Renal TransplantationPhase 4PSIDRTGNCT00935298
Initial Dosage Range of Tacrolimus by Genotyping in Chinese Renal Transplantation
A Phase 4 study testing Tacrolimus in people with Renal Transplantation, run by The Second Artillery General Hospital at 5 sites in China.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Renal Transplantation
- What is being tested?
- Tacrolimus
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 145 participants
- Where
- 5 sitesChina
- Study dates
- Jul 2009to Jun 2011
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Show all 10Show fewer
- 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.
Trial locations and contacts
5 sites in 1 country.
5 sites in 1 country
China5 sites
Chaoyang Hospital, affiliated Hospital of Capital Medical University
Beijing, Beijing Municipality, 100020
General Hospital of Air Force of Chinese PLA
Beijing, Beijing Municipality, 100036
The Second Artillery Gernal Hospital
Beijing, Beijing Municipality, 100088
Changzheng Hospital, the Second Affiliated Hospital of the Second Military Medical University
Shanghai, Shanghai Municipality, 200003
The First Affiliated Hospital of Zhengzhou University
Zhengzhou, Henan, 450052
About this study
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)
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.
Read more
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
Read the 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.
- Conditions
- Renal Transplantation
- Being tested
- Tacrolimus
- Keywords
- Renal Transplantation, Tacrolimus, CYP3A5, Genotyping
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TacrolimusDrug
Also called Prograf® capsules (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).
| Study group | Role | What they receive |
|---|---|---|
| T | Experimental | 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 Receives: Drug: Tacrolimus |
What is being measured
The primary outcome is the main question the study is designed to answer.
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)
Measured: 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).
Measured: 1 w
Secondary outcomes (4)
The total number of determination of FK506 therapeutic concentration (for safety, efficiency or dose insufficiency reasons)
Tacrolimus blood concentration were measured 1566 times
Measured: 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.
Measured: 3months
Survival of the grafts at M3
In three months, 145 cases, 144 patients survived
Measured: 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.
Measured: 3 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Jul 2009 (estimated)
- Study startJul 2009
- Primary completionDec 2010
- Study completionJun 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Renal TransplantationStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 145 participants (actual)
Sponsor and investigators
- Lead sponsor
- The Second Artillery General Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- Capital Medical University, Shanghai Changzheng Hospital, Pharmacology Research Institute, Air Force General Hospital of the PLA, Health Department of General Logistics
- Responsible party
- Sponsor
- Investigators
- LIHong LIU, MD Ph.D, Study chair, The Second Artillery Genaral Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00935298
- Sponsor's protocol ID
- 20071016
- Other IDs
- 20090403
- Acronym
- PSIDRTG
- Status last verified
- Dec 2011
- First submitted
- 7 Jul 2009
- Last updated
- 22 Dec 2011
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 22 Dec 2011. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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)
- ClinicalTrials.gov ID
- NCT00935298
- Acronym / sponsor ID
- PSIDRTG / 20071016
- Conditions
- Renal Transplantation
- Keywords
- Renal Transplantation, Tacrolimus, CYP3A5, Genotyping
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 145 participants (actual)
- Lead sponsor
- The Second Artillery General HospitalUniversity, hospital or other
- Collaborators
- Capital Medical University, Shanghai Changzheng Hospital, Pharmacology Research Institute, Air Force General Hospital of the PLA, Health Department of General Logistics
- Study start
- Jul 2009
- Primary completion
- Dec 2010 (actual)
- Study completion
- Jun 2011 (actual)
- First posted
- 9 Jul 2009 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| T | Experimental | Drug: TacrolimusThe 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 |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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.
Key exclusion criteria (10 listed)
- 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).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TacrolimusAlso: Prograf® capsules (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). | Drug | T |
Primary outcome
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)
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).
4 secondary outcomes
The total number of determination of FK506 therapeutic concentration (for safety, efficiency or dose insufficiency reasons)
Time frame: 3 months
After transplantation,the average daily tacrolimus dose, occurrence of acute rejection，delayed renal graft events
Time frame: 3months
Survival of the grafts at M3
Time frame: 3months
Duration of the hospitalizations during the first 3 months
Time frame: 3 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Dec 2011.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
LIHong LIU, MD Ph.D study chair
The Second Artillery Genaral Hospital
5 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Tacrolimus in people with Renal Transplantation, run by The Second Artillery General Hospital at 5 sites in China.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Dec 2011. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in China. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The time to obtain first target concentration of FK506 (8-13ng/ml) (time frame: 1w). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Dec 2011.