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
Overview
- Phase
- Phase 1
- Intervention
- BAR502
- Conditions
- Non-Alcoholic Fatty Liver Disease
- Sponsor
- BAR Pharmaceuticals s.r.l.
- Locations
- 1
- Primary Endpoint
- Incidence of Treatment-Emergent Adverse Events
- Status
- Withdrawn
- Last Updated
- last year
Overview
Brief Summary
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
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.
Investigators
Eligibility Criteria
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
- •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.
Arms & Interventions
BAR 502
Each subject will receive an oral single-dose of BAR 502.
Intervention: BAR502
Placebo
Each subject will receive an oral single-dose of placebo.
Intervention: Placebo
Outcomes
Primary Outcomes
Incidence of Treatment-Emergent Adverse Events
Time Frame: Through study completion, an average of 2 months
Safety will be evaluated through the assessment of adverse events
Assessment of physical examination
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)
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
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
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)
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).
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
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)..
Safety will be evaluated through the assessment of vital signs
Secondary Outcomes
- 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)