Calcineurin Inhibitor Minimisation in Renal Transplant Recipients With Stable Allograft Function

Chronic Allograft Nephropathy Clinical Trial

— CNIM-SRT  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT00541814
• Other study ID #: RRK3367
• Secondary ID: ISRCTN No. 60081
• Status: Recruiting
• Phase: Phase 4
• First received: October 9, 2007
• Last updated: September 5, 2008
• Start date: October 2007
• Est. completion date: February 2010

Study information

• Verified date: September 2008
• Source: University Hospital Birmingham
• Contact: Richard Borrows, MRCP
• Phone: 00 44 1216275715
• Email: richard.borrows[@]uhb.nhs.uk
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 90
• Est. completion date: February 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

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

Related Conditions & MeSH terms

• Chronic Allograft Nephropathy

Intervention

Drug:
• Cyclosporine
Target drug level 50-100 ng/ml or cyclosporine withdrawal

Locations

Country	Name	City	State
United Kingdom	University Hospital Birmingham NHS Foundation Trust	Birmingham	West Midlands

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital Birmingham	Novartis

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To compare renal allograft markers of damage and evolving injury in biopsies immediately pre study and at the end of the study		16 months
Secondary	To compare markers of kidney transplant function		16 months
Secondary	To compare markers of immune function		16 months
Secondary	Infection episodes		16 months
Secondary	To assess changes in independent cardiovascular risk factors		16 months
Secondary	Malignancy		16 months
Secondary	Patient Survival		16 months

External Links

•   Sponsor website