Effects of Probiotics (P. Pentosaceus, L. Lactis or L. Helveticus) in Patients With Nonalcoholic Hepatitis
Phase: PHASE1
Conditions: Non-Alcoholic Fatty Liver Disease, MASLD - Metabolic Dysfunction-Associated Steatotic Liver Disease
Sponsor: Chuncheon Sacred Heart Hospital

Confidential
Clinical Trial Protocol
A Study to Evaluate the Therapeutic Effect and 
Safety of Metagenomics-Based Probiotics in 
Patients with Non-Alcoholic Fatty Liver Disease 
(NAFLD)
Protocol No.
:
PRO-NASH
NCT NO              :    NCT04555434
Version
:
1.9
Date                   :    2020. Aug. 18
Confidential
The information contained in this study protocol constitutes the proprietary property of Chong Kun 
Dang Bio Co., Ltd. and Hallym University Chuncheon Sacred Heart Hospital. It is provided solely for 
the use of the clinical trial site director, principal investigator and study staff, relevant administrative 
authorities, and the Institutional Review Board (IRB) of the study site. This protocol may be used only 
for the purposes of conducting or evaluating the clinical trial. Unless prior written consent is obtained 
from Chong Kun Dang Bio Co., Ltd. and Hallym University Chuncheon Sacred Heart Hospital, the 
information may not be used, disclosed, published, or otherwise released.

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◎ Summary
Clinical Trial Title
A Study to Evaluate the Therapeutic Effect and Safety of Metagenomics-Based 
Probiotics in Patients with Non-Alcoholic Fatty Liver Disease (NAFLD)
Study Site:
Hallym University Chuncheon Sacred Heart Hospital
7 Sakju-ro, Chuncheon-si, Gangwon-do, Republic of Korea
* Subject recruitment and study visits will be conducted at Hallym University 
Chuncheon Sacred Heart Hospital. Human-derived sample analysis will be 
performed by ChunLab, Inc.
Principal Investigator
Prof. Ki Tae Seok, Department of Gastroenterology,
Hallym University Chuncheon Sacred Heart Hospital
Study Phase:
Investigator-Initiated Clinical Trial
Sponsor
CKD Bio Corporation
Study 
Period
Study 
Period
From IRB approval date to April 30, 2022
Disease Target
Non-Alcoholic Fatty Liver Disease (NAFLD)
Study Objective
To evaluate the therapeutic effect of probiotics on improving non-alcoholic fatty liver 
disease in patients diagnosed with NAFLD.
Study Design
8-week, single-center, randomized, double-blind, placebo-controlled, parallel-group 
clinical trial
Investigational 
Products:
- Capsule containing Pediococcus pentosaceus KID7 (9×10^9 CFU/day)
- Capsule containing Lactobacillus helveticus CKDB001 (9×10^9 CFU/day)
- Capsule containing Lactobacillus lactis CKDB001 (9×10^9 CFU/day)
Control Product
Placebo (identical appearance, containing microcrystalline cellulose, without 
probiotic strains)
Inclusion Criteria
Participants who meet all of the following criteria will be enrolled in the study:
1. Individuals who voluntarily agree to participate and provide written informed 
consent.
2. Male or female adults aged 20 years or older.
Inclusion Criteria
3. Patients diagnosed with non-alcoholic fatty liver disease (NAFLD).
- Alcohol-related liver disease exclusion threshold:
- Average daily alcohol consumption ≥ 60 g/day in the past year (≥ 30 g/day for 
women).
- Reference examples:
Soju 360 mL, 20% alcohol = 72 g of alcohol
Beer 500 mL (330 mL for commercial bottles), 5% alcohol = 25 g (16.5 g)
4. Patients with elevated liver enzyme levels above the normal range.
   - Reference normal ranges:
     - AST, ALT: ≤ 40 U/L
     - ALP: 20–130 U/L
     - GOT: 0–30 U/L
     - GPT: 0–38 U/L
     - GGT: 10–62 U/L (male), 7–35 U/L (female)
Exclusion Criteria
Participants who meet any of the following conditions will be excluded:
1. Use of probiotics (e.g., lactic acid bacteria), prebiotics (e.g., dietary fiber, 
fructooligosaccharides), synbiotics, or fermented dairy products within the past 1 
month.
2. Continuous use of antibiotics within the past 2 months, or individuals likely to 
require antibiotic therapy during the study period.
Individuals who have continuously taken medications or health functional foods that 
may affect liver function within the past 1 month.

3. Individuals who have participated in another clinical trial within the past 1 month
4. Participation in medical device trials is exempted from this criterion.
5. Individuals with any of the following conditions:
Alcoholic liver disease, hereditary metabolic disorders, or autoimmune hepatitis 
Systemic inflammatory diseases or immune-mediated disorders, Hepatocellular 
carcinoma, Uncontrolled cardiopulmonary disease, Other significant systemic 
disorders involving the heart, lungs, hematologic system, or endocrine system. 
Individuals with a history of malignant tumors diagnosed within the past 5 years, 
Pregnant or breastfeeding women. Individuals with known hypersensitivity to the 
investigational product/placebo or any of their components, or those with a history 
of severe allergic reactions. Individuals deemed unsuitable for participation in the 
clinical trial at the investigator’s discretion.
Sample Size:
Target enrollment is 120 subjects (30 subjects per group, accounting for 10% 
dropout).
Methods 
Treatment Group 1: Investigational Product 1 + Legalon® (n=30)
Treatment Group 2: Investigational Product 2 + Legalon® (n=30)
Treatment Group 3: Investigational Product 3 + Legalon® (n=30)
Control Group: Control Treatment + Legalon® (n=30)
• Visit 1 (Week –2): Screening
• Visit 2 (Week 0): Randomization / Baseline
• Visit 3 (Week 4): Intermediate Assessment
• Visit 4 (Week 8): Completion / Final Assessment
END POINT  
1) Primary Efficacy Endpoint:
- Change in liver enzyme levels (AST, ALT)
2) Secondary Efficacy Endpoints: 
- Change in GGT, albumin
- Lipid profile changes (cholesterol, triglycerides)
- Inflammatory cytokine levels (TNF-α, IL-6)
- BMI changes
- Imaging changes (Ultrasound/CT, FibroScan)
- MELD score
- Child–Pugh score
- Hepatic decompensation events (encephalopathy, ascites, variceal bleeding, 
SBP)
- Hospitalization, mortality, liver transplantation
- Stool habit changes
- Quality of life
- Gut microbiome composition
3) Human-derived specimen research and genetic testing
For participants who provide separate written consent for human-derived specimen 
research and genetic testing, blood, serum, and stool samples will be collected. 
These specimens will be used independently from this clinical trial as research 
materials to investigate the prevention, diagnosis, and treatment of chronic liver 
diseases.

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Analysis method
Primary Efficacy Endpoint Analysis
After administering the investigational product or comparator for 8 weeks to the 
four randomized groups, changes in liver enzymes (AST, ALT) from baseline will 
be calculated for each group. Based on the results of normality and homogeneity 
of variance tests, a two-sample t-test or Mann–Whitney U test will be performed. 
Additional subgroup analyses may be conducted as needed.
Secondary Efficacy Endpoint Analysis
After 8 weeks of administration of the investigational product or comparator to the 
four randomized groups, the following parameters will be analyzed for changes 
from baseline using the same analytic approach: serum GGT and albumin levels; 
serum lipid profile (cholesterol, triglycerides); inflammatory cytokines (TNF-α, IL-
6); BMI; imaging-based histologic parameters (abdominal ultrasound/CT, 
FibroScan); MELD score; Child–Pugh score; worsening of liver disease (hepatic 
encephalopathy, ascites, variceal bleeding, spontaneous bacterial peritonitis, liver-
related hospitalization, death or liver transplantation, and all-cause mortality); 
bowel habits (frequency, stool volume, stool consistency and form, time required 
for defecation); quality of life (questionnaire-based); and gut microbiome 
composition. Additional subgroup analyses may also be performed.
Stool Sample Analysis
Stool samples will be obtained from participants who provide written informed 
consent for human biospecimen research. Microbiome analysis will be conducted 
by ChunLab, a specialized bioinformatics analysis company.
SAFETY ANALYSIS
Adverse events, vital signs, and clinical laboratory tests (blood and urine)

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◎ Study Timeline
Procedure
Screening
Baseline
Treatment
End of study
Visit
1
2
3
4
Week
-2
01)
4
8
Window period (day)
±7
±7
±7
Informed Consent of Study Participants
√
Demographic Characteristics
√
Physical Measurements
√
√
√
√
Vital Signs 
(Pulse, Blood Pressure, Body Temperature)
√
√
√
√
Medical and Surgical History Assessment
√
Medication History 
Assessment
√
√
√
√
Alcohol and Smoking History Assessment
√
√
√
√
Screening 
Examinations 
(Blood and Urine 
Tests)
Blood Tests
√
Pregnancy Test
√
Viral Marker 
Testing
√
Assessment of Inclusion and
Exclusion Criteria
√
                 Randomization
√
Study Drug Administration
√
√
Stool Sample Collection and Bowel Habit 
Assessment
√
√
Clinical Laboratory Tests (Blood)
√
√
√
Histopathological Examination
√
√
√
Assessment of Quality-of-Life Improvement
√
√
Liver biopsy
√
√
Monitoring and Assessment of 
Adverse Events
√
√
√
√
Visit 2 (Week 0) shall be conducted at least 2 weeks and within 3 weeks after Visit 1 (Week –2). (Visit 1 and 
Visit 2 may be conducted on the same day.)
Information on sex, date of birth, age, menstrual status, and duration of amenorrhea will be collected.
Body weight, height, and BMI will be measured. (Height will be measured only at Visit 1.)
Participants will visit after a 12-hour fast on the day prior to testing, and blood tests will be performed. (For 
participants with fatty liver disease, only clinically necessary items may be tested at the discretion of the 
principal investigator.)
①
 Blood biochemical tests: AST, ALT, ALP, GGT, albumin, total bilirubin, direct bilirubin, total protein, 
uric acid, BUN, creatinine, glucose, cholesterol, triglycerides (These tests may be omitted for 
participants who have health examination results within the past 4 weeks.)
A urine pregnancy test will be conducted for women of childbearing potential, except for those in confirmed 
menopause (amenorrhea ≥24 months).
Viral marker tests will include HBsAg, anti-HBs, and anti-HCV. (Testing will be performed when results within 
the past 5 years are unavailable and deemed clinically necessary by the investigator.)

Stool samples may be collected up to 3 days after the visit, if needed, and stored in a –80 °C deep freezer 
(performed only at Visits 2 and 4). Bowel habits—including stool frequency, stool volume, stool consistency 
and form (Bristol Stool Scale), and time required for defecation—will be assessed.
Based on the results, microbiome profiling and stool metabolite analyses may be conducted.
Participants will visit after a 12-hour fast on the day prior to testing, and the following laboratory tests will be 
performed. Remaining serum samples will be stored at –80 °C. (Only clinically necessary tests may be 
performed at the discretion of the principal investigator.)
① Hematology tests: RBC, WBC with differential, hemoglobin, hematocrit, and platelet count
② Blood biochemistry tests: AST, ALT, ALP, GGT, albumin, total bilirubin, direct bilirubin, total protein, uric acid, 
BUN, creatinine, glucose, total cholesterol, and triglycerides
③ Coagulation test: Prothrombin time (performed only at Visit 2)
④ Serum cytokine tests: TNF-α, IL-6
Participants will visit after a 12-hour fast on the day prior to testing, and the following assessments will be 
performed. (These tests will be conducted only for participants with fatty liver disease when clinically required as 
part of standard care or for those who provide consent.)
② FibroScan
A questionnaire survey will be administered (performed only at Visit 2 and Visit 4).
The  above procedures will be performed only for participants who provide consent. 

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Contents
◎ Protocol Synopsis
◎ Schedule of Activities
1. Title and Phase of the Clinical Trial 
2. Name and Address of the Clinical Trial Site(s)
3. Names and Titles of the Principal Investigator and Study Staff
4. Name and Title of the Pharmacist Responsible for Investigational Product Management
5. Name and Address of the Sponsor 
6. Background and Objectives of the Clinical Trial 
7. Code Name, Active Ingredient(s), Composition, and Dosage Form of the Investigational Product 
8. Target Disease or Condition 
9.
Inclusion Criteria, Exclusion Criteria, Target Sample Size, and Rationale for Sample Size 
10. Duration of the Clinical Trial 
11. Clinical Trial Methodology
12. Observation Items, Clinical Laboratory Tests, Methods of Assessment, and Procedures for Sample Storage 
and Disposal 
13. Expected Adverse Events and Precautions for Use 
14. Criteria for Discontinuation or Withdrawal of Study Participants 
15. Criteria, Methods, and Interpretation of Efficacy Evaluation 
16. Criteria, Methods, and Reporting of Adverse Events and Safety Evaluation 
17. Participant Information Sheet and Informed Consent Form
18. Compensation Policy for Study-Related Injury 
19. Post-Trial Care and Treatment for Study Participants 
20. Measures for the Protection of Participant Safety 
21. Other Essential Information Required for the Safe and Scientific Conduct of the Clinical Trial

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1. Title and Phase of the Clinical Trial
1.1 Title
A Study to Evaluate the Therapeutic Effects of Metagenomics-Based Probiotics on Non-Alcoholic Fatty Liver 
Disease
1.2 Phase
Investigator-Initiated Clinical Trial (IIT)
2. Name and Address of the Clinical Trial Site(s)
한림대학교춘천성심병원 / 강원도 춘천시 삭주로 7
3. Names and Titles of the Principal Investigator and Study Staff
3.1 Principal Investigator
한림대학교춘천성심병원 소화기내과 석기태 교수
3.2 Study Staff
석기태
3.3 Co-Investigators
한림대학교 춘천성심병원 소화기 내과 신석표 
한림대학교 춘천성심병원 소화기 내과 양영주 
한림대학교 춘천성심병원 소화기 내과 백광호
4. Name and Title of the Pharmacist Responsible for Investigational Product Management
허 연 화, 약제팀 대리 
이 은 경, 약제팀 계장 
오 경 미, 약제팀 계장
5. Name and Address of the Sponsor 
(주)종근당바이오 / 서울특별시 서대문구 충정로 8

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6. Background and Objectives of the Clinical Trial
6.1   Objectives
The objective of this study is to assess the efficacy of probiotics in improving clinical and biochemical 
parameters of non-alcoholic fatty liver disease (NAFLD) in diagnosed patients.
6.2   Background
-Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of conditions ranging from simple 
steatosis, characterized by excessive triglyceride accumulation in hepatocytes, to non-alcoholic 
steatohepatitis (NASH), which involves hepatocellular injury and inflammation, and ultimately to cirrhosis 
resulting from chronic inflammation, hepatocyte destruction, and progressive fibrosis. The pathogenesis of 
NAFLD is multifactorial and includes insulin resistance, lipotoxicity caused by excessive lipid accumulation, 
activation of Kupffer cells and hepatic stellate cells leading to inflammation and fibrogenesis, and 
endoplasmic reticulum stress.
-
Globally, more than 600 million individuals are affected by non-alcoholic fatty liver disease (NAFLD), with 
the majority of cases occurring in the United States, Europe, and China. The prevalence of NAFLD 
continues to rise alongside increasing rates of obesity driven by unhealthy dietary habits and insufficient 
physical activity. In Korea, the number of patients diagnosed with NAFLD increased markedly from 24,379 
in 2013 to 51,256 in 2017, representing an annual growth rate of approximately 21%. Healthcare 
expenditures have also escalated significantly, rising from 4.72 billion KRW in 2013 to 10.53 billion KRW in 
2017, with an average annual increase of 22.7%.
-
-
Various pharmacologic agents have been used in attempts to treat non-alcoholic fatty liver disease 
(NAFLD), including anti-obesity medications (e.g., orlistat), insulin-sensitizing agents (metformin, 
pioglitazone, rosiglitazone), and lipid-lowering agents such as clofibrate, gemfibrozil, bezafibrate, 
atorvastatin, and simvastatin. Hepatoprotective agents aimed at restoring injured hepatocytes—such as 
ursodeoxycholic acid and taurine—along with antioxidants (vitamin E, pentoxifylline) and nutritional 
supplements (lecithin, betaine, N-acetylcysteine) have also been utilized. However, despite these 
therapeutic attempts, no pharmacologic agent has proven definitively effective for the treatment of NAFLD. 
Therefore, lifestyle modification, including dietary intervention, increased physical activity, and weight 
reduction, remains the cornerstone of current management.
-
-
Currently, Intercept’s obeticholic acid (OCA) has demonstrated therapeutic efficacy for NASH in a phase 3 
clinical trial. In addition, several pharmaceutical companies—including Genfit, Gilead, and Allergan—are 
conducting phase 3 trials, and numerous investigational agents with diverse mechanisms of action are in 
phase 2 or phase 1 development.
-
-
Recently, growing interest in the human microbiome has led to extensive research aimed at elucidating the 
relationship between microbial communities and human disease. The liver is directly connected to the gut 
and plays a central role in metabolizing nutrients, making the gut microbiome closely associated with liver 
health and disease. Increasing evidence indicates that intestinal dysbiosis and small intestinal bacterial 
overgrowth (SIBO) can contribute to the development and progression of liver diseases, supporting the 
emerging concept of the gut–liver axis.
-
Lactic acid bacteria (LAB) are microorganisms that produce lactic acid through carbohydrate fermentation 
and have long been used to improve food preservation, flavor, nutritional value, and overall health. Beyond 
their established ability to modulate the gut environment, LAB have been extensively investigated for their 
potential therapeutic effects across various diseases. The strain Pediococcus pentosaceus KID7 used in 
this study is listed as an approved ingredient in the Korean Food Code and is currently incorporated in 
commercially available foods and dietary supplements. In addition, Lactobacillus helveticus and 
Lactobacillus bulgaricus are recognized as standardized probiotic ingredients under the Ministry of Food 
and Drug Safety (MFDS) Health Functional Food Code, allowing their use as probiotics in functional foods.
-
-
During the initial planning of the study, Lactobacillus bulgaricus CKDB001 was intended to be used instead 
of Pediococcus pentosaceus KID7. However, discrepancies were identified in the genetic analysis of L. 
bulgaricus CKDB001 compared with previous data, and additional time was required to clarify the cause of 
these differences. As a result, delays in strain identification and production led to the temporary 
replacement of the investigational strain with P. pentosaceus KID7. Subsequently, animal studies using L. 
bulgaricus CKDB001 yielded favorable outcomes, and this strain has been verified as suitable for use in 
commercially available probiotic formulations in Korea. Given its safety for human consumption and 
promising preclinical results, the decision was made to include L. bulgaricus CKDB001 in the investigational 
product, and the study will therefore be conducted with four arms.

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-
In preclinical studies using a Western diet–induced mouse model of non-alcoholic fatty liver disease 
(NAFLD), administration of Lactobacillus bulgaricus CKDB001 and Lactobacillus helveticus CKDB001 
resulted in significant improvements, including reductions in body weight and liver weight, attenuation of 
hepatic steatosis and steatohepatitis, and decreased serum liver enzymes (AST and ALT). Based on these 
findings, the present study aims to evaluate the efficacy and safety of L. bulgaricus CKDB001 or L. 
helveticus CKDB001 in patients with NAFLD.
-
-
The marker strain of Pediococcus pentosaceus KID7 is approved as a probiotic ingredient for human 
consumption under the Korean Food Code and is already incorporated into commercially available 
formulations. Similar to the previously evaluated strains, P. pentosaceus KID7 demonstrated beneficial 
effects in a Western diet–induced NAFLD mouse model, including reductions in liver-to-body weight ratio, 
hepatic lipid accumulation, and inflammatory responses. Its administration also lowered serum liver 
enzymes (AST, ALT) and decreased hepatic expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) 
at both the gene and protein levels, along with a favorable modulation of the gut microbiome. These results 
were consistent with those observed in studies using L. bulgaricus CKDB001, providing strong justification 
for its inclusion as an investigational strain. Taken together, these preclinical data support the expectation 
that similar therapeutic benefits may be observed in patients with NAFLD.
-
-
The strain was initially identified in 2015 as Lactobacillus delbrueckii subsp. bulgaricus using 16S rRNA 
sequencing, which is one of the most commonly used methods for bacterial identification. Prior to initiating 
the clinical trial, whole genome sequencing (WGS) was conducted in 2019 to ensure accurate strain 
characterization. The WGS analysis revealed that the strain is Lactobacillus delbrueckii subsp. lactis. 
Accordingly, the strain name has been updated, and the study will proceed using the corrected taxonomic 
designation.
-
The strain Lactobacillus delbrueckii subsp. lactis is listed as an approved ingredient for use in food 
according to the Korean Food Code, and products containing L. lactis are already commercially available 
as foods and health functional supplements. The strain is also certified by the Food and Agriculture 
Organization (FAO) and the World Health Organization (WHO) and is included in international food 
standards. It has been reported to lack mucin-degrading activity, biogenic amine production, hemolytic 
activity, and DNase activity, supporting its safety for human consumption.
-
-
Functionally, L. delbrueckii subsp. lactis contributes to the proliferation of beneficial probiotics, 
suppression of harmful bacteria, and improvement of bowel habits. In a Western diet–induced mouse 
model of non-alcoholic fatty liver disease (NAFLD), oral administration of L. lactis CKDB001 resulted in a 
reduction in liver-to-body weight ratio, decreased hepatic lipid accumulation and inflammation, reduced 
serum liver enzyme levels (AST, ALT), and lowered gene and protein expression of pro-inflammatory 
cytokines (TNF-α, IL-1β, IL-6). Favorable modulation of the gut microbiome was also observed.
-
No participants were enrolled or administered the investigational product labeled as L. bulgaricus prior 
to the strain name change to Lactobacillus delbrueckii subsp. lactis.
Background Summary

Non-alcoholic fatty liver disease progresses through stages of fatty liver, steatohepatitis, and cirrhosis, 
and may eventually lead to hepatocellular carcinoma, resulting in significantly increased mortality.

The high prevalence of non-alcoholic fatty liver disease (NAFLD) both in Korea and globally imposes a 
substantial social and economic burden.

There is currently no approved pharmacologic therapy for non-alcoholic fatty liver disease (NAFLD).

The gut–liver axis theory has emerged, suggesting a strong association between the gut microbiome 
and the development of chronic liver diseases.

Probiotic administration is expected to improve non-alcoholic fatty liver disease (NAFLD).

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7. Code Name, Active Ingredient(s), Composition, and Dosage Form of the Investigational Product
7.1 Investigational Product (IP)
7.1.1 Active Ingredient: P. pentosaceus KID7, L. lactis CKDB001 or L. helveticus CKDB001 (containing 9 
× 10⁹ CFU per day)
7.1.2 Dosage Form: Capsules
7.1.3 Strength: 300 mg
7.1.4
Storage Conditions: refrigerated condition at 4–8°C
7.2 Comparator
7.2.1 Active Ingredient: Microcrystalline Cellulose
7.2.2 Dosage Form: Capsules
7.2.3 Strength: 300 mg
7.2.4 Storage Conditions: refrigerated condition at 4–8°C
7.3 Mixing Ratio
(Mixing Ratio, %)
7.4 Packaging and Labeling
The investigational product will be manufactured and packaged by the sponsoring organization, Chong Kun 
Dang Bio Co., Ltd. (CKD Bio), and supplied to the clinical trial site through the designated research nurse. 
Labeling of the investigational product will comply with all applicable regulations governing investigational 
medicinal products and will include the required information as described below. The label will also provide space 
for recording the subject’s allocation number and visit number to facilitate proper identification and tracking of the 
investigational product.
- As follows -
1. The statement “For Clinical Trial Use Only”
2. Product name or the generic name of the active ingredient
3. Expiration date
4. Storage conditions
5. Name and address of the sponsor approved for the clinical trial
6. The statement “Not for use outside the clinical trial”
7 Labeling
원료명
Investigational
Investigational
Investigational
Control
Product 1
Product
2
Product 3
Product
P. pentosaceus KID7
50
-
-
-
L. helveticus CKDB001
-
50
-
-
L. lactis CKDB001
-
-
50
Microcrystalline Cellulose
47
47
47
97
Silicon Dioxide
2
2
2
2
Magnesium Stearate
1
1
1
1
Total
100.0
100.0
100.0
100.0

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7.5 Management and Accountability
All investigational medicinal products will be supplied to the clinical trial site by the sponsor, Chong Kun Dang 
Bio Co., Ltd. The designated investigational product manager is responsible for verifying the receipt, quantity, and 
condition of all products delivered to the site. The manager must maintain complete records of receipt, dispensing, 
and return of all investigational products used in the clinical trial.
7.6 Dispensing
Dispensing of investigational medicinal products used in this clinical trial shall be conducted only upon receipt 
of a prescription signed by the Principal Investigator or an authorized sub-investigator participating in the study.
7.7 Storage
The investigational product manager shall record the subject’s English initials, allocation number, prescription 
date, and quantity dispensed in the drug accountability log. The manager is responsible for storing and managing 
these records, monitoring the usage status of all investigational products, and maintaining complete 
documentation of product receipt, dispensing, and return for the clinical trial.
7.8 Return of Unused Investigational Product
The investigational product manager shall return all unused investigational medicinal products to the sponsor, 
Chong Kun Dang Bio Co., Ltd. If any investigational products are discarded or lost at the clinical trial site, the 
manager must document the event in the investigational product accountability records. At the end of the clinical 
trial, all unused investigational products—including those not dispensed to subjects and those returned by 
subjects—must be returned to the sponsor. A shipment record confirming the returned products shall be attached 
when sending the investigational products back to the sponsor.
8.Target Disease or Condition
Non-alcoholic fatty liver disease (NAFLD)
9. Inclusion Criteria, Exclusion Criteria, Target Sample Size, and Rationale for Sample Size 
9.1 Inclusion Criteria
Subjects who meet all of the following criteria will be eligible for inclusion in the study.
1) Individuals who agree to participate in the study and have voluntarily signed the written informed consent 
form.
2) Male and female adults aged 20 years or older.
3) Patients diagnosed with non-alcoholic fatty liver disease (NAFLD).
※ Alcohol-related liver disease will be excluded based on the following criteria:

Individuals with an average daily alcohol intake of ≥60 g for at least one year prior to the visit (≥30 g for women).

(Reference examples: 360 mL of soju at 20% alcohol ≈ 72 g of alcohol; 500 mL of beer at 5% alcohol ≈ 25 g, or 330 
mL ≈ 16.5 g).
4) Patients with elevated liver enzyme levels above the normal range.
※ (Reference Ranges for Adult Liver Enzymes
• AST (GOT): 0–30 U/L (upper limit ≤40 U/L)
• ALT (GPT): 0–38 U/L (upper limit ≤40 U/L)
• ALP: 20–130 U/L
• GGT:
 – Male: 10–62 U/L
 – Female: 7–35 U/L

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9.2 Exclusion Criteria
Individuals who meet any of the following conditions will be excluded from the study.
1) Individuals who have consumed probiotics (e.g., lactic acid bacteria), prebiotics (e.g., dietary fiber, 
fructooligosaccharides), synbiotics, or fermented dairy products within the past 1 month.
2) Individuals who have taken antibiotics continuously within the past 2 months are expected to require 
antibiotic use during the study period.
3) Individuals who have continuously taken medications or health functional supplements that may affect liver 
function within the past 1 month.
4) Individuals who have participated in another clinical trial within the past 1 month (excluding medical device 
clinical trials).
5) Individuals with any of the following medical conditions:
① Alcoholic liver disease, hereditary metabolic liver disorders, or autoimmune hepatitis
② Systemic inflammatory diseases or immune-mediated disorders
③ Hepatocellular carcinoma
④ Uncontrolled cardiac or pulmonary diseases
⑤ Any other severe systemic disorders involving the heart, lungs, hematologic system, or endocrine system
6) Individuals with a history of malignant tumors diagnosed within the past 5 years.
7) Pregnant or breastfeeding women.
8) Individuals with known hypersensitivity or a history of severe allergic reactions to the investigational 
product, placebo, or any of their components.
9) Individuals deemed unsuitable for participation in the clinical trial at the discretion of the investigator.
9.3 Target Sample Size, and Rationale 
(Sample size, n)
Treatment 
Group 1 
Treatment 
Group 2
Treatment 
Group 3
Control 
Group
Total
Final number of subjects for evaluation
27
27
27
27
108
Number of subjects considering a 
10% drop-out rate
30
30
30
30
120
This study will be conducted in patients with non-alcoholic fatty liver disease (NAFLD) at our institution. Based on 
a two-group comparison in which the independent variable is binary (probiotic vs. control) and the primary 
outcome variable is continuous, and allowing for a 10% drop-out rate, 30 subjects per group are required.
- Null Hypothesis (H₀): There is no difference in liver function test values among the four groups, including the 
probiotic group and the control group.
- Alternative Hypothesis (H₁): There is a difference in liver function test values among the four groups, including 
the probiotic group and the control group.
Continuous Endpoint, Two Independent Sample Study 
Sample Size: Group 1 27, Group 2 27
Study Parameters
Mean, group 1 50, Mean, group 2 40

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Alpha 0.05 Beta 0.2 Power 0.8 
[View Power Calculations]
Δ = |μ2-μ1| = absolute difference between two means 
σ1, σ2 = variance of mean #1 and #2
n1 = sample size for group #1 
n2 = sample size for group #2
α = probability of type I error (usually 0.05) 
β = probability of type II error (usually 0.2) 
z = critical Z value for a given α or β
k = ratio of sample size for group #2 to group #1
※ The total number of human-derived specimens (stool 
samples) to be collected is 240. 
((30 + 30 + 30 + 30) × 2 = 240 samples)
10. Duration of the Clinical Trial 
After IRB approval –2022.4.30
Study Details
Study 
timeline
Remarks
19.8
9-10
11-12
20.1-2
3-4
5-6
7
IRB submission
●
IRB approval
●
●
●
Clinical trial
●
●
●
●
●
●
Stool analysis
●
●
●
Data organization and 
manuscript submission
●
Study Details
Study 
timeline
8
9
10
11-12
21.01
2
3
4
IRB submission
IRB approval
Clinical trial
●
●
●
●
●
●
●
●
Stool analysis
●
●
●
●
●
●
●
●
Data organization and 
manuscript submission

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Study Details
Study 
timeline
5
6
7
8
9
10
11
12
IRB submission
IRB approval
Clinical trial
●
●
●
●
●
●
●
●
Stool analysis
●
●
●
●
●
●
●
●
Data organization and 
manuscript submission
Study Details
Study 
timeline
22.1
2
3
4
IRB submission
IRB approval
Clinical trial
●
●
●
●
Stool analysis
●
●
●
●
Data organization and 
manuscript submission
●
●
11.Clinical Trial Methodology
11.1 Study Design
Participants who voluntarily sign the informed consent form at Visit 1 (–2 weeks) will undergo screening to 
determine eligibility based on the inclusion and exclusion criteria. Eligible subjects will complete a 2-week run-in 
period and, at Visit 2 (Week 0), will be randomly assigned—according to the order of enrollment—to one of four 
groups: Treatment Group 1, Treatment Group 2, Treatment Group 3, or the Control Group. Subjects will then 
receive the investigational product or control product for 8 weeks, after which the outcomes specified in the study 
assessments will be analyzed.
11.2 Dosage, Administration Method, and Duration of Intake
11.2.1 Daily Dosage and Administration Method
The clinical trial will be conducted with a total of four groups. Beginning the day after Visit 2 (Week 0), each 
group will receive the investigational product or control product orally three times daily for 8 weeks, taken 
after meals with an adequate amount of water (lukewarm water)..

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Category   
Mor
ning
Aft
ern
oon
Eve
nin
g
Treatment Group 1
●
●
●
Treatment Group 2
●
●
●
Treatment Group 3
●
●
●
Control Group
  ○
  ○
○
●Investigational Product (IP) 1, 2, or 3
○ Control Product
11.2.2 Duration of Intake 
8 weeks (56 days)
11.3 Randomization
Only subjects who meet all inclusion criteria and do not meet any exclusion criteria will be assigned a 
randomization number (random No.) at Visit 2 (Week 0), in the order of enrollment. The treatment allocation 
corresponding to each randomization number will follow a computer-generated randomization list prepared in 
advance by an independent third party not involved in the study.
Block randomization will be used to allocate subjects into four groups—Treatment Group 1, Treatment Group 2, 
Treatment Group 3, and the Control Group—in a 1:1:1:1 ratio. The gender distribution across groups will be 
balanced to the greatest extent possible.
As this study follows a double-blind design, the group assignment for each subject must remain concealed from 
both investigators and participants until completion of the clinical trial.

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12. Observation Items, Clinical Laboratory Tests, Methods of Assessment, and Procedures for Sample 
Storage and Disposal 
12.1 Study Timeline
Procedure
Screening
Baseline
Treatment
End of 
study
Visit
1
2
3
4
Week
-2
01)
4
8
Window period (day)
±7
±7
±7
Informed consent
√
Demographic characteristics
√
Anthropometric 
measurements
√
√
√
√
Vital signs 
(pulse, blood pressure, body temperature)
√
√
√
√
Medical and surgical history
√
Medication history
√
√
√
√
Alcohol and smoking history
√
√
√
√
Screening tests 
(blood and 
urine)
Blood tests
√
Pregnancy test
√
Viral marker 
testing
√
Assessment of inclusion and 
exclusion criteria
√
Randomization
√
Administration of 
investigational product
√
√
Stool sample collection and 
assessment of bowel habits
√
√
Clinical laboratory tests (blood)
√
√
√
Histopathological examination
√
√
√
Quality of life assessment
√
√
Liver biopsy
√
√
Assessment of adverse events
√
√
√
√
1) Visit 2 (Week 0) will be conducted 2 to 3 weeks after Visit 1 (–2 weeks). (Visit 1 and Visit 2 may be conducted 
on the same day if necessary.)
2) Sex, date of birth, age, menstrual status, and duration of amenorrhea (if applicable) will be recorded.
3) Body weight, height, and BMI will be measured. Height will be measured only at Visit 1.
4) Participants will undergo blood testing after a 12-hour overnight fast prior to the visit. (For participants with 
hepatic steatosis, the investigator may select only clinically necessary tests based on clinical judgment.)
① Blood chemistry tests: AST, ALT, ALP, GGT, albumin, total bilirubin, direct bilirubin, total protein, 
uric acid, BUN, creatinine, glucose, cholesterol, triglyceride
(These tests may be omitted for subjects who have available health examination results within the past 4 weeks.)
5) A urine pregnancy test will be performed for women of childbearing potential, except for those confirmed to 
be postmenopausal (amenorrhea for ≥24 months).

6) Viral marker testing will include HBsAg, Anti-HBs, and Anti-HCV. (Testing will be performed if results 
within the past 5 years are not available or if clinically indicated by the investigator.)
7) Stool samples may be collected up to 3 days after the visit if necessary and will be stored in a –80°C deep 
freezer.
Assessment of bowel habits (conducted only at Visit 2 and Visit 4):
Bowel movement frequency, stool volume, stool consistency and form (Bristol Stool Scale), and time required 
for defecation.
8) Participants will visit after a 12-hour overnight fast for the following tests. Remaining serum samples will be 
stored at –80°C. (The investigator may selectively perform only clinically necessary tests based on medical 
judgment.)
① Hematology: RBC, WBC & differential count, hemoglobin, hematocrit, platelet count: RBC, WBC & 
differential, hemoglobin, hematocrit, platelet
② Blood chemistry: AST, ALT, ALP, GGT, albumin, total bilirubin, direct bilirubin, total protein, uric 
acid, BUN, creatinine, glucose, l cholesterol, triglyceride
③ Coagulation test: Prothrombin time (performed only at Visit 2)
➃ Serum cytokines: TNF-α, IL-6
9) Participants will visit after a 12-hour overnight fast for the following examinations (performed only for subjects 
who have provided consent):
① Abdominal ultrasound or CT scan
② Fibroscan
10) Questionnaires will be administered (conducted only at Visit 2 and Visit 4).
11) Procedures will be performed only for subjects who provide consent.

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12.2 Outcome measures
12.2.1 Informed consent 
At Visit 1 (–2 weeks), prior to any study-related procedures, the study objectives and details will be 
thoroughly explained to each potential participant. Subjects who voluntarily agree to participate will sign the 
written informed consent form and will be assigned a Screening Number (Screening No.) in sequential order. 
The case report form (CRF) will document consent status, date of consent, and participant initials. 
12.2.2 Demographic characteristics
At Visit 1 (–2 weeks), sex, date of birth, age, menstrual status, and duration of amenorrhea (if applicable) will be 
recorded.
12.2.3 Anthropometric measurements 
Body weight, height, and BMI will be measured at Visit 1 (–2 weeks), Visit 2 (Week 0), Visit 3 (Week 4), and 
Visit 4 (Week 8). Height will be measured only at Visit 1 (–2 weeks). Measurements will be taken with shoes 
and outerwear removed and in the lightest clothing possible. Efforts will be made to ensure that the same 
equipment, time window, and study personnel are used across visits. Results will be recorded to the exact 
decimal places generated by the measurement device.
12.2.4 Vital signs 
At each visit, pulse, blood pressure, and body temperature will be measured after the subject has rested for 
at least 10 minutes. Efforts will be made to use the same equipment, time window, and study personnel 
across visits
12.2.5 Medical and surgical history
At Visit 1 (–2 weeks), medical history will be reviewed through interviews and past medical records. Medical 
events within the past 5 years will be documented, including onset date (year or year/month), persistence, 
and investigator comments. Surgical history within the past 5 years will also be recorded, including date of 
diagnosis, date of discharge, and investigator comments.
12.2.6 Medication history
On each visit, use of medications, herbal medicines, and health supplements will be assessed. At Visit 1 (–2 
weeks), all medications, herbal products, and supplements taken within the past 2 months will be reviewed. 
Any medication or supplement taken during the study will be documented, including type, dose, and duration.
12.2.7 Alcohol and smoking history 
At each visit, smoking history (status, duration, amount) and alcohol intake (status, duration, amount) will be 
assessed.
12.2.8 Screening tests (blood and urine)
At Visit 1 (–2 weeks), after a 12-hour overnight fast, blood chemistry tests, a pregnancy test, and viral marker 
testing will be performed. Blood chemistry testing may be omitted for subjects with available health 
examination results within the past 4 weeks.
The investigator may selectively perform only clinically necessary tests.

Pregnancy test: A urine human chorionic gonadotropin (hCG) test will be performed for women of 
childbearing potential, except those confirmed to be postmenopausal (amenorrhea ≥24 months).

Viral markers: HBsAg, Anti-HBs, Anti-HCV (Performed if no results within the past 5 years or if 
clinically indicated.
12.2.9 Assessment of inclusion and exclusion criteria 
Eligibility will be determined using data collected at Visit 1 (informed consent, demographics, anthropometry, 
vital signs, medical/surgical history, medication history, alcohol/smoking history, blood/urine tests), applying the 
inclusion and exclusion criteria described in Section 9.

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12.2.10 Randomization 
Eligible subjects will be randomized at Visit 2 (Week 0) into Treatment Group 1, Treatment Group 2, 
Treatment Group 3, or the Control Group according to the randomization procedure described in Section 
11.3.
12.2.11 Administration of investigational product
Subjects will receive the assigned investigational product or control product for 8 weeks starting from Visit 2 
(Week 0). All administrations will be documented.
12.2.12 Stool Sample Collection and Bowel Habit Assessment
At Visit 2 (Week 0) and Visit 4 (Week 8), stool samples will be collected. If necessary, samples may be 
collected within 3 days after the visit. Bowel habits will be assessed using a questionnaire, including stool 
frequency, stool volume, stool form (Bristol Stool Scale), and time required for defecation.
12.2.13 Clinical Laboratory Tests (Blood)
At Visit 2 (Week 0), Visit 3 (Week 4), and Visit 4 (Week 8), subjects will visit after a 12-hour overnight fast for 
laboratory testing.
At Visit 2, results within the past 4 weeks may be used.
① Hematology: RBC, WBC & differential, hemoglobin, hematocrit, platelet
② Blood chemistry: AST, ALT, ALP, GGT, albumin, total bilirubin, direct bilirubin, total protein, uric 
acid, BUN, creatinine, glucose, cholesterol, triglyceride
③ Coagulation: Prothrombin time (Visit 2 only)
➃ Cytokines: TNF-α, IL-6
Clinically significant abnormal results should be documented in the CRF along with the investigator’s 
assessment.
12.2.14 Histopathological Examinations
At Visit 2, Visit 3, and Visit 4, subjects will visit after a 12-hour fast for examinations if clinically indicated or 
consented.
① Abdominal ultrasound or CT: To assess the degree of hepatic steatosis
② Fibroscan: To quantitatively assess hepatic stiffness and fibrosis
12.2.15 Quality of Life Assessment
Quality of life will be assessed using a questionnaire at Visit 2 and Visit 4.
12.2.16 Liver biopsy
Liver biopsy will be performed at Visit 2 and Visit 4 only for subjects who provide consent.
12.2.17 Assessment of Adverse Events
Adverse events will be assessed at every visit.
12.2.18 Additional Visits (If Needed)
Unscheduled visits may occur if re-testing, follow-up of adverse events, or other investigator-judged needs 
arise.
12.3 Storage and Disposal of Collected Samples
Stool samples will be stored at –80°C and analyzed by a specialized microbiome analysis company (ChunLab). 
After analysis, samples will be discarded.
Blood samples will also be stored at –80°C and discarded after analysis.

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13. Expected Adverse Events and Precautions for Use 
13.1Expected Adverse Events 
Temporary gastrointestinal symptoms such as gas, abdominal bloating or discomfort, diarrhea, or constipation 
may occur after ingestion of the investigational product.
13.2Precautions for Use 
1) The daily recommended intake should be followed.
2) Store the product in a cool environment (4–8°C), avoiding direct sunlight.
14. Discontinuation and Withdrawal of Study Participants
14.1 Criteria for Discontinuation and Withdrawal
1) If a serious adverse event (SAE) occurs in the participant.
2) If the participant or the participant’s legal representative requests discontinuation of the study.
3) If the investigator or the participant violates the study protocol.
4) If the participant withdraws consent to participate in the study.
5) If the participant becomes lost to follow-up.
6) If the investigator determines that continued participation is not appropriate for the participant.
14.2 Management of Protocol Deviations
The principal investigator and sub-investigators must be thoroughly familiar with the study protocol and 
adhere strictly to its requirements to prevent protocol deviations. Study participants must follow the assigned 
administration instructions and comply with the study visit schedule. To support accurate dosing and 
adherence to scheduled visits, the investigator should take appropriate measures, such as providing written 
reminders of upcoming visits and conducting telephone monitoring as necessary.
In cases of major protocol deviations—such as violations of inclusion/exclusion criteria or failure to obtain 
informed consent—that may significantly affect participant safety or study outcomes, the participant should 
be withdrawn from the study (drop-out) as a general principle.
For minor deviations, the nature, extent, and reasons for the deviation must be documented accurately, 
and the investigator should evaluate whether the deviation may impact the study results during data analysis.
15. Criteria, Methods, and Interpretation of Efficacy Evaluation
15.1 Primary Efficacy Endpoint Analysis
After 8 weeks of administration of the investigational products or control product in the four randomized 
groups, the change in liver enzyme levels (AST and ALT) from baseline will be calculated for each group. 
Based on the results of the normality test and homogeneity of variance test, statistical comparisons between 
groups will be performed using either the two-sample t-test or the Mann–Whitney U test. Additional subgroup 
analyses may be conducted as needed.
15.2 Secondary Efficacy Endpoint Analysis
For the four randomized groups, after 8 weeks of administration of the investigational product or control 
product, changes from baseline will be analyzed for serum GGT, albumin, serum lipid parameters 
(cholesterol and triglycerides), inflammatory cytokines (TNF-α and IL-6), BMI, histopathological and imaging 
findings (abdominal ultrasound/CT and Fibroscan), MELD score, Child–Pugh score, worsening of liver 
disease (hepatic encephalopathy, ascites, variceal bleeding, spontaneous bacterial peritonitis, liver-related 
hospitalization, death or liver transplantation, and all-cause mortality), bowel habits (frequency of defecation, 
stool volume, stool consistency and form, time required for defecation), quality of life (questionnaire), and gut 
microbiome composition. The same statistical methods applied to the primary endpoint will be used for these 
analyses. Additional subgroup analyses may be conducted as needed.

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15.3 Method for Stool Analysis
Among participants who provide separate written informed consent for human-derived material research, 
stool samples will be collected and submitted to ChunLab, a specialized bioinformatics analysis company, for 
microbiome analysis.
16. Criteria, Methods, and Reporting of Adverse Events and Safety Evaluation 
16.1 Definitions of Terms
An adverse event (AE) refers to any untoward and unintended sign (including abnormal laboratory findings), 
symptom, or disease that occurs in a participant who has received the investigational product, regardless of 
whether a causal relationship with the investigational product exists.
An adverse drug reaction (ADR) refers to any noxious and unintended response to the investigational 
product that occurs at any dosage and for which a causal relationship with the investigational product cannot 
be ruled out.
A serious adverse event (SAE) refers to any adverse event occurring at any dose of the investigational 
product that results in any of the following outcomes:
- As follows -
An unexpected adverse drug reaction refers to a reaction whose nature or severity is not consistent with the 
available product information, such as the investigator’s brochure or the product’s labeling/insert.
16.2 Safety Evaluation Population
Safety evaluations will be conducted for all participants who have taken the investigational product at least once.
16.3 Criteria and Methods for Adverse Event Evaluation
Adverse events will be evaluated by considering the frequency and severity of events documented in each 
participant’s adverse event log, as well as abnormalities identified in laboratory tests (hematology, blood 
chemistry, urinalysis) and vital signs. Clinically significant abnormalities in laboratory results or vital signs will 
be recorded in the adverse event section of the case report form (CRF).
For each adverse event, the following information will be documented in the CRF: occurrence of the event, 
signs and symptoms, date of onset and resolution, severity, relationship to the investigational product, 
actions taken regarding the study drug, treatments administered, and clinical outcome.
Death or a life-threatening condition
A need for hospitalization or prolongation of existing hospitalization
(Hospitalizations solely for the purpose of conducting study procedures, hospitalizations related to 
the underlying NAFLD condition, or hospitalizations due to unrelated medical conditions will not 
be classified as SAEs.)
Persistent or significant disability/incapacity
A congenital anomaly or birth defect
A medically important condition that may require intervention to prevent one of the
outcomes listed above.

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16.4 Severity of Adverse Events
The severity of adverse events will be classified according to their maximal intensity based on the following 
criteria.
No.
          Criteria
내용
1
Mild, Grade 1
Does not interfere with the participant’s normal daily activities, causes 
minimal discomfort, and is easily tolerated.
2
Moderate, Grade 2
Causes noticeable discomfort and interferes with the participant’s normal 
daily activities or functioning.
3
 Severe, Grade 3
Prevents the participant from performing normal daily activities or 
functioning.
16.5 Relationship to the investigational product
The investigator will assess the relationship between the investigational product and each adverse event by 
reviewing the participant’s medical history, current health status, timing of administration, dosing conditions, and 
other relevant factors, and will determine causality according to the following criteria.

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No.
Criteria
Content
1
   Certain
There is clear evidence that the investigational product was administered
The temporal relationship between administration of the investigational 
product and the onset of the adverse event is clinically plausible
The adverse event is more reasonably explained by the investigational 
product than by other causes
The adverse event resolves or improves after discontinuation of the 
investigational product (positive dechallenge)
The adverse event recurs upon re-administration of the investigational 
product, if rechallenge is performed (positive rechallenge)
The nature of the adverse event is consistent with known information 
regarding the investigational product or other agents in the same class
2
Probable/likely
There is clear evidence that the investigational product was administered
The temporal relationship between administration of the investigational 
product and the onset of the adverse event is clinically plausible
The adverse event is more plausibly explained by the investigational 
product than by other causes
The adverse event resolves or improves after discontinuation of the 
investigational product (positive dechallenge)
3
   Possible
There is clear evidence that the investigational product was administered
The temporal relationship between administration of the investigational 
product and the onset of the adverse event is clinically plausible 
The investigational product is considered as likely a cause of the 
adverse event as other plausible etiologies 
The adverse event resolves or improves after discontinuation of the 
investigational product (positive dechallenge)
4
  Unlikely
There is clear evidence that the investigational product was administered.
There are other causes that are more likely to explain the adverse event.
The adverse event does not resolve, or the findings are inconclusive, 
after discontinuation of the investigational product (negative or equivocal 
dechallenge).
The adverse event does not recur, or the findings are inconclusive, after 
re-administration of the investigational product if performed (negative or 
equivocal rechallenge)
5
    None
 The participant did not receive the investigational product; or
 The temporal relationship between drug administration and the onset of 
the adverse event is not plausible; or
 There is a clear alternative explanation for the adverse event.
6
Unassessable
There is partial information regarding the adverse event, but the available 
data are insufficient to determine its relationship to the investigational 
product.
16.6 Actions taken with respect to the investigational product
1) Dose increased
2) Dose not changed
3) Dose reduced
4) Temporarily discontinued
5) Permanently discontinued
6) Not applicable
7) Unknown

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16.7 Medication for Adverse Events
1) Medication administered for the adverse event
2) No medication administered for the adverse event
16.8 Outcome of Adverse Event
1) Recovered (resolved)
2) Recovering (resolving)
3) Not recovered (not resolved)
4) Recovered with sequelae
5) Fatal
6) Unknown
16.9 Methods for Reporting Adverse Events
The responsibilities of each party regarding any serious adverse event (SAE) that occurs during the clinical trial 
are as follows.
16.9.1 Responsibilities of the Principal Investigator
If a serious adverse drug reaction (SADR) occurs during the clinical trial, the principal investigator must 
report it to the sponsor immediately, and no later than 1 business day from the date the investigator becomes 
aware of the event. A follow-up report containing detailed information shall also be submitted subsequently.
In the case of an unexpected serious adverse drug reaction (USADR), the investigator must promptly report 
the event to both the sponsor and the Institutional Review Board (IRB).
If a fatal case is reported, the principal investigator shall provide the sponsor and the IRB with additional 
documentation, such as the autopsy report (if performed) and the death certificate or other relevant medical 
documentation.
16.9.2 Responsibilities of the Sub-Investigator
If a serious adverse event related to the investigational product occurs during the clinical trial, the sub-
investigator (study staff) must immediately report the event to the principal investigator and the sponsor, and 
subsequently submit a follow-up report containing detailed information.
In the case of an unexpected serious adverse drug reaction (USADR), the sub-investigator must promptly 
report the event to both the sponsor and the Institutional Review Board (IRB).
16.9.3 Responsibilities of the Institutional Review Board (IRB)
If an unexpected serious adverse drug reaction or any new information arises that may negatively affect 
participant safety or the conduct of the clinical trial, the Institutional Review Board (IRB) shall require the 
principal investigator to take appropriate actions as necessary.
16.9.4 Responsibilities of the Sponsor
The sponsor shall report all serious and unexpected adverse drug reactions (SADRs/USADRs) to the 
relevant investigators, and when necessary, to the Institutional Review Board (IRB) and the Ministry of Food 
and Drug Safety (MFDS), within 15 days from the date the sponsor receives notification from the principal 
investigator or sub-investigator, or from the date the sponsor otherwise becomes aware of the event.
In cases where the adverse reaction results in death or is life-threatening, the sponsor shall report the event 
within 7 days of becoming aware of it and shall submit a follow-up report with detailed information within 8 
days of the initial report. When submitting an adverse drug reaction report, the sponsor shall include the 
information provided by the principal investigator or sub-investigator.
The sponsor must provide additional safety information periodically until the adverse drug reaction is 
considered resolved (i.e., the reaction has subsided, or further follow-up is not possible). In such cases, the 
investigator shall actively cooperate by providing all necessary data and supporting information required for 
ongoing reporting.

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16.10 Pregnancy Reporting Procedures
Pregnancy itself is not considered an adverse event during the clinical trial. In addition, hospitalization for 
elective termination without complications (excluding therapeutic abortion) or for normal delivery of a healthy 
newborn is not considered an adverse event.
Once a pregnancy is identified, the investigator must complete an Initial Pregnancy Report and notify the 
sponsor within 24 hours of becoming aware of the pregnancy. The investigator shall follow and document the 
course and outcome of all pregnancies, even if the participant withdraws consent or discontinues participation 
in the clinical trial.
Furthermore, the investigator must complete a Pregnancy Outcome Report and notify the sponsor within 24 
hours after becoming aware of the outcome of the pregnancy.
17. Participant Information Sheet and Informed Consent Form
The Participant Information Sheet and Informed Consent Form (ICF) may be used only after approval by the 
Institutional Review Board (IRB). The investigator must obtain informed consent from each participant in 
accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice (GCP) 
guidelines.
Prior to performing any procedures related to this clinical trial, the investigator shall fully explain the study to 
the participant (or the participant’s legally authorized representative) and obtain written informed consent. 
The investigator must retain the signed original copy of the consent form in the investigator’s file, and provide 
the participant (or legally authorized representative) with a signed copy of the consent form along with the 
information sheet that was explained.
If any revisions are made to the Participant Information Sheet or the Informed Consent Form, the revised 
documents must receive prior re-approval from the IRB. Participants who are currently enrolled in the study 
(or their legally authorized representatives) must also undergo re-consent using the approved revised 
version. In such cases, the investigator must document the individuals notified, the date and time of 
notification, and the content delivered as source documentation.
18. Compensation for Injury
In the event that an adverse reaction caused by the investigational product, or an injury arising from medical 
interventions performed to manage such adverse reactions, results in harm to a participant, the participant 
will be compensated in accordance with the Compensation for Injury Policy, provided that the injury is 
directly attributable to the investigational product.
19. Post-Trial Medical Care and Treatment Guidelines
Participants who discontinue the clinical trial prematurely, as well as those who complete the study, will 
receive subsequent medical care and treatment according to the standard clinical practices and established 
guidelines for patients with liver disease.
20. Safety Protection Measures for Study Participants
20.1 Clinical Trial Institution
The head of the clinical trial institution shall ensure that the necessary clinical trial facilities, equipment, and 
qualified personnel required for each stage of the study are fully secured and properly prepared so that the 
clinical trial can be conducted appropriately and safely.
20.2 Principal Investigator
The principal investigator shall be fully familiar with the adverse events, precautions, and safety information 
described in this clinical trial protocol. If any serious adverse event occurs during the trial, the principal 
investigator must immediately report it to the Institutional Review Board (IRB) and the sponsor.
20.3 Sub-Investigator
The sub-investigator shall be fully familiar with the expected adverse events and precautions specified in this 
protocol. If a serious adverse event occurs during the conduct of the clinical trial, the sub-investigator must 
immediately report it to the principal investigator and the sponsor.

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21. Other Requirements for the Safe and Scientific Conduct of the Clinical Trial
21.1 Compliance with GCP and the Declaration of Helsinki
The procedures described in this protocol have been developed to ensure that the investigator and the 
sponsor conduct, evaluate, and document the clinical trial in compliance with ICH-GCP, the Korean Good 
Clinical Practice (KGCP) guidelines, and the ethical principles outlined in the Declaration of Helsinki. This 
clinical trial will be conducted in accordance with all applicable domestic laws and regulatory requirements.
21.2 Informed Consent
The investigator must thoroughly explain all relevant aspects of the clinical trial to the participant and/or the 
participant’s legally authorized representative, providing sufficient opportunity to ask questions and 
understand all foreseeable implications of participation. All informed consent must be documented in writing.
The investigator must sign the informed consent form to confirm that the consent process was properly 
conducted. No procedures performed solely for the purposes of the clinical trial may be initiated until 
informed consent has been obtained from the participant.
21.3 Approval of the Clinical Trial Protocol
Before initiating the clinical trial, the protocol and all related documents must be submitted to the Institutional 
Review Board (IRB) in accordance with applicable regulations. The clinical trial may begin only after IRB 
approval has been obtained.
21.4 Confidentiality
All participant names will remain confidential, and participants will be identified in records and evaluations 
only by the subject identification number assigned within the clinical trial. Participants will be informed that all 
clinical trial data will be stored in a secure computer system and handled strictly confidentially. When 
transferring clinical trial data from the clinical trial site, all personally identifiable information (including name, 
address, or any direct identifiers) must be removed, and only the subject identification code may be 
transmitted.
Signed informed consent forms will be retained by the principal investigator. By signing this protocol, the 
principal investigator agrees to obtain informed consent appropriately from each participant and to allow 
audits or inspections upon request. The principal investigator must maintain a list linking subject names to 
subject identification numbers, which must be kept securely for record verification.
The informed consent forms and subject identification list shall be stored in a designated archiving room for 
three years from the product approval date (or three years from study completion if the product is not 
intended for approval). After this period, the documents may be disposed of.
21.5 Familiarization with the Clinical Trial Protocol
The principal investigator and all study staff must thoroughly review, understand, and adhere to the clinical trial 
protocol prior to conducting the study.
21.6 Clinical Trial Monitoring and Audits
The sponsor shall conduct a pre-study visit before trial initiation. To ensure that the clinical trial is conducted 
in compliance with KGCP and that the clinical trial data can be accepted for domestic or international 
regulatory submission, the sponsor will conduct monitoring and audits throughout the trial.
During monitoring visits, the monitor will verify that case report forms (CRFs) are complete and accurate and 
compare CRF entries with source documents in the presence of the investigator or designated study staff. 
The investigator must always cooperate fully with the sponsor.