Fixed Dose MMF vs Concentration Controlled MMF After Renal Transplantation

An Open, Prospective, Randomised, Controlled, Multi-Center Study Comparing Fixed Dose vs Concentration Controlled Mycophenolate Mofetil Regimens for de Novo Patients Following Transplantation

Determine the value of a clinically feasible strategy of therapeutic drug monitoring compared with fixed dosing in de novo MMF treated renal transplant recipients with respect to the incidence of treatment failure.

Study Overview

• Status: Completed
• Conditions: De Novo Renal Transplant Recipient.
• Intervention / Treatment: Drug: Mycophenolate Mofetil

Detailed Description

For treatment with mycophenolate mofetil the contribution of TDM still has to be determined, although circumstantial evidence suggests the measurement of mycophenolic acid plasma concentrations adds to patient management.

A concerted effort to test the hypothesis that TDM will improve outcome in mycophenolate mofetil therapy in a prospective randomised trial is to be made if we want to have a solid base for the continued measurements of mycophenolic acid concentrations in the future. This trial aims to demonstrate the added value of TDM for mycophenolic acid, by comparing fixed dose treatment with concentration controlled mycophenolate mofetil treatment in kidney transplant recipients.

• Study Type: Interventional
• Enrollment (Actual): 901
• Phase: Phase 4

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • New Lambton, New South Wales, Australia, 2305
      • John Hunter Hospital
  • Queensland
    • Brisbane, Queensland, Australia, 4102
      • Princess Alexandra Hospital
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Medical Centre
    • Melbourne, Victoria, Australia, 3065
      • St Vincent's Hospital
    • Parkville, Victoria, Australia, 3052
      • Royal Melbourne Hospital
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Sir Charles Gairdner Hospital
    • Perth, Western Australia, Australia, 6847
      • Royal Perth Hospital
• Austria
  • Graz, Austria, 8036
    • Med. Univ. Klinik
  • Vienna, Austria, Vienna
    • AKH Wien
• Belgium
  • Leuven, Belgium, 3000
    • University Hospitals Leuven
• Brazil
  • Sao Paulo, Brazil, CEP 0438-002
    • Hospital do Rim e Hipertensão
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V5Z 1M9
      • Vancouver General Hospital
• China
  • Shanghai
    • Shanghai, Shanghai, China, 200001
      • Ruijin Hospital
  • Sichuan
    • Chengdu, Sichuan, China
      • West China Hospital of Sichuan University
• Denmark
  • Odense, Denmark, 5000
    • Odense University Hospital
• Estonia
  • Tartu, Estonia, 51014
    • Surgical Clinic Of Tartu University Clinics
• France
  • Bordeaux, France, 33076
    • Hopital Pellegrin, C.H.R.de Bordeaux
  • Dijon, France, 21000
    • Hospital du Bocage
  • Grenoble, France, 38043
    • Chu de Grenoble
  • Kremlin Bicêtre, France, 94275
    • CHU Kremlin Bicetre
  • Lille, France, 59037
    • Hopital Calmette
  • Lille, France, 59037
    • Hopital Jeanne de Flandres
  • Limoges, France, 87042
    • Centre Hospitalier Régional Universitaire
  • Nantes, France, 44093
    • Chu Hotel Dieu
  • Paris, France, 75020
    • Hopital Tenon
  • Paris, France, 75015
    • Hopital Necker
  • Pierre Benite, France, 69495
    • Centre Hospitalier Lyon Sud
  • Suresnes, France, 92151
    • Hopital Foch
  • Toulouse, France, 31059
    • CHU Rangueil
  • Toulouse, France, 31059
    • CHU Purpan
  • Vandoeuvre-les-Nancy, France, 54511
    • CHU de Nancy-Brabois
• Germany
  • Berlin, Germany, 10098
    • Universitätsklinikum Charité
  • Freiburg, Germany, 79106
    • Chirurgische Universitätsklinik
  • Heidelberg, Germany, 69120
    • University of Heidelberg
  • Heidelberg, Germany, 69120
    • UniversitatsKlinikum Heidelberg
  • Koln, Germany, 51009
    • Stadt Kliniken Koln
  • Wurzburg, Germany, 97080
    • University Hospital Wurzburg
• Lithuania
  • Vilnius, Lithuania, 2021
    • Vilnius University Hospital
• Netherlands
  • Leiden, Netherlands, 2333
    • Leids Universitair Medisch Centrum
  • Rotterdam, Netherlands, 3000
    • Erasmus Medical Center Rotterdam
• Norway
  • Oslo, Norway, 0027
    • Rikshopitalet
• Poland
  • Warsaw, Poland, 02-006
    • Institute of Transplantology, Medical University of Warsaw
  • Warsaw, Poland, 04-736
    • Children's Memorial Health Institute
• Spain
  • Badajoz, Spain, 06080
    • Hospital Infanta Christa
  • Barcelona, Spain, 08003
    • Hospital del Mar
  • Barcelona, Spain, 8950
    • Hospital Sant Joan de Déu
  • Barcelona, Spain, 08035
    • Valle de Hebron
  • Cordoba, Spain, 14004
    • Hospital Reina Sofia
  • Granada, Spain, 18014
    • Hospital de las Nieves
  • Madrid, Spain, 28040
    • Fundacion Jimenez Diaz
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos
  • Madrid, Spain, 28034
    • Hospital Ramon y Cajal
  • Madrid, Spain, 28046
    • La Paz
  • Santiago De Compostela, Spain, 15706
    • Complejo Hospitalario Univeritario de Santiago
  • Sevilla, Spain, 41013
    • Hospital Virgen del Rocío
  • Valencia, Spain
    • Hospital Dr. Peset
  • 07014
    • Palma De Mallorca, 07014, Spain
      • Hospital Son Dureta
• Sweden
  • Malmo, Sweden, 205 02
    • University Hospital, Malmo
  • Stockholm, Sweden, 141 86
    • Karolinska University Hospital, Huddinge
  • Uppsala, Sweden, 751 85
    • University Hospital A
• Taiwan
  • Taipei, Taiwan
    • National Taiwan University Hospital
• United Kingdom
  • London, United Kingdom, NW3 2QG
    • Royal Free Hospital
  • London, United Kingdom, SW17 ORE
    • St George's Hospital
  • London, United Kingdom, SE1 9RT
    • Guys and St Thomas's Hospital
• Venezuela
  • Caracas, Venezuela
    • Hospital "Miguel Perez Carreno"
  • Caracas, Venezuela
    • Hospital Universitario de Caracas
  • Maracaibo, Venezuela
    • Hospital Universitario de Maracaibo

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Renal transplant recipients who have completed their second birthday,
• Recipients from living (related or unrelated), cadaveric (non-heart beating or heart beating) donors,
• Single organ recipient (kidney only),
• Women of childbearing potential should have a negative serum or urine pregnancy test with a sensitivity of at least 50 mIU/ml within 1 week prior to beginning MMF treatment. Effective contraception must be used before beginning therapy, during therapy and for 6 weeks following discontinuation of therapy, even where there has been a history of infertility, unless due to hysterectomy,
• Patients or patient's parent/guardian providing written informed consent,
• Patients co-operative and able to complete all the assessment procedures.

Exclusion Criteria:

• Patients receiving immunosuppressive therapy (except steroid treatment) within the preceding 28 days, except that immunosuppressive medication may be initiated up to 48 hours before transplantation. Furthermore, all patients should receive 1 g [adults] or 600 mg/m2 [paediatric patients] of MMF therapy within 6 hours prior to transplantation,
• PRA > 50% within 6 months prior to enrolment,
• Cold ischaemia time >48 hours,
• History of malignancy (except localised non-melanotic skin cancer) or the presence of any active malignancy at the time of transplant,
• Active peptic ulcer disease,
• Active infection,
• Mandatory intake of prohibited drugs or it is probable that the patient will require treatment with such drugs after transplant,
• Pregnant or lactating females,
• Women of child-bearing potential not willing to use a reliable form of contraception,
• Patient is allergic or intolerant to polysorbate 80 (TWEEN), phenylalanine (aspartame), steroids, MMF, MPA, tacrolimus or cyclosporin,
• Patient or donor with positive tests for HIV or hepatitis B surface antigen,
• Patients with liver cirrhosis or clinical evidence of portal hypertension or other indication of moderate or severe liver disease. (Note: it is strongly recommended that patients with hepatitis C have a liver biopsy performed prior to transplantation),
• Incompatible ABO blood type and/or positive crossmatch,
• Patient has any form of substance abuse, psychiatric disorder or condition, which, in the opinion of the investigator, may invalidate communication with the investigator or with study procedures,
• Patients whose laboratory results reveal severe anaemia (as defined by a haemoglobin value <6 mmol/L [9.7 g/dL] for adults receiving erythropoietin, <4.1 mmol/L [6.6 g/dL] for paediatric patients [regardless of erythropoietin treatment]), leukopenia (as defined by a WBC value of <2500/mm3) or thrombocytopenia (as defined by a platelet count of <75,000/mm3).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Fixed Dose; 1 g MMF twice-daily (bid) for adults or 600 mg/m2 bid for paediatric patients. Treatment to be given orally unless it is not possible, in which case it is administered via intravenous (iv) infusion.	Drug: Mycophenolate Mofetil; 1 g for adult patients and 300 mg/m2 for paediatric patients. Fixed dose arm: 1 g twice a day (bid) for adults and 600mg/m2 bid for paediatric patients. Concentration controlled arm: initial dose will be 1 g bid for adults and 600mg/m2 bid for paediatric patients. Abbreviated AUCs (taken at timepoints: 0, 30min and 120min in fasted patients) on Days 3 and 10, Week 4, Months 3, 6 and 12 will be performed to determine mycophenolic acid levels in plasma.; Other Names: CellCept
Active Comparator: Concentration Controlled; 1 g MMF bid for adults or 600 mg/m2 bid for paediatric patients. Thereafter, MMF doses will be adjusted to MPA AUC0-12 between 30-60mg.h/L based on 3-point abbreviated AUCs (taken at timepoints: 0, 30 min and 120 min always in fasted patients, except for pediatric patients on concomitant tacrolimus) on Days 3 and 10, Week 4, Months 3, 6 and 12 will be performed to determine MPA levels in plasma.	Drug: Mycophenolate Mofetil; 1 g for adult patients and 300 mg/m2 for paediatric patients. Fixed dose arm: 1 g twice a day (bid) for adults and 600mg/m2 bid for paediatric patients. Concentration controlled arm: initial dose will be 1 g bid for adults and 600mg/m2 bid for paediatric patients. Abbreviated AUCs (taken at timepoints: 0, 30min and 120min in fasted patients) on Days 3 and 10, Week 4, Months 3, 6 and 12 will be performed to determine mycophenolic acid levels in plasma.; Other Names: CellCept

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Treatment failure including the occurrence of the first one of any of the following: biopsy-proven acute rejection, graft loss, death or discontinuation of MMF therapy during the first 12 months following transplantation.	12 Months

Secondary Outcome Measures

Outcome Measure	Time Frame
Proportion of patients treated for acute rejection during the first 3, 6, 12 months post-transplantation,	3, 6 and 12 Months
Time to first acute rejection,	12 Months
Number of acute rejection episodes per patient in the first year post-transplantation,	12 Months
Overall treatment outcome at 12 months post-transplantation which is composed of any one of the following:	12 Months
Graft loss,	12 Months
Death,	12 Months
Discontinuation of MMF therapy,	12 Months
Patient lost to follow-up.	12 Months

Collaborators and Investigators

• Sponsor: Erasmus Medical Center
• Collaborators: Hoffmann-La Roche
• Investigators: Principal Investigator: Teun van Gelder, Dr, Erasmus Medical Center

Publications and helpful links

General Publications

• van Gelder T, Hilbrands LB, Vanrenterghem Y, Weimar W, de Fijter JW, Squifflet JP, Hene RJ, Verpooten GA, Navarro MT, Hale MD, Nicholls AJ. A randomized double-blind, multicenter plasma concentration controlled study of the safety and efficacy of oral mycophenolate mofetil for the prevention of acute rejection after kidney transplantation. Transplantation. 1999 Jul 27;68(2):261-6. doi: 10.1097/00007890-199907270-00018.
• van Gelder T, Silva HT, de Fijter JW, Budde K, Kuypers D, Tyden G, Lohmus A, Sommerer C, Hartmann A, Le Meur Y, Oellerich M, Holt DW, Tonshoff B, Keown P, Campbell S, Mamelok RD. Comparing mycophenolate mofetil regimens for de novo renal transplant recipients: the fixed-dose concentration-controlled trial. Transplantation. 2008 Oct 27;86(8):1043-51. doi: 10.1097/TP.0b013e318186f98a.
• Hocker B, van Gelder T, Martin-Govantes J, Machado P, Tedesco H, Rubik J, Dehennault M, Garcia Meseguer C, Tonshoff B; FDCC Study Group. Comparison of MMF efficacy and safety in paediatric vs. adult renal transplantation: subgroup analysis of the randomised, multicentre FDCC trial. Nephrol Dial Transplant. 2011 Mar;26(3):1073-9. doi: 10.1093/ndt/gfq450. Epub 2010 Jul 28.
• van Gelder T, Tedesco Silva H, de Fijter JW, Budde K, Kuypers D, Arns W, Soulillou JP, Kanellis J, Zelvys A, Ekberg H, Holzer H, Rostaing L, Mamelok RD. Renal transplant patients at high risk of acute rejection benefit from adequate exposure to mycophenolic acid. Transplantation. 2010 Mar 15;89(5):595-9. doi: 10.1097/TP.0b013e3181ca7d84.
• van Schaik RH, van Agteren M, de Fijter JW, Hartmann A, Schmidt J, Budde K, Kuypers D, Le Meur Y, van der Werf M, Mamelok R, van Gelder T. UGT1A9 -275T>A/-2152C>T polymorphisms correlate with low MPA exposure and acute rejection in MMF/tacrolimus-treated kidney transplant patients. Clin Pharmacol Ther. 2009 Sep;86(3):319-27. doi: 10.1038/clpt.2009.83. Epub 2009 Jun 3.

Study record dates

Study Major Dates

• Study Start: May 1, 2003
• Primary Completion (Actual): March 1, 2005
• Study Completion (Actual): April 1, 2006

Study Registration Dates

• First Submitted: September 9, 2005
• First Submitted That Met QC Criteria: September 9, 2005
• First Posted (Estimate): September 14, 2005

Study Record Updates

• Last Update Posted (Estimate): February 12, 2009
• Last Update Submitted That Met QC Criteria: February 11, 2009
• Last Verified: February 1, 2009

More Information

Terms related to this study

• Keywords: Therapeutic Drug Monitoring; Paediatric kidney transplantation; Mycophenolate mofetil; Adult kidney transplantation
• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Mycophenolic Acid
• Other Study ID Numbers: FDCC