimus
Mycophenolic Acid
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
 Pharmacologic Actions
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on May 21, 2013