Calcineurin Inhibitor Minimisation in Renal Transplant Recipients With Stable Allograft Function (CNIM-SRT)

September 5, 2008 updated by: University Hospital Birmingham

Calcineurin Inhibitor Minimisation in Renal Transplant Recipients With Stable Allograft Function: A Prospective Randomised Controlled Trial

The purpose of this trial is to ascertain whether the withdrawal of calcineurin inhibitors (CNI) will lead to less kidney transplant damage when compared with minimisation. The investigators will assess this by comparing the degree of damage on kidney biopsies taken before and after minimisation/withdrawal of CNI.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Renal transplantation is the most effective form of treatment for end-stage renal failure. It doubles long-term survival and has major socioeconomic and health benefits compared to patients who remain on dialysis. Graft survival in the UK is 90% at one year and greater than 75% at 5 years [UKTransplant, 2004], with better survival of grafts from living donors compared with deceased. However, by 15 years post-transplantation, over 50% of recipients who are still alive have returned to dialysis. Indeed, premature allograft failure is now one of the leading causes of end stage renal disease. As short-term outcomes of renal transplantation continue to improve, increasing attention is being paid to this late attrition of renal allografts.

It is recognised that calcineurin inhibitor (CNI) nephrotoxicity is a major factor in late renal allograft failure and dysfunction. In fact, withdrawal of CNI from patients with deteriorating graft function may improve graft function. However, there is abundant evidence that histological renal allograft damage may progress even in the absence of changes in renal function - i.e. declining renal function is a late marker of renal damage, and therefore institution of therapies (including CNI minimisation) to slow this process may be "too little, too late".

CNI minimisation may be optimised by three major routes. Firstly, by minimising the CNI beyond 12 months post transplantation when the risk of acute rejection is at its greatest. Secondly, by performing a renal biopsy in patients prior to CNI minimisation and avoiding CNI minimisation in patients with inflammation on the biopsy. Finally, converting azathioprine to mycophenolate prior to CNI minimisation should have a renoprotective effect.

The type of CNI we will investigate is cyclosporine.

Patients who fulfill the study entry criteria will require a renal allograft biopsy prior to randomisation to exclude acute rejection, recurrent disease or de novo glomerulonephritis. Those patients with an acceptable biopsy will proceed to randomisation on a 1:1 basis into 2 groups:

Group 1: CNI [Cyclosporine] minimisation; Group 2: CNI [Cyclosporine] withdrawal.

At this point participants will undergo assessment of the primary and secondary outcome measures. The treatment period comprises three stages:

Firstly, a 2 week period during which the patient will be stabilised on mycophenolate sodium 720mg twice daily (in place of azathioprine);

Secondly, a 3 month period during which the CNI [Cyclosporine} will be either targeted to a specified low blood level of 50-100ng/ml, or withdrawn completely (depending on randomisation);

Thirdly, a 12 month maintenance period on the new immunosuppression regimen.

During the first two stages, patients will be reviewed every 2 weeks. This 2-weekly follow-up will continue for the first two months of the third stage of the study, and then visits will be reduced to monthly. At these visits routine blood and urine analysis will be performed as per routine clinical practice.

At the end of the third stage of the study (i.e. 16 months after randomisation) the participants will undergo the second assessment of the primary and secondary outcome measures. This will signify study end for the individual study participant.

Study Type

Interventional

Enrollment (Anticipated)

90

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United Kingdom
    • West Midlands
      • Birmingham, West Midlands, United Kingdom, B15 2TH
        • Recruiting
        • University Hospital Birmingham NHS Foundation Trust

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • The patient must be an adult recipient of a first kidney transplant
  • A functioning kidney allograft with estimated (e)GFR by MDRD > 30 ml/min/1.73 m2, and be between 1 and 5 years post transplantation
  • Stable allograft function, as defined by no greater than 10% rise in serum creatinine in the preceding 6 months, on cyclosporine and azathioprine based immunosuppression
  • Minimal proteinuria, evidenced as urine albumin: creatinine ratio < 50 mg/mmol

Exclusion Criteria:

  • > = 18 years of age
  • Pregnancy or suspicion of pregnancy confirmed by positive b-HCG pregnancy test
  • Female patients unwilling to take effective contraception for study duration
  • Untreated ureteric obstruction on ultrasound of allograft
  • Recurrent urosepsis
  • Severe systemic infection
  • Untreated significant (> 50%) renal artery stenosis on magnetic resonance angiography performed prior to study
  • History of acute allograft rejection
  • History of myocardial infarction
  • History of malignancy in previous 5 years (excluding non-melanomatous tumours limited to skin)
  • Symptomatic ischaemic heart disease
  • Hepatitis B surface antigen positive, Hepatitis C positive, or HIV positive
  • Recipient of combined organ transplantation (e.g. pancreas/kidney; liver/kidney)
  • Recipient of ABO-incompatible kidney
  • Greater than 1 HLA mismatch at either the "B" or "DR" locus
  • Peak HLA antibody Panel Reactivity (PRA) greater than 10%
  • Recipient who underwent HLA desensitisation procedure prior to transplantation

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: 1
CNI [Cyclosporine] minimisation Group. Conversion from azathioprine to Myfortic followed by a three month period of cyclosporine weaning to target blood level of 50-100 ng/ml.
Drug: Cyclosporine
Target drug level 50-100 ng/ml or cyclosporine withdrawal
Other Names:
  • Neoral
Experimental: 2
CNI [Cyclosporine] withdrawal Group. Conversion from azathioprine to Myfortic followed by a three month period of cyclosporine weaning to the point of withdrawal.
Drug: Cyclosporine
Target drug level 50-100 ng/ml or cyclosporine withdrawal
Other Names:
  • Neoral

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
To compare renal allograft markers of damage and evolving injury in biopsies immediately pre study and at the end of the study
Time Frame: 16 months
16 months

Secondary Outcome Measures

Outcome Measure
Time Frame
To compare markers of kidney transplant function
Time Frame: 16 months
16 months
To compare markers of immune function
Time Frame: 16 months
16 months
Infection episodes
Time Frame: 16 months
16 months
To assess changes in independent cardiovascular risk factors
Time Frame: 16 months
16 months
Malignancy
Time Frame: 16 months
16 months
Patient Survival
Time Frame: 16 months
16 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University Hospital Birmingham

Collaborators

Novartis

Investigators

  • Principal Investigator: Richard Borrows, MRCP, University Hospital Birmingham NHS Foundation Trust

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2007

Study Completion (Anticipated)

February 1, 2010

Study Registration Dates

First Submitted

October 9, 2007

First Submitted That Met QC Criteria

October 9, 2007

First Posted (Estimate)

October 10, 2007

Study Record Updates

Last Update Posted (Estimate)

September 8, 2008

Last Update Submitted That Met QC Criteria

September 5, 2008

Last Verified

September 1, 2008

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • RRK3367
  • ISRCTN No. 60081949

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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