MMF and Calcineurin Inhibitor Withdrawal in CAN

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