Study to Compare the Safety and Efficacy of Sirolimus (Rapamune) to Tacrolimus (Advagraf) Associated to Mycophenolate Mofetil (CellCept) Between 12 and 36 Months After Kidney Transplantation

Study Overview
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Brief Summary
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The use of tacrolimus in the long term as part of the immunosuppressive regimen after transplantation is associated to complications such as chronic nephrotoxicity, impaired glucose metabolism (diabetes mellitus) and an increase of the incidence of neoplasia. The conversion from a tacrolimus based therapy to a sirolimus based therapy associated with mycophenolate mofetil could improve the incidence of such complications. The aim of this study is to assess the risk/benefit ratio of this switch performed in stable renal transplant recipient between 12 months and 36 months after transplantation. The incidence of a composite endpoint (worsening of GFR evaluated by MDRD formula, incidence of cancer and diabetes) will be assessed 24 months after conversion.

Detailed Description
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Two doses of Sirolimus will be evaluated accorded to the CYP 3A5 genotype. Patients carrying at least CYP 3A5 *1 allele will receive 4 mg per day whereas the others (CYP 3A5 *3/*3) will receive 2 mg.

Official Title
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A Prospective, Comparative, Multicenter, Randomized Study to Compare the Safety and Efficacy of Sirolimus (Rapamune) to Tacrolimus (Advagraf) Associated to Mycophenolate Mofetil (CellCept) Between 12 and 36 Months After Kidney Transplantation

Conditions
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Kidney Transplantation

Intervention / Treatment
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* Drug: Sirolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Recipient age ≥18 and ≤ 75 ans. Patients having received a first or second renal transplant from a cadaveric or living related donor between 12 and 24 months prior the inclusion. Peak panel reactive antibody (PRA) < 30 % Patients with a stable renal function during the 3 months prior to inclusion (variation of serum creatinine lower than 20 %) Creatinine clearance ≥ 40 ml/mn/1.73 m26. Patients receiving as a stable immunosuppressive treatment associating: Mycophenolate mofetil (MPA AUC > 30 mg.h/L) and Tacrolimus with a trough level > 4 ng/ml, with or without corticoids Exclusion Criteria: Multiorgan recipients Patients receiving cyclosporine Pregnancy Recipients of ABO incompatible graft Use of other immunosuppressive drugs. Historical peak reactive antibody ≥ 30 % Past medical history of humoral rejection, 2 episodes of acute cellular rejection Past medical history of sub-clinical rejection on routine allograft biopsy Calculated creatinine clearance < 40 ml/mn/1.73 m2 24h proteinuria > 1 g/24H Patients with severe diarrhea HTLV1 or HIV positivity Known hypersensitivity to tacrolimus, mycophenolate mofetil, or sirolimus. Total white blood cells < 2500/mm3 or hemoglobin < 9 g/dl

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 76 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: Sirolimus<br>Group A : Sirolimus introduction and tacrolimus withdrawal Tacrolimus : 33 % decrease of daily dose with complete withdrawal at day 14. Sirolimus daily dose according to CYP3A5 genotype CYP3A5*1/*1 or *1/*3: 4 mg/d CYPY3A5*3/*3 : sirolimus 2 mg/j Adjusted to obtain a trough level between 6 and10 ng/ml | Drug: Sirolimus<br>* Sirolimus introduction and tacrolimus withdrawal Tacrolimus : 33 % decrease of daily dose with complete withdrawal at day 14. Sirolimus daily dose according to CYP3A5 genotype CYP3A5*1/*1 or *1/*3: 4 mg/d CYPY3A5*3/*3 : sirolimus 2 mg/j Adjusted to obtain a trough level between 6 and10 ng/ml<br>|
| Active Comparator: B<br>Tacrolimus (Advagraf) dose to obtain a trough level between 4 and 10 ng/ml | Drug: Sirolimus<br>* Sirolimus introduction and tacrolimus withdrawal Tacrolimus : 33 % decrease of daily dose with complete withdrawal at day 14. Sirolimus daily dose according to CYP3A5 genotype CYP3A5*1/*1 or *1/*3: 4 mg/d CYPY3A5*3/*3 : sirolimus 2 mg/j Adjusted to obtain a trough level between 6 and10 ng/ml<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of a composite endpoint (worsening of GFR estimated with MDRD formula, incidence of cancer and incidence of post-transplant diabetes mellitus) will be assessed 24 months after conversion. |  | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| *Renal function by calculated creatinine clearance* Incidence of biopsy proven acute rejection *Incidence of de novo diabetes mellitus *Incidence of hypertension *Incidence of skin cancer *Incidence of Chronic Rejection |  | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sirolimus, Tacrolimus, Kidney transplantation, Kidney Transplant Recipients