Immunosuppressive Drugs and Gut Microbiome: Pharmacokinetic- and Microbiome Diversity Effects (MicrobioTac)

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Kidney Transplant; Complications; Immune Suppression
• Intervention / Treatment: Drug: Mycophenolate Mofetil 500 mg Tab; Drug: Tacrolimus capsule

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 Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 4

Contacts and Locations

Study Locations

• Norway
  • Oslo, Norway, 0424
    • Oslo University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Mycophenolate mofetil; In the subgroup of living donor recipients included before transplantation this group will be treated with mycophenolate mofetil (750 mg BID) for one week	Drug: Mycophenolate Mofetil 500 mg Tab; Twice daily dosing of MMF only for a week before transplantation in this subgroup. All patients will get maintenance treatment With MMF in combination With tacrolimus and steroids after transplantation.; Other Names: MMF-arm
Active Comparator: Tacrolimus; In the subgroup of living donor recipients included before transplantation this group will be treated with tacrolimus (BID, dose by weight) for one week	Drug: Tacrolimus capsule; Twice daily dosing of tacrolimus only for a week before transplantation in this subgroup. All patients will get maintenance treatment With tacrolimus in combination With MMF and steroids after transplantation.; Other Names: Tac-arm

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
integrate the updated knowledge on mycophenolate and tacrolimus pharmacokinetics following renal transplantation in a combined population pharmacokinetic model for individualized dosing	Relative predictive error (PE%) of the developed pharmacokinetic model	1 year
integrate the updated knowledge on mycophenolate and tacrolimus pharmacokinetics following renal transplantation in a combined population pharmacokinetic model for individualized dosing	Relative root mean squared error (RMSE%) of the developed pharmacokinetic model	1 year

Collaborators and Investigators

• Sponsor: Oslo University Hospital
• Investigators: Principal Investigator: Karsten Midtvedt, MD, PhD, Oslo University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): October 30, 2019
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 31, 2025

Study Registration Dates

• First Submitted: December 17, 2019
• First Submitted That Met QC Criteria: December 18, 2019
• First Posted (Actual): December 20, 2019

Study Record Updates

• Last Update Posted (Actual): April 4, 2024
• Last Update Submitted That Met QC Criteria: April 3, 2024
• Last Verified: April 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antitubercular Agents; Antibiotics, Antitubercular; Calcineurin Inhibitors; Tacrolimus; Mycophenolic Acid
• Other Study ID Numbers: MicrobioTac-MPA

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Not allowed by Norwegian Law to share data without specific contract. Upon contact With the responsible investigator it is however possible to share data under a specified contract

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No