A Study To Compare Sirolimus Versus Tacrolimus In De Novo Simultaneous Pancreas- Kidney Allograft Recipients Receiving An Induction Therapy With Antithymocyte Globulin Plus Mycophenolate Mofetil Plus Corticosteroids

An Open-Label, Comparative, Randomized, Prospective Study To Compare Sirolimus Versus Tacrolimus In De Novo Simultaneous Pancreas- Kidney Allograft Recipients Receiving An Induction Therapy With Antithymocyte Globulin Plus Mycophenolate Mofetil Plus Corticosteroids

Experience with tacrolimus in pancreas transplantation has become a standard for immunosuppression in almost all pancreas centers over the world. Several centers have shown very good results in simultaneous pancreas-kidney (SPK) transplant recipients receiving antithymocyte globulin induction and maintenance immunosuppression consisting of calcineurin inhibitor and mycophenolate mofetil with or without corticosteroids.

The use of sirolimus in SPK transplant patients has for the moment only been studied, with good results, in association with tacrolimus or cyclospsorine (CsA). In renal transplantation, there is also evidence that sirolimus (Rapamune) is a potent immunosuppressant that significantly reduces the incidence of acute rejection when given with CsA, effective as base therapy in the post-induction period. Because of Rapamune's effectiveness and different safety profile, it might be advantageous in terms of reduced nephrotoxicity to avoid completely calcineurin inhibitors without increased incidence of acute rejection.

To explore this further, the following study is designed to assess the use of SRL versus TAC, both treatment groups including rATG plus MMF and a 3-month course of steroids in de novo simultaneous pancreas-kidney transplant recipients.

The main objective is to compare renal and pancreas graft survivals at 12 months after simultaneous pancreas-kidney transplantation in patients receiving either a regimen combining sirolimus (SRL) plus mycophenolate mofetil (MMF) following an antibody induction (rATG) or a regimen combining tacrolimus (TAC) plus mycophenolate mofetil following an antibody induction (rATG). In both regimens corticosteroids (CS) will be withdrawn three months after transplantation.

In addition, the two treatment groups will be compared for acute rejection, renal and pancreas functions and patient survival after transplantation at 12 months and for a total period of 5 years of follow-up.

Inclusion Criteria:

• Recipient age ≥ 18 and ≤ 60 years.
• Patients receiving a first cadaveric simultaneous pancreas-kidney transplant for insulin-dependent diabetes associated with end-stage renal disease.
• Women who are of childbearing potential must have a negative serum pregnancy test and agree to use a medically acceptable method of contraception throughout the treatment period and for 3 months following discontinuation.
• Signed and dated informed consent.

Exclusion Criteria:

• Donor age ≤ 15 years and ≥ 60 years.
• Evidence of active systemic or localized major infection.
• Evidence of infiltrate, cavitation, or consolidation on chest x-ray.
• Use of any investigational drug or treatment (in particular immuno-suppressive drugs) up to 4 weeks prior to enrollment to the study and during the 12-month treatment phase.
• History of malignancy (with the exception of adequately treated localized squamous cell or basal cell carcinoma, without recurrence within 5 years of enrolment into the study).
• Graft from a living donor.
• Double renal graft.
• Pregnancy.
• Known hypersensitivity to sirolimus and its derivatives or to tacrolimus.
• Known hypersensitivity to rabbit's proteins.
• Multiple organ transplants or recipients of previously transplanted organs other than kidney.
• Treatment with cisapride (PrépulsidÒ), pimozide (OrapÒ), ketoconazole (NizoralÒ), fluconazole (TriflucanÒ) or millepertuis (ProcalmilÒ, Arkogélules MillepertuisÒ), that is not discontinued within 24 hours prior to transplant.
• Total white blood cell count ≤ 2 x 109/L or platelet count ≤ 70.000/mm3 at baseline.
• Patients with evidence of active histological or biological hepatic disease during the six months period before the transplantation.
• HIV positive recipients.
• Non-heart beating donor.