MMF and Calcineurin Inhibitor Withdrawal in CAN

Kidney Transplantation Clinical Trial

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00204230
• Other study ID #: 1
• Status: Terminated
• Phase: N/A
• First received: September 12, 2005
• Last updated: September 12, 2005
• Start date: October 1999
• Est. completion date: September 2002

Study information

• Verified date: September 2005
• Source: University Hospital Muenster
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial 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

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 information / eligibility

• Status: Terminated
• Enrollment: 86
• Est. completion date: September 2002
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Immunosuppressive Agents
• Kidney Failure, Chronic
• Kidney Transplantation
• Renal Insufficiency

Intervention

Drug:
• mycophenolate mofetil (drug)

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital Muenster	Hoffmann-La Roche

References & Publications (1)

Suwelack B, Gerhardt U, Hohage H. Withdrawal of cyclosporine or tacrolimus after addition of mycophenolate mofetil in patients with chronic allograft nephropathy. Am J Transplant. 2004 Apr;4(4):655-62. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	course of renal function over 35 weeks
Secondary	after 35 weeks of follow up:
Secondary	incidence of
Secondary	-acute rejections
Secondary	-infections
Secondary	-malignomas
Secondary	-gastrointestinal disorders
Secondary	development of blood pressure over 35 weeks
Secondary	number of antihypertensive drugs
Secondary	lipid state at entry and after 35 weeks
Secondary	blood glucose ,HBA1c at entry and after 35 weeks
Secondary	uric acid at entry and after 35 weeks
Secondary	Comparison of the development of 1/creatinine within each group at entry and 35 weeks after therapy conversion
Secondary	area under the curve (AUC) determination of mycophenolic acid (MPA)
Secondary	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