Kidney Transplant RejectionNCT04825262
Efficacy of Achieving Early Target Trough Levels of Tacrolimus Using CYP3A5 Guided Dosing Versus Weight-based Dosing in a Multi-ethnic Population of Kidney Transplant Recipients in Singapore
A study testing Tacrolimus in people with Kidney Transplant Rejection and Kidney Transplant; Complications, run by Singapore General Hospital at 1 site in Singapore.
Trial summary
The investigators hypothesise that the adaptation of CYP3A5 genotype-based Tacrolimus (FK) dosing will lead to earlier FK target achievement and consequently, better clinical outcome after kidney transplantation (RTx). Read more about this study
- Who is it for?
- Ages 21 to 75 years
- Conditions the study is for
- Kidney Transplant Rejection, Kidney Transplant; Complications
- What is being tested?
- Tacrolimus
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 74 participants
- Where
- 1 siteSingapore
- Study dates
- 1 Feb 2021to 9 Apr 2024
- Phase
- Interventional
- 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 21 to 75 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- On follow up at SGH between the ages of 21 and 75 years old who had received or are scheduled to receive a living donor renal transplant between January 2016 to January 2023
- Has to receive tacrolimus (FK) (Prograf®; Astellas Pharma, Singapore), mycophenolic acid (MPA) (Cellcept®; Roche, Basel, Switzerland or Myfortic®; Novartis Pharma AG, Basel, Switzerland) and prednisolone as triple immunosuppressive drug maintenance regimen
Who cannot join
- Planned to be initiated on non-standard doses of tacrolimus (e.g. planned to initiate on sub-therapeutic doses of tacrolimus)
- Evidence of active liver disease or gastrointestinal disorder that might interfere with the ability to absorb oral medication
- Contraindications to tacrolimus (FK) - e.g. hypersensitivity
- Takes concurrent medications which are known to severely interact with FK (e.g. verapamil, azoles, rifampicin, erythromycin or clarithromycin
Trial locations and contacts
1 site in 1 country.
About this study
The investigators hypothesise that the adaptation of CYP3A5 genotype-based Tacrolimus (FK) dosing will lead to earlier FK target achievement and consequently, better clinical outcome after kidney transplantation (RTx).
This study aims to shed light on the possible impact of CYP3A genotype-based FK dosing on FK target achievement and clinical outcome after RTx in a multi-ethnic population where current evidence is lacking. This data would be helpful to the physicians so that by knowing the genotype of the patient before undergoing transplantation, practitioners would be able to decide on the starting dose of FK so as to avoid low trough levels and risk of acute rejection or high trough levels and risk of nephrotoxicity.
Read the detailed description
Tacrolimus (FK) remains the cornerstone of maintenance immunosuppressants after renal transplantation. However, it is characterised by narrow therapeutic index and large inter-individual variability in its pharmacokinetics, particularly in the dose required to reach target trough blood concentrations. Among several factors investigated for their possible influence on tacrolimus pharmacokinetics, polymorphisms in genes coding for biotransformation enzymes (cytochrome P450 (CYP) isoenzymes 3A4 and 3A5) have received much attention. Exposure to FK correlates with the cytochrome P450 (CYP) 3A4 and CYP3A5 which are polymorphically expressed. This is in part explained by the presence of single-nucleotide polymorphisms (SNPs) in the CYP3A5 and CYP3A4 genes.
To date, renal transplant (RTx) recipients receive standard weight-based dosing of FK and therapeutic drug monitoring is employed for subsequent dose adjustment to ensure target FK concentration is attained. However, the current weight-based dosing strategies to guide the initial FK dosing have been poorly predictive of the actual FK dose required to attain therapeutic FK level. With the increased possibility of sub-therapeutic FK level during the early phase post renal transplantation, it puts them at a higher risk of developing acute rejection.
There has been increasing evidence to suggest the implementation of pre-transplantation genotyping to guide the initial FK dose to achieve target FK concentrations as quickly as possible. On the contrary, there are a few studies that report contradictory results of genotype-guided FK dosing as being useful in attainment of target therapeutic levels.
Given the differences in CYP3A5 genotype prevalence among races and the controversy in clinical benefits of such a pro-active dosage strategy, the impact of CYP3A5 genotype-guided dosing on clinical outcome remains to be answered, especially in the local multi-ethnic population. This pro-active approach may also sound promising for the local multi-ethnic population where majority of the renal transplant population are CYP3A5 expressers who may require a higher initial dose of FK based on genotyping profile.
- Being tested
- Tacrolimus
- Keywords
- kidney transplant, tacrolimus, CYP3A5, Pharmacogenomics
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TacrolimusDrug
Starting dose based on CYP3A5 genotype
| Study group | Role | What they receive |
|---|---|---|
| Intervention genotyping group | Experimental | Patients who are scheduled to receive renal transplant from a living donor between January 2021 to January 2023. They will be assigned to receive the initial CYP3A5 genotype-based tacrolimus (FK) dose as determined by their CYP3A5 genotype.
CYP3A5 expresser (extensive or intermediate metabolizer) - 0.20mg/kg CYP3A5 non-expresser (poor metabolizer) - 0.15mg/kg
The starting dose of the intervention arm will be reviewed for every 10 patients recruited based on the drug levels achieved. Receives: Drug: Tacrolimus |
| Historical Control Group | No intervention | Patients who received renal transplant from a living donor between January 2016 - December 2020 and received standard weight-based dosing of tacrolimus |
What is being measured
The primary outcome is the main question the study is designed to answer.
Proportion of patients within the desired FK trough level at first steady state
E.g. Proportion of patients within target FK levels on the morning of day 3 after five unaltered FK doses
Measured: 3 days
Proportion of patients within the desired FK trough level at 7 days
E.g. Proportion of patients within target FK levels on the morning of day 7 post initiation of FK
Measured: 7 days
Secondary outcomes (10)
Average FK level during the first 1 weeks after transplantation
Measured: 1 week
Average daily dose of FK the first 90 days post transplantation [days 3, 7, 14±3, 30±3, 60±3, 90±3 days post transplantation]
Measured: 90 days
Average concentration-to-dose ratio of FK during the first 90 days post transplantation [days 3, 7, 14±3, 30±3, 60+±3, 90±3 days post transplantation]
Measured: 90 days
Time to reach the first target FK range
Measured: 90 days
Number of FK dose adjustments required to reach the target FK level
Measured: 90 days
Number of markedly sub-therapeutic FK level (defined as <4 ng/mL) and markedly supra-therapeutic FK level (defined as > 20 ng/mL)
Measured: 90 days
Incidence of biopsy-proven acute rejection (BPAR), with histologic characteristics described accordingly to the Banff criteria [Banff 1997 scoring system with 2007 modifications] and/or clinically presumed acute rejection
Measured: 90 days
Incidence of graft loss (defined as failure to discontinue dialysis or if patient undergoes graft nephrectomy)
Measured: 90 days
Renal function at month 3 after transplantation. Estimated GFR (eGFR) will be calculated using CKDEPI equation. [Time Frame: at day 7, 14, 30±3, 60±3 and 90±3 days after transplantation ]
Measured: 90 days
Proportion of patients within target FK levels on day 7 post renal transplant
Measured: 7 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Apr 2021
- Study start1 Feb 2021
- Primary completion16 Jan 2024
- Study completion9 Apr 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Kidney Transplant RejectionStudies of the same condition, open and under way.
- More trials run by Singapore General HospitalThe sponsor's other registered studies.
- 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 N/A
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Model description
- Single interventional group with historical control group
- Masking
- Single blind
- Who is masked
- Participant
- Enrolment
- 74 participants (actual)
Sponsor and investigators
- Lead sponsor
- Singapore General Hospital
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04825262
- Sponsor's protocol ID
- 2019/2599
- Status last verified
- Nov 2024
- First submitted
- 26 Mar 2021
- Last updated
- 13 Nov 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Shuker N, Bouamar R, van Schaik RH, Clahsen-van Groningen MC, Damman J, Baan CC, van de Wetering J, Rowshani AT, Weimar W, van Gelder T, Hesselink DA. A Randomized Controlled Trial Comparing the Efficacy of Cyp3a5 Genotype-Based With Body-Weight-Based Tacrolimus Dosing After Living Donor Kidney Transplantation. Am J Transplant. 2016 Jul;16(7):2085-96. doi: 10.1111/ajt.13691. Epub 2016 Feb 26.
PubMed 26714287Chen SY, Li JL, Meng FH, Wang XD, Liu T, Li J, Liu LS, Fu Q, Huang M, Wang CX. Individualization of tacrolimus dosage basing on cytochrome P450 3A5 polymorphism--a prospective, randomized, controlled study. Clin Transplant. 2013 May-Jun;27(3):E272-81. doi: 10.1111/ctr.12101. Epub 2013 Feb 24.
PubMed 23432535Birdwell KA, Decker B, Barbarino JM, Peterson JF, Stein CM, Sadee W, Wang D, Vinks AA, He Y, Swen JJ, Leeder JS, van Schaik R, Thummel KE, Klein TE, Caudle KE, MacPhee IA. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing. Clin Pharmacol Ther. 2015 Jul;98(1):19-24. doi: 10.1002/cpt.113. Epub 2015 Jun 3.
PubMed 25801146
Study at a glance
From the registry record, last updated by the sponsor on 13 Nov 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Efficacy of Achieving Early Target Trough Levels of Tacrolimus Using CYP3A5 Guided Dosing Versus Weight-based Dosing in a Multi-ethnic Population of Kidney Transplant Recipients in Singapore
- ClinicalTrials.gov ID
- NCT04825262
- Acronym / sponsor ID
- 2019/2599
- Keywords
- kidney transplant, tacrolimus, CYP3A5, Pharmacogenomics
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 74 participants (actual)
- Lead sponsor
- Singapore General HospitalUniversity, hospital or other
- Study start
- 1 Feb 2021 (actual)
- Primary completion
- 16 Jan 2024 (actual)
- Study completion
- 9 Apr 2024 (actual)
- First posted
- 1 Apr 2021 (actual)
- 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.
The investigators hypothesise that the adaptation of CYP3A5 genotype-based Tacrolimus (FK) dosing will lead to earlier FK target achievement and consequently, better clinical outcome after kidney transplantation (RTx).
This study aims to shed light on the possible impact of CYP3A genotype-based FK dosing on FK target achievement and clinical outcome after RTx in a multi-ethnic population where current evidence is lacking. This data would be helpful to the physicians so that by knowing the genotype of the patient before undergoing transplantation, practitioners would be able to decide on the starting dose of FK so as to avoid low trough levels and risk of acute rejection or high trough levels and risk of nephrotoxicity.
Detailed description
Tacrolimus (FK) remains the cornerstone of maintenance immunosuppressants after renal transplantation. However, it is characterised by narrow therapeutic index and large inter-individual variability in its pharmacokinetics, particularly in the dose required to reach target trough blood concentrations. Among several factors investigated for their possible influence on tacrolimus pharmacokinetics, polymorphisms in genes coding for biotransformation enzymes (cytochrome P450 (CYP) isoenzymes 3A4 and 3A5) have received much attention. Exposure to FK correlates with the cytochrome P450 (CYP) 3A4 and CYP3A5 which are polymorphically expressed. This is in part explained by the presence of single-nucleotide polymorphisms (SNPs) in the CYP3A5 and CYP3A4 genes.
To date, renal transplant (RTx) recipients receive standard weight-based dosing of FK and therapeutic drug monitoring is employed for subsequent dose adjustment to ensure target FK concentration is attained. However, the current weight-based dosing strategies to guide the initial FK dosing have been poorly predictive of the actual FK dose required to attain therapeutic FK level. With the increased possibility of sub-therapeutic FK level during the early phase post renal transplantation, it puts them at a higher risk of developing acute rejection.
There has been increasing evidence to suggest the implementation of pre-transplantation genotyping to guide the initial FK dose to achieve target FK concentrations as quickly as possible. On the contrary, there are a few studies that report contradictory results of genotype-guided FK dosing as being useful in attainment of target therapeutic levels.
Given the differences in CYP3A5 genotype prevalence among races and the controversy in clinical benefits of such a pro-active dosage strategy, the impact of CYP3A5 genotype-guided dosing on clinical outcome remains to be answered, especially in the local multi-ethnic population. This pro-active approach may also sound promising for the local multi-ethnic population where majority of the renal transplant population are CYP3A5 expressers who may require a higher initial dose of FK based on genotyping profile.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- Single blind (participant)
- Number of arms
- 2
- Model description
- Single interventional group with historical control group
| Arm | Type | Receives |
|---|---|---|
| Intervention genotyping group | Experimental | Drug: TacrolimusPatients who are scheduled to receive renal transplant from a living donor between January 2021 to January 2023. They will be assigned to receive the initial CYP3A5 genotype-based tacrolimus (FK) dose as determined by their CYP3A5 genotype. CYP3A5 expresser (extensive or intermediate metabolizer) - 0.20mg/kg CYP3A5 non-expresser (poor metabolizer) - 0.15mg/kg The starting dose of the intervention arm will be reviewed for every 10 patients recruited based on the drug levels achieved. |
| Historical Control Group | No intervention | –Patients who received renal transplant from a living donor between January 2016 - December 2020 and received standard weight-based dosing of tacrolimus |
Who may qualify
- Ages
- 21 to 75 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (2 listed)
- On follow up at SGH between the ages of 21 and 75 years old who had received or are scheduled to receive a living donor renal transplant between January 2016 to January 2023
- Has to receive tacrolimus (FK) (Prograf®; Astellas Pharma, Singapore), mycophenolic acid (MPA) (Cellcept®; Roche, Basel, Switzerland or Myfortic®; Novartis Pharma AG, Basel, Switzerland) and prednisolone as triple immunosuppressive drug maintenance regimen
Key exclusion criteria (4 listed)
- Planned to be initiated on non-standard doses of tacrolimus (e.g. planned to initiate on sub-therapeutic doses of tacrolimus)
- Evidence of active liver disease or gastrointestinal disorder that might interfere with the ability to absorb oral medication
- Contraindications to tacrolimus (FK) - e.g. hypersensitivity
- Takes concurrent medications which are known to severely interact with FK (e.g. verapamil, azoles, rifampicin, erythromycin or clarithromycin
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 |
|---|---|---|
| TacrolimusStarting dose based on CYP3A5 genotype | Drug | Intervention genotyping group |
Primary outcome
Proportion of patients within the desired FK trough level at first steady state
Time frame: 3 days
E.g. Proportion of patients within target FK levels on the morning of day 3 after five unaltered FK doses
Proportion of patients within the desired FK trough level at 7 days
Time frame: 7 days
E.g. Proportion of patients within target FK levels on the morning of day 7 post initiation of FK
10 secondary outcomes
Average FK level during the first 1 weeks after transplantation
Time frame: 1 week
Average daily dose of FK the first 90 days post transplantation [days 3, 7, 14±3, 30±3, 60±3, 90±3 days post transplantation]
Time frame: 90 days
Average concentration-to-dose ratio of FK during the first 90 days post transplantation [days 3, 7, 14±3, 30±3, 60+±3, 90±3 days post transplantation]
Time frame: 90 days
Time to reach the first target FK range
Time frame: 90 days
Number of FK dose adjustments required to reach the target FK level
Time frame: 90 days
Number of markedly sub-therapeutic FK level (defined as <4 ng/mL) and markedly supra-therapeutic FK level (defined as > 20 ng/mL)
Time frame: 90 days
Incidence of biopsy-proven acute rejection (BPAR), with histologic characteristics described accordingly to the Banff criteria [Banff 1997 scoring system with 2007 modifications] and/or clinically presumed acute rejection
Time frame: 90 days
Incidence of graft loss (defined as failure to discontinue dialysis or if patient undergoes graft nephrectomy)
Time frame: 90 days
Renal function at month 3 after transplantation. Estimated GFR (eGFR) will be calculated using CKDEPI equation. [Time Frame: at day 7, 14, 30±3, 60±3 and 90±3 days after transplantation ]
Time frame: 90 days
Proportion of patients within target FK levels on day 7 post renal transplant
Time frame: 7 days
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 13 Nov 2024.
- Background: PubMed 26714287Shuker N, Bouamar R, van Schaik RH, Clahsen-van Groningen MC, Damman J, Baan CC, van de Wetering J, Rowshani AT, Weimar W, van Gelder T, Hesselink DA. A Randomized Controlled Trial Comparing the Efficacy of Cyp3a5 Genotype-Based With Body-Weight-Based Tacrolimus Dosing After Living Donor Kidney Transplantation. Am J Transplant. 2016 Jul;16(7):2085-96. doi: 10.1111/ajt.13691. Epub 2016 Feb 26.
- Background: PubMed 23432535Chen SY, Li JL, Meng FH, Wang XD, Liu T, Li J, Liu LS, Fu Q, Huang M, Wang CX. Individualization of tacrolimus dosage basing on cytochrome P450 3A5 polymorphism--a prospective, randomized, controlled study. Clin Transplant. 2013 May-Jun;27(3):E272-81. doi: 10.1111/ctr.12101. Epub 2013 Feb 24.
- Background: PubMed 25801146Birdwell KA, Decker B, Barbarino JM, Peterson JF, Stein CM, Sadee W, Wang D, Vinks AA, He Y, Swen JJ, Leeder JS, van Schaik R, Thummel KE, Klein TE, Caudle KE, MacPhee IA. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing. Clin Pharmacol Ther. 2015 Jul;98(1):19-24. doi: 10.1002/cpt.113. Epub 2015 Jun 3.
- Individual participant dataSharing planned: Undecided
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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.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Tacrolimus in people with Kidney Transplant Rejection and Kidney Transplant; Complications, run by Singapore General Hospital at 1 site in Singapore.
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 2 inclusion and 4 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 13 Nov 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Singapore. 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.
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?
Proportion of patients within the desired FK trough level at first steady state (time frame: 3 days). 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?
On the ClinicalTrials.gov record for NCT04825262, which also lists 3 linked publications.
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 13 Nov 2024.