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Initial Dosage Range of Tacrolimus by Genotyping in Chinese Renal Transplantation (PSIDRTG)

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ClinicalTrials.gov Identifier: NCT00935298
Recruitment Status : Completed
First Posted : July 9, 2009
Last Update Posted : December 22, 2011
Sponsor:
Collaborators:
Capital Medical University
Shanghai Changzheng Hospital
Pharmacology Research Institute
Air Force General Hospital of the PLA
Health Department of General Logistics
Information provided by (Responsible Party):
The Second Artillery General Hospital

Brief Summary:

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


Condition or disease Intervention/treatment Phase
Renal Transplantation Drug: Tacrolimus Phase 4

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 145 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Prospective Study:Clinical Trial on the Tacrolimus Dosage Range in Chinese Renal Transplant Recipients With Different Genetic Phenotypes of Drug Metabolizing Enzymes(CYP3A5)
Study Start Date : July 2009
Actual Primary Completion Date : December 2010
Actual Study Completion Date : June 2011

Resource links provided by the National Library of Medicine

Drug Information available for: Tacrolimus

Arm Intervention/treatment
Experimental: T

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).
Other Name: Prograf® capsules (tacrolimus)




Primary Outcome Measures :
  1. The time to obtain first target concentration of FK506 (8-13ng/ml) [ Time Frame: 1w ]
    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)

  2. The proportion of patients reaching therapeutic concentration on Day 3 and 7 without dosage schedule adjustments [ Time Frame: 1 w ]
    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).


Secondary Outcome Measures :
  1. The total number of determination of FK506 therapeutic concentration (for safety, efficiency or dose insufficiency reasons) [ Time Frame: 3 months ]
    Tacrolimus blood concentration were measured 1566 times

  2. After transplantation,the average daily tacrolimus dose, occurrence of acute rejection,delayed renal graft events [ Time Frame: 3months ]

    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.


  3. Survival of the grafts at M3 [ Time Frame: 3months ]
    In three months, 145 cases, 144 patients survived

  4. Duration of the hospitalizations during the first 3 months [ Time Frame: 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.



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients of renal inadequacy , necessary to receive renal transplantation , male or female , 18 to 65 years old;
  • Patients receiving a first isolated renal graft with administration of FK506;
  • Patient willing to provide informed consent prior to the specimen collection procedure.

Exclusion Criteria:

  • Patients who received another clinical pharmaceutical study less than 3 months before the entry in this study , and who have already completed or dropped out of this study.
  • Patients with contraindications of FK506 in immunosuppressive therapy : being in pregnancy and being allergic or intolerant with FK506 or other macrolides.
  • Patients suffering from severe diseases of cardiovascular system (essential hypertension), liver (anamnesis of type B hepatitis , type C hepatitis) , hemopoietic system , nervous system , and psychotics.
  • Patients interfered with their blood concentrations of FK506 by administration of cytochrome P4503A4 and P4503A5 enzyme inhibitors , such as lidocaine , midazolam , nicardipine , niludipine , cortisone , itraconazole , fluconazole , ketoconazole , miconazole , clotrimazole ,Bromocriptine and so on.
  • Patients having anaemia (hemoglobin lower than 7g/dl).
  • Patients Diagnosed DM.
  • Patients interfered with their capacity to absorb FK506 by anorexia nervosa , malabsorption syndrome or gastro-intestinal resection according to the viewpoint of the investigators.
  • Patients who lacks understanding of the medicinal knowledge of tacrolimus and the risks of the study according to the viewpoint of the investigators.
  • Patients with allergic constitution or a history of serious allergy.
  • Patients with bad compliance according to viewpoint of the investigators.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00935298


Locations
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China, Beijing
Chaoyang Hospital, affiliated Hospital of Capital Medical University
BeiJing, Beijing, China, 100020
General Hospital of Air Force of Chinese PLA
Beijing, Beijing, China, 100036
The Second Artillery Gernal Hospital
BeiJing, Beijing, China, 100088
China, Henan
The First Affiliated Hospital of Zhengzhou University
Zhengzhou, Henan, China, 450052
China, Shanghai
Changzheng Hospital, the Second Affiliated Hospital of the Second Military Medical University
Shanghai, Shanghai, China, 200003
Sponsors and Collaborators
The Second Artillery General Hospital
Capital Medical University
Shanghai Changzheng Hospital
Pharmacology Research Institute
Air Force General Hospital of the PLA
Health Department of General Logistics
Investigators
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Study Chair: LIHong LIU, MD Ph.D The Second Artillery Genaral Hospital

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Responsible Party: The Second Artillery General Hospital
ClinicalTrials.gov Identifier: NCT00935298     History of Changes
Other Study ID Numbers: 20071016
20090403
First Posted: July 9, 2009    Key Record Dates
Last Update Posted: December 22, 2011
Last Verified: December 2011

Keywords provided by The Second Artillery General Hospital:
Renal Transplantation
Tacrolimus
CYP3A5
Genotyping

Additional relevant MeSH terms:
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Tacrolimus
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Calcineurin Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action