Vitamin B1 Deficiency, Thiamine Deficiency
Conditions
Keywords
Drug-induced vitamin deficiency
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.
Interventions
DRUGTrimethoprim
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.
DRUGMetformin
1000mg of metformin will be given in combination with 5mg thiamine and compared to 5mg thiamine only in Part 1 of the study.
DIETARY_SUPPLEMENTVitamin B1
5mg of thiamine will be given alone and in combination for both Parts 1 and 2 of the study.
Sponsors
Tufts University
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
University of California, Davis
University of California, San Francisco
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
Part 1: Three-arm randomized crossover study design Part 2: Two-arm randomized crossover study design
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Concentration (Cmax) of Thiamine in Plasma Between the Combination Arm(s) and Single Agent Arm | The highest concentration of a thiamine observed in the blood plasma after drug administration | 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. Cmax is determined by taking blood samples at various time points after drug administration and analyzing the thiamine concentration in plasma. |
| Area Under the Curve From 0 to 24 (AUC0-24)Hours of Thiamine in Plasma Between the Combination Arm(s) and Single Agent Arm | 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. | 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. AUC0-24 (Area Under the Curve from 0 to 24 hours) is a pharmacokinetic (PK) parameter that represents the total drug exposure in the body over a 24-hour period. It is calculated as the area under the plasma thiamine concentration vs. time curve (from time zero to 24 hours after drug administration). |
Countries
United States
Participant flow
Pre-assignment details
7 subjects were randomized into one of two arms; each arm had two cycles (which were separated by a washout period of 5-14 days), and each cycle was three days in duration. During the Cycle 1, subjects were administered either a) 5 mg thiamine (n = 4) or b) 5 mg thiamine and 300 mg trimethoprim with 500 mL of water (n = 3). And during the Cycle 2, patients receive the other treatment.
Participants by arm
| Arm | Count |
|---|---|
| Thiamine Alone, Thiamine Co-administered With Trimethoprim Subjects were randomized into one of two arms; each arm had two cycles (which were separated by a washout period of 5-14 days), and each cycle was three days in duration. During the Cycle 1, subjects were administered either a) 5 mg thiamine (n = 4) or b) 5 mg thiamine and 300 mg trimethoprim with 500 mL of water (n = 3). And during the Cycle 2, patients receive the other treatment. | 7 |
| Total | 7 |
Baseline characteristics
| Characteristic | Thiamine Alone, Thiamine Co-administered With Trimethoprim |
|---|---|
| Age, Continuous | 46 years STANDARD_DEVIATION 15 |
| Baseline Thiamine (Thiamine arm) | 12.3 nM STANDARD_DEVIATION 24 |
| Baseline Thiamine (Trimethoprim + Thiamine arm) | 4.5 nM STANDARD_DEVIATION 4.3 |
| BMI | 26.4 kg/m^2 STANDARD_DEVIATION 4.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Height | 170 cm STANDARD_DEVIATION 7.3 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 3 Participants |
| Weight | 76 kg STANDARD_DEVIATION 16 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 7 | 0 / 7 |
| other Total, other adverse events | 0 / 7 | 0 / 7 |
| serious Total, serious adverse events | 0 / 7 | 0 / 7 |
Outcome results
Primary
Area Under the Curve From 0 to 24 (AUC0-24)Hours of Thiamine in Plasma Between the Combination Arm(s) and Single Agent Arm
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. AUC0-24 (Area Under the Curve from 0 to 24 hours) is a pharmacokinetic (PK) parameter that represents the total drug exposure in the body over a 24-hour period. It is calculated as the area under the plasma thiamine concentration vs. time curve (from time zero to 24 hours after drug administration).
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Thiamine Alone | Area Under the Curve From 0 to 24 (AUC0-24)Hours of Thiamine in Plasma Between the Combination Arm(s) and Single Agent Arm | 50 nM*hr | Standard Deviation 30 |
| Thiamine Co-administered With Trimethoprim | Area Under the Curve From 0 to 24 (AUC0-24)Hours of Thiamine in Plasma Between the Combination Arm(s) and Single Agent Arm | 189 nM*hr | Standard Deviation 138 |
Primary
Maximum Concentration (Cmax) of Thiamine in Plasma Between the Combination Arm(s) and Single Agent Arm
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. Cmax is determined by taking blood samples at various time points after drug administration and analyzing the thiamine concentration in plasma.
Time frame: The highest concentration of a thiamine observed in the blood plasma after drug administration
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Thiamine Alone | Maximum Concentration (Cmax) of Thiamine in Plasma Between the Combination Arm(s) and Single Agent Arm | 15 nM | Standard Deviation 9.5 |
| Thiamine Co-administered With Trimethoprim | Maximum Concentration (Cmax) of Thiamine in Plasma Between the Combination Arm(s) and Single Agent Arm | 32 nM | Standard Deviation 22 |