Condition category
Injury, Occupational Diseases, Poisoning
Date applied
Date assigned
Last edited
Retrospectively registered
Overall trial status
Recruitment status
No longer recruiting

Plain English Summary

Not provided at time of registration

Trial website

Contact information



Primary contact

Dr J W de Fijter


Contact details

Leiden University Medical Centre
Department of Nephrology
P.O. Box 9600
2300 RC
+31 (0)71 5262169

Additional identifiers

EudraCT number number

Protocol/serial number


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



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


Secondary study design

Randomised controlled trial

Trial setting


Trial type


Patient information sheet


Renal transplant


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



Not Specified

Drug names

Primary outcome measures

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


Overall trial end date


Reason abandoned


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


Age group




Target number of participants


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


Recruitment end date



Countries of recruitment


Trial participating centre

Leiden University Medical Centre
2300 RC

Sponsor information


Leiden University Medical Centre (LUMC) (The Netherlands)

Sponsor details

Albinusdreef 2
P.O. Box 9600
2300 RC

Sponsor type

Hospital/treatment centre



Funder type

Not defined

Funder name

Not provided at time of registration

Alternative name(s)

Funding Body Type

Funding Body Subtype


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

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes