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

The recruitment status of this study is unknown because the information has not been verified recently.
Verified September 2008 by University Hospital Birmingham.
Recruitment status was  Recruiting
Sponsor:
Collaborator:
Novartis
Information provided by:
University Hospital Birmingham
ClinicalTrials.gov Identifier:
NCT00541814
First received: October 9, 2007
Last updated: September 5, 2008
Last verified: September 2008
  Purpose

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.


Condition Intervention Phase
Chronic Allograft Nephropathy
Drug: Cyclosporine
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Prevention
Official Title: Calcineurin Inhibitor Minimisation in Renal Transplant Recipients With Stable Allograft Function: A Prospective Randomised Controlled Trial

Resource links provided by NLM:


Further study details as provided by University Hospital Birmingham:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 90
Study Start Date: October 2007
Estimated Study Completion Date: February 2010
Arms Assigned Interventions
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 Name: 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 Name: Neoral

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00541814

Contacts
Contact: Richard Borrows, MRCP 00 44 1216275715 richard.borrows@uhb.nhs.uk
Contact: Jason Moore, MRCP 00 44 1216275715 j.moore.3@bham.ac.uk

Locations
United Kingdom
University Hospital Birmingham NHS Foundation Trust Recruiting
Birmingham, West Midlands, United Kingdom, B15 2TH
Sponsors and Collaborators
University Hospital Birmingham
Novartis
Investigators
Principal Investigator: Richard Borrows, MRCP University Hospital Birmingham NHS Foundation Trust
  More Information

Additional Information:
No publications provided

ClinicalTrials.gov Identifier: NCT00541814     History of Changes
Other Study ID Numbers: RRK3367, ISRCTN No. 60081949
Study First Received: October 9, 2007
Last Updated: September 5, 2008
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by University Hospital Birmingham:
Renal Transplantation
Calcineurin Inhibitor
Cyclosporine
Withdrawal
Minimisation

Additional relevant MeSH terms:
Cyclosporins
Cyclosporine
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Therapeutic Uses
Dermatologic Agents
Antirheumatic Agents

ClinicalTrials.gov processed this record on September 22, 2014