Optimum Immunosuppression in Renal Transplant Recipients.New Onset Diabetes After Transplantation

Study Overview
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Brief Summary
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New onset diabetes after renal transplantation (NODAT) is a common and severe complication negatively influencing graft and patient survival. Cyclosporine (CsA) and Tacrolimus are the basis of modern immunosuppression. Tacrolimus is superior to CsA in terms of acute rejection and graft function. However, Tacrolimus increases 2 times the risk of NODAT as compared to CsA.

Detailed Description
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New onset diabetes after renal transplantation (NODAT) is a common and severe complication negatively influencing graft and patient survival. CsA and Tacrolimus are the basis of modern immunosuppression. Tacrolimus is superior to CsA in terms of acute rejection and graft function. However, increases 2 times the risk of NODAT as compared to CsA. Objectives: a) To compare the incidence of NODAT and glucose intolerance with 3 different regimes: Tacrolimus with rapid steroid withdrawal; Tacrolimus with steroids minimization; and CsA with steroid minimization; b) To compare acute rejection rate, renal function and graft and patient survival between different regimes; and c) to investigate the influence of different regimes on subclinical atheromatosis. A total of 210 patients will be randomized. The primary efficacy variable will be NODAT or glucose intolerance at 1 year; secondary efficacy variables will be acute rejection, renal function, and changes of carotid intima-media thickness over time.

Official Title
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Optimum Immunosuppression in Renal Transplant Recipients at High Risk of Developing New Onset Diabetes After Transplantation: A Multicenter, Prospective, Controlled and Randomized Trial.

Conditions
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Diabetes Mellitus, Adult-Onset

Intervention / Treatment
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* Drug: Tacrolimus with rapid steroid withdrawal
* Drug: Tacrolimus with steroids minimization
* Drug: CsA with steroid minimization


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Primary renal transplant recipients with end stage renal disease No prior history of diabetes mellitus before transplant Absence of Immunologic risk defined by the investigator criterion and Panel Reactive Antibody (PRA) < 50% Absence of severe infection and hepatitis C or B infection Efficient contraception in women during the study Additionally must meet one of these Metabolic Criteria Recipient age >or =60 or Recipient age between 45 and 59 years and at least one of the following metabolic criteria: Prior to transplantation Triglycerides (TGS) >200mg/dl or the combination of a body mass index (BMI)> 27 and Triglycerides>150 mg/dl or the combination of HDL-cholesterol<40 mg/dl for men or <50 mg/dl for women and Triglycerides >150 mg/dl. Exclusion Criteria: Patients with type I or II diabetes prior to transplantation defined by the American Diabetes Association (ADA) criteria Recipient age under 45 Patients receiving a second renal transplant Patients with high immunological risk or PRA (panel reactive antibody level) >or =50% Severe infection or hepatitis C or B infection. Dual renal transplant or double transplant with any other organ.

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tacrolimus with rapid steroid withdrawal<br>Basiliximab induction. Tacrolimus plus Mycophenolate mofetil (MMF), and corticosteroids with rapid withdrawal after one week. | Drug: Tacrolimus with rapid steroid withdrawal<br>* Basiliximab induction (4 mg i.v., days 0 and 4). Corticosteroids: 0.5 gr of i.v. Methylprednisolone (MP) intraoperatively and 125 mg on the first day, followed by oral doses of prednisone rapidly tapered from 30 mg/day to complete discontinuation by postoperative day 7. Tacrolimus: 0.15 mg/Kg/day to achieve target trough levels of 8-12 ng/ml for the first month and then 5-8 ng/ml. Mycophenolate mofetil 1 gr b.i.d. for the first month and then 500 mg b.i.d.<br>* Other names: Simulect; Dacortin; Prograf/Advagraf; Cellcept/Myfortic.;|
| Active Comparator: Tacrolimus with steroids minimization<br>Basiliximab induction.Tacrolimus plus Mycophenolate mofetil (MMF) and low-dose corticosteroids for 6 months with subsequent removal | Drug: Tacrolimus with steroids minimization<br>* Basiliximab induction (4 mg i.v., days 0 an 4) Corticosteroids: 0.5 gr of i.v. MP intraoperatively and 60 mg on the first day, followed by oral doses of prednisone starting with 0.3 mg/Kg/day, and gradual weekly tapering to complete discontinuation over 6 months. Tacrolimus 0.15 mg/Kg/day to achieve target trough levels of 8-12 ng/ml for the first month and then 5-8 ng/ml. Mycophenolate mofetil 1 gr b.i.d. for the first month and then 500 mg b.i.d.<br>* Other names: Simulect; Dacortin; Prograf/Advagraf; Cellcept/Myfortic.;|
| Experimental: CsA with steroid minimization<br>Basiliximab induction. Ciclosporin A (CsA) plus Mycophenolate mofetil (MMF) and low-dose corticosteroids for 6 months with subsequent removal | Drug: CsA with steroid minimization<br>* Basiliximab induction (4 mg i.v., days 0 an 4) Corticosteroids: 0.5 gr of i.v. MP intraoperatively and 60 mg on the first day, followed by oral doses of prednisone starting with 0.3 mg/Kg/day, and gradual weekly tapering to complete discontinuation over 6 months. CsA 5 mg/Kg/day to achieve target trough of 150-200 ng/ml the first month and then 100-150 ng/ml. Mycophenolate mofetil 1 gr b.i.d<br>* Other names: Simulect; Dacortin; Sandimmun Neoral; Cellcept/Myfortic.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Outcome Measure New Onset Diabetes After Renal Transplantation (NODAT) | American Diabetes Association criteria (ADA) including an oral glucose tolerance test. | 1 year | 
| Patients Treated With Insulin or Oral Antidiabetic Drugs |  | 1 year | 
| Primary Outcome Measure (Glucose Intolerance) | Glycemia >=140 and <200 mg/dl, 2 hours after a standard oral glucose tolerance test. Measured values: glucose intolerance at 1 year defined by ADA criteria. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rejection | Biopsy proven acute rejection. Measured variable: Rate of Biopsy proven acute rejection. | 1 year | 
| Renal Function | Estimated Glomerular Filtration Rate (ml/min/1.73 m^2) | 1 year | 
| Proteinuria |  | 1 year | 
| Blood Pressure | Systolic pressure (mmHg) | 1 year | 
| Blood Pressure | Diastolic pressure (mmHg) | 1 year | 
| Number of Antihypertensive Drugs Patients Reported Taking. |  | 1 year | 
| Lipidic Profile (Triglycerides) |  | 1 year | 
| Lipidic Profile (Cholesterol) | Lipidic Profile (total cholesterol) | 1 year | 
| Lipidic Profile (HDL-c) |  | 1 year | 
| Lipidic Profile (LDL-c) |  | 1 year | 
| Percentage of Patients Using Statins |  | 1 year | 
| Changes of Carotid Intima-media Thickness Over Time | absolute difference between carotid intima-media thickness at study end versus baseline. | 1 year | 
| Percentage of Patients Using Acetylsalicylic Acid (ASA) |  | 1 year |