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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00541814
Recruitment Status : Unknown
Verified September 2008 by University Hospital Birmingham.
Recruitment status was:  Recruiting
First Posted : October 10, 2007
Last Update Posted : September 8, 2008
Information provided by:
University Hospital Birmingham

Tracking Information
First Submitted Date  ICMJE October 9, 2007
First Posted Date  ICMJE October 10, 2007
Last Update Posted Date September 8, 2008
Study Start Date  ICMJE October 2007
Primary Completion Date Not Provided
Current Primary Outcome Measures  ICMJE
 (submitted: October 9, 2007)
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 ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 9, 2007)
  • To compare markers of kidney transplant function [ Time Frame: 16 months ]
  • To compare markers of immune function [ Time Frame: 16 months ]
  • Infection episodes [ Time Frame: 16 months ]
  • To assess changes in independent cardiovascular risk factors [ Time Frame: 16 months ]
  • Malignancy [ Time Frame: 16 months ]
  • Patient Survival [ Time Frame: 16 months ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Calcineurin Inhibitor Minimisation in Renal Transplant Recipients With Stable Allograft Function
Official Title  ICMJE Calcineurin Inhibitor Minimisation in Renal Transplant Recipients With Stable Allograft Function: A Prospective Randomised Controlled Trial
Brief Summary 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.
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  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE Chronic Allograft Nephropathy
Intervention  ICMJE Drug: Cyclosporine
Target drug level 50-100 ng/ml or cyclosporine withdrawal
Other Name: Neoral
Study Arms  ICMJE
  • 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.
    Intervention: Drug: Cyclosporine
  • 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.
    Intervention: Drug: Cyclosporine
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: October 9, 2007)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 2010
Primary Completion Date Not Provided
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT00541814
Other Study ID Numbers  ICMJE RRK3367
ISRCTN No. 60081949
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Not Provided
Study Sponsor  ICMJE University Hospital Birmingham
Collaborators  ICMJE Novartis
Investigators  ICMJE
Principal Investigator: Richard Borrows, MRCP University Hospital Birmingham NHS Foundation Trust
PRS Account University Hospital Birmingham
Verification Date September 2008

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP