1. Study Objective
<Part 1> To evaluate the safety and pharmacokinetic/pharmacodynamic characteristics of HSG4112 after multiple oral administration in healthy female subjects.
<Part 2> To evaluate the safety and pharmacokinetic/pharmacodynamic characteristics of HSG4112 after multiple oral administration in obese subjects.

2. Background
The previous phase 1 clinical trials investigating HSG4112 only included healthy male subjects, and food effect was observed in theses studies - the plasma exposure to HSG4112 following administration under fed conditions was approximately 2.5 times higher compared to the exposure following administration under fasted conditions. Therefore, this study is designed to evaluate the safety of HSG4112 in healthy female subjects and obese subjects following the administration of HSG4112 under fed conditions.

3. Number of Subjects
This study is a phase 1 clinical trial designed to evaluate the safety and pharmacokinetic/pharmacodynamic characteristics of HSG4112 following 14-day multiple oral administration. As an exploratory study which does not require hypothesis testing, the planned number of subjects were determined to meet the minimum sample size needed to fulfill the objective of this study instead of applying the general formula used for hypothesis testing. Also, in order to ensure objectivity in safety evaluation, a fixed ratio of subjects will be randomized to each dose group. Based on the designs of previously conducted phase 1 clinical studies, the planned number of subjects per dose group in this study has been set to 10.

4. Study Design and Plan
<Part 1> This study is a dose block-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. In each dose group, 8 subjects will be randomized to receive HSG4112 and 2 subjects will be randomized to receive placebo. 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 consecutive days. After the Post-Study Visit of the last volunteer in the 480 mg dose group, the Investigator will review all the available safety data in a blinded manner to ensure if it is safe to proceed with the 720 mg dose group. 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 pharcokinetic/pharmacodynamic characteristics of HSG4112.
<Part 2> This study is a dose block-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. In each dose group, 8 subjects will be randomized to receive HSG4112 and 2 subjects will be randomized to receive placebo. 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 consecutive days. 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 pharcokinetic/pharmacodynamic characteristics of HSG4112.

Treatment

480 mg
Active: 60 mg HSG4112 tablet, 8 tablets, once-daily, 14-day multiple oral administration
Placebo: 60 mg placebo tablet, 8 tablets, once-daily, 14-day multiple oral administration

720 mg
Active: 60 mg HSG4112 tablet, 12 tablets, once-daily, 14-day multiple oral administration
Placebo : 60 mg placebo tablet, 12 tablets, once-daily, 14-day multiple oral administration

Arm Label

Target Number of Participant

Arm Type

Arm Description

60 mg HSG4112 tablet, 8 tablets, once-daily, 14-day multiple oral administration

Arm Label

Target Number of Participant

Arm Type

Arm Description

60 mg placebo tablet, 8 tablets, once-daily, 14-day multiple oral administration

Arm Label

Target Number of Participant

Arm Type

Arm Description

60 mg HSG4112 tablet, 12 tablets, once-daily, 14-day multiple oral administration

Arm Label

Target Number of Participant

Arm Type

Arm Description

60 mg placebo tablet, 12 tablets, once-daily, 14-day multiple oral administration

Gender

Age

Description

<Part 1>
1) Able to comprehend and willing to sign an informed consent form approved by the IRB before screening.
2) Females between 19 and 50 years of age at screening.
3) Body mass index (BMI) between 18.0 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 ECG, and clinical laboratory evaluations at screening, or subjects who are deemed acceptable by the Investigator regardless of the test results.
5) Not pregnant or lactating, with a regular menstrual cycle (i.e., 28±7 days).

<Part 2> 
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) of 30.0 or higher, with a waist circumference of 90 cm or higher for males and 85 cm or higher for females. 
   ☞ BMI (kg/m2) = Body weight (kg) / {Height (m)2}
4) Deemed acceptable by the Investigator through medical history, physical examination, vital signs, 12-lead ECG, and clinical laboratory evaluations at screening, or subjects who are deemed acceptable by the Investigator regardless of the test results.

<Part 1>
1) Significant history or clinical manifestation of any hepatic, kidney, neurological, immune, respiratory, endocrine, hematological, neoplastic, cardiovascular, psychiatric diseases or 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, aspirin, antibiotics).
4) One or more of the following laboratory test results at screening:
   - ALT > 60 IU/L
   - Glucose (fasting) 
5) Systolic blood pressure of < 90 mmHg or > 150 mmHg, or diastolic blood pressure of < 60 mgHg or > 100 mmHg as determined by vital signs monitored after resting in sitting position for 3 minutes or longer.
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 14 days prior to dosing, or any nonprescription medications/products (i.e., over-the-counter (OTC) drugs), health products, or vitamins 7 days prior to dosing, unless deemed acceptable by the Investigator. 
8) Participation in any clinical study or bioequivalence study involving administration of an investigational drug, including any study investigating HSG4112, 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 3 months 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.
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 (black tea, green tea, etc.), soft drinks, coffee milk, energy drinks, sports drinks) during the admission period.
14) One or more of the following contraception- or pregnancy-related exclusion criteria:
   - Females of childbearing potential who are unable or unwilling to use contraceptive methods during the study period. 'A female of childbearing potential' refers to premenopausal females (i.e., females who have experienced amenorrhoea for 12 months or longer) who are capable of becoming pregnant following menarche and have not been surgically sterilized (e.g., hysterectomy, bilateral tubal ligation, bilateral salpingectomy, bilateral oophorectomy).
   ☞ Acceptable contraceptive methods include: intrauterine device that has been proven highly effective, physical contraception (e.g., diaphragm, uterine cap, condom) used with chemical sterilization (e.g., spermicide), or surgical sterilization of the subject or the subject's male partner (e.g., vasectomy, hysterectomy, tubal ligation, salpingectomy).
   - Intend to use hormonal contraceptive methods during the study period.
   - Females of childbearing potential who have tested positive for pregnancy, determined by the pregnancy test.
15) Subjects who, in the opinion of the Investigator, should not participate in in this study based on clinical laboratory test results or other reasons.

<Part 2>
1) Significant history or clinical manifestation of any hepatic, kidney, neurological, immune, respiratory, endocrine, hematological, neoplastic, cardiovascular, psychiatric diseases or 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, aspirin, antibiotics).
4) One or more of the following laboratory test results at screening:
   - AST > 100 IU/L
   - ALT > 100 IU/L
   - Cholesterol > 300 mg/dL (subjects who need treatment for their cholesterol level will be excluded)
   - Triglyceride > 300 mg/dL
   - Glucose (fasting) of 126 mg/dL or higher (subjects in need of treatment for their cholesterol level will be excluded)
5) Systolic blood pressure of < 90 mmHg or > 150 mmHg, or diastolic blood pressure of < 60 mgHg or > 100 mmHg as determined by vital signs monitored after resting in sitting position for 3 minutes or longer.
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 14 days prior to dosing, or any nonprescription medications/products (i.e., over-the-counter (OTC) drugs), health products, or vitamins 7 days prior to dosing, unless deemed acceptable by the Investigator. 
8) Participation in any clinical study or bioequivalence study involving administration of an investigational drug, including any study investigating HSG4112, 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 3 months 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.
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 (black tea, green tea, etc.), soft drinks, coffee milk, energy drinks, sports drinks) during the admission period.
14) Females who have tested positive in a urine HCG test, are pregnant, or lactating before the dosing of an investigational product, excluding females who have experienced amenorrhoea for 12 months or longer or have been surgically sterilized (e.g., hysterectomy, bilateral tubal ligation, bilateral salpingectomy, bilateral oophorectomy).
15) Unable or unwilling to use contraceptive methods during the study period, up to 30 days after the last day of dosing. 
   ☞ Acceptable contraceptive methods include:
   - Use of an intrauterine device that has been proven highly effective by the subject or the subject's partner.
   - Physical contraception (e.g., diaphragm, uterine cap, condom) used with chemical sterilization (e.g., spermicide)
   - Surgical sterilization of the subject or the subject's partner (e.g., vasectomy, hysterectomy, tubal ligation, salpingectomy).
16) Subjects who, in the opinion of the Investigator, should not participate in in this study based on clinical laboratory test results or other reasons.

Maximum Plasma Concentration (Cmax), Area Under the Plasma Concentration-Time Curve Over Dosing Interval (AUCtau), Area Under the Plasma Concentration-Time Curve from Time Zero to the Last Measurable Point (AUClast), Area Under the Plasma Concentration-Time Curve from Time Zero to Infinity (AUCinf), Minimum Plasma Concentration (Cmin), Time to Maximum Observed Plasma Concentration (tmax), Half-life (t1/2), Oral Clearance (CL/F), Volume of Distribution (Vd/F)

Day 1 pre-dose and Hours 0.5, 1, 2, 3, 4, 6, 8, 10, 12, Day 2 Hour 0 (Hour 24), Day 12 Hour 0, Day 13 Hour 0, Day 14 pre-dose and Hours 0.5, 1, 2, 3, 4, 6, 8, 10, 12, Day 15 Hour 0 (Hour 24), Day 15 Hour 12 (Hour 36), Day 16 Hour 0 (Hour 48), Day 17 Hour 0 (Hour 72), Day 18 Hour 0 (Hour 96), Day 20 Hour 0 (Hour 144), and Day 22 Hour 0 (Hour 192) post-dose

Body weight and waist circumference

From pre-dose up to Day 22

Leptin, Adiponectin, Insulin, C-peptide, IL-6, TNF-a, CCL2

Day 1 and 14 pre-dose