A Study to Investigate the Safety, Tolerability, Pharmacokinetic/Pharmacodynamic Characteristics and Food Effect of HGR4113 in Healthy Subjects

Study Overview
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Brief Summary
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Study Objective: The objective of this study is to evaluate the safety, tolerability, pharmacokinetic/pharmacodynamic characteristics, and food effect of HGR4113 after single and multiple oral administration in healthy subjects. Study Design and Plan: This study is a randomized, double-blind, placebo controlled, single and multiple dosing, dose-escalation phase 1 clinical trial. Volunteers who have been deemed eligible based on the inclusion/exclusion criteria will be given a random number. Each subject will be assigned to one of the dose groups in a 6:2 ratio to HGR4113 (active) or placebo. Subjects will be studied in a double-blind manner and will receive the investigational product per protocol. Dose will be escalated once safety data is collected up to the last pharmacokinetic blood collection timepoint and safety and tolerability has been deemed acceptable following the review of the Safety Review Committee. Assessments including vital signs, 12-lead ECG, clinical laboratory, reproductive hormones, physical examination, and monitoring of adverse events concomitant medications will be conducted to evaluate safety and tolerability. Blood will be collected to evaluate the pharmacokinetic/pharmacodynamic characteristics.

Official Title
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A Randomized, 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 HGR4113 in Healthy Subjects

Conditions
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Diabetes Mellitus, Type 2

Intervention / Treatment
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* Drug: HGR4113
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to comprehend and willing to sign an informed consent form approved by the IRB before Screening. Adult volunteers between 19 and 50 years of age at Screening. Body mass index (BMI) between 18.0 and 24.9. ☞ BMI (kg/m^2) = body weight (kg) / (height [m])^2 In good health, determined by no clinically significant findings from medical history, physical examination, vital signs, 12-lead electrocardiogram, and clinical laboratory tests at Screening, or subjects who are deemed acceptable by the Investigator regardless of the test results. Exclusion Criteria: Significant history or clinical manifestation of any hepatic, kidney, neurological, immune, respiratory, endocrine, hematological, neoplastic, or cardiovascular disease, or psychiatric disorder (e.g., mood disorder, obsessive-compulsive disorder). History of stomach or intestinal disorders (e.g., Chron's disease, ulcer) or surgeries - not including appendectomy, hemorrhoidectomy, or herniotomy - which may affect the safety or pharmacokinetic/pharmacodynamic evaluation of the investigational product. Significant history or clinical manifestation of hypersensitivity to any drug including licorice or other drug (e.g., aspirin, antibiotics). One or more of the following laboratory test results at Screening: ANC < 1000 AST, ALT, GGT, total bilirubin > 1.5x upper limit normal Fasting glucose ≥ 126 mg/dL or HbA1c ≥ 6.5% despite two retests eGFR < 60 (CKD-EPI). Systolic blood pressure < 90 mmHg or > 150 mmHg, or diastolic blood pressure < 60 mgHg or > 100 mmHg as determined by vital signs monitored after resting in sitting position for at least 3 minutes. History of drug/chemical abuse or tested positive in urine drug screen. Used 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. Participation in any clinical study or bioequivalence study within 6 months prior to dosing. 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. Alcohol consumption > 21 units/week (1 unit = 10 g of pure alcohol) or unable to abstain from consuming alcohol 3 days prior to first dosing until the last pharmacokinetic blood sampling. History of smoking within 90 days prior to dosing (however, participation is acceptable if the subject has quit at least 90 days prior to dosing) or unable to abstain from smoking 90 days prior to dosing until the last pharmacokinetic blood sampling. Ingestion of grapefruit-containing foods or beverages 24 hours 3 days prior to dosing until the last pharmacokinetic blood sampling, or unable to abstain from ingesting such foods or beverages during the same period. Unable to abstain from ingesting caffeine-containing foods or beverages (e.g., coffee, tea [e.g., black tea, green tea], soft drinks, coffee milk, energy drinks, sports drinks) 3 days prior to dosing until the last pharmacokinetic blood sampling. Females, excluding those who have amenorrhea for at least 12 months or have been surgically sterilized (e.g., bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), who are pregnant or lactating, evidenced by a positive urine hCG pregnancy test. Subject or subject's partner is unable or unwilling to use a medically acceptable means of contraception during and for 90 days following the last dosing or willing to donate sperm during the same period. - Acceptable contraceptive methods include: Use of an intrauterine device that has been proven highly effective Male or female physical contraceptive used with chemical sterilization Surgical sterilization of the subject or the subject's partner (e.g., vasectomy, hysterectomy, tubal ligation, salpingectomy). Subjects who, in the opinion of the Investigator, should not participate in in this study based on other reasons.

Ages Eligible for Study
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Minimum Age: 19 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HGR4113 300 mg Single Dose<br>Single oral dosing of HSG4112 300 mg | Drug: HGR4113<br>* Once-daily oral administration<br>|
| Placebo Comparator: Placebo 300 mg Single Dose<br>Single oral dosing of placebo 300 mg | Drug: Placebo<br>* Once-daily oral administration<br>|
| Experimental: HGR4113 600 mg Single Dose<br>Single oral dosing of HSG4112 600 mg | Drug: HGR4113<br>* Once-daily oral administration<br>|
| Placebo Comparator: Placebo 600 mg Single Dose<br>Single oral dosing of placebo 600 mg | Drug: Placebo<br>* Once-daily oral administration<br>|
| Experimental: HGR4113 1200 mg Single Dose<br>Single oral dosing of HSG4112 1200 mg | Drug: HGR4113<br>* Once-daily oral administration<br>|
| Placebo Comparator: Placebo 1200 mg Single Dose<br>Single oral dosing of placebo 1200 mg | Drug: Placebo<br>* Once-daily oral administration<br>|
| Experimental: HGR4113 300 mg Multiple Dose<br>Multiple oral dosing of HSG4112 300 mg | Drug: HGR4113<br>* Once-daily oral administration<br>|
| Placebo Comparator: Placebo 300 mg Multiple Dose<br>Multiple oral dosing of placebo 300 mg | Drug: Placebo<br>* Once-daily oral administration<br>|
| Experimental: HGR4113 600 mg Multiple Dose<br>Multiple oral dosing of HSG4112 600 mg | Drug: HGR4113<br>* Once-daily oral administration<br>|
| Placebo Comparator: Placebo 600 mg Multiple Dose<br>Multiple oral dosing of placebo 600 mg | Drug: Placebo<br>* Once-daily oral administration<br>|
| Experimental: HGR4113 1200 mg Multiple Dose<br>Multiple oral dosing of HSG4112 1200 mg | Drug: HGR4113<br>* Once-daily oral administration<br>|
| Placebo Comparator: Placebo 1200 mg Multiple Dose<br>Multiple oral dosing of placebo 1200 mg | Drug: Placebo<br>* Once-daily oral administration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability Assessment by Adverse Event Monitoring | Number of participants with observed adverse events | Day 1 to 7 days after day of last administration | 
| Safety and Tolerability Assessment by Number of Patients with Change in Physical Examination | Number of participants with clinically significant change in physical examination | Day 1 to 7 days after day of last administration | 
| Safety and Tolerability Assessment by Number of Participants with Change in Vital Signs | Number of participants with clinically significant change in vital signs including blood pressure, heart rate, and body temperature | Day 1 to 7 days after day of last administration | 
| Safety and Tolerability Assessment by Number of Participants with Change in Laboratory Test | Number of participants with clinically significant change in laboratory test assessed through hematology, blood biochemistry, urinalysis, blood coagulation, and hormone tests | Day 1 to 7 days after day of last administration | 
| Safety and Tolerability Assessment by Number of Participants with Change in 12-Lead Electrocardiogram | Number of participants with clinically significant change in 12-lead electrocardiogram | Day 1 to 7 days after day of last administration | 
| Safety and Tolerability Assessment by Number of Participants with Change in Semen Parameters | Number of participants with clinically significant change in semen assessed through semen volume, semen pH, sperm count, sperm concentration, sperm motility, and sperm morphology | From Screening to 12 weeks after day of last administration | 
| Pharmacokinetic Assessment by Maximum Plasma Concentration of HGR4113 | Maximum Plasma Concentration of HGR4113 (Cmax) | Hour 0 to 96 | 
| Pharmacokinetic Assessment by Area Under the Plasma Concentration-Time Curve of HGR4113 Over Dosing Interval | Area Under the Plasma Concentration-Time Curve of HGR4113 Over Dosing Interval (AUCtau) | Hour 0 to 24 | 
| Pharmacokinetic Assessment by Area Under the Plasma Concentration-Time Curve of HGR4113 from Time Zero to the Last Measurable Point | Area Under the Plasma Concentration-Time Curve of HGR4113 from Time Zero to the Last Measurable Point (AUClast) | Hour 0 to 96 | 
| Pharmacokinetic Assessment by Area Under the Plasma Concentration-Time Curve of HGR4113 from Time Zero to Infinity | Area Under the Plasma Concentration-Time Curve of HGR4113 from Time Zero to Infinity (AUCinf) | Hour 0 to 96 | 
| Pharmacokinetic Assessment by Half-Life of HGR4113 | Half-life of HGR4113 (T1/2) | Hour 0 to 96 | 
| Pharmacokinetic Assessment by Time to Maximum Observed Plasma Concentration of HGR4113 | Time to Maximum Observed Plasma of HGR4113 (Tmax) | Hour 0 to 96 | 
| Pharmacokinetic Assessment by Oral Clearance of HGR4113 | Oral Clearance of HGR4113 (CL/F) | Hour 0 to 96 | 
| Pharmacokinetic Assessment by Apparent Volume of Distribution of HGR4113 | Volume of Distribution of HGR4113 (Vz/F) | Hour 0 to 96 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacodynamic Assessment by Change in Paraoxonase 1 Activity | Change in paraoxonase 1 activity | Day -1 to 17 | 
| Pharmacodynamic Assessment by Change in Plasma Glucose | Change in plasma glucose level | Day -1 to 17 | 
| Pharmacodynamic Assessment by Change in Plasma HbA1c | Change in plasma HbA1c level | Day -1 to 17 | 
| Pharmacodynamic Assessment by Change in Plasma Insulin | Change in plasma insulin level | Day -1 to 17 | 
| Pharmacodynamic Assessment by Change in Plasma C-peptide | Change in plasma c-peptide level | Day -1 to 17 |