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

Kidney Transplant; Complications Clinical Trial

— MicrobioTac  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04207177
• Other study ID #: MicrobioTac-MPA
• Status: Active, not recruiting
• Phase: Phase 4
• Start date: October 30, 2019
• Est. completion date: December 31, 2025

Study information

• Verified date: April 2024
• Source: Oslo University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 100
• Est. completion date: December 31, 2025
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Immune Suppression
• Kidney Transplant; Complications

Intervention

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.
• 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.

Locations

Country	Name	City	State
Norway	Oslo University Hospital	Oslo

Sponsors (1)

Lead Sponsor	Collaborator
Oslo University Hospital

Country where clinical trial is conducted

Norway, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Primary	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
Primary	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	association between microbiome diversity and 12-hour tacrolimus AUC	Association between microbiome diversity measures and AUC0-tau of tacrolimus	1 year
Secondary	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
Secondary	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
Secondary	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
Secondary	Association between microbiome diversity measures and Cmax of tacrolimus	Association between microbiome diversity measures and Cmax of tacrolimus	1 year
Secondary	Association between microbiome diversity measures and absolute bioavailability (F) of tacrolimus	Association between microbiome diversity measures and F of tacrolimus	1 year
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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