A Phase 4 interventional study of Tacrolimus in Renal Transplantation, sponsored by The Second Artillery General Hospital. Completed at 5 sites in China. Open to participants aged 18 Years to 65 Years. Per ClinicalTrials.gov, last updated 2011-12-22.
Sponsored by The Second Artillery General Hospital · Phase 4, Interventional, and Treatment
Acute rejection (AR) is the main complication after transplantation, which is a severe risk of chronic rejection and implant devitalization.
Tacrolimus (FK506) is an immunosuppressant used for the prevention of episodes of acute rejection. Tacrolimus is characterized by a narrow therapeutic index and important interindividual variations of its pharmacokinetic characteristics.
Tacrolimus is metabolized through the liver by the cytochrome P450 system, the cytochrome P450 3A5 (CYP 3A5) isoenzyme specifically. Polymorphisms in the CYP 3A5 gene have been associated with changes in metabolic function of the translated isoenzyme. These polymorphisms result in metabolism acceleration of tacrolimus as compared to subjects having the wild type gene, consequently leading to insufficiency of tacrolimus; it is theorized that this leads to higher risk of acute rejection. Several retrospective studies suggested an association between a genetic polymorphism of CYP3A5 and the interindividual variations of tacrolimus blood concentration. In particular, our initial study showed that adult renal transplant recipients with the CYP3A5*1/*3 and *1/*1 （expressors） genotype require higher, fixed, starting dose compared with CYP3A5*3/*3 （nonexpressor）to reach the predefined target exposure early after transplantation.
This prospective study is designed to evaluate whether genetic testing of CYP 3A5 can improve tacrolimus initiation better than usual care. This study is a prospective, multicentric, open, parallel , efficacy study. 300 receivers of a renal transplant in 8 centres will be included.
The genotyping of gene CYP3A5 will be carried out in the 4-7days before renal transplantation. After transplantation, the patients will be treated by MMF, corticosteroids and tacrolimus at a dosage adapted to their genotype(0.15mg/kg/d for CYP3A5*1/*1 type and CYP3A5*1/*3 type，0.08mg/kg/d for CYP3A5*3/*3 type).
The determination of tacrolimus blood concentration will be carried out on Day 3,5,7,14,18,21,28,35,49,63,77,90. The daily amounts of tacrolimus could be modified if necessary to reach the desired blood concentrations. The total duration of the study for a patient is 3 months after transplantation.
The objective of this study is to determine the initial dosage of tacrolimus in Chinese renal transplantation patients by genotyping of the cytochrome P450 3A5
VISITS
The participation of the patient in this study will be 3 months. For this period, 9 visits are planned
•Before transplantation
Visit 1: inclusion visit(in the 4-7 days before transplantation),A blood taking will be carried out on EDTA tube for CYP 3A5 genotyping in the 4-7 days before renal transplantation.
Visit 2: D3
Visit 3: D5
Visit 4: D7
Visit 5: D14
Visit 6: D21
Visit 7: M1 + - 3 days
Visit 8: M2 + - 3 days
Visit 9: M3 + - 3 days
Treatment
After transplantation, the patients will be treated by MMF, corticosteroids and tacrolimus at a dosage adapted to their genotype(CYP3A5*1/*1 type and CYP3A5*1/*3 type administer 0.15mg/kg/d，CYP3A5*3/*3 type administer 0.08mg/kg/d).
The MMF will be given according to weight in 3 months after transplantation as follows:
below 50 kilogram(kg) 0.25g bid (0.5g pre day)
50\~70kg 0.50g bid (1.0g pre day)
70\~90kg 0.75g bid (1.5g pre day)
Exceed 90kg 1.0g bid (2.0g pre day)
Corticosteroid therapy in decreasing amount as follows:
D0 - D15: 20 Mg
D16 - D30: 15 Mg
D30 - D45: 10 Mg
D46 - M3 5 Mg
The determination of tacrolimus blood concentration will be carried out on Day 3,5,7,14,18,21,28,35,49,63,77,90. The daily amounts of Tacrolimus could be modified if necessary to reach the desired blood concentrations. The total duration of the study for a patient is 3 months after transplantation.
If the present study is able to confirm an advantage for a genotype-driven algorithm, in terms of improved efficiency, therapeutic efficacy, especially, safety, a pharmacogenetics approach to dosing can be recommended as the basis wide quality improvement initiative that should improve patient outcomes, reduce resource use (costs of achieving safe and therapeutic immunosuppression), and reduce adverse clinical events.
The Second Artillery General Hospital is the lead sponsor of 2 studies on the registry; none are open to participants now.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
The genotyping of gene CYP3A5 will be carried out in the 4-7days before renal transplantation.After transplantation, the patients will be treated by MMF, corticosteroids and tacrolimus at a dosage adapted to their genotype(CYP3A5\*1/\*3 and \*1/\*1 ,expressors; CYP3A5\*3/\*3 nonexpressor）. The objective is to determine the initial dosage Range of tacrolimus in Chinese renal transplantation patients by genotyping of the cytochrome P450 3A5
Drug: Tacrolimus
The genotyping of gene CYP3A5 will be carried out in the 4-7days before renal transplantation. After transplantation, the patients will be treated by MMF, corticosteroids and tacrolimus at a dosage adapted to their genotype(CYP3A5\*1/\*1 type and CYP3A5\*1/\*3 type administer 0.15mg/kg/d，CYP3A5\*3/\*3 type administer 0.08mg/kg/d).
Also known as: Prograf® capsules (tacrolimus)
The time to obtain first target concentration of FK506 (8-13ng/ml)
The interval time (median) after transplantation to achieve first target tacrolimus blood concentration range (7\~13ng/ml) by genotype was 7 days (3 to 28) for CYP3A5\*1/\*3\&\*1/\*1 patients (N=59) and 3 days (3 to 14) for CYP3A5 \*3/\*3 patients (N=86)
Time frame: 1w
The proportion of patients reaching therapeutic concentration on Day 3 and 7 without dosage schedule adjustments
As compared with patients with cyp3A5\*1/\*3 (expression，n=59)，patients with the CYP3A5\*3/\*3 (nonexpression, n=86) had a decreased time to the first tacrolimus blood concentration within the therapeutic range，but had a increased proportion of patients reaching therapeutic range on Day 3-7 after tranplantration（91.8% vs. 64.4%，P = 0.021).
Time frame: 1 w
The total number of determination of FK506 therapeutic concentration (for safety, efficiency or dose insufficiency reasons)
Tacrolimus blood concentration were measured 1566 times
Time frame: 3 months
After transplantation,the average daily tacrolimus dose, occurrence of acute rejection，delayed renal graft events
There were one acute rejection and thirteen delayed renal allograft function events involving 14 patients, The acute rejection event occurred within the first 14 days after the initiation of tacrolimus treatment at a mean dose of 0.11 mg/kg per day and a median TBC of 4.5ng/ml (range, 3.2 to 6.2ng/ml),and this patient was heterozygous for CYP3A5\*1/\*3. Thirteen delayed renal allograft function occurred within the first 3 months including in 5 patients with CYP3A5\*1/\*3 genotype and in 8 patients with CYP3A5\*3/\*3 genotype.
Time frame: 3months
Survival of the grafts at M3
In three months, 145 cases, 144 patients survived
Time frame: 3months
Duration of the hospitalizations during the first 3 months
The average length of hospitalization for CYP3A5 \*3/\*3 and CYP3A5 \*1/\*3\& \*1/\*1 patients were 38 days and 35 days, respectively (P\>0.05) ,sod there was no statistically significant difference.
Time frame: 3 months
This study is completed, as verified in Dec 2011. You cannot join it, but the record below documents what was studied.
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The Second Artillery General Hospital