Clinical trial NCT06705998: To Investigate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of BAR502 in Healthy Subjects
Official title: A Phase I, Two Parts Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Ascending Doses of BAR502 in Healthy Subjects
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: NASH
Keywords: Non-alcoholic Fatty Liver DIsease
Lead sponsor: BAR Pharmaceuticals s.r.l.
Sponsor class: NETWORK
First posted: 2024-11-26
Enrollment: 52
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: The Part A of the study follows a randomised, double-blind, placebo-controlled, parallel group design. The participants are enrolled in 4 consecutive cohorts of 8 healthy subjects each. In each cohort, the first 2 groups include 2 subjects each, while the 3rd group in each cohort includes 4 subjects. Each group of subjects is exposed to the treatment under investigation only if the Investigator's evaluation of the previous group's safety data up to 72 h post-dose is satisfactory and if the competent Ethics Committee gives written authorisation to continue with the next group. At the end of each cohort, before proceeding to the next dose level, safety and tolerability results up to 168 h post-dose (Day 8) are evaluated by a Data Safety Monitoring Board.

Part B of the study: Two ascending doses of IMP identified in study Part A, are subsequentially administered as daily multiple doses for 2 consecutive weeks (14 days) in two cohorts of 10 healthy subjects each.
Primary purpose: OTHER

Brief summary: First-in-human, single centre, two parts, dose-escalation, parallel-group, safety, tolerability, pharmacokinetic and pharmacodynamic Phase I study. Part A: randomised, double-blind, placebo-controlled, single ascending dose study.

Part B: open label, multiple ascending dose study.

Detailed description: First-in-human, single centre, two parts, dose-escalation, parallel-group, safety, tolerability, pharmacokinetic and pharmacodynamic Phase I study. Part A: randomised, double-blind, placebo-controlled, single ascending dose study to evaluate the safety and tolerability of BAR502 and matching placebo across 4 single ascending doses administered to 4 cohorts of 8 healthy subjects each.

Part B: open label, multiple ascending dose study to evaluate the safety and tolerability of two ascending doses of BAR502, considered as safe in study Part A, when administered as multiple doses to 2 cohorts of 10 healthy subjects each.

Eligibility criteria: Inclusion Criteria:

1. Informed consent: signed written informed consent before inclusion in the study
2. Sex and Age: men/women, 18-55 years old inclusive
3. Body Mass Index: 18.5-30 kg/m2 inclusive
4. Vital signs: systolic blood pressure 100-139 mmHg, diastolic blood pressure 50-89 mmHg, heart rate 50-99 bpm, measured after 5 min at rest in the sitting position
5. Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks and side effects; ability to co-operate with the Investigator and to comply with the requirements of the entire study
6. Renal functionality: 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
7. Tobacco: non-smokers, non-users of nicotine containing products and non-users of Vapo e-cigarettes for at least 3 months prior to study screening
8. Contraception and fertility (women only): women of non-child-bearing potential or in post-menopausal status for at least 1 year, defined as such when there is either:

   1. 12 months of spontaneous amenorrhea or
   2. 6 weeks documented postsurgical bilateral oophorectomy with or without hysterectomy will be admitted. For all women, pregnancy test result must be negative at screening and on Day -1 of each study part.
9. Contraception (men only): men will either be sterile or agree to use one of the following approved methods of contraception from the first investigational medicinal product administration until at least 90 days after the last administration, also in case their partner is currently pregnant:

   1. A male condom with spermicide
   2. A sterile sexual partner or a partner in post-menopausal status for at least 1 year
   3. Use by the female sexual partner of an IUD, a female condom with spermicide, a contraceptive sponge with spermicide, a diaphragm with spermicide, a cervical cap with spermicide, or hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the screening visit or: True abstinence

Exclusion Criteria:

1. ECG 12-leads (supine position): clinically significant abnormalities, in particular QTcF \> 450 ms
2. Physical findings: clinically significant abnormal physical findings which could interfere with the objectives of the study
3. Laboratory analyses: clinically significant abnormal laboratory values at screening indicative of physical illness or any acute laboratory abnormality at Screening which, in the opinion of the Investigator, should preclude participation in the study of an investigational compound. INR \> 1.2
4. Diseases: significant history of renal, hepatic (in particular, liver or hepatobiliary diseases as indicated by serum alanine aminotransferase, aspartate aminotransferase or total bilirubin levels exceeding the upper limit of normality), gastrointestinal, cardiovascular, respiratory, skin, haematological, endocrine or neurological diseases that may interfere with the aim of the study
5. Gallbladder: history of cholecystectomy, presence of gallstones or clinically significant gallbladder abnormalities that may interfere with the aim of the study
6. Allergy: ascertained or presumptive hypersensitivity to the active principle and/or formulations' ingredients; history of anaphylaxis to drugs or allergic reactions in general, which the Investigator considers may affect the outcome of the study
7. Medications: medications, including over the counter medications, homeopathic preparations, vitamins, food supplements and herbal remedies for 3 weeks before the start of the study
8. Investigative drug studies: participation in the evaluation of any investigational product for 3 months before this study. The 3-month interval is calculated as the time between the first calendar day of the month that follows the last visit of the previous study and the first day of the present study
9. Blood donation: blood donations for 3 months before this study
10. Drug, alcohol, caffeine, tobacco: history of drug, alcohol \[\>1 drink/day for females and \>2 drinks/day for men, defined according to the USDA Dietary Guidelines 2020-2025\] or caffeine (\>5 cups coffee/tea/day) abuse
11. SARS-CoV-2 test: positive Covid-19 rapid test at Day -1
12. Cotinine: positive cotinine test at screening
13. Drug test: positive result at the urine drug screening test at screening or Day -1
14. Alcohol test: positive alcohol saliva test at screening or Day -1
15. Diet: abnormal diets (\<1600 or \>3500 kcal/day) or substantial changes in eating habits in the 4 weeks before this study; vegetarians and vegans
16. Pregnancy (women only): positive or missing pregnancy test at screening or Day -1; child-bearing potential, pregnant or lactating women.

Primary outcomes:
measure: Treatment-emergent adverse events
timeFrame: PART A: Day-15/-2; Day-1 to Day4; Day 8; Day15 - PART B: Day-15/-2 to Day18; Day30
measure: Change in vital sign - BP
timeFrame: PART A: Day-1 to Day4; Day 8; - PART B: Day-15/-2 to Day15; Day18
measure: Change in vital sign - HR
timeFrame: PART A: Day-1 to Day4; Day 8; - PART B: Day-15/-2 to Day15; Day18
Secondary outcomes:
measure: Plasma BAR502 - Study Part A
timeFrame: Day1 (pre- and post- dose), Day2, Day3, Day4
measure: Urine BAR502 - Study Part A
timeFrame: Day1 (pre- and post- dose), Day2, Day3
measure: Plasma BAR505 - Study Part A
timeFrame: Day1 (pre- and post- dose), Day2, Day3, Day4
measure: Urine BAR505 - Study Part A
timeFrame: Day1 (pre- and post- dose), Day2, Day3
measure: Plasma BAR502 PK: Cmax - Study Part A
timeFrame: Day1 (pre- and post- dose), Day2, Day3, Day4
measure: Plasma BAR502 PK: t_max - Study Part A
timeFrame: Day1 (pre- and post- dose), Day2, Day3, Day4
measure: Plasma BAR502 PK: AUC0-t - Study Part A
timeFrame: Day1 (pre- and post- dose), Day2, Day3, Day4
measure: Urine BAR502 PK: Ae0-t - Study Part A
timeFrame: Day1 (pre- and post- dose), Day2, Day3
measure: Urine BAR502 PK: Fe0-t - Study Part A
timeFrame: Day1 (pre- and post- dose), Day2, Day3
measure: Urine BAR502 PK: Rmax - Study Part A
timeFrame: Day1 (pre- and post- dose), Day2, Day3
measure: Urine BAR502 PK: AUR_Clast - Study Part A
timeFrame: Day1 (pre- and post- dose), Day2, Day3
measure: Urine BAR502 PK: REC% - Study Part A
timeFrame: Day1 (pre- and post- dose), Day2, Day3
measure: Urine BAR502 PK: tu_max - Study Part A
timeFrame: Day1 (pre- and post- dose), Day2, Day3
measure: Urine BAR502 PK: Cl_r r - Study Part A
timeFrame: Day1 (pre- and post- dose), Day2, Day3
measure: Serum biomarker FGF19 - Study Part A
timeFrame: Day1 (pre- and post- dose), Day2, Day3
measure: Serum biomarker C4 - Study Part A
timeFrame: Day1 (pre- and post- dose), Day2, Day3
measure: Serum biomarker GLP-1 - Study Part A
timeFrame: Day1 (pre- and post- dose), Day2, Day3
measure: Serum PD: Cb_max - Study Part A
timeFrame: Day1 (pre- and post- dose), Day2, Day3
measure: Serum PD: Cb_min - Study Part A
timeFrame: Day1 (pre- and post- dose), Day2, Day3
measure: Serum PD: tb_max - Study Part A
timeFrame: Day1 (pre- and post- dose), Day2, Day3
measure: Serum PD: tb_min - Study Part A
timeFrame: Day1 (pre- and post- dose), Day2, Day3
measure: Serum PD: AUbC_0-24 - Study Part A
timeFrame: Day1 (pre- and post- dose), Day2, Day3
measure: Serum PD: partial AUbC - Study Part A
timeFrame: Day1 (pre- and post- dose), Day2, Day3
measure: Serum total bile acids - Study Part A
timeFrame: Day1 (pre- and post- dose), Day2, Day3
measure: Plasma BAR502 concentration - Study Part B
timeFrame: daily from Day1 to Day14 (pre- and post- dose); Day15 to Day18
measure: Plasma BAR505 concentration - Study Part B
timeFrame: daily from Day1 to Day14 (pre- and post- dose); Day15 to Day18
measure: Plasma BAR502 PK: Cmax - Study Part B
timeFrame: daily from Day1 to Day14 (pre- and post- dose); Day15 to Day18
measure: Plasma BAR502 PK: t_max - Study Part B
timeFrame: daily from Day1 to Day14 (pre- and post- dose); Day15 to Day18
measure: Plasma BAR502 PK: AUC_0-24 - Study Part B
timeFrame: daily from Day1 to Day14 (pre- and post- dose); Day15 to Day18
measure: Plasma BAR502 PK: AUC_0-t - Study Part B
timeFrame: daily from Day1 to Day14 (pre- and post- dose); Day15 to Day18
measure: Serum biomarker GLP-1 - Study Part B
timeFrame: daily from Day1 to Day14 (pre- and post- dose); Day15 to Day17
measure: Serum biomarker C4 - Study Part B
timeFrame: daily from Day1 to Day14 (pre- and post- dose); Day15 to Day17
measure: Serum biomarker FGF19 - Study Part B
timeFrame: daily from Day1 to Day14 (pre- and post- dose); Day15 to Day17
measure: Serum PD: Cb_max - Study Part B
timeFrame: daily from Day1 to Day14 (pre- and post- dose); Day15 to Day17
measure: Serum PD: Cb_min - Study Part B
timeFrame: daily from Day1 to Day14 (pre- and post- dose); Day15 to Day17
measure: Serum PD: tb_max - Study Part B
timeFrame: daily from Day1 to Day14 (pre- and post- dose); Day15 to Day17
measure: Serum PD: tb_min - Study Part B
timeFrame: daily from Day1 to Day14 (pre- and post- dose); Day15 to Day17
measure: Serum PD: AUbC_0-24 - Study Part B
timeFrame: daily from Day1 to Day14 (pre- and post- dose); Day15 to Day17
measure: Serum PD: partial AUbC - Study Part B
timeFrame: daily from Day1 to Day14 (pre- and post- dose); Day15 to Day17
measure: Serum total bile acids - Study Part B
timeFrame: Daily from Day1 to Day17
measure: Change in body weight
timeFrame: PART A: Day1; Day 8 - PART B: Day1; Day18; Day30
measure: Check for Physical abnormalities
timeFrame: PART A: Day1; Day 8 - PART B: Day1; Day18; Day30
measure: hepatic parameters: AST
timeFrame: PART A: Day2; Day3; Day 8; - PART B: daily from Day2 to Day13; Day15; Day18
measure: hepatic parameters: ALT
timeFrame: PART A: Day2; Day3; Day 8; - PART B: daily from Day2 to Day13; Day15; Day18
measure: hepatic parameters: Total bilirubin
timeFrame: PART A: Day2; Day3; Day 8; - PART B: daily from Day2 to Day13; Day15; Day18
measure: hepatic parameters: Direct bilirubin
timeFrame: PART A: Day2; Day3; Day 8; - PART B: daily from Day2 to Day13; Day15; Day18
measure: hepatic parameters: Indirect bilirubin
timeFrame: PART A: Day2; Day3; Day 8; - PART B: daily from Day2 to Day13; Day15; Day18
measure: hepatic parameters: Total cholesterol
timeFrame: PART A: Day2; Day3; Day 8; - PART B: daily from Day2 to Day13; Day15; Day18
measure: hepatic parameters: HDL cholesterol
timeFrame: PART A: Day2; Day3; Day 8; - PART B: daily from Day2 to Day13; Day15; Day18
measure: hepatic parameters: LDL cholesterol
timeFrame: PART A: Day2; Day3; Day 8; - PART B: daily from Day2 to Day13; Day15; Day18
measure: Change in Gallbladder contraction - Study Part B
timeFrame: daily from Day2 to Day13; Day15
measure: Change in Gallbladder volume - Study Part B
timeFrame: daily from Day2 to Day13; Day15
measure: Change in ECG trace: PR
timeFrame: PART A: daily from Day1 to Day 4 - PART B: daily from Day to Day15
measure: Change in ECG trace: QRS
timeFrame: PART A: daily from Day1 to Day 4 - PART B: daily from Day to Day15
measure: Change in ECG trace: QT
timeFrame: PART A: daily from Day1 to Day 4 - PART B: daily from Day to Day15
measure: Change in ECG trace: QTcB
timeFrame: PART A: daily from Day1 to Day 4 - PART B: daily from Day to Day15
measure: Change in ECG trace: QTcF
timeFrame: PART A: daily from Day1 to Day 4 - PART B: daily from Day to Day15
measure: Change in ECG: Heart rate
timeFrame: PART A: daily from Day1 to Day 4 - PART B: daily from Day to Day15
Other outcomes:
Locations:
city: Arzo
country: Switzerland
facility: CROSS Research S.A. Phase I Unit
Study officials:
affiliation: CROSS Research S.A., Phase I Unit
name: Milko Radicioni, MD
role: PRINCIPAL_INVESTIGATOR
References: