A Study to Investigate the Safety, Tolerability, Pharmacokinetic/Pharmacodynamic Characteristics and Food Effect of HSG4112 in High Doses

A Randomized, Open-label or Double-blind, Placebo Controlled, Single and Multiple Dosing, Dose-escalation Phase 1 Clinical Trial to Evaluate the Safety, Tolerability, Pharmacokinetic/Pharmacodynamic Characteristics and Food Effect After Oral Administration of HSG4112 in Healthy Subjects

1. Study Objective

   i) To evaluate the safety, tolerability and pharmacokinetic/pharmacodynamic characteristics of HSG4112 after single and multiple oral administration of high doses in healthy subjects.

   ii) To evaluate the food effect on the pharmacokinetic characteristics of HSG4112 after a single oral administration of 1200 mg (6 tablets of HSG4112 200 mg) in healthy subjects.

2. Background

   The previous phase 1 clinical trials investigating HSG4112 included dosage only up to 720 mg of HSG4112 in both healthy and obese subjects. Since obese patients have various comorbidities, unexpected drug interactions may occur due to concomitant drugs. Securing a 2- to 5-fold safety margin is needed to tolerate this issue. Therefore, this study is designed to evaluate the safety, tolerability, pharmacokinetic/pharmacodynamic characteristics and food effects of high-dose HSG4112 in healthy subjects.

3. Study Design and Plan

<Part 1> This study is a randomized, open-label, single dosing, phase 1 clinical study. A unique randomization number will be assigned to each subject deemed eligible to participate in the study based on the inclusion/exclusion criteria. Each subject will be randomized to one of the two dose groups. 8 subjects will receive 800 mg of HSG4112 with a high-fat meal, and 12 subjects will be randomized to 2 different sequential groups. Each subject will receive a single dose of HSG4112 1200 mg via oral administration with a high-fat meal and in fasted condition, with a washout period of 21 days in between each dosing. When escalating the dose, the Investigator will review all of the available safety data from the preceding dose in a blinded manner to ensure if it is safe to escalate the dose. In order to evaluate safety and tolerability, assessments, such as vital signs, 12-lead ECG, laboratory test, pregnancy test, physical examination, and adverse event monitoring will be performed. Blood samples will be collected to evaluate the pharmacokinetic/pharmacodynamic characteristics of HSG4112.

<Part 2> This study is a randomized, double-blind, placebo-controlled, multiple dosing, phase 1 clinical study. A unique randomization number will be assigned to each subject deemed eligible to participate in the study based on the inclusion/exclusion criteria. Each subject will be randomized to one of the two dose groups (800 mg or 1200 mg of HSG4112). In each dose group, 6 subjects will be randomized to receive 800 mg of HSG4112, and 2 subjects will be randomized to receive placebo, both with a high-fat meal. The subjects will be studied in a double-blind manner and will receive the investigational product (i.e., HSG4112 or placebo) via once-daily oral administration for 14 days. When escalating the dose, the Investigator will review all of the available safety data from the preceding dose in a blinded manner to ensure if it is safe to escalate the dose. In order to evaluate safety and tolerability, assessments, such as vital signs, 12-lead ECG, laboratory test, pregnancy test, physical examination, and adverse event monitoring will be performed. Blood samples will be collected to evaluate the pharmacokinetic/pharmacodynamic characteristics of HSG4112.

Inclusion Criteria:

1. Able to comprehend and willing to sign an informed consent form approved by the IRB before screening.

2. Adults between 19 and 50 years of age at screening.

3. Body mass index (BMI) between 18 and 24.9.

   • BMI (kg/m2) = Body weight (kg) / {Height (m)2}

4. In good health, determined by no clinically significant findings from medical history, physical examination, vital signs, 12-lead electrocardiogram, and clinical laboratory test at screening, or subjects who are deemed acceptable by the Investigator regardless of the test results.

5. For Part 2 (i.e., the multiple dose study), female subjects who have regular menstrual cycles(28±7 days) and who are not pregnant or lactating.

Exclusion Criteria:

1. Significant history or clinical manifestation of any hepatic, kidney, neurological, immune, respiratory, endocrine, hematological, neoplastic, cardiovascular disease, or psychiatric disorder (e.g., mood disorder, obsessive-compulsive disorder).

2. History of stomach or intestinal disorders (e.g., Chrons disease, ulcer) or surgeries - not including appendectomy, hemorrhoidectomy, or herniotomy - which may affect the pharmacokinetic or pharmacodynamic evaluation of the investigational product.

3. Significant history or clinical manifestation of hypersensitivity to any drug compound (e.g., licorice-containing drugs, aspirin, antibiotics).

4. One or more of the following laboratory test results at screening:

   • ALT (SGPT) > 60 IU/L
   • Glucose (fasting) > 110 mg/dL or < 70 mg/dL

5. Systolic blood pressure of < 90 mmHg or > 150 mmHg, or diastolic blood pressure of < 60 mmHg or > 100 mmHg as determined by vital signs monitored after resting in sitting position for at least 3 minutes.

6. History of drug/chemical abuse or tested positive in urine drug screen.

7. Use or intend to use any prescription medications/products or phytotherapeutic/herbal/plant-derived preparations within 14 days prior to dosing, or any nonprescription medications/products (i.e., over-the-counter (OTC) drugs), health products, or vitamins within 7 days prior to dosing, unless deemed acceptable by the Investigator.

8. Participation in any clinical study or bioequivalence study involving the administration of an investigational drug, including any study investigating HSG4112, within 6 months prior to dosing (i.e., within 6 months of the last dose from the previous study).

9. Whole blood donation within 2 months prior to dosing, plasma/platelet donation within 1 month prior to dosing, or receipt of blood products within 1 month prior to dosing.

10. Smoker. However, participation is acceptable if the subject has quit smoking at least 90 days prior to dosing.

11. Alcohol consumption of > 21 units/week (1 unit = 10 g of pure alcohol) or unable to abstain from consuming alcohol during the study period, starting from 3 days prior to dosing.

12. Ingestion of grapefruit-containing foods or beverages 24 hours prior to dosing until discharge, or unable to abstain from ingesting such foods or beverages during the same period.

13. Unable to abstain from caffeine-containing foods or beverages (e.g., coffee, tea (e.g., black tea, green tea), soft drinks, coffee milk, energy drinks, sports drinks) during the admission period.

14. Unable or unwilling to use acceptable contraceptive methods for themselves or their spouse/partner during the entire study period and up to 28 days after the last dosing and subjects who satisfy at least one of the pregnancy-related criteria below:

    • females of childbearing potential who plan to use hormonal contraceptives or oral contraceptives during the study period

    • females of childbearing potential confirmed "positive" in a pregnancy test

      • "females of childbearing potential" refer to females who have experienced menarche and have not undergone a successful surgical sterilization procedure (i.e., hysterectomy, bilateral tubal ligation, bilateral salpingectomy, bilateral oophorectomy) or is not menopause (i.e., 12 months without menstruation).

        • Acceptable contraceptive methods include:

          1. Use of an intrauterine device, which has been proven highly effective.
          2. Physical contraception for subject or spouse/partner used with chemical sterilization (e.g., spermicide).
          3. Surgical sterilization (e.g., vasectomy, hysterectomy, tubal ligation, salpingectomy).

15. Subjects who, in the opinion of the Investigator, should not participate in this study based on clinical laboratory test results or other reasons.