MMF and Calcineurin Inhibitor Withdrawal in CAN

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

Eligibility Criteria:
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 \>=1 year after renal allografting \>=5 mg/day Prednisolone or equivalent dose

Exclusion Criteria:

Malignomas Gravidity or Lactation Participation in other studies Severe infections gastrointestinal Ulcer Age \<18 and \>70 years Leukopenia with less that 3000/dl leucocytes, Anaemia Hb \> 9 g/dl Therapy with mycophenolatmofetil in the past 6 months Acute rejections in the past 6 months

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