Fixed Dose MMF vs Concentration Controlled MMF After Renal Transplantation

NCT ID: NCT00166244

Last Updated: 2009-02-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 901 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2003-05-31
• Study Completion Date: 2006-04-30

Brief Summary

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.

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.

Conditions

De Novo Renal Transplant Recipient.

Study Design

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

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Mycophenolate Mofetil

Intervention Type: DRUG

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.

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.

Group Type: ACTIVE_COMPARATOR

Mycophenolate Mofetil

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: DRUG

Other Intervention Names

CellCept

Eligibility Criteria

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).

• Minimum Eligible Age: 2 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: collaborator

Erasmus Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Erasmus Medical Center

Principal Investigators

Teun van Gelder, Dr

Role: PRINCIPAL_INVESTIGATOR

Erasmus Medical Center

Locations

John Hunter Hospital

New Lambton, New South Wales, Australia

Princess Alexandra Hospital

Brisbane, Queensland, Australia

Monash Medical Centre

Clayton, Victoria, Australia

St Vincent's Hospital

Melbourne, Victoria, Australia

Royal Melbourne Hospital

Parkville, Victoria, Australia

Sir Charles Gairdner Hospital

Nedlands, Western Australia, Australia

Royal Perth Hospital

Perth, Western Australia, Australia

Med. Univ. Klinik

Graz, , Austria

AKH Wien

Vienna, , Austria

University Hospitals Leuven

Leuven, , Belgium

Hospital do Rim e Hipertensao

São Paulo, , Brazil

Vancouver General Hospital

Vancouver, British Columbia, Canada

Ruijin Hospital

Shanghai, Shanghai Municipality, China

West China Hospital of Sichuan University

Chengdu, Sichuan, China

Odense University Hospital

Odense, , Denmark

Surgical Clinic Of Tartu University Clinics

Tartu, , Estonia

Hopital Pellegrin, C.H.R.de Bordeaux

Bordeaux, , France

Hospital du Bocage

Dijon, , France

CHU de Grenoble

Grenoble, , France

CHU Kremlin Bicêtre

Le Kremlin-Bicêtre, , France

Hopital Calmette

Lille, , France

Hopital Jeanne de Flandres

Lille, , France

Centre Hospitalier Regional Universitaire

Limoges, , France

CHU Hotel Dieu

Nantes, , France

Hopital Necker

Paris, , France

Hopital Tenon

Paris, , France

Centre Hospitalier Lyon Sud

Pierre-Bénite, , France

Hopital Foch

Suresnes, , France

CHU Purpan

Toulouse, , France

CHU Rangueil

Toulouse, , France

CHU de Nancy-Brabois

Vandœuvre-lès-Nancy, , France

Universitatsklinikum Charite

Berlin, , Germany

Stadt Kliniken Koln

Cologne, , Germany

Chirurgische Universitätsklinik

Freiburg im Breisgau, , Germany

Universitatsklinikum Heidelberg

Heidelberg, , Germany

University of Heidelberg

Heidelberg, , Germany

University Hospital Wurzburg

Würzburg, , Germany

Vilnius University Hospital

Vilnius, , Lithuania

Leids Universitair Medisch Centrum

Leiden, , Netherlands

Erasmus Medical Center Rotterdam

Rotterdam, , Netherlands

Rikshopitalet

Oslo, , Norway

Institute of Transplantology, Medical University of Warsaw

Warsaw, , Poland

Children's Memorial Health Institute

Warsaw, , Poland

Hospital Son Dureta

Palma de Mallorca, 07014, Spain

Hospital Infanta Christa

Badajoz, , Spain

Hospital Del Mar

Barcelona, , Spain

Valle de Hebron

Barcelona, , Spain

Hospital Sant Joan de Deu

Barcelona, , Spain

Hospital Reina Sofia

Córdoba, , Spain

Hospital de las Nieves

Granada, , Spain

Hospital Ramon Y Cajal

Madrid, , Spain

Fundacion Jimenez Diaz

Madrid, , Spain

Hospital Clinico San Carlos

Madrid, , Spain

La Paz

Madrid, , Spain

Complejo Hospitalario Univeritario de Santiago

Santiago de Compostela, , Spain

Hospital Virgen del Rocio

Seville, , Spain

Hospital Dr. Peset

Valencia, , Spain

University Hospital, Malmo

Malmo, , Sweden

Karolinska University Hospital, Huddinge

Stockholm, , Sweden

University Hospital A

Uppsala, , Sweden

National Taiwan University Hospital

Taipei, , Taiwan

Royal Free Hospital

London, , United Kingdom

Guys and St Thomas's Hospital

London, , United Kingdom

St George's Hospital

London, , United Kingdom

Hospital "Miguel Perez Carreno"

Caracas, , Venezuela

Hospital Universitario de Caracas

Caracas, , Venezuela

Hospital Universitario de Maracaibo

Maracaibo, , Venezuela

Countries

Australia; Austria; Belgium; Brazil; Canada; China; Denmark; Estonia; France; Germany; Lithuania; Netherlands; Norway; Poland; Spain; Sweden; Taiwan; United Kingdom; Venezuela

References

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.

Reference Type: BACKGROUND

PMID: 10440399 (View on PubMed)

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.

Reference Type: RESULT

PMID: 18946341 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 20670958 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 20124953 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 19494809 (View on PubMed)

Other Identifiers

FDCC

Identifier Type: -

Identifier Source: org_study_id