ImmunosuppressionFreeTACNCT04657562
The New LC-MS/MS Method for Determination of Unbound Tacrolimus in Plasma
An observational study of Immunosuppression and Kidney Transplant Rejection, run by National Science Centre, Poland at 1 site in Poland.
Trial summary
Tacrolimus (TAC) is characterized by a narrow therapeutic window, as well as high inter- and intra-individual variability in pharmacokinetics. Both under- and overexposure may lead to severe adverse effects. Therapeutic drug monitoring (TDM) is an essential element of post-transplant patient care. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Immunosuppression, Kidney Transplant Rejection, Kidney Transplant; Complications
- What is being tested?
- Tacrolimus, Unbound tacrolimus measurement and CYP3A4 and CYP3A5 genotyping
- How many people
- 380 participants
- Where
- 1 sitePoland
- Study dates
- 1 Aug 2020to May 2023
- How long will I take part?
- 2 Weeks
- Phase
- Observational
- 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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Study population: 1. 40 consecutive de novo adult kidney or liver transplant recipients on TAC-based immunosuppression. 2. 300 adult kidney transplant recipients attending the local outpatient clinic. 3. 40 adult kidney transplant recipients experiencing acute rejection of the renal allograft.
Who may be able to join
- adult (>18 yo), recipient of kidney or liver transplant from the Regional Qualification Center, tacrolimus-based immunosuppression
Who cannot join
- the use of agents significantly influencing TAC metabolism, double organ recipients, HBV, HCV and HIV infection, neurological disorders.
Trial locations and contacts
1 site in 1 country.
Poland1 site, 1 recruiting
- Recruiting
Department of General and Transplant Surgery, Medical University of Warsaw
Warsaw, 02-006
Karola Warszyszynska, MD, 225021784 ext. +48, karola.warzyszynska@gmail.com
Karola Warzyszynska, MD
About this study
Official title: Development and Validation of New LC-MS/MS Method for Determination of Unbound Tacrolimus in Plasma in CYP3A5 Expressors and Non-Expressors
Tacrolimus (TAC) is characterized by a narrow therapeutic window, as well as high inter- and intra-individual variability in pharmacokinetics. Both under- and overexposure may lead to severe adverse effects. Therapeutic drug monitoring (TDM) is an essential element of post-transplant patient care. Most transplantation centers use C0 to adjust TAC dosage. Some controversies remain about relationship between C0 and clinical outcome.
It is generally accepted that only protein-unbound drug molecules can cross cellular membranes, which imply that TDM of free tacrolimus fraction may be of paramount importance and improve clinical management of organ recipients.
Read more
Whole blood TAC concentrations and dose requirements are strongly associated with CYP3A5 polymorphism. Routine CYP3A5 genotyping on the waiting lists might be useful to guide tacrolimus dosing.
This interdisciplinary project tackles the research problem from three angles - biochemistry, genetics and clinical observation. The primary goal of the study is to evaluate clinical usefulness of different TDM protocols in patients after kidney and liver transplantation.
Read the detailed description
As there are over 15.000 patients in Poland on continuous tacrolimus (TAC) therapy, the identification and validation of more sensitive and specific biomarkers is of utmost importance. The investigators propose a multiple step assessment of TAC therapeutic drug monitoring (TDM) in kidney and liver recipients. A role of genetic profiling on drug concentration and clinical effects will also be addressed. The project will significantly contribute to understanding tacrolimus pharmacokinetics and body response to drug exposure. Moreover, the proposed project is the first attempt to integrate both different TDM measure methods and patient genetics in a rigorous, prospective study with the assessment of the clinical over- and underexposure TAC effects. It is expected to provide an argument for implementation of even more personalized, predictable immunosuppressive therapy.
The investigators hypothesize that:
- There is a correlation of free TAC level with drug toxicity on one hand, and graft rejection and underimmunosuppression despite target whole blood concentration on the other.
- CYP3A5 expressors and non-expressors will present different levels of TAC in both whole blood C0 and free TAC C0 as well as different effectiveness and toxicity profiles.
- The concentration of free TAC is related to changes in the concentration of blood components, thus it is possible to derive the equation for calculating free TAC concentration as a useful tool for the drug dosage adjustment
Study design
Objectives:
Phase 1) A primary objective of this study is to develop and validate a new method for unbound tacrolimus measurement. - Published: 12 March 2022 (https://doi.org/10.3390/pharmaceutics14030632)
Phase 2) A primary objective is to calculate free fraction of TAC from hematocrit level, albumin concentration and routine whole blood TAC C0 to predict dose adjustment more accurately. The generated equation will be plotted against CYP3A polymorphisms.
Phase 3) A primary objective is to look for a correlation between unbound TAC level in an ultrafiltrate with graft rejection episodes.
Secondary endpoints:
A complex comparison of different methods of determination of TAC concentration in whole blood, plasma and ultrafiltrate is planned.
The benefit of genotyping before administration of TAC for dose prediction will be evaluated.
The studied groups:
- 40 consecutive kidney or liver transplant recipients on TAC-based immunosuppression.
- 300 kidney transplant recipients attending the local outpatient clinic.
- 40 kidney transplant recipients experiencing acute rejection of the renal allograft.
TAC measurements:
Measurements of unbound tacrolimus concentrations in plasma ultrafiltrate and tacrolimus concentrations in plasma and whole blood will be performed using a Nexera LC System with LCMS-8050 MS triple quadrupole with ascomycin and deuterated tacrolimus as internal standards.
Genotyping:
DNA of patients will be purified and analyzed using RT-PCR for CYP3A4 and CYP3A5 polymorphisms Study duration: The study is scheduled for 3 years: 2.5 years for collection of samples, 0.5 year for analysis and publication of the results.
Efficacy variables: Standard monitoring of blood and urine laboratory parameters, whole blood TAC trough level (C0), plasma TAC concentration, free TAC concentration in plasma ultrafiltrate, TAC daily doses.
- Conditions
- Immunosuppression, Kidney Transplant Rejection, Kidney Transplant; Complications, Liver Transplant Rejection, Liver Transplant; Complications, Metabolism Medication Toxicity
- Being tested
- Tacrolimus, Unbound tacrolimus measurement, CYP3A4 and CYP3A5 genotyping
- Keywords
- Kidney transplant, liver transplant, CYP3A, unbound tacrolimus, therapeutic drug monitoring
- Medical subject headings
- Genetic Predisposition to Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TacrolimusDrug
Also called Prograf, Advagraf
Prevention of rejection in kidney or liver transplant: a standard immunosuppressive therapy according to international protocols.
Unbound tacrolimus measurementDiagnostic test
Unbound tacrolimus measurement in plasma ultrafiltrate.
CYP3A4 and CYP3A5 genotypingDiagnostic test
DNA purification and genotyping
| Study group | Role | What they receive |
|---|---|---|
| De novo renal/liver transplant recipients | The group of 40 consecutive adult (age > 18 years) male and female recipients of deceased kidney or liver transplant from the Regional Qualification Center (Warsaw, Poland). Receives: Drug: Tacrolimus; Diagnostic Test: Unbound tacrolimus measurement; Diagnostic Test: CYP3A4 and CYP3A5 genotyping | |
| Random renal transplant recipients | The group of 300 random adult (age > 18 years) male and female recipients of deceased kidney attending the local outpatient clinic. Receives: Drug: Tacrolimus; Diagnostic Test: Unbound tacrolimus measurement; Diagnostic Test: CYP3A4 and CYP3A5 genotyping | |
| Renal transplant recipients experiencing graft rejection | The group of 40 consecutive adult (age > 18 years) male and female recipients of deceased kidney experiencing acute rejection of the renal allograft. Receives: Drug: Tacrolimus; Diagnostic Test: Unbound tacrolimus measurement; Diagnostic Test: CYP3A4 and CYP3A5 genotyping |
What is being measured
The primary outcome is the main question the study is designed to answer.
Development and validation of the new LC-MS/MS measurement method
Development and validation of the extremely sensitive method for unbound tacrolimus determination using the EMA and FDA guidelines
Measured: 1 year
A comparison of different TAC TDM protocols depending on the matrix
- concentration of unbound tacrolimus in plasma ultrafiltrate
- concentration of tacrolimus in plasma
- concentration of tacrolimus in whole blood The measures will be obtained with the use of LC-MS/MS method.
Measured: 1 year
Equation to calculate unbound TAC concentration
Development of the equation (using the concentration of free TAC, plasma and whole blood, and blood components) by statistical methods.
Measured: 1 year
A correlation between free TAC and symptoms of underimmunosuppresion
Biopsy proven acute rejection
Measured: 1 year
Secondary outcomes (3)
A correlation between free TAC and nephrotoxicity
Calcineurin inhibitor toxicity confirmed with the biopsy
Measured: 1 year
CYP3A expression
SNP genotyping to address CYP3A genetic variations (CYP3A4 and CYP3A5)
Measured: 1 year
Blood components
Hematocrit, plasma proteins, albumins, LDL, HDL, total cholesterol, triglycerid
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Dec 2020
- Study start1 Aug 2020
- Primary completionDec 2022 (estimated)
- Study completionMay 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (24)Papers the sponsor has linked to this study.
- Other trials for ImmunosuppressionStudies 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
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 380 participants (estimated)
- Target duration
- 2 Weeks
Sponsor and investigators
- Lead sponsor
- National Science Centre, Poland
- Sponsor type
- Other government
- Collaborators
- Medical University of Warsaw
- Responsible party
- Principal investigator, Karola Warzyszyńska, National Science Centre, Poland
- Investigators
- Karola Warzyszyńska, MD, Principal investigator, Department of General and Transplant Surgery, Medical University of Warsaw
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04657562
- Sponsor's protocol ID
- 2019/33/N/NZ7/01631
- Acronym
- FreeTAC
- Status last verified
- Apr 2022
- First submitted
- 24 Nov 2020
- Last updated
- 22 Apr 2022
- Results posted
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: All IPD that underlie results in a publication will be available
Publications
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x.
PubMed 19845597European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Liver transplantation. J Hepatol. 2016 Feb;64(2):433-485. doi: 10.1016/j.jhep.2015.10.006. Epub 2015 Nov 17. No abstract available.
PubMed 26597456Bittersohl H, Schniedewind B, Christians U, Luppa PB. A simple and highly sensitive on-line column extraction liquid chromatography-tandem mass spectrometry method for the determination of protein-unbound tacrolimus in human plasma samples. J Chromatogr A. 2018 Apr 27;1547:45-52. doi: 10.1016/j.chroma.2018.03.010. Epub 2018 Mar 7.
PubMed 29544893Brunet M, van Gelder T, Asberg A, Haufroid V, Hesselink DA, Langman L, Lemaitre F, Marquet P, Seger C, Shipkova M, Vinks A, Wallemacq P, Wieland E, Woillard JB, Barten MJ, Budde K, Colom H, Dieterlen MT, Elens L, Johnson-Davis KL, Kunicki PK, MacPhee I, Masuda S, Mathew BS, Millan O, Mizuno T, Moes DAR, Monchaud C, Noceti O, Pawinski T, Picard N, van Schaik R, Sommerer C, Vethe NT, de Winter B, Christians U, Bergan S. Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy: Second Consensus Report. Ther Drug Monit. 2019 Jun;41(3):261-307. doi: 10.1097/FTD.0000000000000640.
PubMed 31045868Ekberg H, Tedesco-Silva H, Demirbas A, Vitko S, Nashan B, Gurkan A, Margreiter R, Hugo C, Grinyo JM, Frei U, Vanrenterghem Y, Daloze P, Halloran PF; ELITE-Symphony Study. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007 Dec 20;357(25):2562-75. doi: 10.1056/NEJMoa067411.
PubMed 18094377Pascual J, Berger SP, Witzke O, Tedesco H, Mulgaonkar S, Qazi Y, Chadban S, Oppenheimer F, Sommerer C, Oberbauer R, Watarai Y, Legendre C, Citterio F, Henry M, Srinivas TR, Luo WL, Marti A, Bernhardt P, Vincenti F; TRANSFORM Investigators. Everolimus with Reduced Calcineurin Inhibitor Exposure in Renal Transplantation. J Am Soc Nephrol. 2018 Jul;29(7):1979-1991. doi: 10.1681/ASN.2018010009. Epub 2018 May 11.
PubMed 29752413Stienstra NA, Sikma MA, van Dapperen AL, de Lange DW, van Maarseveen EM. Development of a Simple and Rapid Method to Measure the Free Fraction of Tacrolimus in Plasma Using Ultrafiltration and LC-MS/MS. Ther Drug Monit. 2016 Dec;38(6):722-727. doi: 10.1097/FTD.0000000000000351.
PubMed 27805928Bouamar R, Shuker N, Hesselink DA, Weimar W, Ekberg H, Kaplan B, Bernasconi C, van Gelder T. Tacrolimus predose concentrations do not predict the risk of acute rejection after renal transplantation: a pooled analysis from three randomized-controlled clinical trials(dagger). Am J Transplant. 2013 May;13(5):1253-61. doi: 10.1111/ajt.12191. Epub 2013 Mar 8.
PubMed 23480233Israni AK, Riad SM, Leduc R, Oetting WS, Guan W, Schladt D, Matas AJ, Jacobson PA; DeKAF Genomics Investigators. Tacrolimus trough levels after month 3 as a predictor of acute rejection following kidney transplantation: a lesson learned from DeKAF Genomics. Transpl Int. 2013 Oct;26(10):982-9. doi: 10.1111/tri.12155. Epub 2013 Jul 24.
PubMed 23879408Kershner RP, Fitzsimmons WE. Relationship of FK506 whole blood concentrations and efficacy and toxicity after liver and kidney transplantation. Transplantation. 1996 Oct 15;62(7):920-6. doi: 10.1097/00007890-199610150-00009.
PubMed 8878385Zahir H, McCaughan G, Gleeson M, Nand RA, McLachlan AJ. Changes in tacrolimus distribution in blood and plasma protein binding following liver transplantation. Ther Drug Monit. 2004 Oct;26(5):506-15. doi: 10.1097/00007691-200410000-00008.
PubMed 15385833Zahir H, Nand RA, Brown KF, Tattam BN, McLachlan AJ. Validation of methods to study the distribution and protein binding of tacrolimus in human blood. J Pharmacol Toxicol Methods. 2001 Jul-Aug;46(1):27-35. doi: 10.1016/s1056-8719(02)00158-2.
PubMed 12164257Hendijani F, Azarpira N, Kaviani M. Effect of CYP3A5*1 expression on tacrolimus required dose for transplant pediatrics: A systematic review and meta-analysis. Pediatr Transplant. 2018 Jun 19:e13248. doi: 10.1111/petr.13248. Online ahead of print.
PubMed 29920880Rojas L, Neumann I, Herrero MJ, Boso V, Reig J, Poveda JL, Megias J, Bea S, Alino SF. Effect of CYP3A5*3 on kidney transplant recipients treated with tacrolimus: a systematic review and meta-analysis of observational studies. Pharmacogenomics J. 2015 Feb;15(1):38-48. doi: 10.1038/tpj.2014.38. Epub 2014 Sep 9.
PubMed 25201288Haufroid V, Wallemacq P, VanKerckhove V, Elens L, De Meyer M, Eddour DC, Malaise J, Lison D, Mourad M. CYP3A5 and ABCB1 polymorphisms and tacrolimus pharmacokinetics in renal transplant candidates: guidelines from an experimental study. Am J Transplant. 2006 Nov;6(11):2706-13. doi: 10.1111/j.1600-6143.2006.01518.x.
PubMed 17049058
Study at a glance
From the registry record, last updated by the sponsor on 22 Apr 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Development and Validation of New LC-MS/MS Method for Determination of Unbound Tacrolimus in Plasma in CYP3A5 Expressors and Non-Expressors
- ClinicalTrials.gov ID
- NCT04657562
- Acronym / sponsor ID
- FreeTAC / 2019/33/N/NZ7/01631
- Conditions
- Immunosuppression, Kidney Transplant Rejection, Kidney Transplant; Complications, Liver Transplant Rejection, Liver Transplant; Complications, Metabolism Medication Toxicity
- Keywords
- Kidney transplant, liver transplant, CYP3A, unbound tacrolimus, therapeutic drug monitoring
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 380 participants (estimated)
- Lead sponsor
- National Science Centre, PolandOther government
- Collaborators
- Medical University of Warsaw
- Study start
- 1 Aug 2020 (actual)
- Primary completion
- Dec 2022 (estimated)
- Study completion
- May 2023 (estimated)
- First posted
- 8 Dec 2020 (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.
Tacrolimus (TAC) is characterized by a narrow therapeutic window, as well as high inter- and intra-individual variability in pharmacokinetics. Both under- and overexposure may lead to severe adverse effects. Therapeutic drug monitoring (TDM) is an essential element of post-transplant patient care. Most transplantation centers use C0 to adjust TAC dosage. Some controversies remain about relationship between C0 and clinical outcome.
It is generally accepted that only protein-unbound drug molecules can cross cellular membranes, which imply that TDM of free tacrolimus fraction may be of paramount importance and improve clinical management of organ recipients.
Whole blood TAC concentrations and dose requirements are strongly associated with CYP3A5 polymorphism. Routine CYP3A5 genotyping on the waiting lists might be useful to guide tacrolimus dosing.
This interdisciplinary project tackles the research problem from three angles - biochemistry, genetics and clinical observation. The primary goal of the study is to evaluate clinical usefulness of different TDM protocols in patients after kidney and liver transplantation.
Detailed description
As there are over 15.000 patients in Poland on continuous tacrolimus (TAC) therapy, the identification and validation of more sensitive and specific biomarkers is of utmost importance. The investigators propose a multiple step assessment of TAC therapeutic drug monitoring (TDM) in kidney and liver recipients. A role of genetic profiling on drug concentration and clinical effects will also be addressed. The project will significantly contribute to understanding tacrolimus pharmacokinetics and body response to drug exposure. Moreover, the proposed project is the first attempt to integrate both different TDM measure methods and patient genetics in a rigorous, prospective study with the assessment of the clinical over- and underexposure TAC effects. It is expected to provide an argument for implementation of even more personalized, predictable immunosuppressive therapy.
The investigators hypothesize that:
- There is a correlation of free TAC level with drug toxicity on one hand, and graft rejection and underimmunosuppression despite target whole blood concentration on the other.
- CYP3A5 expressors and non-expressors will present different levels of TAC in both whole blood C0 and free TAC C0 as well as different effectiveness and toxicity profiles.
- The concentration of free TAC is related to changes in the concentration of blood components, thus it is possible to derive the equation for calculating free TAC concentration as a useful tool for the drug dosage adjustment
Study design
Objectives:
Phase 1) A primary objective of this study is to develop and validate a new method for unbound tacrolimus measurement. - Published: 12 March 2022 (https://doi.org/10.3390/pharmaceutics14030632)
Phase 2) A primary objective is to calculate free fraction of TAC from hematocrit level, albumin concentration and routine whole blood TAC C0 to predict dose adjustment more accurately. The generated equation will be plotted against CYP3A polymorphisms.
Phase 3) A primary objective is to look for a correlation between unbound TAC level in an ultrafiltrate with graft rejection episodes.
Secondary endpoints:
A complex comparison of different methods of determination of TAC concentration in whole blood, plasma and ultrafiltrate is planned.
The benefit of genotyping before administration of TAC for dose prediction will be evaluated.
The studied groups:
- 40 consecutive kidney or liver transplant recipients on TAC-based immunosuppression.
- 300 kidney transplant recipients attending the local outpatient clinic.
- 40 kidney transplant recipients experiencing acute rejection of the renal allograft.
TAC measurements:
Measurements of unbound tacrolimus concentrations in plasma ultrafiltrate and tacrolimus concentrations in plasma and whole blood will be performed using a Nexera LC System with LCMS-8050 MS triple quadrupole with ascomycin and deuterated tacrolimus as internal standards.
Genotyping:
DNA of patients will be purified and analyzed using RT-PCR for CYP3A4 and CYP3A5 polymorphisms Study duration: The study is scheduled for 3 years: 2.5 years for collection of samples, 0.5 year for analysis and publication of the results.
Efficacy variables: Standard monitoring of blood and urine laboratory parameters, whole blood TAC trough level (C0), plasma TAC concentration, free TAC concentration in plasma ultrafiltrate, TAC daily doses.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Target follow-up
- 2 Weeks
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| De novo renal/liver transplant recipients | – | Drug: Tacrolimus, Diagnostic Test: Unbound tacrolimus measurement, Diagnostic Test: CYP3A4 and CYP3A5 genotypingThe group of 40 consecutive adult (age > 18 years) male and female recipients of deceased kidney or liver transplant from the Regional Qualification Center (Warsaw, Poland). |
| Random renal transplant recipients | – | Drug: Tacrolimus, Diagnostic Test: Unbound tacrolimus measurement, Diagnostic Test: CYP3A4 and CYP3A5 genotypingThe group of 300 random adult (age > 18 years) male and female recipients of deceased kidney attending the local outpatient clinic. |
| Renal transplant recipients experiencing graft rejection | – | Drug: Tacrolimus, Diagnostic Test: Unbound tacrolimus measurement, Diagnostic Test: CYP3A4 and CYP3A5 genotypingThe group of 40 consecutive adult (age > 18 years) male and female recipients of deceased kidney experiencing acute rejection of the renal allograft. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- 1. 40 consecutive de novo adult kidney or liver transplant recipients on TAC-based immunosuppression. 2. 300 adult kidney transplant recipients attending the local outpatient clinic. 3. 40 adult kidney transplant recipients experiencing acute rejection of the renal allograft.
Key inclusion criteria (1 listed)
- adult (>18 yo), recipient of kidney or liver transplant from the Regional Qualification Center, tacrolimus-based immunosuppression
Key exclusion criteria (1 listed)
- the use of agents significantly influencing TAC metabolism, double organ recipients, HBV, HCV and HIV infection, neurological disorders.
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, AdvagrafPrevention of rejection in kidney or liver transplant: a standard immunosuppressive therapy according to international protocols. | Drug | De novo renal/liver transplant recipients, Random renal transplant recipients, Renal transplant recipients experiencing graft rejection |
| Unbound tacrolimus measurementUnbound tacrolimus measurement in plasma ultrafiltrate. | Diagnostic test | De novo renal/liver transplant recipients, Random renal transplant recipients, Renal transplant recipients experiencing graft rejection |
| CYP3A4 and CYP3A5 genotypingDNA purification and genotyping | Diagnostic test | De novo renal/liver transplant recipients, Random renal transplant recipients, Renal transplant recipients experiencing graft rejection |
Primary outcome
Development and validation of the new LC-MS/MS measurement method
Time frame: 1 year
Development and validation of the extremely sensitive method for unbound tacrolimus determination using the EMA and FDA guidelines
A comparison of different TAC TDM protocols depending on the matrix
Time frame: 1 year
1. concentration of unbound tacrolimus in plasma ultrafiltrate 2. concentration of tacrolimus in plasma 3. concentration of tacrolimus in whole blood The measures will be obtained with the use of LC-MS/MS method.
Equation to calculate unbound TAC concentration
Time frame: 1 year
Development of the equation (using the concentration of free TAC, plasma and whole blood, and blood components) by statistical methods.
A correlation between free TAC and symptoms of underimmunosuppresion
Time frame: 1 year
Biopsy proven acute rejection
3 secondary outcomes
A correlation between free TAC and nephrotoxicity
Time frame: 1 year
CYP3A expression
Time frame: 1 year
Blood components
Time frame: 1 year
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Apr 2022.
- Background: PubMed 19845597Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x.
- Background: PubMed 26597456European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Liver transplantation. J Hepatol. 2016 Feb;64(2):433-485. doi: 10.1016/j.jhep.2015.10.006. Epub 2015 Nov 17. No abstract available.
- Background: PubMed 29544893Bittersohl H, Schniedewind B, Christians U, Luppa PB. A simple and highly sensitive on-line column extraction liquid chromatography-tandem mass spectrometry method for the determination of protein-unbound tacrolimus in human plasma samples. J Chromatogr A. 2018 Apr 27;1547:45-52. doi: 10.1016/j.chroma.2018.03.010. Epub 2018 Mar 7.
- Background: PubMed 31045868Brunet M, van Gelder T, Asberg A, Haufroid V, Hesselink DA, Langman L, Lemaitre F, Marquet P, Seger C, Shipkova M, Vinks A, Wallemacq P, Wieland E, Woillard JB, Barten MJ, Budde K, Colom H, Dieterlen MT, Elens L, Johnson-Davis KL, Kunicki PK, MacPhee I, Masuda S, Mathew BS, Millan O, Mizuno T, Moes DAR, Monchaud C, Noceti O, Pawinski T, Picard N, van Schaik R, Sommerer C, Vethe NT, de Winter B, Christians U, Bergan S. Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy: Second Consensus Report. Ther Drug Monit. 2019 Jun;41(3):261-307. doi: 10.1097/FTD.0000000000000640.
- Background: PubMed 18094377Ekberg H, Tedesco-Silva H, Demirbas A, Vitko S, Nashan B, Gurkan A, Margreiter R, Hugo C, Grinyo JM, Frei U, Vanrenterghem Y, Daloze P, Halloran PF; ELITE-Symphony Study. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med. 2007 Dec 20;357(25):2562-75. doi: 10.1056/NEJMoa067411.
- Background: PubMed 29752413Pascual J, Berger SP, Witzke O, Tedesco H, Mulgaonkar S, Qazi Y, Chadban S, Oppenheimer F, Sommerer C, Oberbauer R, Watarai Y, Legendre C, Citterio F, Henry M, Srinivas TR, Luo WL, Marti A, Bernhardt P, Vincenti F; TRANSFORM Investigators. Everolimus with Reduced Calcineurin Inhibitor Exposure in Renal Transplantation. J Am Soc Nephrol. 2018 Jul;29(7):1979-1991. doi: 10.1681/ASN.2018010009. Epub 2018 May 11.
- Background: PubMed 27805928Stienstra NA, Sikma MA, van Dapperen AL, de Lange DW, van Maarseveen EM. Development of a Simple and Rapid Method to Measure the Free Fraction of Tacrolimus in Plasma Using Ultrafiltration and LC-MS/MS. Ther Drug Monit. 2016 Dec;38(6):722-727. doi: 10.1097/FTD.0000000000000351.
- Background: PubMed 23480233Bouamar R, Shuker N, Hesselink DA, Weimar W, Ekberg H, Kaplan B, Bernasconi C, van Gelder T. Tacrolimus predose concentrations do not predict the risk of acute rejection after renal transplantation: a pooled analysis from three randomized-controlled clinical trials(dagger). Am J Transplant. 2013 May;13(5):1253-61. doi: 10.1111/ajt.12191. Epub 2013 Mar 8.
- Background: PubMed 23879408Israni AK, Riad SM, Leduc R, Oetting WS, Guan W, Schladt D, Matas AJ, Jacobson PA; DeKAF Genomics Investigators. Tacrolimus trough levels after month 3 as a predictor of acute rejection following kidney transplantation: a lesson learned from DeKAF Genomics. Transpl Int. 2013 Oct;26(10):982-9. doi: 10.1111/tri.12155. Epub 2013 Jul 24.
- Background: PubMed 8878385Kershner RP, Fitzsimmons WE. Relationship of FK506 whole blood concentrations and efficacy and toxicity after liver and kidney transplantation. Transplantation. 1996 Oct 15;62(7):920-6. doi: 10.1097/00007890-199610150-00009.
- Background: PubMed 15385833Zahir H, McCaughan G, Gleeson M, Nand RA, McLachlan AJ. Changes in tacrolimus distribution in blood and plasma protein binding following liver transplantation. Ther Drug Monit. 2004 Oct;26(5):506-15. doi: 10.1097/00007691-200410000-00008.
- Background: PubMed 12164257Zahir H, Nand RA, Brown KF, Tattam BN, McLachlan AJ. Validation of methods to study the distribution and protein binding of tacrolimus in human blood. J Pharmacol Toxicol Methods. 2001 Jul-Aug;46(1):27-35. doi: 10.1016/s1056-8719(02)00158-2.
- Individual participant dataSharing planned: Yes. All IPD that underlie results in a publication will be available
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Non-Invasive Monitoring of Pediatric Kidney Transplant Recipients and Immunosuppression Personalization: an Open-labeled Multicenter Randomized Controlled Study
Pediatric Kidney Disease, Transplant;Failure,Kidney
Not yet recruitingPhase 2
(TNX-1500) in Kidney Transplant Recipients
Kidney Transplant, Kidney Transplant Failure and Rejection
RecruitingPhase 2
Expanding Liver Transplant Immunosuppression Minimization Via Everolimus
Liver Transplant
Active, not recruitingPhase 1
CD4^LVFOXP3 in Participants With IPEX
IPEX
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.
Karola Warzyszyńska, MD principal investigator
Department of General and Transplant Surgery, Medical University of Warsaw
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Immunosuppression and Kidney Transplant Rejection, run by National Science Centre, Poland at 1 site in Poland.
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 1 inclusion and 1 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: status not confirmed, as of the sponsor's last update on 22 Apr 2022. 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 Poland. 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?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Karola Warzyszyńska, MD (+48225021783, karola.warzyszynska@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Development and validation of the new LC-MS/MS measurement method (time frame: 1 year). The study lists 4 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 NCT04657562, which also lists 24 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 22 Apr 2022.