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The Effect of SLC19A3 Inhibition on the Pharmacokinetics of Thiamine

Primary Purpose

Vitamin B1 Deficiency, Thiamine Deficiency

Status

Completed

Phase

Phase 4

Locations

United States

Study Type

Interventional

Intervention

Trimethoprim

Metformin

Vitamin B1

About this trial

This is an interventional basic science trial for Vitamin B1 Deficiency focused on measuring Drug-induced vitamin deficiency

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Male or female between the ages of 18-65 years old.
Eats a wide variety of food and willing to consume study diet (i.e. not on a specific diet such as Atkins, Fodmap, etc.).
Written informed consent obtained from the subject and ability for subject to comply with the requirements of the study.

Exclusion Criteria:

Subjects who are pregnant, breastfeeding, or unwilling to practice birth control during participation in the study.
Self-reported severe food allergies or diet restrictions (vegans, vegetarians, Atkins, Fodmap, etc.) that would prevent consumption of study diets.
Subjects with extreme obesity (BMI > 35).
Subjects who are smokers or have smoked in the past year and/or have smoked or ingested THC/marijuana in the past week, or who are unwilling to comply with a 1-week washout.
Subjects with any disease affecting or impairing the function of the liver, kidney or heart.
Subjects with moderate to severe hypertension.
Subjects with diabetes mellitus, hyperthyroidism, hypothyroidism, cardiovascular disease, glaucoma.
Subjects with gastrointestinal disease, gastrointestinal disorder, or gastrointestinal surgery.
Subjects with known infection with HIV, Hepatitis B (HBsAg) or Hepatitis C (no laboratory diagnostics concerning these diseases will be performed within the present study. Volunteers who are cured of past HepC infection are eligible to participate with doctor's approval letter).
Alcohol use on average > 2 servings/day or > 14 servings/wk (Serving size: 12oz beer/4oz wine/2oz hard liquor) or self-reported binge drinking.
Subjects that are on vitamin B supplements or multi-vitamins or who have taken vitamin B supplements or multi-vitamins in the past 30 days, or are not willing to comply with a 30-day washout of vitamin B supplements.
Subjects with possible folate deficiency.
Subjects taking any other clinically significant drugs as judged by the investigator.
Subjects with a condition, disease, or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data.
Female subjects undergoing treatment for infertility or hormone replacement therapy (Volunteers using hormonal birth control will not be excluded).
Subjects who have taken antimalarials in the past 60 days.
Participating in another research study while participating in this research study.
Non-English speaking
Subjects with abnormal laboratory results at screening as judged by the investigator or study physician.

Sites / Locations

Jean Mayer USDA Human Nutrition Research Center on Aging

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Experimental

Arm Label

Thiamine only

Trimethporim + thiamine combination

Metformin + thiamine combination

Arm Description

5mg thiamine tablet by mouth. This arm will be included in both Parts 1 and 2 of the study.

5mg thiamine tablet and 300mg trimethoprim tablet by mouth. This arm will be included in both Parts 1 and 2 of the study.

5mg thiamine tablet and 1000mg metformin tablet by mouth. This arm will be included in only Part 1 of the study.

Outcomes

Primary Outcome Measures

Area Under the Concentration-Time Curve (AUC 0-72h)

Blood samples were obtained and plasma concentrations were determined using a validated high-pressure liquid chromatography method.

Assess the effects of SLC19A3 inhibitors by Cmax

In Parts 1 and 2, assess the effects of SLC19A3 inhibitors on the absorption and distribution of thiamine as measured by the change in maximum concentration (Cmax) between the combination arm(s) and single agent arm.

Secondary Outcome Measures

Investigate metabolic signatures reflecting the activity of TPP-dependent enzymes

In Parts 1 and 2, investigate metabolic signatures reflecting the activity of TPP-dependent enzymes after the administration of thiamine or a combination of the thiamine and SLC19A3 inhibitor. Metabolic signatures are measured in blood samples by LC-MS (measurement tool). The units of measure are relative abundance, which is expressed as a percentage of the total metabolites detected.

Determine the effect of genetic variants of thiamine transporters

The investigators will use Sanger Sequencing of two thiamine transporters (SLC19A2 and SLC19A3) to identify genetic variants in DNA extracted from blood samples. Sanger sequencing is done by Polymerase Chain Reaction (PCR) instrumentation and the unit of measure is single nucleotide polymorphism (SNPs) detected.

Full Information

NCT ID

NCT03746106

First Posted

November 8, 2018

Last Updated

August 10, 2023

Sponsor

University of California, San Francisco

Collaborators

Tufts University, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), University of California, Davis

1. Study Identification

Unique Protocol Identification Number

NCT03746106

Brief Title

The Effect of SLC19A3 Inhibition on the Pharmacokinetics of Thiamine

Official Title

The Effect of SLC19A3 Inhibition on the Pharmacokinetics of Thiamine

Study Type

Interventional

2. Study Status

Record Verification Date

August 2023

Overall Recruitment Status

Completed

Study Start Date

January 28, 2019 (Actual)

Primary Completion Date

August 10, 2023 (Actual)

Study Completion Date

August 10, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of California, San Francisco

Collaborators

Tufts University, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), University of California, Davis

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

In Part 1, subjects will be administered thiamine, thiamine with metformin, and thiamine with trimethoprim. Part 2 will expand on Part 1 and subjects will be administered thiamine and thiamine with trimethoprim. The goal is to determine whether taking a drug and a vitamin together affects the body's ability to absorb, distribute, and eliminate thiamine (Vitamin B1).

Detailed Description

Thiamine is an essential vitamin meaning humans must consume thiamine from their diet in order to stay healthy. Low thiamine levels can lead to adverse events. Thiamine is absorbed in the intestine by a transporter protein. This is made by the SLC19A3 gene. The SLC19A3 gene provides instructions for making the thiamine transporter protein, which moves thiamine into cells. Certain drugs, like metformin and trimethoprim, have been shown to interrupt function of the SLC19A3 gene. Metformin is a first-line therapy for patients with Type 2 diabetes and is associated with improvements in diabetic complications. Trimethoprim is an anti-bacterial drug that is often prescribed to treat infections such as urinary tract infections. At different phases of this study, participants will be administered thiamine, thiamine with metformin, and/or thiamine with trimethoprim to determine whether taking a drug and a vitamin together affects the body's ability to absorb, distribute, and eliminate thiamine. The levels of thiamine in the participants' blood and urine will be measured before and after taking thiamine or thiamine in combination with metformin and/or trimethoprim.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Vitamin B1 Deficiency, Thiamine Deficiency

Keywords

Drug-induced vitamin deficiency

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 4

Interventional Study Model

Crossover Assignment

Model Description

Part 1: Three-arm randomized crossover study design Part 2: Two-arm randomized crossover study design

Masking

None (Open Label)

Allocation

Randomized

Enrollment

7 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Thiamine only

Arm Type

Active Comparator

Arm Description

5mg thiamine tablet by mouth. This arm will be included in both Parts 1 and 2 of the study.

Arm Title

Trimethporim + thiamine combination

Arm Type

Experimental

Arm Description

5mg thiamine tablet and 300mg trimethoprim tablet by mouth. This arm will be included in both Parts 1 and 2 of the study.

Arm Title

Metformin + thiamine combination

Arm Type

Experimental

Arm Description

5mg thiamine tablet and 1000mg metformin tablet by mouth. This arm will be included in only Part 1 of the study.

Intervention Type

Drug

Intervention Name(s)

Trimethoprim

Other Intervention Name(s)

Primsol

Intervention Description

300mg of trimethoprim will be given in combination with 5mg thiamine and compared to 5mg thiamine only for both Parts 1 and 2 of the study.

Intervention Type

Drug

Intervention Name(s)

Metformin

Other Intervention Name(s)

Glucophage

Intervention Description

1000mg of metformin will be given in combination with 5mg thiamine and compared to 5mg thiamine only in Part 1 of the study.

Intervention Type

Dietary Supplement

Intervention Name(s)

Vitamin B1

Other Intervention Name(s)

Thiamine

Intervention Description

5mg of thiamine will be given alone and in combination for both Parts 1 and 2 of the study.

Primary Outcome Measure Information:

Title

Area Under the Concentration-Time Curve (AUC 0-72h)

Description

Blood samples were obtained and plasma concentrations were determined using a validated high-pressure liquid chromatography method.

Time Frame

As determined by blood/urine levels taken over the course of 2-3 cycles (each cycle is 3 days with a 5-14 day washout in between cycles)

Title

Assess the effects of SLC19A3 inhibitors by Cmax

Description

Time Frame

As determined by blood/urine levels taken over the course of 2-3 cycles (each cycle is 3 days with a 5-14 day washout in between cycles)

Secondary Outcome Measure Information:

Title

Investigate metabolic signatures reflecting the activity of TPP-dependent enzymes

Description

Time Frame

As determined by blood/urine levels taken over the course of 2-3 cycles (each cycle is 3 days with a 5-14 day washout in between cycles)

Title

Determine the effect of genetic variants of thiamine transporters

Description

Time Frame

As determined by blood/urine levels taken over the course of 2-3 cycles (each cycle is 3 days with a 5-14 day washout in between cycles)]

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

65 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Male or female between the ages of 18-65 years old. Eats a wide variety of food and willing to consume study diet (i.e. not on a specific diet such as Atkins, Fodmap, etc.). Written informed consent obtained from the subject and ability for subject to comply with the requirements of the study. Exclusion Criteria: Subjects who are pregnant, breastfeeding, or unwilling to practice birth control during participation in the study. Self-reported severe food allergies or diet restrictions (vegans, vegetarians, Atkins, Fodmap, etc.) that would prevent consumption of study diets. Subjects with extreme obesity (BMI > 35). Subjects who are smokers or have smoked in the past year and/or have smoked or ingested THC/marijuana in the past week, or who are unwilling to comply with a 1-week washout. Subjects with any disease affecting or impairing the function of the liver, kidney or heart. Subjects with moderate to severe hypertension. Subjects with diabetes mellitus, hyperthyroidism, hypothyroidism, cardiovascular disease, glaucoma. Subjects with gastrointestinal disease, gastrointestinal disorder, or gastrointestinal surgery. Subjects with known infection with HIV, Hepatitis B (HBsAg) or Hepatitis C (no laboratory diagnostics concerning these diseases will be performed within the present study. Volunteers who are cured of past HepC infection are eligible to participate with doctor's approval letter). Alcohol use on average > 2 servings/day or > 14 servings/wk (Serving size: 12oz beer/4oz wine/2oz hard liquor) or self-reported binge drinking. Subjects that are on vitamin B supplements or multi-vitamins or who have taken vitamin B supplements or multi-vitamins in the past 30 days, or are not willing to comply with a 30-day washout of vitamin B supplements. Subjects with possible folate deficiency. Subjects taking any other clinically significant drugs as judged by the investigator. Subjects with a condition, disease, or abnormality that in the opinion of the Investigator would compromise the safety of the patient or the quality of the data. Female subjects undergoing treatment for infertility or hormone replacement therapy (Volunteers using hormonal birth control will not be excluded). Subjects who have taken antimalarials in the past 60 days. Participating in another research study while participating in this research study. Non-English speaking Subjects with abnormal laboratory results at screening as judged by the investigator or study physician.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Kathleen M Giacomini

Organizational Affiliation

University of California, San Francisco

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Andrew S Greenberg

Organizational Affiliation

Tufts University

Official's Role

Principal Investigator

Facility Information:

Facility Name

Jean Mayer USDA Human Nutrition Research Center on Aging

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02111

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

The Effect of SLC19A3 Inhibition on the Pharmacokinetics of Thiamine

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