Condition category
Urological and Genital Diseases
Date applied
28/09/2007
Date assigned
28/09/2007
Last edited
14/10/2014
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Not provided at time of registration

Trial website

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

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 measures

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

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

http://www.dh.gov.uk/Home/fs/en

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

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes