CAlciNeurin-inhibitor Nephrotoxicity and Efficacy Study

ISRCTN	ISRCTN55817881
DOI	https://doi.org/10.1186/ISRCTN55817881
Protocol serial number	NTR390
Sponsor	Leiden University Medical Centre (LUMC) (The Netherlands)
Funder	Not provided at time of registration

Submission date: 19/12/2005
Registration date: 19/12/2005
Last edited: 23/10/2008

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Injury, Occupational Diseases, Poisoning

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Record updated in last year

Plain English summary of protocol

Not provided at time of registration

Contact information

Dr J W de Fijter
Scientific

Leiden University Medical Centre
Department of Nephrology, C3-P22
P.O. Box 9600
Leiden
2300 RC
Netherlands

Phone	+31 (0)71 5262169
Email	jwdefijter@lumc.nl

Study information

Primary study design	Interventional
Study design	Multicentre, randomised, active controlled factorial trial
Secondary study design	Randomised controlled trial
Scientific title	A prospective, open, randomised, multicentre study comparing once-daily versus twice-daily dosing of cyclosporin A (Neoral®) or tacrolimus (Prograf®) on renal graft structure and function at 6 and 12 months
Study acronym	CANNES
Study objectives	We believe that a routine graft biopsy at 6 and 12 months together with graft function represents the best surrogate marker for late graft loss.
Ethics approval(s)	Received from the local medical ethics committee
Health condition(s) or problem(s) studied	Renal transplant
Intervention	Before transplantation, patients will be randomised 1:1 to receive either a standard CsA-based or tacrolimus-based immunosuppressive regimen and either a twice daily (bid) or once daily (od) dosing schedule. In the first four days after implantation Neoral or Prograft will be given twice daily schedule at approximately 12 hours intervals starting before surgery. The initial target 12 hours trough level (= C0) in these first days will be aimed at 225 ng/ml (range 200 to 250) and 12.5 ng/ml (range 10 to 15) for Neoral and Prograft respectively. On day 4, in patients assigned to the once daily schedule the total bid dose of CsA or tacrolimus will be given once daily in the morning. At the end of the first week CsA or tacrolimus full 'area under the concentration curves' (AUCs) will be studied to assess true drug-exposure. Subsequent dose-adjustments will be made to achieve the defined AUCs for Neoral (AUC12 = 5400 ngh/ml) and Prograft (AUC12 = 210 ngh/ml) using a three-point sampling method (at C0, C2, C3). Such an approach is required since CsA trough levels do not predict drug exposure 6,9 while the experience with tacrolimus pharmacokinetics is limited. AUCs will be calculated with an algorithm based on three-point sampling. After the first 6 post-transplant weeks the defined AUC for Neoral (AUC12) is 3250 ngh/ml) and for Prograft (AUC12) 125 ngh/ml. In the first 6 weeks after transplantation C0, C2 and C3 hour levels will be assessed weekly. Thereafter these levels will be assessed at the regular visits to the out-patient clinic. Dose-adjustment in each patient will be guided by computer-assisted AUC extrapolation based on C0, C2, C3 drug levels.
Intervention type	Other
Primary outcome measure(s)	1. To investigate which drug regimen is associated with the best graft structure and function at 6 and 12 months 2. Degree of inflammation and fibrosis in renal biopsies taken at 6 and 12 months after implantation. Biopsies will be evaluated according to the Banff '97 Criteria for Renal Allograft Biopsy Interpretation and morphometric analysis of the interstitial fibrous tissue will be performed using the digital image analysis technique available in our department. 3. Graft function will be assessed by measuring glomerular filtration rate (GFR) using 125I-iothalamate and protein excretion rate
Key secondary outcome measure(s)	1. Patient and graft survival 2. Rejection episodes: number of (biopsy-proven) acute rejection episodes, their severity, histopathological pattern and time to first rejection episode 3. Side effect profile: blood pressure, cholesterol, fasting glucose, HbA1c, uric acid, need for supportive treatment, infectious complications, lymphoproliferative disorders 4. Calcineurin inhibition 5. Plasma levels of TGF-b 6. MPA-levels and IMPDH activity over time 7. mRNA expression of collagen in biopsies 8. Functional analysis of T lymphocytes. Assessment of the CMV-specific CD4+ T cell proliferation
Completion date	21/10/2002

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	All
Target sample size at registration	126
Key inclusion criteria	1. Female or male, aged between 18 and 70 years 2. Recipient of a kidney graft (first or second) from a cadaveric donor or living (non-human leukocyte antigen [HLA] identical) donor 3. The patient understands the purpose and risks of the study and has given written informed consent to participate in the study
Key exclusion criteria	1. Patients who are receiving a simultaneous pancreas kidney transplant or a double kidney transplant 2. Patients who are receiving a third or fourth transplant 3. Patients who have greater than 50% (current or historic) panel reactive antibodies 4. Female patients who are pregnant or unwilling to use adequate contraception during the study 5. Patients on other investigational drugs 6. Patients who are unable to take medication orally 7. Patients with a life expectancy less than 1 year
Date of first enrolment	29/09/2000
Date of final enrolment	21/10/2002

Locations

Countries of recruitment

Netherlands

Study participating centre

Leiden University Medical Centre

Leiden
2300 RC
Netherlands

Results and Publications

Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Not provided at time of registration
IPD sharing plan