Improving Secretion of Insulin in New Onset Diabetes After Renal Transplantation

Study Overview
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Brief Summary
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New onset diabetes after transplantation (NODAT) is a frequent and feared complication after kidney transplantation and leads to an increase in cardiovascular complications as well as in the rate of graft loss. Very little data exist on how patients in which NODAT has been diagnosed should be treated. It is suspected that Cylosporine A (Sandimmun, TM) is less diabetogenic than Tacrolimus (Prograf, TM). Furthermore, it has been described that early initiation of insulin treatment in Diabetes mellitus type 2 can preserve and improve the function of the insulin secreting cells in the pancreas. Therefore, the investigators test the effects of conversion from Tacrolimus to Cyclosporine A in patients with newly diagnosed NODAT who have just started early treatment with insulin. The hypothesis is that patients who are treated with insulin and who are switched to Cyclosporine A have improved glucose metabolism compared to patients who are treated with insulin and who remain on Tacrolimus therapy.

Official Title
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A Randomized, Prospective Trial to Evaluate the Effect of Conversion From Tacrolimus to Cyclosporine A After Early Initiation of Insulin Therapy in Patients With New-onset Diabetes Mellitus After Kidney Transplantation

Conditions
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New Onset Diabetes Mellitus After Renal Transplantation

Intervention / Treatment
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* Drug: Cyclosporine A
* Drug: Tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Newly diagnosed NODAT defined by pathologic OGTT (2h, 75mg glucose): glucose ≥ 200mg/dl Defect in insulin secretion as judged by OGTT and HOMA B Renal transplantation (deceased or living donor) and treatment with the standard immunosuppression at our center, consisting of tacrolimus, mycophenolate mofetil, prednisone triple therapy without any induction stable graft function for more than 3 months post transplant informed consent of the patient Exclusion Criteria: patients with prior history of type 1 or type 2 diabetes time since transplantation more than 20 years allergy against long-acting insulin or cyclosporine A body mass index (BMI) > 35 pregnancy

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 |
| --- | --- |
| Experimental: Cyclosporine A<br>Patients in this arm will be switched from immunosuppressive therapy with Tacrolimus to Cyclosporine A. Furthermore, patients in this arm will commence insulin treatment with NPH-insulin to reach normoglycemia. After the achievement of normoglycemia the insulin treatment will be continued for three more weeks and than terminated. | Drug: Cyclosporine A<br>* Patients randomized into arm A will be switched from Tacrolimus to Cyclosporine A. Conversion will be done by a stop and go protocol. Patients will take their last dose Tacrolimus in the morning of the day of conversion and will start taking Cyclosporine A in the evening of the same day at a dose of 3mg/kg/d. The first measurement of Cyclosporine A trough levels will be performed 3 days after conversion and the dose will then be adjusted if necessary. Furthermore, treatment with NPH insulin once daily in the morning will be initiated.<br>|
| Active Comparator: Tacrolimus<br>Patients in this arm will remain on their immunosuppressive therapy with Tacrolimus. Furthermore, patients in this arm will commence insulin treatment with NPH-insulin to reach normoglycemia. After the achievement of normoglycemia the insulin treatment will be continued for three more weeks and than terminated. | Drug: Tacrolimus<br>* Patients in arm B will remain on their immunosuppressive therapy with Tacrolimus. Furthermore, treatment with NPH insulin once daily in the morning will be initiated.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 90 days OGTT | The primary endpoint will be the difference in the 2h glucose value obtained from an oral glucose tolerance test (OGTT) after 90 days compared to baseline. | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Beta cell function | One secondary endpoint is the change in beta cell function after 90 days compared to baseline as determined by a frequent sampling oral glucose glucose tolerance test. | 90 and 180 days | 
| Graft rejection | The rate of episodes of acute allograft rejection will be compared between the two treatment arms. | whole study period | 
| Hypoglycemia | The rate of clinically relevant hypoglycemic episodes will be desribed. | whole study period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NODAT, kidney transplantation, beta cell function, insulin, Tacrolimus, Cyclosporine A