Clinical trial NCT04207177: Immunosuppressive Drugs and Gut Microbiome: Pharmacokinetic- and Microbiome Diversity Effects
Official title: Immunosuppressive Drugs and Gut Microbiome: Pharmacokinetic- and Microbiome Diversity Effects
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE4
Conditions: Kidney Transplant; Complications
Immune Suppression
Lead sponsor: Oslo University Hospital
Sponsor class: OTHER
First posted: 2019-12-20
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: The main study is based on treatment allocation outside of thsi protocol but a subgroup of living donor recipients will be randomized to wither one week tacrolimus or mycophenolate mofetil treatment before transplantation.
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: 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.

Primary outcomes:
measure: investigate the association between microbiome diversity and 12-hour mycophenolate area under the curve (AUC)
timeFrame: 1 year
measure: investigate the association between microbiome diversity and 12-hour mycophenolate Maximum concentration (Cmax)
timeFrame: 1 year
Secondary outcomes:
measure: association between microbiome diversity and 12-hour tacrolimus AUC
timeFrame: 1 year
measure: effects of mycophenolate mofetil treatment on gut microbiome changes in treatment naïve patients and associated mycophenolate AUC changes
timeFrame: 1 week
measure: investigate the effects of tacrolimus treatment on gut microbiome changes in treatment naïve patients and associated tacrolimus AUC changes
timeFrame: 1 week
measure: investigate if Torque Teno Virus (TTV) is a clinical useful "immunometer", i.e. reflect overall immunosuppression of the recipient
timeFrame: 1 year
measure: Association between microbiome diversity measures and Cmax of tacrolimus
timeFrame: 1 year
measure: Association between microbiome diversity measures and absolute bioavailability (F) of tacrolimus
timeFrame: 1 year
measure: effects of mycophenolate mofetil treatment on gut microbiome changes in treatment naïve patients and associated mycophenolate Cmax changes
timeFrame: 1week
measure: effects of mycophenolate mofetil treatment on gut microbiome changes in treatment naïve patients and associated mycophenolate time to Cmax (Tmax) changes
timeFrame: 1week
measure: 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
timeFrame: 1 week
measure: effects of tacrolimus treatment on gut microbiome changes in treatment naïve patients and associated tacrolimus time to Cmax (Tmax) changes
timeFrame: 1 week
measure: effects of tacrolimus treatment on gut microbiome changes in treatment naïve patients and associated tacrolimus time to Cmax (Tmax) changes
timeFrame: 1 week
measure: effects of tacrolimus treatment on gut microbiome changes in treatment naïve patients and associated tacrolimus time to terminal phase elimination rate constant (kel) changes
timeFrame: 1 week
measure: investigate if Torque Teno Virus (TTV) is a clinical useful "immunometer", i.e. reflect overall immunosuppression of the recipient
timeFrame: 1 year
measure: investigate if Torque Teno Virus (TTV) is a clinical useful "immunometer", i.e. reflect overall immunosuppression of the recipient
timeFrame: 1 year
Other outcomes:
measure: integrate the updated knowledge on mycophenolate and tacrolimus pharmacokinetics following renal transplantation in a combined population pharmacokinetic model for individualized dosing
timeFrame: 1 year
measure: integrate the updated knowledge on mycophenolate and tacrolimus pharmacokinetics following renal transplantation in a combined population pharmacokinetic model for individualized dosing
timeFrame: 1 year
Locations:
city: Oslo
country: Norway
facility: Oslo University Hospital
Study officials:
affiliation: Oslo University Hospital
name: Karsten Midtvedt, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: