Phase IV Study to Evaluate Calcineurin Inhibitor Reduced, Steroid Free Immunosuppression After Renal Transplantation

Study Overview
=================
Brief Summary
-----------------
Current practice of immune suppressive standard therapy after renal transplantation in non-risk patients is a triple therapy consisting of steroids, a calcineurin inhibitor and MMF. The aim of this clinical trial is to combine a reduction of CNI using tacrolimus and a concept of not using steroids in order to establish an immunosuppressive regimen in immunologically non-risk patients that is efficient and causes as few side effects as possible.

Detailed Description
-----------------
In this triple arm, prospectively randomized multi centre phase IV study 200 patients per study arm will be investigated for 12 months. Based on the results of the Symphony study the low dose tacrolimus study arm will be modified to further improve efficacy (prevention of BPAR, best possible renal function) and safety (adverse event profile regarding infections, cardiovascular risk factors, malignant tumours) of immunosuppression. For this, CNI will be reduced and in addition the rate of steroid free patients after 1 week will be maximized to achieve a long lasting improved post surgical cardiovascular risk profile (in particular concerning de novo induction of diabetes mellitus and other adverse events caused by steroids). Safety should be increased without loss of efficacy of immunosuppression (measured in rejection rate and allograft loss rate) as compared to an immune suppressive therapy comprising steroids. Therefore, following the successful study arm of the Symphony study, immunosuppression in the first of the three study arms comprises a steroid in combination with Advagraf and CellCept in addition to a two dose induction therapy with Simulect (group A). The regimen of the second study arm is similar but discontinues steroids on day seven after transplantation (group B). Therapy of group three is similar to group B but Simulect is replaced by T-cell depleting polyclonal antibodies (Thymoglobulin) (group C).

Official Title
-----------------
Triple Arm, Prospectively Randomized Multi Centre Study Phase IV to Evaluate Calcineurin Inhibitor Reduced, Steroid Free Immunosuppression After Renal Transplantation in Non-risk Patients

Conditions
-----------------
Disorder Related to Renal Transplantation

Intervention / Treatment
-----------------
* Drug: Basiliximab, Tacrolimus, MMF, Prednisolon
* Drug: Basiliximab, Tacrolimus, MMF
* Drug: Tacrolimus, MMF, rATG


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Post mortal kidney donation or living donation Primary and secondary renal transplantation, unless the graft was lost due to severe rejection within the first year PRA level ≤ 20%. Recipient ≥ 18 to 75 years of age AB0-compatible Negative crosshatch Patients with a signed informed consent form Women of child-bearing age must agree to an efficient contraception Exclusion Criteria: Third or multiple transplantation Transplantation per a non-heart beating donor HLA-identical living donation Incompatibility to study medication (allergy, intolerance, hypersensitivity) Patients with existing malignant underlying disease or tumour anamnesis < 5 years. Exception: basaloma or squamous cell carcinoma of the skin after successful therapy Female patients who do not use a safe method of contraception Patients with clinically significant, uncontrolled infectious diseases (incl. HIV) and/or severe diarrhoea, emesis, active malabsorption of the upper gastrointestinal tract or active peptic ulcer Patients currently, resp. within the last 30 days, participating in other studies Primary focal-sclerosing glomerulonephritis and membranoproliferative glomerulonephritis as an underlying disease Autoimmune disease as underlying disease (collagen diseases, colitis, HUS, SLE) which might require chronic cortisone therapy Additional disease requiring temporary or chronic cortisone therapy (including inhalation medicine) Chronic hepatitis B and hepatitis C infection Thrombopenia < 70.000/mm3 or leukopenia < 2.500/mm3 or neutropenia < 1500/ mm3. Patients with hepatocirrhosis Child B or C or another severe disease of the liver Patients with symptoms of a significant somatic or psychiatric / mental illness. Patients who are not able to realize nature, relevance and consequences of the clinical trial and who are not able to comply, to cooperate and communicate adequately and to follow the instructions of the study or even to give their informed consent (according to § 40 article 4 and § 41 article 2 and 3 AMG). Patients who possibly depend on the sponsor or the trial physician Patients with signs of drug abuse or alcohol abuse Patients taking additional medicines with known interactions with the immune suppressive substances (MMF and tacrolimus) that preclude an adequate control of the immunosuppression Cold ischemia time of donor kidney > 30 hours Pregnant or nursing patients

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: A<br>Standard: Advagraf, CellCept, Decortin H + 2x Simulect Day 0 + 4 | Drug: Basiliximab, Tacrolimus, MMF, Prednisolon<br>* Control group. Therapy with Prednisolon.<br>* Other names: Decortin;|
| Experimental: B<br>Steroidfree: Advagraf, Cellcept, Decortin H until Day 8, 2x Simulect Day 0 + 4 | Drug: Basiliximab, Tacrolimus, MMF<br>* No Prednisolon after 7 days<br>* Other names: CellCept;|
| Experimental: C<br>Steroidfree: Advagraf, Cellcept, Decortin H until Day 8, 3 x Thymoglobulin | Drug: Tacrolimus, MMF, rATG<br>* Induction therapy: rATG instead of Basiliximab. No Prednisolon.<br>* Other names: Thymoglobulin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of immunosuppression measured in rejection rate confirmed by biopsy according to BANFF 97, modified 2005. |  | one year after transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of patients with steroid-free immunosuppression | Rate of patients with steroid-free immunosuppression |  | 
| patient and graft survival rate | patient and graft survival rate |  | 
| graft function (calculated by the Cock- croft-Gault and MDRD-IV formula respectively calculated creatinine clearance by the Nankivell formula respectively cystatin C measurement) | graft function (calculated by the Cock- croft-Gault and MDRD-IV formula respectively calculated creatinine clearance by the Nankivell formula respectively cystatin C measurement) |  | 
| Number of steroid-resistant rejections | Number of steroid-resistant rejections |  | 
| blood pressure level and also amount and types of blood pressure medications | blood pressure level and also amount and types of blood pressure medications |  | 
| Lipid levels and also amount and types of lipid-lowering medications | Lipid levels and also amount and types of lipid-lowering medications |  | 
| body weight, relative weight gain [kg], BMI | body weight, relative weight gain [kg], BMI |  | 
| infection rate, infection type and infection severity | infection rate, infection type and infection severity |  | 
| anemia requiring erythropoietin treatment | anemia requiring erythropoietin treatment |  | 
| PTLD incidence | PTLD incidence |  | 
| tumor incidence | tumor incidence |  | 
| incidence of diabetes mellitus nd incidence of abnormal fasting blood sugar levels respectively incidence of impaired glucose tolerance, incidence of de novo insulin-requiring or oral-antidiabetic-requiring treatment over ≥30 days | incidence of diabetes mellitus (ADA criteria, venous blood glucose concentration on an empty stomach ≥7.0 mmol/l, pathologic OGTT) and incidence of abnormal fasting blood sugar levels respectively incidence of impaired glucose tolerance, incidence of de novo insulin-requiring or oral-antidiabetic-requiring treatment over ≥30 days | 30 days | 
| incidence of cataracts | incidence of cataracts |  | 
| incidence of avascular necrosis | incidence of avascular necrosis |  | 
| incidence of osteoporosis | incidence of osteoporosis (assessment of fracture rate, osteodensitometry) |  | 
| Wound healing disorders | Wound healing disorders |  | 
| incidence of chronic allograft nephropathy (CAN) (12-month histology) | incidence of chronic allograft nephropathy (CAN) (12-month histology) |  | 
| incidence of CMV disease (qPCR >1000 copies/μL) | incidence of CMV disease (qPCR >1000 copies/μL) |  | 
| incidence of BKV disease (qPCR >1000 copies/μL) | incidence of BKV disease (qPCR >1000 copies/μL) |  | 
| incidence of EBV disease (qPCR >1000 copies/μL) | incidence of EBV disease (qPCR >1000 copies/μL) |  | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Kidney transplant status, Steroid free, Reduced, Calcineurin, Inhibitor, Immunosuppression