Steroid Free Immunosuppression or Calcineurin Inhibitor Minimization After Basiliximab Induction Therapy in Kidney Transplantation: Comparison With a Standard Quadruple Immunosuppressive Regimen

Study Overview
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Brief Summary
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A prospective, open, randomized trial, in which the investigators aim to achieve optimal immunosuppression after renal renal transplantation with maximal reduction of side effects, especially of vascular injury, chronic allograft nephropathy, osteoporosis and malignancies. Immunosuppression without steroids and CNI minimization is compared to standard immunosuppression, consisting of tacrolimus OD, mycophenolic acid and corticosteroids.

Detailed Description
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Before transplantation 300 patients will be randomized 1:1:1 in three groups. Group 1 will be treated with basiliximab induction and a three day course of steroids followed by a steroid free maintenance regimen consisting of standard-dose tacrolimus OD and mycophenolic acid. Group 2 will be treated with Basiliximab induction followed by standard-dose tacrolimus OD, mycophenolic acid and steroids. Group 3 will be treated with basiliximab induction followed by standard-dose tacrolimus OD for six months, whereafter the dose will be reduced plus mycophenolic acid and steroids. The total study period will be 2 years. Primary endpoint will be renal function, proteinuria and microalbuminuria measured 24 months after transplantation. Renal function will be measured by serum Creatinine, Creatinine clearances and CKD-EPI. Secondary endpoints will be the degree of tubular atrophy and interstitial fibrosis and the degree of arteriolar hyalinosis in renal biopsies taken at 12 and 24 months after transplantation. Biopsies will be evaluated according to the Banff Criteria for Renal Allograft Biopsy Interpretation. Quantitative morphometric analysis of interstitial fibrous tissue will be performed using the digital image analysis technique. Other secondary endpoints are patient and graft survival, the incidence of allograft rejection, cardiovascular accidents, pulse wave velocity, blood pressure, the number of antihypertensives, lipid profile, the incidence of malignancies, the incidence of infectious complications, the incidence of post transplant diabetes mellitus and the development of osteoporosis.

Official Title
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Steroid Free Immunosuppression or Calcineurin Inhibitor Minimization After Basiliximab Induction Therapy in Kidney Transplantation: Comparison With a Standard Quadruple Immunosuppressive Regimen

Conditions
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Renal Insufficiency, Kidney Transplantation

Intervention / Treatment
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* Drug: tacrolimus OD, mycophenolic acid, prednisolone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: recipient of a kidney graft (first of second) from a deceased or living (non-HLA identical) donor Exclusion Criteria: patients with multi-organ transplants patients who are receiving a third or fourth transplant patients who have > 75% (current of historic) panel reactive antibodies patients receiving a kidney from a HLA identical living donr female patients who are pregnant or unwilling to used adequate contraception during the study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: standard immunosuupression<br>triple maintenance immunosuppression with tacrolimus OD (maintenance 6-10 ng/ml), mycophenolic acid 2 dd 540mg and prednisolone 7.5 mg | Drug: tacrolimus OD, mycophenolic acid, prednisolone<br>* tacrolimus maintenance 6-10 ng/ml, in the low dose tacrolimus group after 6 months fixed dose reduction of 50% tacrolimus through levels will be 3-5 ng/ml mycophenolic acid 2 dd 720mg, after 2 weeks reduced to 2 dd 540 mg in all groups methylprednisolone 500, 250, 125 mg on day 0, 1, and 2 in all groups prednisolone 1 dd 10 mg, and from week 6 prednisolone 7.5 mg in the standard immunosuppression and low dose tacrolimus group No prednisolone will be given the steroid free group<br>* Other names: advagraf, mycophenolic acid;|
| Experimental: steroidfree<br>maintenance immunosuppression with tacrolimus OD (target range 6-10 ng/ml), mycophenolic acid (2 dd 540 mg) | Drug: tacrolimus OD, mycophenolic acid, prednisolone<br>* tacrolimus maintenance 6-10 ng/ml, in the low dose tacrolimus group after 6 months fixed dose reduction of 50% tacrolimus through levels will be 3-5 ng/ml mycophenolic acid 2 dd 720mg, after 2 weeks reduced to 2 dd 540 mg in all groups methylprednisolone 500, 250, 125 mg on day 0, 1, and 2 in all groups prednisolone 1 dd 10 mg, and from week 6 prednisolone 7.5 mg in the standard immunosuppression and low dose tacrolimus group No prednisolone will be given the steroid free group<br>* Other names: advagraf, mycophenolic acid;|
| Experimental: low dose tacrolimus<br>triple maintenance immunosuppression with tacrolimus OD (maintenance 6-10 ng/ml), mycophenolic acid 2 dd 540mg and prednisolone 7.5 mg. After 6 months lowering of tacrolimus OD maintenance 3-5 ng/ml | Drug: tacrolimus OD, mycophenolic acid, prednisolone<br>* tacrolimus maintenance 6-10 ng/ml, in the low dose tacrolimus group after 6 months fixed dose reduction of 50% tacrolimus through levels will be 3-5 ng/ml mycophenolic acid 2 dd 720mg, after 2 weeks reduced to 2 dd 540 mg in all groups methylprednisolone 500, 250, 125 mg on day 0, 1, and 2 in all groups prednisolone 1 dd 10 mg, and from week 6 prednisolone 7.5 mg in the standard immunosuppression and low dose tacrolimus group No prednisolone will be given the steroid free group<br>* Other names: advagraf, mycophenolic acid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| renal function parameters | renal function as measured by serum Creatinine and Creatinine Clearance, CKD-EPI, proteinuria | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| tubular atrophy and interstitial fibrosis | tubular atrophy and interstitial fibrosis in renal biopsies | 24 months | 
| rejection episodes | number of treated biopsy proven acute rejection episodes (as scored by pathologist via Banff classification) | two years | 
| graft and patient survival | graft and patient survival | two years | 
| myocardial infarctions | number of myocardial infarctions | two years | 
| cerebrovascular accidents | number of cerebrovascular accidents | two years | 
| number of participants with infectious complications | bacterial and viral infections as measured by culture (bacterial infections) or PCR (viral infections) | two years | 
| number of participants with osteoporosis | as established by dexa bone densitometry | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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kidney transplantation, immunosuppression, steroids, tacrolimus OD