Trial of Steroid Avoidance and Low-dose CNI by ATG-induction in Renal Transplantation

Study Overview
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Brief Summary
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Balancing immunosuppressive treatment in organ transplantation in order to achieve effective prevention of rejection on one side and avoidance of negative side effects on the other side is a major challenge, leading to developing different immunosuppressive protocols. Cornerstones of immunosuppressive treatment such as Corticosteroids (CS) and Calcineurin Inhibitors (CNI) are known to cause an increased incidence of diabetes, cardiovascular morbidity, nephrotoxicity and malignancies. The investigators believe that both avoidance of CS and minimization of CNI, while using Anti-ThymocyteGlobuline(ATG) induction (instead of interleucin-2 receptor blockers) and mycofenolate mofetil(MMF) therapeutic drug monitoring is going to reduce negative side effects, without increased rejection frequency in renal transplanted patients.

Official Title
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A Controlled Randomized, Open-label, Multi-centre Study Evaluating if a Steroid-free Immunosuppressive Protocol, Based ATG-induction, Low Tacrolimus-dose and Therapeutic Drug Monitoring of Mycophenolate Mofetil, Reduces the Incidence of New Onset Diabetes After Transplantations, in Comparison With Standard Steroid-based Protocol With Low-dose Tacrolimus.

Conditions
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Diabetes Mellitus

Intervention / Treatment
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* Drug: Steroid-free low TAC-arm: Thymoglobulin Standard low-TAC arm: Simulect, prednisolon


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: First or second single kidney (cadaveric or living donors) transplant recipients. Considered for a standard immunosuppressive protocol. Must be capable of giving written informed connect for participation in the study for 24 months. Exclusion Criteria: Diabetes mellitus or plasma glucose >11,1 at admission. Receiving steroids at the time of transplantation or likely to need steroids after transplantation. Multiorgan transplants and/or previously transplanted with any other organ than kidney. Panel reacting antibodies(PRA) >25% in most recent test or considered to be of high risk for rejection which requires an enhanced immunosuppression. Renal transplants from HLA-identical sibling. Hypersensitivity to, or disability to take immunosuppressive drugs. Blood group(ABO)-incompatible transplants. Unlikely to comply with the study requirements. Transplant from donor positive for HIV, HBsAg, Hepatitis C. Female of childbearing potential planing/being pregnant or unwilling to use contraception.

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 |
| --- | --- |
| Experimental: Steroid-free low TAC-arm<br>Induction therapy: Thymoglobulin i.v. 2,5 mg/kg day 0 and 1, preceded by methylprednisolone i.v. 250 mg day 0 and 50 mg day 1. Maintenance therapy: Advagraf(TAC) 0,2 mg/kg p.o. started day1 (target concentration 5-10 ng/ml, after 3 months 4-7 ng/ml; MMF 1g x 2 p.o. (target Area Under Curve, AUC 40-60 mg.h/L); No steroids p.o. | Drug: Steroid-free low TAC-arm: Thymoglobulin Standard low-TAC arm: Simulect, prednisolon<br> <br> |
| Active Comparator: Standard low-TAC arm<br>Induction therapy: Simulect i.v. 20 mg day 0 and 4; Steroids i.v. according to local practice. Maintenance therapy: Advagraf(TAC) p.o. 0,2 mg/(target concentration 5-10 ng/ml, after 3 months 4-7 ng/ml); MMF 1g x 2 p.o. (target AUC 40-60 mg.h/L); Steroids p.o. according to hospital practice (but not less than 5mg daily after 6 months). | Drug: Steroid-free low TAC-arm: Thymoglobulin Standard low-TAC arm: Simulect, prednisolon<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence of New Onset of Diabetes After Transplantation(NODAT) |  | 12 month after transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative incidence of NODAT |  | 3, 6, 24 month after transplantation | 
| Composite measure | Freedom from acute rejection, graft and patient survival | 12, 24 months | 
| Renal function | Evaluated by measured glomerular filtration rate (mGFR) | 12, 24 months | 
| Incidence of acute rejection and chronic changes | Analysed by protocol biopsies, evaluated by the Banff system. | 12 months | 
| Incidence of hypertension | Standardized measurement. | 3, 12, 24 months | 
| Antihypertensive treatment | Number and type of antihypertensive drugs. | 3, 12, 24 months | 
| Lipid lowering drugs | Number and type of lipid lowering drugs. | 12, 24 months | 
| Incidence of antibody-mediated rejection | Analysed by biopsies, evaluated by the Banff system, and by donor-specific HLA antibodies | 12, 24 months | 
| Cumulative frequency of cardiovascular complications and events. | Collecting Adverse Events (AE) reports | 10 days, 3, 12, 24 months | 
| Cumulative frequency of malignancy. | Collecting AE reports | 6, 12, 24 months | 
| Cumulative frequency of infections | Collecting AE reports | 10 days, 3, 6, 12, 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal transplantation, Corticosteroids avoidance, CNI minimization, NODAT