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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
DOUBLE
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).
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
BlueClinical Phase I
Porto, Portugal
Incidence of Treatment-Emergent Adverse Events
Safety will be evaluated through the assessment of adverse events
Time frame: 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.
Time frame: 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).
Time frame: 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)
Time frame: 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
Time frame: 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)..
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Maximum concentration (Cmax)
Determination of BAR 502 concentrations in plasma, to investigate the pharmacokinetics
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: From treatment administration to day 4 of the study
Time to Rmax (tumax)
Determination of BAR 502 concentrations in urine to investigate the pharmacokinetics
Time frame: From treatment administration to day 4 of the study
Renal clearance (CLR)
Determination of BAR 502 concentrations in urine to investigate the pharmacokinetics
Time frame: 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
Time frame: 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)
Time frame: 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)
Time frame: 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)
Time frame: 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