Cross-over Randomized Study to Determine Dose-dependent Kinetics of Thiamin in Healthy Volunteers with and Without Functional OCT1 Hepatic Transporters
试验速览
- 阶段
- 不适用
- 状态
- Enrolling By Invitation
- 发起方
- 入组人数
- 36
- 试验地点
- 2
- 主要终点
- Thiamin plasma concentrations expressed as Area under the Curve (AUC0-24 hours)
研究概览
简要总结
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:
- To determine the influence of OCT1 genetic variants on dose-dependent thiamin kinetics after oral administration.
- To elucidate whether OCT1 genetic variants impact the kinetic properties of orally vs. intravenously administered thiamin.
详细描述
The study is designed as a 5-arm cross-over, open-label, randomized single oral dose comparison (5 mg, 10 mg, 50 mg, and 200 mg thiamin). A fifth arm includes applying 5 mg thiamin intravenously.
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 decided to administer a single i.v. dose of 5 mg thiamin in arm 5.
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- None
盲法说明
This study is an opel-label study.
入排标准
- 年龄范围
- 18 Years 至 50 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •age between 18 and 50 years
- •OCT1 wild type: homozygous for OCT1*1 OCT "poor transporter": homozygous or heterozygous for OCT1*3, *4, *5, *6
- •understands the study purpose and design
- •contractually capable and provides signed informed consent form
- •healthy condition or mild and/or well-treated forms of allergies, asthma, hypertension, and orthopedic diseases
- •a maximum of 3 chronically taken drugs not interfering with OCT1 activity
排除标准
- •BMI > 32 kg/m2 and < 17 kg/m2
- •body weight < 48 kg
- •known pregnancy or lactation period
- •women: positive urine pregnancy test at screening or kinetic visit 1 of each arm
- •men: hemoglobin < 13 g/dl (8,07 mmol/l) women: hemoglobin < 12 g/dl (7,45 mmol/l)
- •elevated liver function tests (1 or more of ALAT, ASAT, yGT, Bilirubin > 2x ULN)
- •reduced renal function (eGFRMDRD < 60 ml/min/1,7 m2)
- •QTcF > 450 ms in screening ECG
- •psychiatric disease requiring recent or actual treatment
- •drug dependency at the time of visit
- •use of recreational drugs more than twice a week
- •any known hypersensitivity or allergic reactions to thiamin
- •history of severe hypersensitivity reactions and/or anaphylaxis
- •clinically proven vitamin B1 deficiency
- •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
- •individuals who have taken vitamin B supplements or multi-vitamins in the past 2 days before kinetic visit 1 of each arm
- •poor venous conditions that make it impossible to place a peripheral venous catheter and regularly draw blood through it
结局指标
主要结局
Thiamin plasma concentrations expressed as Area under the Curve (AUC0-24 hours)
时间窗: 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
次要结局
- Cmax of thiamin and its phosphorylated esters, TMP and TDP(24 hours)
- Tmax of thiamin and its phosphorylated esters, TMP and TDP(24 hours)
- Total and renal clearance of thiamin and its phosphorylated esters, TMP and TDP(24 hours)
- Apparent volume of distribution of thiamin and its phosphorylated esters, TMP and TDP(24 hours)
- Plasma concentrations of known endogenous biomarkers such as isobutyrylcarnitine and propionylcarnitine(24 hours)
研究者
Stefan Engeli, MD
Prof. Dr. med Stefan Engeli
University Medicine Greifswald