Contact information
Type
Scientific
Primary contact
Dr Iain MacPhee
ORCID ID
Contact details
Division of Renal Medicine
St George's Hospital Medical School
Cranmer Terrace
Tooting
London
SW17 0RE
United Kingdom
+44 (0)20 8725 5035
imacphee@sghms.ac.uk
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
N0236169543
Study information
Scientific title
A pharmacogenetic approach to immunosuppression for renal transplantation
Acronym
Study hypothesis
Individualisation of initial tacrolimus dosing based on the CYP3A5 genotype will increase the proportion of patients who achieve target blood concentrations during the early period after transplantation with the potential to reduce the rate of allograft rejection without increasing drug toxicity. Sub Study of 'The effect of a genetic polymorphism that determines the expression of cytochrome P450 on tacrolimus pharmacokinetics'.
Ethics approval
Not provided at time of registration
Study design
Randomised controlled trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Condition
Urological and Genital Diseases: Renal transplantation
Intervention
Patients identified as being genetic expressors of CYP3A5 (at least one CYP3A5*1 allele in the absence of CYP3A5*6 or 7*) will be randomised to initial tacrolimus dosing on their CYP3A5 genotype or to our current empirical starting dose.
From our previous observations, we would predict that 25% of the individuals typed will fall into this group, giving 20-25 eligible patients annually. With our current protocol patients receive an initial loading dose of 0.2 mg/kg tacrolimus followed by 0.1 mg/kg twice daily. CYP3A5 expressers will be randomised to this starting dose or a loading dose of 0.4 mg/kg followed by 0.2 mg/kg twice daily. Subsequent drug dosing will be modified based on whole blood 12-hour post dose (trough) blood concentrations of tacrolimus measured three times weekly for the first two weeks of the study using an immunoassay (Tacrolimus II, Abbott Diagnostics, performed on an IMx clinical analyser). The laboratory is a member of the International Tacrolimus Proficiency Testing Scheme. The target range will be 15-20 ng/ml during the first 7 days after transplantation and 10-15 ng/ml during the following 3 months.
The following clinical data will be recorded at the time of transplant: age, sex, ethnic group, original renal disease, serum albumin and haemoglobin concentrations, concurrent medications, type of transplant: cadaveric/asystolic donor/live-donor, degree of HLA mismatch, % panel reactivity (peak and current), history of diabetes mellitus.
Calcineurin inhibitor toxicity will be defined as follows:
Diabetes mellitus will be diagnosed by the requirement for any hypoglycaemic treatment in patients who had not been diabetic pre-transplant. A glucose tolerance test will be performed at 3 months post-transplant with a 2-hour glucose of greater than 11.1 mmol/L taken as diagnosing diabetes mellitus will be taken as all patients still requiring hypoglycaemic treatment one year after transplantation.
Neurotoxicity is difficult to define with objectivity. A pragmatic approach will be employed. The following symptoms, recorded prospectively either reported by the patient or found on physical examination, will be regarded as evidence of neurotoxicity: tremor, paraesthesia, acute confusion.
Nephrotoxicity will be diagnosed when a renal biopsy performed to diagnosed renal dysfunction excludes rejection and shows changes compatible with calcineurin inhibitor toxicity (tubular vacuolation, hyaline deposits in arterioles), or there is a fall of at least 20% in serum creatinine on reduction of the tacrolimus dose for clinical suspension of toxicity.
Intervention type
Other
Phase
Not Applicable
Drug names
Primary outcome measure
The proportion of patients achieving target blood tacrolimus concentrations, tacrolimus measurements within the target range of 15-20 ng/ml during the first 7 days after transplantation and 10-15 ng/ml during the following 7 days.
Secondary outcome measures
1. The incidence of all episodes of rejection including episodes treated as rejection without biopsy confirmation
2. The serum creatinine concentration at one year after transplantation with glomerular filtration rate calculated using the MDRD formula
3. The incidence of calcineurin inhibitor toxicity
Overall trial start date
19/09/2005
Overall trial end date
19/09/2007
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
All non-black (genetically from Sub-Saharan Africa) patients on the transplant waiting list for St George's Hospital will be invited to participate. We already give black patients an increased starting dose of tacrolimus as standard practice. At present there are 170 patients on the waiting list and we would anticipate performing 80-100 renal transplant operations annually. All subjects will be given written informed consent.
Individuals will be genotyped for SNPs using DNA prepared from peripheral blood leucocytes. We will type for CYP3A5*1/*3, CYP3A%*6 and CYP3A5*7. CYP3A5*6 and CYP3A5*7 are present in <10% of the population and may coexist with CYP3A5*1 resulting in non-expression of CYP3A5. We will determine the genotype of the SNPs in exons 12,21 and 26 of MDR-1 to define the haplotypeas has been recently suggested to be a more satisfactory approach than looking at single polymorphisms. We have established methods based on reverse transcriptase polymerase chain reaction (PCR) followed by use of restriction fragment length polymorphisms (RFLP) for MDR-1 genotyping. CYP3A5 genotyping will be performed using a LightCycler™.
Participant type
Patient
Age group
Not Specified
Gender
Not Specified
Target number of participants
100
Participant exclusion criteria
Not provided at time of registration
Recruitment start date
19/09/2005
Recruitment end date
19/09/2007
Locations
Countries of recruitment
United Kingdom
Trial participating centre
Division of Renal Medicine
London
SW17 0RE
United Kingdom
Sponsor information
Organisation
Record Provided by the NHSTCT Register - 2007 Update - Department of Health (UK)
Sponsor details
The Department of Health
Richmond House
79 Whitehall
London
SW1A 2NL
United Kingdom
+44 (0)20 7307 2622
dhmail@doh.gsi.org.uk
Sponsor type
Government
Website
Funders
Funder type
Government
Funder name
St George's Healthcare NHS Trust (UK)
Alternative name(s)
Funding Body Type
Funding Body Subtype
Location
Funder name
NHS R&D Support Funding (UK)
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