Immunosuppressive Drugs and Gut Microbiome: Pharmacokinetic- and Microbiome Diversity Effects

Phase 4

Active, not recruiting

• Conditions: Kidney Transplant; Complications; Immune Suppression
• Interventions: Drug: Tacrolimus capsule; Drug: Mycophenolate Mofetil 500 mg Tab

• Registration Number: NCT04207177
• Lead Sponsor: Oslo University Hospital

Brief Summary

Kidney transplant recipients of living- and deceased donor grafts and treated with both mycophenolate mofetil (MMF) and tacrolimus (Tac) will be included. A 12-hour pharmacokinetic (PK) investigation of both mycophenolate (MPA) and Tac will be performed in pharmacokinetic steady state conditions between 3 to 8 weeks and one year after transplantation. Feces samples will be collected before (if possible), 1 week after transplantation and at the day of the 12-hour PK investigations. Data on dietary intake and physical activity will be obtained in association with the feces sampling in all patients. Patients will be invited to a follow-up visit one year after transplantation where the 12-hour PK investigation, feces sampling, dietary and activity data collection is repeated. Standard follow-up data after renal transplantations, such as acute rejection episodes, infections, renal function, post transplant diabetes mellitus (PTDM), protocol biopsies, adherence to immunosuppressive drugs, graft loss and death will be collected for all patients up to 5 years after transplantation according to standard schedule at the transplant center.

A subgroup of kidney transplant recipients scheduled for living donor transplantation will be included before transplantation for pre-transplant investigations in addition to the investigations after transplantation. These patients will be randomized to either receive one week of treatment with MMF or Tac before transplantation. Feces samples and a 12-hour PK investigation will be performed after one week of treatment (before transplantation).

Detailed Description

The analyses of feces samples will be performed by utilizing shotgun, next generation sequencing in order to determine the bacterial, fungal sand viral microbiome. Drug concentrations will be analyzed with high performance Liquid chromatography With double mass spectrometry detector (HPLC-MS/MS) technology and both free and total plasma MPA concentrations, total mycophenolate glucoronide (MPAG) concentrations and total whole blood Tac and methylated Tac-metabolite concentrations will be determined.

Study Timeline

• Study Start: 2019-10-30
• Study First Submitted: 2019-12-17
• Study First Submitted QC: 2019-12-18
• Study First Posted: 2019-12-20
• Status Verified: 2024-04
• Last Update Submitted: 2024-04-03
• Last Update Posted: 2024-04-04
• Primary Completion: 2025-12-31
• Study Completion: 2025-12-31

Recruitment & Eligibility

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

Inclusion Criteria

• De novo standard risk kidney transplant recipients.
• Patients scheduled to receive tacrolimus and mycophenolate mofetil as part of their immunosuppressive therapy following transplantation (clinical decision not influenced by this study).
• First kidney transplant only.
• Adult patients.

Exclusion Criteria

• Pregnant or lactating female patients.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Tacrolimus	Tacrolimus capsule	In the subgroup of living donor recipients included before transplantation this group will be treated with tacrolimus (BID, dose by weight) for one week
Mycophenolate mofetil	Mycophenolate Mofetil 500 mg Tab	In the subgroup of living donor recipients included before transplantation this group will be treated with mycophenolate mofetil (750 mg BID) for one week

Primary Outcome Measures

Name	Time	Method
investigate the association between microbiome diversity and 12-hour mycophenolate area under the curve (AUC)	1 year	Association between microbiome diversity measures and AUC of mycophenolate for a dose interval (AUC0-tau)
investigate the association between microbiome diversity and 12-hour mycophenolate Maximum concentration (Cmax)	1 year	Association between microbiome diversity measures and Cmax of mycophenolate

Secondary Outcome Measures

Name	Time	Method
investigate the effects of tacrolimus treatment on gut microbiome changes in treatment naïve patients and associated tacrolimus AUC changes	1 week	Changes in microbiome diversity measures and tacrolimus AUC0-tau with one week of tacrolimus treatment
effects of mycophenolate mofetil treatment on gut microbiome changes in treatment naïve patients and associated mycophenolate Cmax changes	1week	Changes in microbiome diversity measures and mycophenolate Cmax with one week of mycophenolate mofetil treatment.
association between microbiome diversity and 12-hour tacrolimus AUC	1 year	Association between microbiome diversity measures and AUC0-tau of tacrolimus
effects of mycophenolate mofetil treatment on gut microbiome changes in treatment naïve patients and associated mycophenolate AUC changes	1 week	Changes in microbiome diversity measures and mycophenolate AUC0-tau, with one week of mycophenolate mofetil treatment.
investigate if Torque Teno Virus (TTV) is a clinical useful "immunometer", i.e. reflect overall immunosuppression of the recipient	1 year	Associations between TTV viral load (DNAemia) and opportunistic bacterial infections requiring hospitalization
Association between microbiome diversity measures and Cmax of tacrolimus	1 year	Association between microbiome diversity measures and Cmax of tacrolimus
Association between microbiome diversity measures and absolute bioavailability (F) of tacrolimus	1 year	Association between microbiome diversity measures and F of tacrolimus
effects of mycophenolate mofetil treatment on gut microbiome changes in treatment naïve patients and associated mycophenolate time to Cmax (Tmax) changes	1week	Changes in microbiome diversity measures and mycophenolate Tmax with one week of mycophenolate mofetil treatment.
effects of tacrolimus treatment on gut microbiome changes in treatment naïve patients and associated tacrolimus time to Cmax (Tmax) changes	1 week	Changes in microbiome diversity measures and tacrolimus Tmax with one week of tacrolimus treatment.
effects of mycophenolate mofetil treatment on gut microbiome changes in treatment naïve patients and associated mycophenolate time to terminal phase elimination rate constant (kel)changes	1 week	Changes in microbiome diversity measures and mycophenolate kel with one week of mycophenolate mofetil treatment.
effects of tacrolimus treatment on gut microbiome changes in treatment naïve patients and associated tacrolimus time to terminal phase elimination rate constant (kel) changes	1 week	Changes in microbiome diversity measures and tacrolimus kel with one week of tacrolimus treatment.

Trial Locations

Locations (1)

Oslo University Hospital; 🇳🇴 Oslo, Norway