The Effects of Microbiota Composition on Immunosuppression Protocols in Transplantation

• Conditions: Immunosuppression; Transplant Failure; Kidney Transplant; Complications
• Interventions: Drug: Tacrolimus

• Registration Number: NCT04360031
• Lead Sponsor: Université Catholique de Louvain

Brief Summary

Solid organ transplantation is the treatment of choice for patients suffering from end-stage organ disease, including for chronic kidney failure. The implementation of effective immunosuppressive therapies has already significantly improved the prognosis for graft survival. However, these therapies are often associated with considerable inter- and intra-individual variability both in terms of response or in terms of pharmacokinetics. Innovative approaches must be considered, such as studying the involvement of intestinal microbiota in the pharmacology of these drugs.

The general aim of the study is therefore to relate the variabilities observed in the pharmacology (mainly pharmacokinetics) of immunosuppressive drugs used in renal transplantation (tacrolimus and mycophenolate mofetil) and the composition of the intestinal microbiota of renal transplant patients.

Detailed Description

Solid-organ transplantation often requires the implementation of a lifelong immunosuppressive therapy. A combination of tacrolimus (TAC), mycophenolate mofetil (MMF), together with steroids is currently used in over 60% of cases. In some patients however, these therapies are associated with high levels of variability, either in terms of response to treatments or in terms of pharmacokinetics, which remains unexplained. To address the issue, new approaches are being considered, in this study we will investigate the involvement of the intestinal microbiota in the pharmacology of these drugs. This is a particularly promising avenue for drugs with a low therapeutic index and large intra- and inter-individual pharmacokinetic variabilities such as tacrolimus and mycophenolate mofetil. Despite promising preliminary data for tacrolimus, the influence of the gut microbiota in these pharmacokinetic variabilities remains unclear, even less data are available about the involvement of the microbiota in the pharmacokinetics of mycophenolate mofetil.

We expect that this study will produce additional information on the effect of immunosuppression drugs on gut microbiota, and the relationship between microbiota composition and variabilities.

Study Timeline

• Status Verified: 2020-02
• Study Start: 2020-02-10
• Study First Submitted: 2020-04-21
• Study First Submitted QC: 2020-04-21
• Last Update Submitted: 2020-04-21
• Study First Posted: 2020-04-24
• Last Update Posted: 2020-04-24
• Primary Completion: 2021-03
• Study Completion: 2021-03

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 100

Inclusion Criteria

• Patients within 1 to 8 years post transplantation
• Aged between 18 and 75 years old
• Patients receiving tacrolimus and mycophenolate mofetil as part of their immunosuppressive therapy
• French speaking
• BMI between 18 and 30.

Exclusion Criteria

• Use of tobacco
• Potential Alcohol problems (less than two positive answers to the CAGE questionnaire)
• Use of antibiotic medication within 3 months of the sample collection
• Use of laxative medication within 2 weeks of the sample collection
• Use of anti-fungal medication within 2 weeks of the sample collection
• Pregnant or lactating patients.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Tacrolimus / Mycophenolate Mofetil	Tacrolimus	All patients receive maintenance immunosuppressive treatment of tacrolimus in combination with Mycophenolate Mofetil.

Primary Outcome Measures

Name	Time	Method
Study of the links between immunosuppressive drugs pharmacology and intestinal microbiota composition	24 months	The general aim of the study is to relate the variabilities observed in the pharmacology (mainly pharmacokinetics) of immunosuppressive drugs used in kidney transplantation (tacrolimus and mycophenolate mofetil) and the composition of the intestinal microbiota of these patients.

Secondary Outcome Measures

Name	Time	Method
Identify links between oral dosage and concentrations found in feces	18 months	Study the concentrations of Tacrolimus and Mycophenolate (MPA) Mofetil in feces and highlight predictors depending on microbiota composition
Identify genetic factors underlying the links between microbiota and Tacrolimus/Mycophenolate Mofetil	18 months	Investigate microbial genes responsible for associations between microbiota composition and immuno-suppressant pharmacology
Tacrolimus concentrations and microbiota	18 months	Identify links between microbiota composition and Tacrolimus concentrations in blood.
Tacrolimus concentrations and genetic polymorphisms	18 months	Identify genetic factors able to influence Tac concentrations in blood.
Tacrolimus concentration and demographics	18 months	Investigate the effect of sex and age on Tac concentrations in blood.
Mycophenolate Mofetil concentration and microbiota	18 months	Identify links between microbiota composition and MPA Mofetil concentration in blood and urine.
Mycophenolate Mofetil concentration and polymorphisms	18 months	Identify genetic factors able to influence MPA Mofetil concentrations in blood and urine.
Mycophenolate Mofetil concentration and demographics	18 months	Investigate the effect of sex and age on MPA Mofetil concentrations in blood and urine.
Investigate potential markers of kidney function in metabolites	18 months	Study metabolomics in urine from patients to identify specific markers of kidney function

Trial Locations

Locations (1)

Cliniques universitaires Saint-Luc; 🇧🇪 Bruxelles, Belgium