Kidney Transplant Failure and RejectionTIPSNCT04526431
Tacrolimus Pharmacokinetic Subpopulations
An observational study of Kidney Transplant Failure and Rejection and Immunosuppression-related Infectious Disease, run by University Hospital, Grenoble at 2 sites in France.
Trial summary
This prospective study will investigate the concentrations of tacrolimus metabolites (M-I and M-III) over the four first years post-transplantation. A differential metabolism might result in different metabolites' concentration and explain a kidney survival difference between "high rate metabolism" (defined as a… Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Kidney Transplant Failure and Rejection, Immunosuppression-related Infectious Disease
- What is being tested?
- Dosage Forms Oral
- Type of treatment
- Pill or oral medicine
- How many people
- 180 participants
- Where
- 2 sitesFrance
- Study dates
- 28 Jul 2020to 1 Aug 2027
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
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: The study population is made of kidney transplant patients with living or deceased donors at Grenoble University Hospital, Saint Etienne University Hospital or Clermont-Ferrand University Hospital.
Who may be able to join
- Kidney transplant patients at the CHUGA, CHU Saint-Etienne or CHU Clermont-Ferrand, whose new transplant is no more than 7 days old (inclusive)
- Patients initially treated with tacrolimus as an immunosuppressant, combined with mycophenolate (MMF), mycophenolic acid (MPA) or everolimus (EVR), with or without corticotherapy.
- No plans to remove tacrolimus from the patient's immunosuppressive treatment (e.g. no plans to switch to belatacept a priori), during the first 4 years post-transplantation.
- Affiliation to or beneficiary of a social security scheme
- Able to read and understand the terms of the protocol
- Informed consent obtained, including specific consent for genetic analysis of target genes.
- For women of childbearing potential, presence of effective contraception (already acquired for patients treated with mycophenolic acid as an immunosuppressant).
Who cannot join
- Contraindication to the use of tacrolimus
- Patient already treated with tacrolimus at the time of transplantation
- Pregnant, parturient or breastfeeding women
- Patient deprived of liberty by judicial or administrative decision
- Patient under guardianship or curatorship, or receiving forced psychiatric care
- Person admitted to a health or social institution
- Subject cannot be contacted in case of emergency
- Subject in period of exclusion from another study
Trial locations and contacts
2 sites in 1 country. Contact the study team or a site near you to ask about taking part.
France2 sites, 2 recruiting
- Recruiting
Grenoble University Hospital
Grenoble, Auvergne-Rhône-Alpes, 38043
Mathilde BUGNAZET, +33476765460, mbugnazet@chu-grenoble.fr
David TARTRY, +33476765460, dtartry@chu-grenoble.fr
- Not yet recruiting
Saint Etienne University Hospital
Saint-Etienne, Auvergne-Rhône-Alpes, 42000
Guillaume CLAISSE, MD, +33477828380, guillaume.claisse@chu-st-etienne.fr
About this study
Official title: Tacrolimus Pharmacokinetic Subpopulations: Prospective Mechanistic Investigations of the Tacrolimus C/D Ratio
This prospective study will investigate the concentrations of tacrolimus metabolites (M-I and M-III) over the four first years post-transplantation.
A differential metabolism might result in different metabolites' concentration and explain a kidney survival difference between "high rate metabolism" (defined as a concentration/dose ratio, C/D ratio, lower than 1.04 µg/l/mg) and other patients.
The primary endpoint is therefore to compare tacrolimus metabolites' concentrations with respect to the group, either < or >= 1.04 µg/l/mg, in order to detect differences in tacrolimus metabolization between these groups.
Read the detailed description
Tacrolimus is the cornerstone of immunosuppression in renal transplantation, but its nephrotoxicity, in particular, makes it a drug with a narrow therapeutic range, requiring regular pharmacokinetic monitoring. Several studies have demonstrated a relationship between concentration (residual tacrolimus) and dose (prescribed daily tacrolimus) ratio, or C/D ratio, and graft survival. "Fast metabolizers" have been identified by a C/D ratio of less than 1.05 and have poorer graft survival than other renal transplant recipients. The determinants of the C/D ratio (the clinical or biological factors influencing the C/D ratio) are not known.
The purpose of the TIPS study is to prospectively identify tacrolimus metabolism patterns, based on the C/D ratio, and to identify the determinants of the C/D ratio.
The investigators assumed that different metabolism profiles are associated with different degradation profiles of tacrolimus. These degradation profiles can be identified by analysis of known plasma metabolites of tacrolimus (M-I and M-III) and by pharmacogenetic analysis of genes involved in the metabolism of tacrolimus. Also, since the pharmacokinetic profile can be associated with the therapeutic strategy (prolonged-release vs. immediate-release tacrolimus form), it will be investigated in the study in parallel. The hypothesis of this work is that the pharmacokinetic parameters of tacrolimus and its metabolites are associated with renal transplant survival and simultaneously with the therapeutic strategy of the drug. The investigators hope that this will explain the relationship between the C/D ratio of tacrolimus and graft survival, in order to tailor tacrolimus treatment to individual patients (adaptation of the therapeutic strategy, choice of optimal dose).
For this prospective tri-centric randomized prospective study, new renal transplant patients who are scheduled to receive immunosuppression including tacrolimus will be included and randomized between two therapeutic strategies (prolonged-release vs. immediate-release tacrolimus form) within 7 days after transplantation. Patients will be followed for 4 years. Regular consultations will be provided (W6, M3, M6, M12, M24, M36 and M48) including usual biological analyses for renal transplant follow-up, full prescriptions and adherence questionnaire (BAASIS) but also a systematic biopsy of the renal transplant (M3 and M12) and an abbreviated pharmacokinetic study of tacrolimus exposure (M3).
- Being tested
- Dosage Forms Oral
- Keywords
- Kidney transplantation, Pharmacokinetic, Tacrolimus, Concentration-dose ratio, Pharmacogenetic
- Medical subject headings
- Rejection, Psychology
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Dosage Forms OralDrug
Dosage form of tacrolimus (extended release tacrolimus or immediate release tacrolimus)
| Study group | Role | What they receive |
|---|---|---|
| Tacrolimus once-daily | Patients receiving tacrolimus as a once-daily formulation (Envarsus) Receives: Drug: Dosage Forms Oral | |
| Tacrolimus bid | Patients receiving tacrolimus as a twice-a-day formulation. Receives: Drug: Dosage Forms Oral |
What is being measured
The primary outcome is the main question the study is designed to answer.
Tacrolimus metabolite concentration
The concentration of tacrolimus metabolites M-I and M-III will be evaluated by liquid chromatography / tandem mass spectrometry (LC-MS/MS) given in micrograms per litre (μg/l).
Measured: month 3
Genotyping
Genotypes of target genes involved in tacrolimus metabolism (CYP450 3A5, CYP450 3A4, ABCB1)
Measured: Enrollment
Tacrolimus residual concentration
In addition to the Tacrolimus residual concentration assessed at each visit, this measure will also be performed at T0, T+1h and T+3h for immediate-release tacrolimus and T0, T+1h and T+8h for prolonged-release tacrolimus after treatment. The measurement at T+8h will be carried out on blotting paper with a drop of capillary blood which will be returned by mail, using an envelope given to the patient during the visit. These three measuring points will be used to identify the abbreviated kinetics of tacrolimus during M3 visit.
Measured: month 3
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted25 Aug 2020
- Study start28 Jul 2020
- Primary completion1 Aug 2026 (estimated)
- Study completion1 Aug 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Kidney Transplant Failure and RejectionStudies 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
- 180 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University Hospital, Grenoble
- Sponsor type
- University, hospital or other
- Collaborators
- Chiesi SA/NV
- Responsible party
- Sponsor
- Investigators
- Thomas JOUVE, MD, PhD, Principal investigator, University Hospital, GrenobleLionel ROSTAING, MD, PhD, Study chair, University Hospital, Grenoble
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04526431
- Sponsor's protocol ID
- TIPS
- Acronym
- TIPS
- Status last verified
- Feb 2021
- First submitted
- 21 Jul 2020
- Last updated
- 10 Feb 2021
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Jouve T, Fonrose X, Noble J, Janbon B, Fiard G, Malvezzi P, Stanke-Labesque F, Rostaing L. The TOMATO Study (Tacrolimus Metabolization in Kidney Transplantation): Impact of the Concentration-Dose Ratio on Death-censored Graft Survival. Transplantation. 2020 Jun;104(6):1263-1271. doi: 10.1097/TP.0000000000002920.
PubMed 31415035Jouve T, Noble J, Rostaing L, Malvezzi P. An update on the safety of tacrolimus in kidney transplant recipients, with a focus on tacrolimus minimization. Expert Opin Drug Saf. 2019 Apr;18(4):285-294. doi: 10.1080/14740338.2019.1599858. Epub 2019 Apr 1.
PubMed 30909754Tholking G, Fortmann C, Koch R, Gerth HU, Pabst D, Pavenstadt H, Kabar I, Husing A, Wolters H, Reuter S, Suwelack B. The tacrolimus metabolism rate influences renal function after kidney transplantation. PLoS One. 2014 Oct 23;9(10):e111128. doi: 10.1371/journal.pone.0111128. eCollection 2014.
PubMed 25340655Egeland EJ, Robertsen I, Hermann M, Midtvedt K, Storset E, Gustavsen MT, Reisaeter AV, Klaasen R, Bergan S, Holdaas H, Hartmann A, Asberg A. High Tacrolimus Clearance Is a Risk Factor for Acute Rejection in the Early Phase After Renal Transplantation. Transplantation. 2017 Aug;101(8):e273-e279. doi: 10.1097/TP.0000000000001796.
PubMed 28452920
Study at a glance
From the registry record, last updated by the sponsor on 10 Feb 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Tacrolimus Pharmacokinetic Subpopulations: Prospective Mechanistic Investigations of the Tacrolimus C/D Ratio
- ClinicalTrials.gov ID
- NCT04526431
- Acronym / sponsor ID
- TIPS / TIPS
- Keywords
- Kidney transplantation, Pharmacokinetic, Tacrolimus, Concentration-dose ratio, Pharmacogenetic
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 180 participants (estimated)
- Lead sponsor
- University Hospital, GrenobleUniversity, hospital or other
- Collaborators
- Chiesi SA/NV
- Study start
- 28 Jul 2020 (actual)
- Primary completion
- 1 Aug 2026 (estimated)
- Study completion
- 1 Aug 2027 (estimated)
- First posted
- 25 Aug 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.
This prospective study will investigate the concentrations of tacrolimus metabolites (M-I and M-III) over the four first years post-transplantation.
A differential metabolism might result in different metabolites' concentration and explain a kidney survival difference between "high rate metabolism" (defined as a concentration/dose ratio, C/D ratio, lower than 1.04 µg/l/mg) and other patients.
The primary endpoint is therefore to compare tacrolimus metabolites' concentrations with respect to the group, either < or >= 1.04 µg/l/mg, in order to detect differences in tacrolimus metabolization between these groups.
Detailed description
Tacrolimus is the cornerstone of immunosuppression in renal transplantation, but its nephrotoxicity, in particular, makes it a drug with a narrow therapeutic range, requiring regular pharmacokinetic monitoring. Several studies have demonstrated a relationship between concentration (residual tacrolimus) and dose (prescribed daily tacrolimus) ratio, or C/D ratio, and graft survival. "Fast metabolizers" have been identified by a C/D ratio of less than 1.05 and have poorer graft survival than other renal transplant recipients. The determinants of the C/D ratio (the clinical or biological factors influencing the C/D ratio) are not known.
The purpose of the TIPS study is to prospectively identify tacrolimus metabolism patterns, based on the C/D ratio, and to identify the determinants of the C/D ratio.
The investigators assumed that different metabolism profiles are associated with different degradation profiles of tacrolimus. These degradation profiles can be identified by analysis of known plasma metabolites of tacrolimus (M-I and M-III) and by pharmacogenetic analysis of genes involved in the metabolism of tacrolimus. Also, since the pharmacokinetic profile can be associated with the therapeutic strategy (prolonged-release vs. immediate-release tacrolimus form), it will be investigated in the study in parallel. The hypothesis of this work is that the pharmacokinetic parameters of tacrolimus and its metabolites are associated with renal transplant survival and simultaneously with the therapeutic strategy of the drug. The investigators hope that this will explain the relationship between the C/D ratio of tacrolimus and graft survival, in order to tailor tacrolimus treatment to individual patients (adaptation of the therapeutic strategy, choice of optimal dose).
For this prospective tri-centric randomized prospective study, new renal transplant patients who are scheduled to receive immunosuppression including tacrolimus will be included and randomized between two therapeutic strategies (prolonged-release vs. immediate-release tacrolimus form) within 7 days after transplantation. Patients will be followed for 4 years. Regular consultations will be provided (W6, M3, M6, M12, M24, M36 and M48) including usual biological analyses for renal transplant follow-up, full prescriptions and adherence questionnaire (BAASIS) but also a systematic biopsy of the renal transplant (M3 and M12) and an abbreviated pharmacokinetic study of tacrolimus exposure (M3).
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Tacrolimus once-daily | – | Drug: Dosage Forms OralPatients receiving tacrolimus as a once-daily formulation (Envarsus) |
| Tacrolimus bid | – | Drug: Dosage Forms OralPatients receiving tacrolimus as a twice-a-day formulation. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
- Study population
- The study population is made of kidney transplant patients with living or deceased donors at Grenoble University Hospital, Saint Etienne University Hospital or Clermont-Ferrand University Hospital.
Key inclusion criteria (7 listed)
- Kidney transplant patients at the CHUGA, CHU Saint-Etienne or CHU Clermont-Ferrand, whose new transplant is no more than 7 days old (inclusive)
- Patients initially treated with tacrolimus as an immunosuppressant, combined with mycophenolate (MMF), mycophenolic acid (MPA) or everolimus (EVR), with or without corticotherapy.
- No plans to remove tacrolimus from the patient's immunosuppressive treatment (e.g. no plans to switch to belatacept a priori), during the first 4 years post-transplantation.
- Affiliation to or beneficiary of a social security scheme
- Able to read and understand the terms of the protocol
Key exclusion criteria (8 listed)
- Contraindication to the use of tacrolimus
- Patient already treated with tacrolimus at the time of transplantation
- Pregnant, parturient or breastfeeding women
- Patient deprived of liberty by judicial or administrative decision
- Patient under guardianship or curatorship, or receiving forced psychiatric care
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 |
|---|---|---|
| Dosage Forms OralDosage form of tacrolimus (extended release tacrolimus or immediate release tacrolimus) | Drug | Tacrolimus bid, Tacrolimus once-daily |
Primary outcome
Tacrolimus metabolite concentration
Time frame: month 3
The concentration of tacrolimus metabolites M-I and M-III will be evaluated by liquid chromatography / tandem mass spectrometry (LC-MS/MS) given in micrograms per litre (μg/l).
Genotyping
Time frame: Enrollment
Genotypes of target genes involved in tacrolimus metabolism (CYP450 3A5, CYP450 3A4, ABCB1)
Tacrolimus residual concentration
Time frame: month 3
In addition to the Tacrolimus residual concentration assessed at each visit, this measure will also be performed at T0, T+1h and T+3h for immediate-release tacrolimus and T0, T+1h and T+8h for prolonged-release tacrolimus after treatment. The measurement at T+8h will be carried out on blotting paper with a drop of capillary blood which will be returned by mail, using an envelope given to the patient during the visit. These three measuring points will be used to identify the abbreviated kinetics of tacrolimus during M3 visit.
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Feb 2021.
- Background: PubMed 31415035Jouve T, Fonrose X, Noble J, Janbon B, Fiard G, Malvezzi P, Stanke-Labesque F, Rostaing L. The TOMATO Study (Tacrolimus Metabolization in Kidney Transplantation): Impact of the Concentration-Dose Ratio on Death-censored Graft Survival. Transplantation. 2020 Jun;104(6):1263-1271. doi: 10.1097/TP.0000000000002920.
- Background: PubMed 30909754Jouve T, Noble J, Rostaing L, Malvezzi P. An update on the safety of tacrolimus in kidney transplant recipients, with a focus on tacrolimus minimization. Expert Opin Drug Saf. 2019 Apr;18(4):285-294. doi: 10.1080/14740338.2019.1599858. Epub 2019 Apr 1.
- Background: PubMed 25340655Tholking G, Fortmann C, Koch R, Gerth HU, Pabst D, Pavenstadt H, Kabar I, Husing A, Wolters H, Reuter S, Suwelack B. The tacrolimus metabolism rate influences renal function after kidney transplantation. PLoS One. 2014 Oct 23;9(10):e111128. doi: 10.1371/journal.pone.0111128. eCollection 2014.
- Background: PubMed 28452920Egeland EJ, Robertsen I, Hermann M, Midtvedt K, Storset E, Gustavsen MT, Reisaeter AV, Klaasen R, Bergan S, Holdaas H, Hartmann A, Asberg A. High Tacrolimus Clearance Is a Risk Factor for Acute Rejection in the Early Phase After Renal Transplantation. Transplantation. 2017 Aug;101(8):e273-e279. doi: 10.1097/TP.0000000000001796.
- 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.
Thomas JOUVE, MD, PhD principal investigator
University Hospital, Grenoble
Lionel ROSTAING, MD, PhD study chair
University Hospital, Grenoble
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Kidney Transplant Failure and Rejection and Immunosuppression-related Infectious Disease, run by University Hospital, Grenoble at 2 sites in France.
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 7 inclusion and 8 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: looking for participants now, as of the sponsor's last update on 10 Feb 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in France. 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?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Thomas JOUVE, MD, PhD (+33476765460, tjouve@chu-grenoble.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Tacrolimus metabolite concentration (time frame: month 3). The study lists 3 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 NCT04526431, which also lists 4 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 10 Feb 2021; AzTrials last refreshed its copy on 30 Oct 2026.