MMF and Calcineurin Inhibitor Withdrawal in CAN

Study Overview
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Brief Summary
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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

Detailed Description
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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: week: 1g/day, 2.week: 1,5g/day, 3.week: 2g/day Ciclosporine A bzw. tacrolimus: Target whole trough blood levels: CsA: 80-120 ng/ml (HPLC) FK506: 4-7 ng/ml (IMX Tacrolimus, Abbott) 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

Official Title
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Randomized Controlled Study: Effect of Mycophenolatmofetil in Patients With Histologically Proven Chronic Allograft Nephropathy

Conditions
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Immunosuppressive Agents, Kidney Failure, Chronic, Kidney Transplantation

Intervention / Treatment
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* Drug: mycophenolate mofetil (drug)


Participation Criteria
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Eligibility Criteria
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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 -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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

| Intervention/Treatment |
| --- |
|Drug: mycophenolate mofetil (drug)|nan|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| course of renal function over 35 weeks |  |  | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| after 35 weeks of follow up: |  |  | 
| incidence of |  |  | 
| -acute rejections |  |  | 
| -infections |  |  | 
| -malignomas |  |  | 
| -gastrointestinal disorders |  |  | 
| development of blood pressure over 35 weeks |  |  | 
| number of antihypertensive drugs |  |  | 
| lipid state at entry and after 35 weeks |  |  | 
| blood glucose ,HBA1c at entry and after 35 weeks |  |  | 
| uric acid at entry and after 35 weeks |  |  | 
| Comparison of the development of 1/creatinine within each group at entry and 35 weeks after therapy conversion |  |  | 
| area under the curve (AUC) determination of mycophenolic acid (MPA) |  |  | 
| vessel wall changes of the carotid arteries IMD , compliance, distensibility and hemodynamic parameters CO, CI, at entry and after after cni withdrawal and MMF addition |  |  | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kidney Failure, Chronic, Kidney Transplantation