MMF and Calcineurin Inhibitor Withdrawal in CAN
- Conditions
- Kidney Failure, ChronicImmunosuppressive AgentsKidney Transplantation
- Registration Number
- NCT00204230
- Lead Sponsor
- University Hospital Muenster
- Brief Summary
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
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
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- All
- Target Recruitment
- 86
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
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
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Primary Outcome Measures
Name Time Method course of renal function over 35 weeks
- Secondary Outcome Measures
Name Time Method number of antihypertensive drugs -malignomas after 35 weeks of follow up: incidence of -infections -gastrointestinal disorders development of blood pressure over 35 weeks 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 -acute rejections 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 Comparison of the development of 1/creatinine within each group at entry and 35 weeks after therapy conversion