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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Oslo University Hospital HF

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Phenomena and Processes [G] - Microbiological Phenomena [G06]

Trial duration

22 May 2024 → ongoing

Decision date (initial)

2024-05-22

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2023-510486-10-00

EudraCT number

2019-002476-14

ClinicalTrials.gov

NCT04207177

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacokinetic

To investigate the association between microbiome diversity and 12-hour mycophenolate pharmacokinetics

Secondary objectives 9

1. To investigate the association between microbiome diversity and 12-hour tacrolimus pharmacokinetics
2. To investigate the effects of mycophenolate mofetil treatment on gut microbiome changes in treatment naïve patients and associated mycophenolate 12-hour pharmacokinetic changes.
3. To investigate the effects of tacrolimus treatment on gut microbiome changes in treatment naïve patients and associated tacrolimus 12-hour pharmacokinetic changes.
4. To investigate the indirect association between microbiome diversity and immunosuppressant molecular pharmacodynamics (PD biomarkers).
5. To compare gut microbiome diversity after kidney transplantation in Norwegian and US patients.
6. Investigate if TTV is a clinical useful “immunometer”, i.e. reflect overall immunosuppression of the recipient.
7. Investigate whether immunosuppressant molecular pharmacodynamics (cytokine responses, intracellular drug and drug target levels and down-stream mediators) can be predictive for rejection and adverse effects.
8. To integrate the updated knowledge on mycophenolate and tacrolimus pharmacokinetics following renal transplantation in a combined population pharmacokinetic model for individualized dosing.
9. Investigate the link between tacrolimus blood concentrations and tacrolimus induced tremor in a PKPD model.

Conditions and MedDRA coding

Kidney transplantation

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

1. De novo, standard risk kidney (only) transplant recipients.
2. Patients scheduled to receive tacrolimus and mycophenolate mofetil as part of their immunosuppressive therapy following transplantation (clinical decision not influenced by this study).
3. First kidney transplant only.
4. Recipients of kidney from deceased or living adult donor
5. ABO-compatible transplantation
6. PRA ≤20%
7. DSA negative
8. Signed informed consent and expected cooperation of the patients for the treatment and follow up must be obtained and documented according to ICH GCP, and national/local regulations.

Exclusion criteria 1

1. Pregnant or lactating female patients.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Association between microbiome diversity measures and AUC0-tau and Cmax of mycophenolate and metabolites.

Secondary endpoints 9

1. Association between microbiome diversity measures and absolute F, AUC0-tau and Cmax of tacrolimus and metabolites.
2. Changes in microbiome diversity measures and mycophenolate (and metabolite) AUC0-tau, Cmax, Tmax and kel with one week of mycophenolate mofetil treatment.
3. Changes in microbiome diversity measures and tacrolimus (and metabolite) AUC0-tau, Cmax, Tmax and kel with one week of tacrolimus treatment
4. To investigate the indirect association between microbiome diversity and immunosuppressant molecular pharmacodynamics (PD biomarkers).
5. Descriptive comparison of microbiome diversity measures between the two populations.
6. Associations between TTV viral load and immunosuppressive drug systemic exposure, acute rejection episodes, protocol biopsy scores and other opportunistic infections, e.g. CMV and BK DNAemia and incidence of bacterial infections.
7. Investigate whether immunosuppressant molecular pharmacodynamics (cytokine responses, intracellular drug and drug target levels and down-stream mediators) can be predictive for rejection and adverse effects.
8. Relative predictive error (PE%) and root mean squared error (RMSE%) of the developed pharmacokinetic model.
9. Relative predictive error (PE%) and root mean squared error (RMSE%) of the developed PKPD model

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Oslo University Hospital HF

Sponsor organisation

Oslo University Hospital HF

Address

Taarnbygget, Kirkeveien 166 Kirkeveien 166

City

Oslo

Postcode

0450

Country

Norway

Scientific contact point

Organisation

Oslo University Hospital HF

Contact name

Anders Åsberg

Public contact point

Organisation

Oslo University Hospital HF

Contact name

Anders Åsberg

Locations

1 EU/EEA country · 1 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

1 submissions — initial application plus substantial / non-substantial modifications