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

December 21, 2011 updated by: The Second Artillery General Hospital

Prospective Study:Clinical Trial on the Tacrolimus Dosage Range in Chinese Renal Transplant Recipients With Different Genetic Phenotypes of Drug Metabolizing Enzymes(CYP3A5)

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

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

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Intervention / Treatment

Intervention / Treatment

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Detailed Description

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.

• After 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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
145

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • China
    • Beijing
      • BeiJing, Beijing, China, 100020
        • Chaoyang Hospital, affiliated Hospital of Capital Medical University
      • BeiJing, Beijing, China, 100088
        • The Second Artillery Gernal Hospital
      • Beijing, Beijing, China, 100036
        • General Hospital of Air Force of Chinese PLA
    • Henan
      • Zhengzhou, Henan, China, 450052
        • The first affiliated hospital of Zhengzhou university
    • Shanghai
      • Shanghai, Shanghai, China, 200003
        • Changzheng Hospital, the Second Affiliated Hospital of the Second Military Medical University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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 Names:
  • Prograf® capsules (tacrolimus)

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
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)
1w
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).
1 w

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
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
3 months
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.
3months
Survival of the grafts at M3
Time Frame: 3months
In three months, 145 cases, 144 patients survived
3months
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.
3 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
The Second Artillery General Hospital

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Capital Medical University
Shanghai Changzheng Hospital
Air Force General Hospital of the PLA
Pharmacology Research Institute
Health Department of General Logistics

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Study Chair: LIHong LIU, MD Ph.D, The Second Artillery Genaral Hospital

Study record dates

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Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
July 1, 2009

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 1, 2010

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
June 1, 2011

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
July 7, 2009

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 8, 2009

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 9, 2009

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
December 22, 2011

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 21, 2011

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
December 1, 2011

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 20071016
  • 20090403

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