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

• Efficacy of immunosuppression measured in rejection rate confirmed by biopsy according to BANFF 97, modified 2005. [ Time Frame: one year after transplantation ] [ Designated as safety issue: No ]
  

• Rate of patients with steroid-free immunosuppression [ Designated as safety issue: No ]
  Rate of patients with steroid-free immunosuppression
  
  
• patient and graft survival rate [ Designated as safety issue: No ]
  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 [ Time Frame: 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
  
  
• 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)
  
  

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).