MMF and Calcineurin Inhibitor Withdrawal in CAN

Overview

Prospective, randomised study: Effect of mycophenolatmofetil (MMF) and CNI withdrawal in patients with histologically proven chronic allograft nephropathy Indication: change in immunosuppressive treatment of chronic allograft nephropathy (CAN)after renal transplantation Hypothesis: Antimetabolite MMF is able to stop progression of CAN and improve blood pressure/ metabolic parameters and structural vessel wall changes Primary Target:effects of CNI withdrawal and MMF on renal function: stabilisation and/or improvement Secondary Targets: Incidence of adverse events Evaluation of the calcineurin inhibitor free MMF treatment effects on blood pressure, lipids, glucose metabolism and on structural and functional vesselwallchanges Method:open prospective, randomized two-tailed, monocentric study

Prospective, randomised study: Effect of mycophenolatmofetil in patients with histologically proven chronic allograft nephropathy SYNOPSIS Indication: change in treatment to improve the course of chronic allograft nephropathy Method: open prospective, randomized two-tailed, non blinded monocentric study Follow up period: 35 Weeks Number of patients: 2 x 86 patients Inclusion criteria: • Written informed consent * Reduction of graft function: Increase of serum creatinine \>/= 0,1mg/dl/month in the previous 6 months before start of the study and/or new occurrence or increasing proteinuria in the last 6 months before start of the study * Serum creatinine \< 4 mg/dl * Biopsy within the last 3 months * histologically proved chronic allograft nephropathy (graft glomerulopathy, chronic rejection ,interstitial fibrosis, tubular atrophy, vascular arteriosclerosis,hyalinosis) * \>1 year after renal allografting * At least 5 mg/day of prednisolone or equivalent dose Exclusion criteria: • Malignomas * Gravidity or Lactation * Participation in other studies * Severe infections * Florid gastrointestinal Ulcer * Age between 18 and 70 years * Leukopenia with less that 3000/l leucocytes, Anaemia Hb  9 g/dl * Therapy with mycophenolatmofetil in the past 6 months * Acute rejections in the apst 6 months Study protocol: Phase I: Week 1.-3. Conversion to Triple-Drug-Therapy, consisting of Mycophenolatmofetil, corticosteroids (e.g. prednisolone) and ciclosporine A or Tacrolimus 1\. Addition of Mycophenolatmofetil (MMF) to the previous immosuppressive treatment, consisting of ciclosporine A (CsA) or Tacrolimus (FK506) in combination with corticosteroids, e.g. prednisolone (P). In the case that azathioprine (AZA) had been given, AZA is replaced by MMF. The therapy with MMF starts 3 days after the elimination of azathioprine. The addition of MMF follows the following scheme if nothing else is indicated: 1. week: 1g/day, 2.week: 1,5g/day, 3.week: 2g/day 2. Ciclosporine A bzw. tacrolimus: Target whole trough blood levels: CsA: 80-120 ng/ml (HPLC) FK506: 4-7 ng/ml (IMX Tacrolimus, Abbott) 3. Corticosteroids, e.g. prednisolone: The previous dosage is continued, but at least 5 mg prednisolone/day (or equivalent) must be given Phase II: week 4.-9. Randomisation at the beginning of week 4: All patients receiving at least 3 x 500 mg MMF per day were randomised as follows Group A: Continuation of the triple therapy Group B: Elimination of CsA bzw. FK506 The ciclosporine A- or tacrolimus-dosage is reduced ba 33% each 2 weeks so that after 6-8 weeks a total elimination of the drugs is reached. Phase III: week 10.-35. Continuous therapy with...: Group A: Triple therapy MMF / CsA bzw. FK506 / Corticosteroids e.g. Prednisolone Group B: Dual therapy MMF / Corticosteroids e.g. Prednisolone Primary Endpoint: Comparison of the development of 1/creatinine in both branches 32 weeks after randomization Secondary Endpoints: * Occurrence of... * acute rejections * infections * malignomas * gastrointestinal disorders * Blood pressure evolution and number of antihypertensive drugs * Changes concerning the lipid state * Changes concerning the glucose metabolism * Changes in metabolism of uric acid * Comparison of the development of 1/creatinine within each branch 6 months before and 6 months after therapy conversion * Comparison of drop out rate in branches A und B * Pharmacokinetics of mycophenolic acid (MPA) based on a new method of abbreviated area under the curve (AUC) determination * vessel wall changes of the carotid arteries measured by high resolultion ultrasound methods and hemodynamic parameters measured by task force equipment before and 9 month after cni withdrawal and MMF addition Criteria for study discontinuation: * Sepsis * Occurrence of acute rejections * Graft loss * Other severe adverse events * patients decision