Tacrolimus Pharmacokinetic Subpopulations

NCT ID: NCT04526431

Last Updated: 2021-02-10

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 180 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2020-07-28
• Study Completion Date: 2027-08-01

Brief 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 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).

Conditions

Kidney Transplant Failure and Rejection; Immunosuppression-related Infectious Disease

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Tacrolimus once-daily

Patients receiving tacrolimus as a once-daily formulation (Envarsus)

Dosage Forms Oral

Intervention Type: DRUG

Dosage form of tacrolimus (extended release tacrolimus or immediate release tacrolimus)

Tacrolimus bid

Patients receiving tacrolimus as a twice-a-day formulation.

Dosage Forms Oral

Intervention Type: DRUG

Dosage form of tacrolimus (extended release tacrolimus or immediate release tacrolimus)

Interventions

Dosage Forms Oral

Dosage form of tacrolimus (extended release tacrolimus or immediate release tacrolimus)

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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).

Exclusion Criteria

• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Chiesi SA/NV

OTHER

Sponsor Role: collaborator

University Hospital, Grenoble

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Thomas JOUVE, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Grenoble

Lionel ROSTAING, MD, PhD

Role: STUDY_CHAIR

University Hospital, Grenoble

Locations

Grenoble University Hospital

Grenoble, Auvergne-Rhône-Alpes, France

Site Status: RECRUITING

Saint Etienne University Hospital

Saint-Etienne, Auvergne-Rhône-Alpes, France

Site Status: NOT_YET_RECRUITING

Countries

France

Central Contacts

Thomas JOUVE, MD, PhD

Role: CONTACT

tjouve@chu-grenoble.fr

+33476765460

Johan NOBLE, MD

Role: CONTACT

jnoble@chu-grenoble.fr

+33476765460

Facility Contacts

Mathilde BUGNAZET

Role: primary

mbugnazet@chu-grenoble.fr

+33476765460

David TARTRY

Role: backup

dtartry@chu-grenoble.fr

+33476765460

Guillaume CLAISSE, MD

Role: primary

guillaume.claisse@chu-st-etienne.fr

+33477828380

References

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.

Reference Type: BACKGROUND

PMID: 31415035 (View on PubMed)

Jouve 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.

Reference Type: BACKGROUND

PMID: 30909754 (View on PubMed)

Tholking 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.

Reference Type: BACKGROUND

PMID: 25340655 (View on PubMed)

Egeland 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.

Reference Type: BACKGROUND

PMID: 28452920 (View on PubMed)

Other Identifiers

TIPS

Identifier Type: -

Identifier Source: org_study_id