Clinical trial NCT00166244: Fixed Dose MMF vs Concentration Controlled MMF After Renal Transplantation
Official title: An Open, Prospective, Randomised, Controlled, Multi-Center Study Comparing Fixed Dose vs Concentration Controlled Mycophenolate Mofetil Regimens for de Novo Patients Following Transplantation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: De Novo Renal Transplant Recipient.
Keywords: Mycophenolate mofetil
Therapeutic Drug Monitoring
Adult kidney transplantation
Paediatric kidney transplantation
Lead sponsor: Erasmus Medical Center
Sponsor class: OTHER
Collaborators: name: Hoffmann-La Roche
First posted: 2005-09-14
Enrollment: 901
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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).

Primary outcomes:
measure: 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.
timeFrame: 12 Months
Secondary outcomes:
measure: Proportion of patients treated for acute rejection during the first 3, 6, 12 months post-transplantation,
timeFrame: 3, 6 and 12 Months
measure: Time to first acute rejection,
timeFrame: 12 Months
measure: Number of acute rejection episodes per patient in the first year post-transplantation,
timeFrame: 12 Months
measure: Overall treatment outcome at 12 months post-transplantation which is composed of any one of the following:
timeFrame: 12 Months
measure: Graft loss,
timeFrame: 12 Months
measure: Death,
timeFrame: 12 Months
measure: Discontinuation of MMF therapy,
timeFrame: 12 Months
measure: Patient lost to follow-up.
timeFrame: 12 Months
Other outcomes:
Locations:
city: New Lambton
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: Brisbane
country: Australia
facility: Princess Alexandra Hospital
state: Queensland
city: Clayton
country: Australia
facility: Monash Medical Centre
state: Victoria
city: Melbourne
country: Australia
facility: St Vincent's Hospital
state: Victoria
city: Parkville
country: Australia
facility: Royal Melbourne Hospital
state: Victoria
city: Nedlands
country: Australia
facility: Sir Charles Gairdner Hospital
state: Western Australia
city: Perth
country: Australia
facility: Royal Perth Hospital
state: Western Australia
city: Graz
country: Austria
facility: Med. Univ. Klinik
city: Vienna
country: Austria
facility: AKH Wien
city: Leuven
country: Belgium
facility: University Hospitals Leuven
city: Sao Paulo
country: Brazil
facility: Hospital do Rim e Hipertensao
city: Vancouver
country: Canada
facility: Vancouver General Hospital
state: British Columbia
city: Shanghai
country: China
facility: Ruijin Hospital
state: Shanghai
city: Chengdu
country: China
facility: West China Hospital of Sichuan University
state: Sichuan
city: Odense
country: Denmark
facility: Odense University Hospital
city: Tartu
country: Estonia
facility: Surgical Clinic Of Tartu University Clinics
city: Bordeaux
country: France
facility: Hopital Pellegrin, C.H.R.de Bordeaux
city: Dijon
country: France
facility: Hospital du Bocage
city: Grenoble
country: France
facility: CHU de Grenoble
city: Kremlin Bicêtre
country: France
facility: CHU Kremlin Bicêtre
city: Lille
country: France
facility: Hopital Calmette
city: Lille
country: France
facility: Hopital Jeanne de Flandres
city: Limoges
country: France
facility: Centre Hospitalier Regional Universitaire
city: Nantes
country: France
facility: CHU Hotel Dieu
city: Paris
country: France
facility: Hopital Necker
city: Paris
country: France
facility: Hopital Tenon
city: Pierre Benite
country: France
facility: Centre Hospitalier Lyon Sud
city: Suresnes
country: France
facility: Hopital Foch
city: Toulouse
country: France
facility: CHU Purpan
city: Toulouse
country: France
facility: CHU Rangueil
city: Vandoeuvre-les-Nancy
country: France
facility: CHU de Nancy-Brabois
city: Berlin
country: Germany
facility: Universitatsklinikum Charite
city: Freiburg
country: Germany
facility: Chirurgische Universitätsklinik
city: Heidelberg
country: Germany
facility: Universitatsklinikum Heidelberg
city: Heidelberg
country: Germany
facility: University of Heidelberg
city: Koln
country: Germany
facility: Stadt Kliniken Koln
city: Wurzburg
country: Germany
facility: University Hospital Wurzburg
city: Vilnius
country: Lithuania
facility: Vilnius University Hospital
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center Rotterdam
city: Oslo
country: Norway
facility: Rikshopitalet
city: Warsaw
country: Poland
facility: Institute of Transplantology, Medical University of Warsaw
city: Warsaw
country: Poland
facility: Children's Memorial Health Institute
city: Palma De Mallorca
country: Spain
facility: Hospital Son Dureta
state: 07014
city: Badajoz
country: Spain
facility: Hospital Infanta Christa
city: Barcelona
country: Spain
facility: Hospital Del Mar
city: Barcelona
country: Spain
facility: Valle de Hebron
city: Barcelona
country: Spain
facility: Hospital Sant Joan de Deu
city: Cordoba
country: Spain
facility: Hospital Reina Sofia
city: Granada
country: Spain
facility: Hospital de las Nieves
city: Madrid
country: Spain
facility: Hospital Ramon Y Cajal
city: Madrid
country: Spain
facility: Fundacion Jimenez Diaz
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos
city: Madrid
country: Spain
facility: La Paz
city: Santiago De Compostela
country: Spain
facility: Complejo Hospitalario Univeritario de Santiago
city: Sevilla
country: Spain
facility: Hospital Virgen del Rocio
city: Valencia
country: Spain
facility: Hospital Dr. Peset
city: Malmo
country: Sweden
facility: University Hospital, Malmo
city: Stockholm
country: Sweden
facility: Karolinska University Hospital, Huddinge
city: Uppsala
country: Sweden
facility: University Hospital A
city: Taipei
country: Taiwan
facility: National Taiwan University Hospital
city: London
country: United Kingdom
facility: Royal Free Hospital
city: London
country: United Kingdom
facility: Guys and St Thomas's Hospital
city: London
country: United Kingdom
facility: St George's Hospital
city: Caracas
country: Venezuela
facility: Hospital "Miguel Perez Carreno"
city: Caracas
country: Venezuela
facility: Hospital Universitario de Caracas
city: Maracaibo
country: Venezuela
facility: Hospital Universitario de Maracaibo
Study officials:
affiliation: Erasmus Medical Center
name: Teun van Gelder, Dr
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.