Clinical trial NCT03746106: 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
Overall status: COMPLETED
Phase: PHASE4
Conditions: Vitamin B1 Deficiency
Thiamine Deficiency
Keywords: Drug-induced vitamin deficiency
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Tufts University
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: University of California, Davis
First posted: 2018-11-19
Enrollment: 7
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Part 1: Three-arm randomized crossover study design Part 2: Two-arm randomized crossover study design
Primary purpose: BASIC_SCIENCE

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.

Eligibility criteria: Inclusion Criteria:

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

Exclusion Criteria:

1. Subjects who are pregnant, breastfeeding, or unwilling to practice birth control during participation in the study.
2. Self-reported severe food allergies or diet restrictions (vegans, vegetarians, Atkins, Fodmap, etc.) that would prevent consumption of study diets.
3. Subjects with extreme obesity (BMI \> 35).
4. 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.
5. Subjects with any disease affecting or impairing the function of the liver, kidney or heart.
6. Subjects with moderate to severe hypertension.
7. Subjects with diabetes mellitus, hyperthyroidism, hypothyroidism, cardiovascular disease, glaucoma.
8. Subjects with gastrointestinal disease, gastrointestinal disorder, or gastrointestinal surgery.
9. 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).
10. 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.
11. 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.
12. Subjects with possible folate deficiency.
13. Subjects taking any other clinically significant drugs as judged by the investigator.
14. 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.
15. Female subjects undergoing treatment for infertility or hormone replacement therapy (Volunteers using hormonal birth control will not be excluded).
16. Subjects who have taken antimalarials in the past 60 days.
17. Participating in another research study while participating in this research study.
18. Non-English speaking
19. Subjects with abnormal laboratory results at screening as judged by the investigator or study physician.

Primary outcomes:
measure: Maximum Concentration (Cmax) of Thiamine in Plasma Between the Combination Arm(s) and Single Agent Arm
timeFrame: The highest concentration of a thiamine observed in the blood plasma after drug administration
measure: Area Under the Curve From 0 to 24 (AUC0-24)Hours of Thiamine in Plasma Between the Combination Arm(s) and Single Agent Arm
timeFrame: Plasma samples were collected at pre-dose and 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 10, 12, and 24 hours post-dose for each cycle.
Secondary outcomes:
Other outcomes:
Locations:
city: Boston
country: United States
facility: Jean Mayer USDA Human Nutrition Research Center on Aging
state: Massachusetts
Study officials:
affiliation: University of California, San Francisco
name: Kathleen M Giacomini
role: PRINCIPAL_INVESTIGATOR
affiliation: Tufts University
name: Andrew S Greenberg
role: PRINCIPAL_INVESTIGATOR
References: