| Source of record | UK Clinical Trials Gateway |
| ISRCTN | ISRCTN39668614 |
| Date ISRCTN assigned | 28/09/2007 |
| Local reference number(s) | N0236169543 |
| Public title | A pharmacogenetic approach to immunosuppression for renal transplantation |
| Scientific title |
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| Acronym | N/A |
| Disease/condition/study domain | Urological and Genital Diseases: Renal transplantation |
| 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'. |
| Design/methodology | Randomised controlled trial |
| Research ethics review | Not provided at time of registration |
| Countries of trial | United Kingdom |
| Participants - inclusion criteria | All non-black (genetically from Sub-Saharan Africa) patients on the transplant waiting list for St. Georges 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 CYP£A5*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 amore 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™. |
| Participants - exclusion criteria | Not provided at time of registration |
| Patient information material |
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| Anticipated start date | 19/09/2005 |
| Anticipated end date | 19/09/2007 |
| Status of trial | Completed |
| Target number of participants | 100 |
| Interventions | 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 0.4mg/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 3 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 15-20ng/ml during the first 7 days after transplantation and 10-15ng/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 11.1mmol/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. |
| Primary outcome measure(s) | 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 10-15ng/ml during the following 7 days. |
| Secondary outcome measure(s) | 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 |
| Sources of funding | St George's Healthcare NHS Trust
NHS R&D Support Funding |
| Sponsor name | Record Provided by the NHSTCT Register - 2007 Update - Department of Health |
| Sponsor details | The Department of Health, Richmond House, 79 Whitehall
London
United Kingdom
SW1A 2NL |
| Sponsor telephone | +44 (0)20 7307 2622 |
| Sponsor fax | +44 |
| Sponsor email | dhmail@doh.gsi.org.uk |
| Sponsor website | http://www.dh.gov.uk/Home/fs/en |
| Contact name | Dr Iain MacPhee |
| Contact details | Division of Renal Medicine
St George's Hospital Medical School
Cranmer Terrace
Tooting
London
United Kingdom
SW17 0RE |
| Contact telephone | +44 020 8725 5035 |
| Contact fax | +44 020 8725 5036 |
| Contact email | imacphee@sghms.ac.uk |
| More information | For more up-to-date information please go to the ISRCTN link below. |
| Link to record in ISRCTN Register | ISRCTN39668614 |
| Date last extracted from ISRCTN register | 17/04/2008 |
