Calcineurin Inhibitor Minimisation in Renal Transplant Recipients With Stable Allograft Function

NCT ID: NCT00541814

Last Updated: 2008-09-08

Basic Information

• Recruitment Status: UNKNOWN
• Clinical Phase: PHASE4
• Total Enrollment: 90 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-10-31
• Study Completion Date: 2010-02-28

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.

Conditions

Chronic Allograft Nephropathy

Keywords

Renal Transplantation; Calcineurin Inhibitor; Cyclosporine; Withdrawal; Minimisation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

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.

Group Type: ACTIVE_COMPARATOR

Cyclosporine

Intervention Type: DRUG

Target drug level 50-100 ng/ml or cyclosporine withdrawal

2

CNI \[Cyclosporine\] withdrawal Group. Conversion from azathioprine to Myfortic followed by a three month period of cyclosporine weaning to the point of withdrawal.

Group Type: EXPERIMENTAL

Cyclosporine

Intervention Type: DRUG

Target drug level 50-100 ng/ml or cyclosporine withdrawal

Interventions

Cyclosporine

Target drug level 50-100 ng/ml or cyclosporine withdrawal

Intervention Type: DRUG

Other Intervention Names

Neoral

Eligibility 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Novartis

INDUSTRY

Sponsor Role: collaborator

University Hospital Birmingham

OTHER

Sponsor Role: lead

Principal Investigators

Richard Borrows, MRCP

Role: PRINCIPAL_INVESTIGATOR

University Hospital Birmingham NHS Foundation Trust

Locations

University Hospital Birmingham NHS Foundation Trust

Birmingham, West Midlands, United Kingdom

Site Status: RECRUITING

Countries

United Kingdom

Central Contacts

Richard Borrows, MRCP

Role: CONTACT

Phone: 00 44 1216275715

Email: richard.borrows@uhb.nhs.uk

Jason Moore, MRCP

Role: CONTACT

Phone: 00 44 1216275715

Email: j.moore.3@bham.ac.uk

Related Links

http://www.uhb.nhs.uk

Sponsor website

Other Identifiers

ISRCTN No. 60081949

Identifier Type: -

Identifier Source: secondary_id

RRK3367

Identifier Type: -

Identifier Source: org_study_id