Dose-dependent Kinetics of Thiamin in Healthy Volunteers With and Without Functional OCT1 Hepatic Transporters

Healthy Clinical Trial

— THIAMO-1  

Official title:

Cross-over Randomized Study to Determine Dose-dependent Kinetics of Thiamin in Healthy Volunteers With and Without Functional OCT1 Hepatic Transporters

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06122701
• Other study ID #: IPHA-2023-007
• Status: Not yet recruiting
• Phase: N/A
• Start date: November 20, 2023
• Est. completion date: December 2024

Study information

• Verified date: November 2023
• Source: University Medicine Greifswald
• Contact: Stefan Engeli, Prof.
• Phone: +49 3834865633
• Email: stefan.engeli[@]med.uni-greifswald.de
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This study investigates the differences in thiamin (vitamin B1) kinetic parameters in two cohorts of healthy volunteers:

Cohort 1) OCT1 wild type genotypes n = 12 Cohort 2) OCT1 deficient genotypes n = 12 Participants will be selected according to their OCT1 genotypes and to achieve best matching according to sex, age, BMI, alcohol consumption, and smoking between Cohort 1 and 2, respectively.

The purpose of this study is:

1. To determine the influence of OCT1 genetic variants on dose-dependent thiamin kinetics after oral administration.

2. To elucidate whether OCT1 genetic variants impact the kinetic properties of orally vs. intravenously administered thiamin.

Description:

The study is designed as a 4-arm cross-over, open-label, randomized single oral dose comparison (5 mg, 10 mg, 50 mg, and 200 mg thiamin). A fifth arm applying thiamin intravenously with a dose selected based on results from the four oral arms is also planned.

A single oral dose of thiamin will be administered in four intervention arms (arm 1: 200 mg, arm 2: 50 mg, arm 3: 10 mg, arm 4: 5 mg) as a drinking solution with 240 ml of still water after an overnight fast. These four arms will be put into practice at the same time with each participant completing all four arms in random order with a wash-out period of at least one week between each arm.

After analyzing the four oral arms, we will administer a single i.v. dose of thiamin in arm 5 at a later time point. The dosage will be determined after analyzing the results of orally administered thiamin in arm 2 to 4.

A total of 15 blood samples will be taken at defined time points (baseline; 0.25; 0.5; 0.75; 1.0; 1.5; 2.0; 2.5; 3.0; 3.5; 4.0; 6.0; 8.0; 10.0; 24.0 h). At each time point, blood will be collected (4.9 ml for plasma and 2.7 ml for whole blood) to determine thiamin, TMP and TDP, and biomarkers of OCT1 transport activity. At baseline, 2x 2.7 ml EDTA blood samples will be collected for DNA isolation if the particular volunteer has not had a genotypical validation in another study of our Institute.

The total amount of blood collected for each participant is 456 ml at eight kinetic visits and 10 ml at the Screening.

After intake of the thiamin solution, participants will drink 100 ml of sparkling water every hour to stimulate gastrointestinal peristalsis. After 4 hours the participants will be served a meal low in thiamin content. Urine will be collected during the first 10 hours after thiamin administration. Monitoring of blood pressure and heart rate will take place for the first 4 hours after administration. Volunteers will stay in the Clinical Research Unit of the Institute of Pharmacology for the first 10 hours after administration.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 24
• Est. completion date: December 2024
• Est. primary completion date: December 2024
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

Inclusion Criteria:

1. any sex

2. age between 18 and 50 years

3. OCT1 wild type: homozygous for OCT1*1 OCT "poor transporter": homozygous or heterozygous for OCT1*3, *4, *5, *6

4. understands the study purpose and design

5. contractually capable and provides signed informed consent form

6. healthy condition or mild and/or well-treated forms of allergies, asthma, hypertension, and orthopedic diseases

7. a maximum of 3 chronically taken drugs not interfering with OCT1 activity

Exclusion Criteria:

1. BMI > 32 kg/m2 and < 17 kg/m2

2. body weight < 48 kg

3. known pregnancy or lactation period

4. women: positive urine pregnancy test at screening or kinetic visit 1 of each arm

5. men: hemoglobin < 13 g/dl (8,07 mmol/l) women: hemoglobin < 12 g/dl (7,45 mmol/l)

6. elevated liver function tests (1 or more of ALAT, ASAT, yGT, Bilirubin > 2x ULN)

7. reduced renal function (eGFRMDRD < 60 ml/min/1,7 m2)

8. QTcF > 450 ms in screening ECG

9. psychiatric disease requiring recent or actual treatment

10. drug dependency at the time of visit

11. use of recreational drugs more than twice a week

12. any known hypersensitivity or allergic reactions to thiamin

13. history of severe hypersensitivity reactions and/or anaphylaxis

14. clinically proven vitamin B1 deficiency

15. individuals taking regular vitamin B1 or multi-vitamin supplements who are not willing to comply with a 48-hour washout of these supplements before each kinetic visit

16. individuals who have taken vitamin B supplements or multi-vitamins in the past 2 days before kinetic visit 1 of each arm

17. poor venous conditions that make it impossible to place a peripheral venous catheter and regularly draw blood through it

Related Conditions & MeSH terms

• Healthy

Intervention

Dietary Supplement:
• Thiamin
A single oral dose of thiamin will be administered in four intervention arms (arm 1: 200 mg, arm 2: 50 mg, arm 3: 10 mg, arm 4: 5 mg) as a drinking solution with 240 ml of still water after an overnight fast. A total of 15 blood samples will be taken at defined time points (baseline; 0.25; 0.5; 0.75; 1.0; 1.5; 2.0; 2.5; 3.0; 3.5; 4.0; 6.0; 8.0; 10.0; 24.0 h). At each time point, blood will be collected (4.9 ml for plasma and 2.7 ml for whole blood) to determine thiamin, TMP and TDP, and biomarkers of OCT1 transport activity. Urine will be collected during the first 10 hours after thiamin administration.

Locations

Country	Name	City	State
Germany	University Medicine Greifswald, Institute of Pharmacology	Greifswald	Mecklenburg-Vorpommern

Sponsors (1)

Lead Sponsor	Collaborator
University Medicine Greifswald

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Thiamin whole blood concentrations expressed as Area under the Curve (AUC0-24 hours)	Difference in thiamin whole blood concentrations expressed as Area under the Curve (AUC0-24 hours) between OCT1 wild type and OCT1 deficiency cohorts (Cohort 1 vs. Cohort 2) in each dose arm	24 hours
Secondary	Thiamin plasma concentrations expressed as Area under the Curve (AUC0-24 hours)	Difference in thiamin plasma concentrations expressed as Area under the Curve (AUC0-24 hours) between OCT1 wild type and OCT1 deficiency cohorts (Cohort 1 vs. Cohort 2) in each dose arm	24 hours
Secondary	Cmax of thiamin and its phosphorylated esters, TMP and TDP	Differences in Cmax of thiamin and its phosphorylated esters, TMP and TDP, between the above-described cohorts in each dose arm	24 hours
Secondary	Tmax of thiamin and its phosphorylated esters, TMP and TDP	Differences in Tmax of thiamin and its phosphorylated esters, TMP and TDP, between the above-described cohorts in each dose arm	24 hours
Secondary	Total and renal clearance of thiamin and its phosphorylated esters, TMP and TDP	Differences in total and renal clearance of thiamin and its phosphorylated esters, TMP and TDP, between the above-described cohorts in each dose arm	24 hours
Secondary	Apparent volume of distribution of thiamin and its phosphorylated esters, TMP and TDP	Differences in the apparent volume of distribution of thiamin and its phosphorylated esters, TMP and TDP, between the above-described cohorts in each dose arm	24 hours
Secondary	Plasma concentrations of known endogenous biomarkers such as isobutyrylcarnitine and propionylcarnitine	Changes in plasma concentrations of known endogenous biomarkers such as isobutyrylcarnitine and propionylcarnitine measured at all time points following thiamin administration	24 hours