Randomized, Double-Blind, Placebo-Controlled, Phase 1 Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Single-Ascending Doses of BAR 502 in Healthy Subjects
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 试验地点
- 1
- 主要终点
- Incidence of Treatment-Emergent Adverse Events
研究概览
简要总结
This is a prospective, single-center, randomized, double-blind, placebo-controlled, single-ascending dose (SAD) phase 1 study to evaluate the safety and tolerability of single-ascending doses of BAR 502 in healthy male and female subjects.
详细描述
This clinical trial will be the first-in-Human (FiH) study of BAR 502.
This study is planned to investigate up to 4 dose levels of BAR 502. Each dose level will consist of 8 healthy male and female subjects (ratio 1:1, male: female) to have 6 subjects being administered BAR 502 and 2 subjects being administered placebo (ratio 3:1, active: placebo).
The study is designed to meet the following objectives:
-
Primary:
-
To evaluate the safety and tolerability of single-ascending doses of BAR 502 in healthy male and female subjects.
-
Secondary:
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Other
- 盲法
- Double (Participant, Investigator)
盲法说明
Double-blind
入排标准
- 年龄范围
- 18 Years 至 55 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Signed informed consent in a language understandable to the subject prior to any study-mandated procedure.
- •Ability to communicate well with the investigator, and to understand and comply with the study requirements.
- •Healthy male or female subject aged between 18 and 55 years (inclusive) at Screening.
- •Body mass index (BMI) of 18.0 to 30.0 kg/m2 (inclusive) at Screening.
- •Systolic blood pressure (SBP) 90-140 mmHg, diastolic blood pressure (DBP) 50-90 mmHg, and pulse rate 45-90 bpm (inclusive), measured on same arm after ≥5 min in the seated position, at Screening.
- •Estimated glomerular filtration rate calculated using the Cockcroft-Gault equation and normalized to an average surface area of 1.73 m2 ≥ 90 mL/min at Screening.
- •If woman, she meets one of the following criteria:
- •is of non-childbearing potential; or
- •is of childbearing potential and agrees to use an accepted non-hormonal or hormonal contraceptive method.
- •If man, he is infertile, vasectomized (i.e. who has received medical assessment of the surgical success) or agrees to abstain from or to use a condom during heterosexual intercourse with a woman of childbearing potential or a pregnant woman, and agrees not to donate sperm, from investigational product administration until at least 90 days after the investigational product administration. In addition, the subject must ensure that his female partner of childbearing potential agrees to consistently and correctly use one of the acceptable contraceptive methods mentioned above, for the same period of time.
排除标准
- •At screening:
- •Previous exposure to BAR
- •Known hypersensitivity to BAR 502, or any of its excipients.
- •Clinically relevant findings on physical examination.
- •Clinically relevant abnormalities on 12-lead ECG, measured after 5 min in a supine position.
- •Clinically relevant findings in clinical laboratory tests (hematology, clinical chemistry, and urinalysis).
- •QTcF > 450 ms in males and > 470 ms in females.
- •Medical history and/or clinical or laboratory evidence of liver or hepatobiliary disease or liver injury as indicated by serum alanine aminotransferase (ALT), AST, gamma-glutamyl transferase (GGT), ALP or total bilirubin levels exceeding the upper limit of normal (ULN).
- •International Normalized Ratio (INR) > 1.
- •Any medical condition, acute, ongoing, recurrent or chronic, that presents a potential risk to the participant and/or that may compromise the objectives of the study.
- •History of major medical or surgical disorders which, in the opinion of the investigator, are likely to interfere with the distribution, metabolism, or excretion of the investigational product.
- •History or clinical evidence of alcoholism or drug abuse within the 3-year period prior to Screening.
- •Previous clinically relevant history of fainting, collapse, syncope, orthostatic hypotension, or vasovagal reactions.
- •Veins unsuitable for intravenous puncture on either arm (e.g., veins that are difficult to locate, access, or puncture, veins with a tendency to rupture during or after puncture).
- •Participation in a clinical study involving investigational product administration within 3 months prior to Screening or in more than 2 clinical studies within 1 year prior to Screening.
- •Excessive methylxanthines consumption, defined as ≥ 800 mg per day.
- •Nicotine intake (e.g., smoking, nicotine patch, nicotine chewing gum, or electronic cigarettes) within 3 months prior to Screening and inability to refrain from nicotine intake from Screening up to End-of-Study (EOS).
- •Loss of 250 mL or more of blood within 3 months prior to Screening.
- •Positive hepatitis B surface antigen (HBsAg) and/or hepatitis C virus antibodies.
- •Positive human immunodeficiency virus (HIV1 and HIV2) antibodies.
- •Positive results in urine drugs-of-abuse, cotinine or ethanol tests.
- •If woman, she is breastfeeding.
- •Positive result in serum pregnancy test.
- •Any other circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol or may render the subject unsuitable for the study.
- •At admission to treatment period:
- •Positive or inconclusive SARS-CoV-2 test result using polymerase chain reaction (PCR) technology prior to Admission to the clinical site.
- •Any recent disease or condition or treatment that, according to the Investigator, would put the subject at undue risk due to study participation or occurred at a timeframe in which may interfere with the study outcomes.
- •Clinically relevant findings on physical examination.
- •Clinically relevant abnormalities on 12-lead ECG, measured after 5 min in a supine position.
- •Clinically relevant findings in clinical laboratory tests.
- •Use of prescription or nonprescription medicinal products, including vitamins, food supplements, herbal supplements (including St John's Wort), within 3 weeks prior to study treatment administration, unless in the Investigator's opinion the medication does not interfere with the pharmacokinetics of study drug or compromise subject safety.
- •Consumption of Seville oranges, pomelo, pomegranate, starfruit or grapefruit products (fresh, canned, or frozen) since Screening.
- •Positive result in urine drugs-of-abuse, cotinine or ethanol tests.
- •Positive result in urine pregnancy test.
- •Any other condition that the investigator considers to render the subject unsuitable for the treatment period.
研究组 & 干预措施
BAR 502
Each subject will receive an oral single-dose of BAR 502.
干预措施: BAR502 (Drug)
Placebo
Each subject will receive an oral single-dose of placebo.
干预措施: Placebo (Drug)
结局指标
主要结局
Incidence of Treatment-Emergent Adverse Events
时间窗: Through study completion, an average of 2 months
Safety will be evaluated through the assessment of adverse events
Assessment of physical examination
时间窗: At screening (Day -21 to Day -3 for male and female subjects of non-childbearing potential, Day -28 to Day -7 for female subjects of childbearing potential) and end of study ( Day 8)
Safety will be evaluated through the assessment of physical examination, which will include: general appearance; skin; head and neck; thorax and abdomen; pulmonary auscultation; cardiac auscultation; abdomen palpation; limbs.
Assessment of 12-lead electrocardiogram
时间窗: At screening (Day -21 to Day -3 for male and female subjects of non-childbearing potential, Day -28 to Day -7 for female subjects of childbearing potential), admission (Day-1), and from day 1 to day 4 of the study
Safety will be evaluated through the assessment of 12-lead ECG. The following variables are to be collected on the eCRF: HR (bpm), and the intervals PR (ms), QRS (ms), QT (ms), QTcB (ms) and QTcF (ms).
Change from baseline at each time point of measurement in supine blood pressure (both systolic and diastolic)
时间窗: At screening (Day -21 to Day -3 for male and female subjects of non-childbearing potential, Day -28 to Day -7 for female subjects of childbearing potential), admission (Day -1), from Day 1 to Day 4 of the study, and at end of study (at Day 8).
Safety will be evaluated through the assessment of vital signs (systolic and diastolic blood pressure)
Change from baseline at each time point of measurement in pulse rate
时间窗: At screening (Day -21 to Day -3 for male and female subjects of non-childbearing potential, Day -28 to Day -7 for female subjects of childbearing potential), admission (Day -1), from day 1 to day 4 of the study, and at end of study (at Day 8)..
Safety will be evaluated through the assessment of vital signs
次要结局
- Serum concentrations of C4 over time up to 24 hours post-dose.(At admission, within 1 hour prior to study treatment administration, and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 16 and 24 hours after treatment administration)
- Serum concentrations of GLP-1 over time up to 24 hours post-dose.(At admission, within 1 hour prior to study treatment administration, and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 16 and 24 hours after treatment administration)
- Maximum concentration (Cmax)(Within 1 hour prior to treatment administration and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48 and 74 hours after treatment administration.)
- Time of occurrence of Cmax (Tmax)(Within 1 hour prior to treatment administration and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48 and 74 hours after treatment administration.)
- Area under the plasma concentration-time curve (AUC) from time zero to last sampling time with quantifiable concentrations (AUC0-t);(Within 1 hour prior to treatment administration and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48 and 74 hours after treatment administration.)
- AUC extrapolated to infinity(Within 1 hour prior to treatment administration and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48 and 74 hours after treatment administration.)
- Apparent terminal elimination rate constant (λz); and apparent terminal elimination half-life (t1/2)(Within 1 hour prior to treatment administration and at 0.25, 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16, 24, 36, 48 and 74 hours after treatment administration.)
- Cumulative amount of drug excreted in urine (AmtCUM)(From treatment administration to day 4 of the study)
- Area under the urine excretion curve (AUR) from time zero to last observed concentration (AURClast)(From treatment administration to day 4 of the study)
- Maximum rate of urinary excretion (Rmax)(From treatment administration to day 4 of the study)
- Percentage of drug recovered in urine (REC%)(From treatment administration to day 4 of the study)
- Time to Rmax (tumax)(From treatment administration to day 4 of the study)
- Renal clearance (CLR)(From treatment administration to day 4 of the study)
- Serum concentrations of total bile acids over time up to 24 hours post-dose(At admission, within 1 hour prior to study treatment administration, and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 16 and 24 hours after treatment administration.)
- Serum concentrations of FGF19 over time up to 24 hours post-dose.(At admission, within 1 hour prior to study treatment administration, and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12 16 and 24 hours after treatment administration)