MMF and Calcineurin Inhibitor Withdrawal in CAN
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
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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