Calcineurin Inhibitor (CNI) Versus Steroid Cessation in Renal Transplantation

Study Overview
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Brief Summary
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This study intends to determine whether steroid withdrawal or calcineurin inhibitor withdrawal is superior for graft function and graft survival. Secondary endpoints for this study are: incidence of tumors and cardiovascular events. The primary objective: To assess if superior graft function (glomerular filtration rate (GFR) difference of 10 ml/min) will be achieved at 1 year after transplantation in cohorts of de novo kidney transplant patients treated with Myfortic-everolimus plus steroids compared to Myfortic-cyclosporine.

Detailed Description
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Methodology: A 5-year, multicentre, prospective, randomized, open-label, controlled study Group 1: Simulect + cyclosporine + Myfortic + steroid stop at 3 months Group 2: Simulect + cyclosporine (decrease dose in one week at month 3 and replace by everolimus) + Myfortic + steroid maintenance. In both groups MPA AUC monitoring will be done at 5-7 days and at 3 months, to ensure sufficient MPA protection. Sample size calculations: A total of 152 patients will be randomized (76 patients per group) Population: De novo kidney transplant recipients. Study duration: 1.5 years inclusion+ follow-up during the first 5 years

Official Title
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Impact of Cyclosporine or Steroid Withdrawal at 3 Months Post Transplantation on Graft Function, Patient Survival and Cardiovascular Surrogate Markers the First 5 Years After Renal Transplantation.

Conditions
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Renal Transplantation

Intervention / Treatment
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* Drug: cyclosporine
* Drug: Everolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female recipients of a de novo kidney transplant, aged above 18 years Women of childbearing potential must have a negative serum or urine pregnancy test with sensitivity equal to at least 50 mIU/ml Patients must be capable of understanding the purpose and risks of the study, and must sign an informed consent form Exclusion Criteria: Multiple organ transplantation (e.g., Kidney-pancreas, kidney-heart, kidney- liver,...) Transplantation of a patient who got another organ transplant previously Recipients of a HLA-identical living-related renal transplant Patients with PRA > 30%, patients who have lost a first graft from rejection within two years after transplantation, and African European patients. Patients with primary renal disease at risk for recurrence: FSGS, MPGN, HUS Pregnant or lactating women WBC < 2.5 x 109/l (IU), platelet count < 100 x 109/l (IU), or Hb < 6 g/dl at the time of entry into the study Active peptic ulcer Severe diarrhea or other gastrointestinal disorder, which might interfere with their ability to absorb oral medication, including diabetic patients with previously diagnosed diabetic gastroenteropathy Known HIV-1 or HTLV-1 positive tests The use of investigational drugs or other immunosuppressive drugs, as those specified in this protocol Patients receiving bile acid sequestrants Psychological illness or condition, interfering with the patient's compliance or ability to understand the requirements of the study

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cyclosporine<br>Simulect + cyclosporine + Myfortic + steroid stop at 3 months | Drug: cyclosporine<br>* Cyclosporine (Group 1): basiliximab dose: 1x20 mg IV on Day 0 and 1x20 mg IV on Day 4 Cyclosporine: 8 mg/kg PO given before surgery, followed by 2x4 mg/kg/d. C-0h levels: month 1: 150-250 ng/ml; month 2: 100-200 ng/ml; month 3: withdrawal steroids: 100-150 ng/ml. C-2h levels: month 1: 900-1100 ng/ml; month 2: 800-1000 ng/ml; month 3: withdrawal steroids: maintain level of 750 ng/ml Enteric-coated mycophenolate(MPA):720mg PO pre-operatively followed by 1.44 g/day. Steroids: pre-operatively: 250mg methylprednisolone IV; day 1:125mg IV. Methylprednisolone:day 2-30:PO 12mg/d; day 31-60:tapered to 8mg/d ,day 61-90 :4mg/d; Month 3:stop<br>* Other names: Simulect;|
| Active Comparator: Everolimus<br>Simulect + cyclosporine (decrease dose in one week at month 3 and replace by Everolimus (Certican)) + Myfortic + steroid maintenance | Drug: Everolimus<br>* Everolimus (Group 2): Basiliximab dose: idem as in group 1 Cyclosporine: first three months idem group 1; month 3: decreased dose by 50%, simultaneously initiate everolimus at a starting dose of 0.75 mg bid. Once the everolimus blood levels range 6 - 12 ng/ml, cyclosporine will be stopped. Enteric-coated mycophenolate (MPA) dosing idem as group 1. Everolimus starting dose: 0.75 mg bid, trough levels: 6-12 ng/ml. Steroid dosing: idem group 1, but maintained at 4 mg methylprednisolone after day 60.<br>* Other names: Simulect;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess if superior graft function (GFR difference of 10 ml/min) will be achieved at 1 year after transplantation in cohorts of de novo kidney transplant patients treated with Myfortic-everolimus plus steroids compared to Myfortic-cyclosporine. |  | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare the evolution of graft function (estimated GFR by means of modified MDRD formula)during the first 5 years post transplantation. |  | 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal Transplantation, graft function, cardiovascular events, malignancy, cyclosporin, steroids, mycophenolate, everolimus, renal biopsies, pharmacokinetics