Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of BAR 502 in Healthy Subjects

Study Overview
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Brief Summary
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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.

Detailed Description
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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: To investigate the pharmacokinetics (PK) of single-ascending doses of BAR 502 in healthy male and female subjects; To investigate the pharmacodynamics (PD) of single-ascending doses of BAR 502 in healthy male and female subjects.

Official Title
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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

Conditions
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Non-Alcoholic Fatty Liver Disease

Intervention / Treatment
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* Drug: BAR502
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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. Exclusion Criteria: - At screening: Previous exposure to BAR 502. 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) > 1.2. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: A maximum of 4 BAR 502 dose levels are preplanned to be investigated in separate sequential cohorts. Each of these cohorts will consist of 8 healthy male and female subjects (3 subjects of either sex on active treatment, 1 of either sex on placebo). Each subject will participate in only one cohort.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BAR 502<br>Each subject will receive an oral single-dose of BAR 502. | Drug: BAR502<br>* Single oral doses of BAR 502/placebo will be administered as film-coated tablets, in the morning of Day 1, with 240 mL of water, after an overnight fasting of at least 8 hours. BAR 502 film-coated tablets are available at dose strengths of 10, 50 and 150 mg. A maximum of 4 dose levels are pre-planned (10 mg, 50 mg, 150 mg, 300 mg).<br>|
| Placebo Comparator: Placebo<br>Each subject will receive an oral single-dose of placebo. | Drug: Placebo<br>* Matching BAR 502 placebo film-coated tablets will be given to 2 out of 8 subjects in each cohort using the same regimen as outlined for the active study treatment<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Treatment-Emergent Adverse Events | Safety will be evaluated through the assessment of adverse events | Through study completion, an average of 2 months | 
| Assessment of physical examination | 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. | 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) | 
| Assessment of 12-lead electrocardiogram | 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). | 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 | 
| Change from baseline at each time point of measurement in supine blood pressure (both systolic and diastolic) | Safety will be evaluated through the assessment of vital signs (systolic and diastolic blood pressure) | 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). | 
| Change from baseline at each time point of measurement in pulse rate | Safety will be evaluated through the assessment of vital signs | 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).. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum concentration (Cmax) | Determination of BAR 502 concentrations in plasma, to investigate the pharmacokinetics | 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) | Determination of BAR 502 concentrations in plasma, to investigate the pharmacokinetics | 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); | Determination of BAR 502 concentrations in plasma, to investigate the pharmacokinetics | 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 | Determination of BAR 502 concentrations in plasma, to investigate the pharmacokinetics | 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) | Determination of BAR 502 concentrations in plasma to investigate the pharmacokinetics | 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) | Determination of BAR 502 concentrations in urine to investigate the pharmacokinetics | From treatment administration to day 4 of the study | 
| Area under the urine excretion curve (AUR) from time zero to last observed concentration (AURClast) | Determination of BAR 502 concentrations in urine to investigate the pharmacokinetics | From treatment administration to day 4 of the study | 
| Maximum rate of urinary excretion (Rmax) | Determination of BAR 502 concentrations in urine to investigate the pharmacokinetics | From treatment administration to day 4 of the study | 
| Percentage of drug recovered in urine (REC%) | Determination of BAR 502 concentrations in urine to investigate the pharmacokinetics | From treatment administration to day 4 of the study | 
| Time to Rmax (tumax) | Determination of BAR 502 concentrations in urine to investigate the pharmacokinetics | From treatment administration to day 4 of the study | 
| Renal clearance (CLR) | Determination of BAR 502 concentrations in urine to investigate the pharmacokinetics | From treatment administration to day 4 of the study | 
| Serum concentrations of total bile acids over time up to 24 hours post-dose | To investigate the pharmacodynamics | 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. | To investigate the pharmacodynamics (biomarkers of Farnesoid X Receptor (FXR) target engagement) | 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 C4 over time up to 24 hours post-dose. | To investigate the pharmacodynamics (biomarkers of Farnesoid X Receptor (FXR) target engagement) | 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. | To investigate the pharmacodynamics (marker of G protein-coupled bile acid-activated receptor 1 (GPBAR1) activation) | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Non-alcoholic fatty liver disease, healthy, BAR 502