CAlciNeurin-inhibitor Nephrotoxicity and Efficacy Study

ISRCTN ISRCTN55817881
DOI https://doi.org/10.1186/ISRCTN55817881
Secondary identifying numbers NTR390
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

Study designMulticentre, randomised, active controlled factorial trial
Primary study designInterventional
Secondary study designRandomised controlled trial
Study setting(s)Hospital
Study typeTreatment
Scientific titleA 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 acronymCANNES
Study objectivesWe 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) studiedRenal transplant
InterventionBefore 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 ng*h/ml) and Prograft (AUC12 = 210 ng*h/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 ng*h/ml) and for Prograft (AUC12) 125 ng*h/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 typeOther
Primary outcome measure1. 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
Secondary outcome measures1. 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
Overall study start date29/09/2000
Completion date21/10/2002

Eligibility

Participant type(s)Patient
Age groupAdult
Lower age limit18 Years
SexBoth
Target number of participants126
Key inclusion criteria1. 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 criteria1. 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 enrolment29/09/2000
Date of final enrolment21/10/2002

Locations

Countries of recruitment

  • Netherlands

Study participating centre

Leiden University Medical Centre
Leiden
2300 RC
Netherlands

Sponsor information

Leiden University Medical Centre (LUMC) (The Netherlands)
Hospital/treatment centre

Albinusdreef 2
P.O. Box 9600
Leiden
2300 RC
Netherlands

Website http://www.lumc.nl/english/start_english.html
ROR logo "ROR" https://ror.org/027bh9e22

Funders

Funder type

Not defined

Not provided at time of registration

No information available

Results and Publications

Intention to publish date
Individual participant data (IPD) Intention to shareNo
IPD sharing plan summaryNot provided at time of registration
Publication and dissemination planNot provided at time of registration
IPD sharing plan