Sirolimus vs Mycophenolate With Tacrolimus in Simultaneous Pancreas and Kidney Transplantation

Study Overview
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Brief Summary
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This is prospective randomized open single center clinical study to compare effect of sirolimus vs mycophenolate tacrolimus based protocol on pancreas and kidney graft survival in simultaneous pancreas and kidney recipients.

Detailed Description
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MTOR (mammalian target of rapamycin) inhibitors represent group of immunosuppressive drugs with mechanism of T-cell blockade complementary to calcineurin inhibitors. The investigators presume that combination of sirolimus with tacrolimus will result in better survival of pancreatic and kidney grafts in simultaneous pancreas and kidney transplantations. The study is proposed as a single-center extension of EUROSPK 002 trial originally started in 2004 by the EUROSPK Study Group. Recruitment of recipients started in 2004 with approval of EUROSPK 002. The patient recruitment has continued in a single center (Institute for Clinical and Experimental Medicine in Prague, Czech Republic) using the same inclusion and exclusion criteria. The recipients of primary kidney and pancreas transplantation have been randomized into 2 arms. In the intervention arm sirolimus is added to protocol at a dose of 5 mg immediately before transplantation, the dose is adjusted to maintained trough sirolimus trough levels between 5-10ng/ml. In the control arm mycophenolate mofetil was added to tacrolimus. Starting with 1g before transplantation, the dose has been increased to 1g bid afterwards. Induction protocol at day 0. consists of ATG (antithymocyte globulin)induction 8mg/kg , Tacrolimus 0.05mg/kg, Methylprednisolone 125mg. Dosing of tacrolimus has been adjusted to maintain trough levels between 5-10ng/ml. ATG was administered at 3mg/kg on days 1.-3. Steroids have been gradually tapered from a dose of 20 mg prednison orally and withdrawn by 6w after transplantation.

Official Title
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Effect of Sirolimus or Mycophenolate With Tacrolimus on Survival of Pancreas and Kidney Grafts in Type 1 Diabetic Recipients After Simultaneous Pancreas and Kidney Transplantation

Conditions
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Diabetes Mellitus, Type 1

Intervention / Treatment
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* Drug: Sirolimus Oral Product
* Drug: Mycophenolate Mofetil


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 1 diabetes mellitus End stage kidney failure Negative CDC crossmatch Female patients of childbearing age must have a negative pregnancy test Patient must have signed the Patient Informed Consent Form. Patient must receive a primary simultaneous pancreas/kidney (SPK) cadaver transplant, Exclusion Criteria: Patient is pregnant or breastfeeding. Patient is allergic or intolerant to Mycophenolate Mofetil, Sirolimus, ATG, Tacrolimus Patient has malignancy or history of malignancy, with the exception of adequately treated localized squamous cell or basal cell carcinoma, without recurrence. Patient has been included in another clinical trial protocol for any investigational drug within 4 weeks prior to randomization. Patient has any form of substance abuse or psychiatric disorder or condition, which invalidate communication. Severe cardiac failure or severe liver failure diagnosed at the time of transplantation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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 |
| --- | --- |
| Active Comparator: mycophenolate mofetil<br>mycophenolate mofetil dosing 1g before transplantation and 1g bid afterwards | Drug: Mycophenolate Mofetil<br>* Mycophenolate Mofetil dosing 1g before transplantation and 1g bid afterwards<br>* Other names: CellCept;|
| Experimental: Sirolimus<br>Sirolimus oral product Dosing 5mg orally 2-6h before transplantation Target trough levels between 5-10ng/ml | Drug: Sirolimus Oral Product<br>* Oral form of sirolimus, daily dosing to achieve target trough levels between 5-10ng/ml since 1.day of transplantation<br>* Other names: Rapamune;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pancreas graft survival | Number of failed pancreatic grafts, failure is defined as graft removal, death, retransplantation or return to intensified insulin regimen. | 10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recipient survival | Long-term recipient survival evaluated with Kaplan-Meyer method | 10 years | 
| Wound healing time | The number of days from transplantation to date of completely healed wound | 1year | 
| Kidney graft survival | Number of failed kidneys evaluated with Kaplan-Meyer method. Failure defined as return to dialysis, death, retransplantation or graft removal | 10 years |