Contact information
Type
Scientific
Primary contact
Dr J W de Fijter
ORCID ID
Contact details
Leiden University Medical Centre
Department of Nephrology
C3-P22
P.O. Box 9600
Leiden
2300 RC
Netherlands
+31 (0)71 5262169
jwdefijter@lumc.nl
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
NTR390
Study information
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
Acronym
CANNES
Study hypothesis
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
Received from the local medical ethics committee
Study design
Multicentre, randomised, active controlled factorial trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Condition
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 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 type
Other
Phase
Not Specified
Drug names
Primary outcome measure
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
Secondary outcome measures
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
Overall trial start date
29/09/2000
Overall trial end date
21/10/2002
Reason abandoned (if study stopped)
Eligibility
Participant 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
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
126
Participant 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
Recruitment start date
29/09/2000
Recruitment end date
21/10/2002
Locations
Countries of recruitment
Netherlands
Trial participating centre
Leiden University Medical Centre
Leiden
2300 RC
Netherlands
Sponsor information
Organisation
Leiden University Medical Centre (LUMC) (The Netherlands)
Sponsor details
Albinusdreef 2
P.O. Box 9600
Leiden
2300 RC
Netherlands
Sponsor type
Hospital/treatment centre
Website
Funders
Funder type
Not defined
Funder name
Not provided at time of registration
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list