The main objective of the study is to demonstrate the utility and safety of the IFN-γ (Interferon Gamma) ELISPOT (Enzyme-linked immunosorbent spot) marker for the stratification of kidney transplant recipients into low and high IS (Immunosuppression) regimens. The enrichment study will test non-inferiority of low IS regimen compared to high IS regimen, assuming 10% of BPAR at 6-months in the control group, and allowing a non-inferiority limit of maximum 10%.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
184
Tacrolimus (for Group B) will be administered orally twice a day (bid). Tacrolimus (for Group B) will be initially given at the 0,1mg/kg bid to achieve a stable 12-hour trough level of 8-10 ng/mL during the first month after transplantation to progressively tapper to 6-8ng/ml thereafter.
MMF (mycophenolate mofetil) will be administered orally to patients in group B at conventional doses (1gr/12h) before transplant procedure and during the first 7 days after transplant. For subjects who develop nausea, diarrhea, or other MMF(mycophenolate mofetil) -related gastrointestinal adverse effects (eg, symptoms fully assessed and deemed not to have an etiology other than intolerability to MMF), the MMF(mycophenolate mofetil) dose may be decreased to the maximally tolerated dose. Subjects unable to tolerate the reduced dose may be converted to mycophenolate sodium (Myfortic™) or to Myfenax. From day 8 on, patients will not receive MMF.
Institut klinické a experimentální mediciny
Prague, Prague 4, Czechia
Centre Hospitalier Universitaire de Nantes
Nantes, France
Department Nephrology and BCRT, Charité Universitätsmedizin Berlin
Berlin, Germany
Universitätsklinikum Hamburg-Eppendorf
assessment of anti-donor T-cell alloresponses using the IFN-γ ELISPOT test
Patients with a positive anti-donor IFN-γ ELISPOT assay result (\>25 spots/300.000 PBMC (peripheral blood mononuclear cells )) will be ruled out of the study and patients with negative anti-donor IFN-γ ELISPOT test (\<25 spots/300.000 PBMC) will be randomized in 2 different groups (1:1). The main objective of the study is to demonstrate the utility and safety of the IFN-γ ELISPOT marker for the stratification of kidney transplant recipients into low and high IS regimens.
Time frame: 6 months
Differences across Treatment arms in eGFR (estimated glomerular Filtration rate) (ml/min)
Time frame: after 3, 6 and 12 months
Differences across Treatment arms in Biopsy proven acute rejection rate (BPAR rate)
Time frame: after 6 and 12 months
Differences across Treatment arms in subclinical rejection rate using renal allograft biopsy
Time frame: after 3 and 12 months
Differences across Treatment arms in Prevalence of death, and graft loss
Time frame: after 6 and 12 months
Differences across Treatment arms in Prevalence of metabolic and cardiovascular co-morbidity (new onset diabetes mellitus (NODAT, dyslipidaemias, hypertension)
Time frame: 12 months
Differences across Treatment arms in Prevalence of subjects that remain MMF and steroid-free
Time frame: after 6 and 12 months
Differences across Treatment arms in Prevalence of Acute and chronic histologic lesions assessed by the Bannf'11 score in protocol biopsies
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At the time of surgery, all patients will receive 500mg of 6-methyl prednisolone (Steroids, Urbason, Methypred). Patients in group B will receive 250mg of 6-methyl prednisolone (or equivalent) on day 2, 125 mg on day 3, 60 mg on day 4 and 30 mg on day 5. From day 6 on, patients will receive 0.25 mg/kg/d of 6-methyl-prednisolone (Steroids, Urbason, Methypred) until month 1, then tapering until discontinuation on month 2 will be performed.
The study group A will receive Tacrolimus (for Group A) (Prograf) to achieve 4-8 ng/ml trough levels during all the duration of the study. Tacrolimus (for Group A) (Tacrolimus) capsules should generally be administered on an empty stomach or at least 1 hour before or 2 to 3 hours after a meal, to achieve maximal absorption.
Mycophenolate mofetil (MMF) (Cellcept, Myfortic, Myfenax) (for Group A) will be administered orally to patients in group A at conventional doses (1gr/12h). For subjects who develop nausea, diarrhea, or other Mycophenolate mofetil (MMF) (for Group A) -related gastrointestinal adverse effects (eg, symptoms fully assessed and deemed not to have an etiology other than intolerability to Mycophenolate mofetil (MMF) (for Group A), the Mycophenolate mofetil (MMF) (for Group A) dose may be decreased to the maximally tolerated dose. Subjects unable to tolerate the reduced dose may be converted to mycophenolate sodium (Myfortic™). The first dose of Mycophenolate mofetil (MMF) (for Group A) should be administered before transplantation.
At the time of surgery, all patients will receive 500 mg of 6-methyl prednisolone (steroids for Group A). Patients in arm A will receive 20 mg/day of 6-methyl prednisolone (steroids for Group A) (or the equivalent) during the first 2 weeks after transplantation, then tapering to 15 mg from week 3 to week 4 to finally be maintained at 5mg/day.
Hamburg, Germany
Universitätsklinikum Regensburg
Regensburg, Germany
Academisch Medisch Centrum bij de Universiteit van Amsterdam
Amsterdam, Netherlands
Hospital Universitari de Bellvitge
L'Hospitalet de Llobregat, Barcelona, Spain
Guy's Hospital, Great Maze Pond
London, United Kingdom
Time frame: after 3 and 12 months
Differences across Treatment arms in Prevalence of patients that remain on Therapy
Time frame: after 12 months
Differences across Treatment arms in Distribution of patients in distinct chronic kidney diseases (CKD) stages
Time frame: after 12 months
Differences across Treatment arms in treatment cost (cost/benefit)
Time frame: after 1,3,6,12 and 24 months
Differences across Treatment arms in development of a Panel reactive T (PRT)-cell response platform to evaluate general anti-HLA T-cell Responses using ELISPOT
Time frame: at pre-transplantation, 3, 6 and 12 months after transplantation as well as at time of BPAR
Differences across Treatment arms in assessment of anti-donor and anti-HLA antibodies by Solid phase assays (Luminex®) and B-cell ELISPOT
Time frame: at pre-transplantation, 3, 6 and 12 months after transplantation as well as at time of BPAR
Differences across Treatment arms in different viral load (CMV, EBV, BKV)
Time frame: at months 1, 2, 3, 6 and 12 after transplantation
Differences across Treatment arms in study of virus-specific T-cell responses (ELISPOT)
Time frame: at at pre-transplantation, 3, 6 and 12 after transplantation
Differences across Treatment arms in prevalence of transcriptional genes by RT-PCR in PBMC (peripheral blood mononuclear cells )
Time frame: at pre-transplantation and months 1, 3, 6 and 12 after transplantation as well as at time of BPAR
Differences across Treatment arms in flow cytometry assessment of peripheral blood mononuclear cells (PBMC)
Time frame: at pre-transplantation and months 1, 3, 6 and 12 after transplantation as well as at time of BPAR
Differences across Treatment arms in Quantitative analyses of urinary IP-10 (Interferon Gamma induced Protein)
Time frame: at 4 weeks and at 3, 6 and 12 month after transplantation as well as at time of BPAR
Differences across Treatment arms in Assessment of protocol biopsies
Time frame: at month 3 and 12 after transplantation
Differences across Treatment arms in MicroRNA assessment in sera and urine
Time frame: at pre-transplantation and months 1, 3, 6 and 12 after transplantation
Differences across Treatment arms in evaluation of FOXP3 (Forkhead box P3) methylation degree at the TSDR (Treg-specific demethylated Region)
Time frame: at pre-transplantation and months 1, 3, 6 and 12 after transplantation as well as at time of rejection