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19 November 2008
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| [ Print-friendly version ] |
| Calcineurin Inhibitor Minimisation in Renal Transplant recipients with Stable allograft function: A prospective randomised controlled trial |
| ISRCTN | ISRCTN60081949 |
| ClinicalTrials.gov identifier | NCT00541814 |
| Public title | Calcineurin Inhibitor Minimisation in Renal Transplant recipients with Stable allograft function: A prospective randomised controlled trial |
| Scientific title | |
| Acronym | CNIM-SRT |
| Serial number at source | RRK3367 |
| Study hypothesis | Calcineurin Inhibitor minimisation is effective in protecting renal transplants from chronic allograft nephropathy. |
| Ethics approval | North Staffordshire Local research Ethics Committee gave approval on the 20th September 2007 (ref: 07/H1204/103) |
| Study design | A prospective, randomised, controlled, open-label, parallel-group trial. |
| Countries of recruitment | United Kingdom |
| Disease/condition/study domain | Renal transplantation; chronic allograft nephropathy |
| Participants - inclusion criteria |
1. Adult recipients of a first kidney transplant
2. A functioning kidney allograft (with estimated Glomerular Filtration Rate [eGFR] by Modification of Diet in Renal Disease [MDRD] >30 ml/min/1.73m^ 2) and be between 1 and 5 years post transplantation 3. Stable allograft function, as defined by no greater than 10% rise in serum creatinine in the preceding 6 months, on ciclosporin and azathioprine based immunosuppression 4. Minimal proteinuria, evidenced as urine albumin:creatinine ratio <50mg/mmol |
| Participants - exclusion criteria |
1. <18 years of age
2. Pregnancy or suspicion of pregnancy confirmed by positive b-HCG pregnancy test 3. Female patients unwilling to take effective contraception for study duration 4. Untreated ureteric obstruction on ultrasound of allograft 5. Recurrent urosepsis 6. Severe systemic infection 7. Untreated significant (>50%) renal artery stenosis on magnetic resonance angiography performed prior to study 8. History of acute allograft rejection 9. History of myocardial infarction 10. History of malignancy in previous 5 years (excluding non-melanomatous tumours limited to skin) 11. Symptomatic ischaemic heart disease 12. Hepatitis B surface antigen positive, hepatitis C positive or HIV positive 13. Recipient of combined organ transplantation (e.g. pancreas / kidney; liver / kidney) 14. Recipient of ABO-incompatible kidney 15. Greater than 1 HLA mismatch at either the “B” or “DR” locus 16. Peak HLA antibody Panel Reactivity (PRA) greater than 10% 17. Recipient who underwent HLA desensitisation procedure prior to transplantation |
| Anticipated start date | 01/08/2007 |
| Anticipated end date | 01/12/2009 |
| Status of trial | Ongoing |
| Patient information material | |
| Target number of participants | 90 |
| Interventions |
Patients who fullfill 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: Cyclosporin minimisation Group 2: Cyclosporin withdrawal At this point paticipants will undergo assessment of the primary and secondary outcome measures. The treatment period comprises three stages: Stage 1: A 2 week period during which the patient will be stabilised on mycophenolate sodium 720 mg twice daily (in place of azathioprine). Stage 2: A 3 month period during which the calcineurin inhibitor will be either targeted to a specified low blood level of 50-100 ng/ml, or withdrawn completely (depending on randomisation). Stage 3: 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. |
| Primary outcome measure(s) |
To compare renal allograft markers of damage and evolving injury in biopsies immediately pre study and at the end of the study. The primary tissue assessments will comprise:
1. Index of chronic damage (an objective measure of the amount of chronic damage, shown to be a powerful indicator of prognosis in non-allograft renal biopsies) 2. Interstitial fibrosis quantification by Sirius Red staining 3. TGF-Beta expression 4. P-selectin expression and leukocyte infiltration (macrophage) 5. Fibroblast function 6. Epithelial mesenchymal transformation markers 7. Markers of apoptosis 8. Electron microscopy |
| Secondary outcome measure(s) |
The following will also be assessed immediately pre study and at the end of the study:
1. Renal: 1.1. Serum creatinine 1.2. Estimated Glomerular Filtration Rate (GFR) 1.3. Isotopic GFR 1.4. Urinary Albumin : Creatinine Ratio (ACR) 1.5. Graft loss 2. Immunological: 2.1. Acute clinical rejection episodes between both groups 2.2. Sub-clinical rejection on month exit biopsy 2.3. Donor specific and non-donor specific anti-HLA antibody formation 2.4. T cell responses 3. Infection: 3.1. Cytomegalovirus (CMV) PCR 3.2. BK polyoma virus PCR 3.3. Bacterial (fever, with identification of an organism by culture) 4. Cardiovascular: 4.1. Fasting lipid profile 4.2. Serum uric acid 4.3. Serum C-Reactive Protein (CRP) 4.4. Serum fibrinogen 4.5. Asymmetric Dimethylarginine (ADMA) levels 4.6. Ambulatory blood pressure 4.7. Arterial stiffness 4.8. Left ventricular mass on echocardiography 5. Malignancy 6. Patient Survival |
| Sources of funding | University Hospital Birmingham Renal Research Fund supported by an unrestricted grant form Novartis Pharmaceuticals (UK) |
| Trial website | |
| Publications | |
| Contact name | Dr Richard Borrows |
| Address |
Department of Nephrology and Renal Transplantation
Queen Elizabeth Hospital Edgbaston |
| City/town | Birmingham |
| Zip/Postcode | B15 2TH |
| Country | United Kingdom |
| Tel | +44 (0)121 627 5715 |
| richard.borrows@uhb.nhs.uk | |
| Sponsor | University Hospital Birmingham NHS Foundation Trust (UK) |
| Address |
Research and Developement Department
4th Floor Nuffield House Queen Elizabeth Hospital |
| City/town | Birmingham |
| Zip/Postcode | B15 2TH |
| Country | United Kingdom |
| Tel | +44 (0)121 472 1311 |
| chris.counsell@uhb.nhs.uk | |
| Sponsor website: | http://www.uhb.nhs.uk |
| Date applied | 16/07/2007 |
| Last edited | 09/10/2008 |
| Date ISRCTN assigned | 22/08/2007 |
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