Remedial Mechanisms of Simvastatin and Ursodeoxycholic Acid in Liver Cirrhosis: Crosstalk Between Bile Secretion, Gut Microbiome, and Host Immune Response
Phase: NA
Conditions: Liver Cirrhosis
Sponsor: Chang Gung Memorial Hospital

 
 
ClINICAL RESEARCH: IRB 202201398A3 
Date of Approval: 2022/11/01 
 
Remedial mechanism of simvastatin and ursodeoxycholic acid 
in liver cirrhosis: crosstalk of bile secretion, gut microbiome, 
and host Immune response 
 
Reprint requests and correspondence: 
Chih-Ming Liang 
Division of Hepatogastroenterology, Kaohsiung Chang Gung Memorial Hospital, 123, 
Ta-Pei Road, Niao-Sung Hsiang, Kaohsiung, 833 Taiwan 
Tel.: 886-7-7317123 ext. 8301, Fax: 886-7-7322402 
E-mail: gimy54861439@gmail.com 
 
 

 
 
Remedial mechanism of simvastatin and ursodeoxycholic acid 
in liver cirrhosis: crosstalk of bile secretion, gut microbiome, 
and host Immune response  
 
Introduction 
There is emerging evidence that the gut milieu plays an important role in the 
progression of complications of cirrhosis [1–3]. Studies have found dysbiosis in the gut 
microbiota in patients with cirrhosis that has the potential to influence complications such 
as hepatic encephalopathy [1,2]. The gut milieu in cirrhosis involves the interaction between 
the microbiota and secreted factors, such as bile acids (BAs) that can also modulate the gut 
barrier [4]. The gut microbiota is known to convert 7a-dehydroxylate primary BAs and 
chenodeoxycholic acid (CDCA) and cholic acid (CA) into the secondary bile acids lithocholic 
acid (LCA) and deoxycholic acid (DCA), respectively [5]. Cirrhotic patients have been shown 
to have a lower proportion of secondary Bas in their bile but the mechanism for this is not 
clear [6]. Since BAs have important downstream pathophysiologic effects, a better 
understanding of the interaction between the intestinal microbiome and BAs is important to 
gain insight into the pathophysiology of cirrhosis [7,8]. In Genta Kakiyama study[9], the 
median abundances of taxa are shown with significantly higher Enterobacteriaceae and 
Veillonellaceae and lower autochthonous bacteria (Blautia, Ruminococcaceae, 
Lachnospiraceae) in cirrhotics, especially advanced cirrhotics compared to healthy controls. 
The total bile acid was 206.5 μg/100 mg dry stool in healthy control, and 39.0 in advanced 
cirrhosis. The secondary BAs were present in a significantly lower percentage of cirrhotics. 
The ratios of all secondary to primary BAs, and specifically of DCA/CA and LCA/CDCA, were 
also the lowest in advanced cirrhosis. Cirrhosis dysbiosis ratio (CDR), the ratio of 
autochthonous/good bacteria (e.g. Lachnospiraceae, Ruminococcaceae and Clostridiales) to 
non-autochthonous/ pathogenic bacteria (e.g. Enterobacteriaceae and Streptococcaceae), is 
significantly higher in controls and patients with compensated cirrhosis than patients with 
decompensated cirrhosis. Incresing CDR could lead to develop the hepatic 
encephalopathy[10].  Bile acids are also the endogenous ligands of Farnesoid X receptor 
(FXR), Takeda G protein receptor 5 (TGR5) and Sphingosine-1-phosphate receptor 2 (S1PR2). 
These receptors are placed at the interface of the host immune system with the intestinal 
microbiota and are highly represented in cells of innate immunity such as intestinal and liver 
macrophages, dendritic cells and natural killer T cells[11]. In human study, ursodeoxycholic 

 
 
acid (UDCA) could enhance the bile synthesis by CYP7A1 altering the gut microbiota 
population. UDCA also has other beneficial effects , such as anticholestatic, antifibrotic, 
antiproliferative, and anti-inflammatory [12-14].  
 In retrospective studies, statins appear to be safe in patients with compensated 
cirrhosis, and evidence suggests that they may significantly reduce fibrosis (HR:0.56, 
p<0.0001)[15]. Preclinical data from studies performed on in vitro and in vivo animal models 
shed light on favorable effects of statins on endothelial function, angiogenesis, PHTN, and 
fibrosis. Suggested mechanisms involve regulation of KLF2, eNOS, thrombomodulin, and C-
natriuretic peptide.  Animal studies evidence suggests that the administration of 
fluvastatin, lovastatin, and simvastatin to primary rat hepatocytes and human hepatoma cell 
line inhibits the paracrine activation of HSCs [16], reduces HSC turnover and activity [17,18]. 
Moreover, Nature (2020) reported statin therapy is associated with lower prevalence of gut 
microbiota dysbiosis. [19] 
The combination of ursodeoxycholic acid and statins is safe in human experiments, and 
the combination of the two has also proved to have a synergistic effect on the reduction of 
bile cholesterol levels [20], but there is no research on improving fibrosis makers or 
improving intestinal flora.  
The goal of the current study was to evaluate our hypothesis model of pathogenesis of 
chornic inflammation of liver cirrhosis. We hypothesized that an adverse microbiome would 
exacerbate the histopathological severity of liver induced by CCL4 in a germ-free mice model. 
We transplanted these mice with human fecal samples from healthy controls, or liver 
cirrhosis treated with staitn, or UDCA. The clinical trial mainly explores whether single statin 
or combined ursodeoxycholic acid can reduce liver fibrosis indicators, inflammatory 
cytokines and intestinal flora imbalance in patients with liver cirrhosis who have been cured 
of chronic hepatitis C or non-viral load hepatitis B. 
Patients and assessments- Study design 
We expect to enroll 120 stable patients who have achieved sustained viral response (SVR) 
(ie, viral eradication) after hepatitis C treatment for 6 months, or non-viral load hepatitis B 
for 6 months, who have been diagnosed with primary cirrhosis (FIB-4 ≥3.25) and met the 
Baveno VII criteria (liver stiffness measurement [LSM] ≥25 kPa) and exclude it (LSM <15 kPa 
and platelet count [PLT] ≥150×109/L) were used. Grey zones were classified into two groups: 
(high – LSM between 20–25 kPa and PLT <150×109/L, or LSM between 15–20 kPa and PLT 
<110×109/L, or low – defined as the remaining patients within the grey zone) [27]. Exclusion 
conditions: already taking statins, diabetes, liver cancer, alcoholic liver, moderate to severe 
fatty liver, liver decompensation (jaundice, ascites, esophagogastric varices, history of 
hepatic coma), chronic kidney disease, antibiotic use within three months and gastric ulcer 
medication(such as PPIs). Randomly divided into three groups: Group 1: control group (n = 

 
 
30), Group 2: treatment group (ursodeoxy Cholic acid (UDCA) (10mg/kg/day) (n = 30), Group 
3: treatment group (simvastatin 40mg) (n = 30), Group 4: treatment group (simvastatin 
40mg/day + ursodeoxy Cholic acid (UDCA) (10mg/kg/day) (n = 30). Fecal bile acid content 
and fecal flora, skin bile acid profile, cytokine markers, biochemical fibrosis biomarker were 
collected at the test base point and six months after treatment. In addition, patients who 
achieved virus eradication without liver cirrhosis (FIB-4 < 1.45, n=30) collected the content of 
fecal bile acid, fecal flora, skin bile acid, and inflammatory cytokines were collected at the 
test base point index, biochemical fibrosis biomarkers. Analysis of flora: 16S ribosomal RNA 
gene sequence analysis from the patient's fecal tube. Analysis of total fecal bile acid: LC-
MS/MS system analysis. Skin bile acid profile:Desorption-Electrospray Ionization Mass Spec- 
trometry (TD-ESI/MS). 
Block randomization 
Patients (n=120) were distributed on one block with 8 numbers and each group 
contained two numbers (1, 2, 3, 4). The admitted patients who were eligible for inclusion 
were given numbers in the order; number 1 was allocated to ( control group) as the study 
group, patients who carried number 2 was allocated to (UDCA group ),patients who carried 
number 3 was allocated to ( simvastatin group ), and number 4 was allocated to 
( simvastatin plus UDCA group ). Therefore, the control and three interventional groups 
were randomized into 1:1:1:1. 
Stool sample preparation and microbiota analysis 
Bile juice and biliary stents samples will be collected in separate sterile containers 
containing 2mL of RNA later and will be stored at room temperature. The samples will be 
transferred to the laboratory within 12 h, stored at 4°C, and used for extracting DNA within 
few weeks. Preliminary experiments will confirm that the bacterial composition data does 
not change in four weeks under the storage conditions used. Genomic DNA will be isolated 
from stool samples using the CTAB/SDS methods (Novogene Laboratories) following the 
manufacture’s protocol. All microbial community DNA samples will be analyzed for V4 
variable region of bacterial 16S ribosomal RNA gene using PCR primers 515F and 806R. The 
PCR products will be separated by 2% agarose gel electrophoresis. Samples with bright main 
strip between 400-450bp will be chosen for further experiments. PCR product will be mixed 
in equidensity ratios. Then, mixture PCR products will be purified with Qiagen Gel Extraction 
Kit (Qiagen, Germany). Sequencing libraries will be generated using TruSeq DNA PCR-Free 
sample Preparation Kit (Illumina, USA) following manufacture’s recommendations and index 
codes will be added. The library quality will be assessed on the Qubit@ 2.0 Fluorometer 
(Thermo Scientific) and Agilent Bioanalyzer 2100 system. At last, the library will be 
sequenced on an IlluminaHiSeq2500 platform and 250 bp paired-end reads will be 
generated. 
Fecal bile acid profile [20]. 
 

 
 
A stool sample was obtained and dried to obtain a lyophilized extract. To lyophilized 
faecal samples weighing 1 g, 80% methanol was added. All samples were sonicated for 
30 min, refluxed for two hours, and then cooled and filtered. The residue was re-suspended 
in chloroform/methanol (1:1, v/v), refluxed for one hour, and filtered. The combined 
extracts were taken to dryness, and re-suspended in 10 ml methanol (MeOH). An aliquot of 
1 ml was added with 2 µl of 1 mg/ml nordeoxycholic acid, and was diluted in 10 ml deionized 
water and deposed on a 300 mg HLB Oasis column, washed with 10 volumes deionized, 1 
volume cyclohexane, and the BAs were then eluted with 5 ml MeOH and were taken to 
dryness and resuspended in 250 µl MeOH. Four microliters were injected on liquid 
chromatography coupled with tandem mass spectrometry (LC-MS/MS) as previously 
described.  
Skin bile acid profile [22]  
TD-ESI source comprised of a direct probe (DP), thermal desorption unit, and 
electrospray ionization device. First, the direct probe (DP) was used for sampling analytes in 
solution or on solid surfaces. For liquid samples, a stainless steel inoculating loop serving as 
a probe (2 mm in diameter) was used to obtain approximately 2 μL of sample solution for 
each analysis. For viscous solutions or solid samples, a straight fine needle (350 μm in 
diameter) was used to either collect analytes of viscous solutions or sweep five times across 
solid surfaces to obtain analytes. Second, the function of the thermal desorption unit was to 
vaporize samples on the DP and introduce desorbed analytes into the ESI plume through a 
quartz tube with single taper (OD= 6 mm, ID= 4 mm, Length= 80 mm) so that effective 
sample ionization can take place. In addition, an opening in the thermal desorption unit was 
created when the direct probe was removed from the unit to sample analytes. The thermal 
desorption unit was sealed after the direct probe was placed back on the thermal desorption 
unit for analysis of sample analytes on the probe. Third, an electrospray ionization device 
was used for post-ionizing desorbed analytes. The high voltage and solvent flow rate 
required to generate an electrospray plume were 5 kV and 2.5 μL/min, respectively. The ESI 
solution was a methanol and water mixture (1:1, v/v) containing 0.1% acetic acid, and was 
delivered through a fused-silica spray capillary (ID= 100 μm, OD= 375 μm, Polymicro, 
Phoenix, AZ) into the mass inlet of the mass spectrometer. The TD-ESI source was attached 
to a triple quadruple mass spectrometer (Agilent 6410) to detect the analyte ions. To obtain 
a stable solvent and analyte ion signal, the electrospray capillary was aligned to the MS  
inlet and the distance from the exit of the TD tube to the electrospray capillary (d1) was kept 
at 8 mm, while the distance from the MS inlet to the electrospray capillary (d2) was 5 mm. 
The temperature in the thermal desorption unit was set at 250 ℃ and was measured by a 
thermistor installed in the source. The flow rate of the nitrogen gas used to deliver desorbed 
analytes into the ESI plume was 0.8 L/min. 
Primary end point: Fibrosis biomarker [23] 

 
 
Molecular markers of fibrogenesis including TGF-β1, and Type IV collagen. Hyaluronic Acid 
in the serum blood test, and clinical labotory FIB-4 Index. 
Secondary end points: 1. Cirrhosis dysbiosis ratio (CDR), the ratio of autochthonous good 
bacteria(e.g. Lachnospiraceae, Ruminococcaceae and Clostridiales) to non-autochthonous/ 
pathogenic bacteria (e.g. Enterobacteriaceae and Streptococcaceae). 2. Total stool bile acid, 
Secondary and primary bile acid ratio. 3. Serum inflammation peptides (IL-6, IL-8, IL-10, and 
TNF-a) 
Sample size : Till now, there was no prospective data to support the evaluation the sample 
size of study in the liver fibrosis deminition after the administrations of stain and UDCA.  
Prior data [24]may indicate the effect of 40 mg simvastatin versus placebo on hepatic portal 
pressure was studied over a period of 3 months. A significant decrease in HVPG (-15%) was 
noted in the experimental group versus no change in the placebo group. The study included 
24 cases in each study arm. Therefore, we plan to enroll 30 participants in each arm. 
Safety 
Initial dose of study drug is 20 mg which can be increased to 40 mg after 4 weeks if the 
participant does not develop side effects. Creatine kinase and standard biochemistry 
including liver enzymes are measured for safety reasons after 2 weeks, to rule out myositis 
and liver damage. Side effects and events are consecutively registered throughout the trial. 
Safety of statins in chronic liver disease has been assessed in only a few clinical trials, but 
reviews of observational studies report high safety and low risk of adverse events, even 
significantly lower the all-cause mortality [25,26] 
Statistical analysis: 
Risks are reported as IRRs along with their 95% confidence intervals and P values. For 
subgroup analyses according to sample characteristics, P values for interaction also are 
assessed. The cumulative proportion of patients developing liver fibosis events during follow-
up is estimated by life table methods and log-rank tests were reported. P values are 2-sided, 
and values of .05 or less are considered statistically significant. All statistical analyses are 
performed using SAS version 9.1 (SAS Institute Inc). 
Limitation 1: 
If post treated human feces contain the trace level of drug, the hypothesis that it is caused 
by microorganisms alone does not hold. We will check the post treated human feces by the 
TD-ESI (LTQ)for simvastatin (Formula: C25H38O5 , Exact mass: 418.57 Da),and Ursodeoxycholic 
acid (UDCA)( Formula : C24H40O4. Exact mass : 392.29 Da ). The pre-test was performed by TD-
ESI (LTQ) as followed figures. 
Limitation 2:  The germ-free mice treated with carbon tetrachloride (CCL4) for 12 weeks 
for liver cirhosis model is novel test. We can not make sure the mortality rate under the 

 
 
treament of CCL4. Germ-free mice are more vulnerable than normal mice. If high mortality of 
Germ-free mice was found, we will shift to normal mice treated with antibiotics before human 
fecal transplantation test. 
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Chang Gung Memorial Hospital, Kaohsiung Branch 
Chang Gung Medical Foundation 
Informed Consent Form 
I. Remedial mechanism of simvastatin and ursodeoxycholic acid in liver cirrhosis: 
crosstalk of bile secretion, gut microbiome, and host Immune response 
II. Basic Study Information 
Medical Record Number: __________________ 
1. IRB Approval Number: IRB 202201398A3 
2. Study Site: Chang Gung Memorial Hospital, Kaohsiung Branch 
3. Department Responsible for Execution: Division of Gastroenterology and 
Hepatology 
4. Sponsoring Organization / Company: Chang Gung Hospital Research 
Project 
5. Principal Investigator: Dr. Chih-Ming Lian 
Affiliation: Division of Gastroenterology and Hepatology 
Title: Attending Physician (Lecturer Level) 
Phone Number: 0975-056-294 
Co-Principal Investigator: Prof. We-Chun Leng 
Associate Investigators: Prof. CHANG-CHUN HSIAO, Pro. Shiea Jentaie. 
Affiliation: Division of Gastroenterology and Hepatology 
Titles: Attending Physicians (Associate Professor Level, Assistant Professor Level, 
and General Attending Level) 
Phone Number: +886-7-731-7123 ext. 2444 
Emergency Contact Number for Participants: 0975-056-294 
6. Participant's Name: 
Participant Study ID Number: 
Gender: 
Date of Birth: 
Mailing Address: 
Contact Phone Number: 
 
III. Introduction 
 Hello. Currently, global treatment outcomes for hepatitis B and C have been quite 
successful. However, for patients with liver cirrhosis who have already achieved viral 
eradication, underlying inflammation often continues to progress. At present, clinical 
management is limited to observation and monitoring. 
Recent studies have found that bile secretion in cirrhotic patients is reduced to between 
one-fifth and two-thirds of that in healthy individuals. This bile acid deficiency leads to gut 
microbiota imbalance, which in turn increases inflammatory markers and may worsen 
cirrhosis or even contribute to the development of liver cancer. Therefore, the 
development of preventive therapies is extremely important. 
In previous animal studies of liver cirrhosis, bile acid supplementation alone was shown to 
improve dysbiosis, reduce gut inflammation, and regulate intestinal immunity. 
Ursodeoxycholic acid (UDCA), an approved treatment for cirrhosis, promotes the secretion 
of endogenous bile acids and compensates for bile acid deficiencies in cirrhosis. Both 
human and animal studies have demonstrated its anti-inflammatory, anti-fibrotic, and 

 
 
metabolic-regulating effects. 
Statins, based on retrospective studies, have been associated with a reduced risk of liver 
fibrosis in patients. Animal research has also shown that statins can directly inhibit hepatic 
stellate cell activation and the differentiation of myofibroblasts, which are key processes 
in liver fibrosis. However, no prospective human trials have yet validated these findings. 
The combination of UDCA and statins has been proven safe in human studies, and the two 
drugs together show a synergistic effect in reducing bile cholesterol content. However, no 
prospective studies have investigated their combined effect on improving liver fibrosis or 
gut microbiota in cirrhotic patients. 
Therefore, this study aims to evaluate whether simvastatin alone or in combination with 
UDCA can reduce liver fibrosis markers, inflammatory cytokines, and gut microbiota 
dysbiosis in patients with liver cirrhosis who have been cured of chronic hepatitis C or 
have non-replicating hepatitis B. 
Before agreeing to participate in this study, your physician will explain the contents of this 
informed consent form to you. Please read it carefully and feel free to ask any questions. 
Participation in this study is completely voluntary. Declining to participate will not affect 
your right to receive proper medical care. 
 
IV. Purpose of the Study 
To evaluate whether simvastatin alone or in combination with ursodeoxycholic acid (UDCA) 
can reduce liver fibrosis markers, pro-inflammatory cytokines, and gut microbiota dysbiosis 
in patients with liver cirrhosis. 
V. Inclusion and Exclusion Criteria 
Inclusion Criteria: 
You are eligible to participate in this study if all of the following conditions are met: 
1. Adults aged 18 to 75 years 
2. Diagnosed with primary liver cirrhosis (FIB-4 ≥ 3.25) 
3. Liver stiffness measurement (LSM) ≥ 25 kPa, or classified into the Baveno VII "grey zone" 
4. Achieved sustained virological response (SVR) at least 6 months after hepatitis C 
treatment, or 
5. Non-replicating hepatitis B infection (undetectable viral load) for at least 6 months 
6. Able and willing to provide informed consent 
Exclusion Criteria: 
You will not be eligible to participate in this study if any of the following conditions apply: 
1. Current or prior use of statins 
2. Liver decompensation (jaundice, ascites, hepatic coma, or esophagogastric varices) 
3. Diagnosed hepatocellular carcinoma or other liver cancers 
4. Alcoholic liver disease or moderate-to-severe fatty liver 
5. Diagnosed diabetes mellitus 
6. Chronic kidney disease 
7. Use of antibiotics within the past 3 months 
8. Use of gastric ulcer medications such as proton pump inhibitors (PPIs) 
9. Pregnancy or breastfeeding 
10. Any condition deemed by the investigator to interfere with study participation or 
outcomes 

 
 
VI. Study Methods and Procedures 
Between November 2022 and December 2025, we plan to recruit 120 stable patients 
with liver cirrhosis at Kaohsiung Chang Gung Memorial Hospital, Taiwan. Eligible 
participants include those who have achieved a sustained virologic response (SVR) for at 
least 6 months after completing treatment for hepatitis C, or those with hepatitis B who 
have had undetectable viral load for at least 6 months while on antiviral therapy, and 
have been diagnosed with cirrhosis (FIB-4 ≥ 3.25). 
Participants will be randomly assigned to one of four groups: 
1. Group 1: Control group (n = 30) – no active treatment 
2. Group 2: UDCA group (n = 30) – receives ursodeoxycholic acid (UDCA) at 10 
mg/kg/day 
3. Group 3: Simvastatin group (n = 30) – receives simvastatin at 40 mg/day 
4. Group 4: Combination group (n = 30) – receives both simvastatin (40 mg/day) and 
UDCA (10 mg/kg/day) 
At baseline and after 6 months of treatment, we will collect: 
• 
Fecal samples for bile acid concentration and microbiota analysis 
• 
Skin swabs for bile acid profiling 
• 
Blood samples (10–15 mL) for inflammatory cytokines and biochemical fibrosis 
markers 
• 
Non-invasive liver stiffness measurements using transient elastography 
In addition, we will collect the same set of baseline and 6-month samples from 30 non-
cirrhotic patients who achieved SVR after hepatitis C and have a FIB-4 score < 1.45. These 
participants will undergo: 
• 
Two fecal samples for bile acid and microbiota analysis 
• 
Skin swabs (collected by gently rubbing a small steel ring on the forehead 2–3 
times, non-invasive and does not cause injury) 
• 
Blood draw (10–15 mL) for cytokine and fibrosis marker analysis 
• 
Liver stiffness measurement using a non-invasive, ultrasound-based device 
VII. Potential Risks, Side Effects, Incidence Rates, and Management 
In general, simvastatin is well tolerated, and most of its side effects are mild and 
temporary in nature. Controlled clinical trials have shown that fewer than 2% of 
patients discontinue simvastatin due to adverse effects. 
Reported side effects include: 
• 
Abdominal pain, constipation, and bloating (approximately 1%) 
• 
Fatigue and headache (0.5–0.9%) 
• 
Myopathy (muscle-related side effects) are rare, occurring in less than 0.1% of 
patients 
• 
Elevated liver transaminases confirmed to be more than 3 times the upper 
limit of normal on repeated testing in 0.21% of patients 

 
 
For ursodeoxycholic acid (UDCA), the overall incidence of side effects is around 2.6%, 
most of which are gastrointestinal in nature: 
• 
Soft stools, diarrhea, nausea, and vomiting occur in approximately 2.26% 
• 
Allergic reactions, such as itching or rash, occur in 0.22% 
• 
Other rare adverse effects account for 0.1% 
 
Management Procedures: 
1. If you experience any discomfort, please inform your attending physician. They 
will provide you with the most appropriate care and treatment. 
2. In the event of an emergency or any unusual symptoms that cannot be 
controlled with standard medical treatment, please contact your physician Dr. 
Chih-Ming Liang at 0975-056-294 or the research staff at 07-342-2121 ext. 2444 
immediately. 
 
VIII. Alternative Treatment Options 
For patients with liver cirrhosis who have achieved viral eradication of chronic hepatitis B 
or C, current clinical guidelines recommend biochemical testing and liver ultrasound 
every 3 to 6 months for monitoring, but do not include any specific medication 
recommendations for ongoing treatment. 
IX. Contraindications and Restrictions Related to This Study 
This study will be conducted in conjunction with your scheduled follow-up visits and 
standard medical care. You will not be required to follow any additional restrictions. 
X. Expected Outcomes of the Study 
In patients with liver cirrhosis, bile acid supplementation or combination therapy with 
simvastatin may help improve the gut microbiota composition, potentially restore total 
bile acid levels, and lead to a reduction in pro-inflammatory cytokines and biochemical 
fibrosis markers. However, further studies are needed to confirm these effects. 
XI. Emergency Management 
If you experience any discomfort or adverse symptoms during the study, please inform your 
study physician immediately. Your doctor will make every effort to provide the most 
appropriate care and treatment. 
In the event of a medical emergency or unusual physical condition that cannot be 
effectively managed with standard medication, please contact your attending physician or 
the Principal Investigator, Dr. Chih-Ming Liang (Division of Gastroenterology and 
Hepatology), at his 24-hour emergency contact number: 0975-056-294, or contact the 
study staff at +886-7-731-7123 ext. 2444. 
XII. Compensation, Cost Responsibility, and Injury Reimbursement 
1. Compensation: 
There is no monetary compensation provided for participation in this study. 
2. Cost Responsibility: 
This study is funded by research grants from Chang Gung Memorial Hospital. Under 
Taiwan’s National Health Insurance system, you will not incur any additional costs 
for participating in this study. 
(1) If an adverse event or injury occurs as a direct result of procedures conducted according 
to the study protocol, the hospital and the principal investigator will bear legal responsibility 
for providing compensation, except for adverse events that are already listed as 
foreseeable in this consent form, which will not be eligible for compensation. 

 
 
(2) In the event of an adverse reaction or injury related to this study, professional medical 
care and consultation will be provided at no cost to you. 
(3) Aside from the above-mentioned compensation and medical care, no additional 
compensation will be offered. If you are not comfortable with this level of risk or 
arrangement, you are advised not to participate in this study. 
(4) Signing this informed consent form does not waive any of your legal rights 
 
XIII. Privacy and Confidentiality Protection 
1. A unique research code will be assigned to represent your identity. This code will 
not contain your name, national ID number, or address. 
2. All diagnostic information and study findings will be handled with strict 
confidentiality by the principal investigator. If research results are published, your 
personal identity will not be disclosed. 
3. By signing this consent form, you agree that your research records may be directly 
accessed by authorized monitors, auditors, the Research Ethics Committee (IRB), 
and regulatory authorities to ensure compliance with applicable laws and 
regulations. These individuals are obligated to maintain the confidentiality of your 
personal information. 
 
XIV. Withdrawal and Discontinuation from the Study 
You, or your legal representative, have the right to withdraw from this study at any time 
and for any reason without affecting your medical care or legal rights. 
Additionally, the principal investigator may terminate your participation or halt the study 
if necessary. 
XV. Subject Rights 
1. The collection, processing, and use of your personal data will be handled by the 
study institution and investigators in accordance with this informed consent form, 
relevant clinical trial regulations, and the Personal Data Protection Act of Taiwan. 
You may exercise the following rights in writing by contacting the study institution 
or investigator: 
(1) Request to access or review your personal data; 
(2) Request a copy of your personal data; 
(3) Request to supplement or correct your personal data; 
(4) Request to stop the collection, processing, or use of your personal data; 
(5) Request deletion of your personal data. 
2. During the course of the study, you will be promptly informed of any significant new 
findings that may affect your willingness to continue participation. If you have any 
questions or concerns during the study, please contact the principal investigator. 
3. If you have questions about your rights as a research participant or believe that you 
have been harmed by participating in this study, you may contact the Institutional 
Review Board (IRB) of this hospital for consultation at: 
(03) 319-6200 ext. 3703, 3705–3709, 3711–3717 
XVI. Ownership of Study Results and Benefits 
If the results of this study lead to academic publications, tangible benefits, or other related 
outcomes, you agree that such outcomes may be donated free of charge to this hospital for 
public interest purposes, such as disease prevention, diagnosis, and treatment. 
 
XVII. Storage and Reuse of Personal Data, Samples, and Derivatives 
This study does not involve any leftover biological samples for future storage or reuse. 
 
XVIII. Declaration 

 
 
The contents of this study and the informed consent form have been fully explained orally 
to the participant by __________________. The participant and/or their legal 
representative has fully understood and agrees to participate in the study. 
This consent form is made in duplicate, and a copy has been provided to the participant. 
 
 
Signatures 
A. Participant: 
Name (Print): _______________ 
Signature: _______________ 
Date: ____ / ____ / ______ (YYYY/MM/DD) 
 
B. Person Obtaining Consent: 
Name (Print): _______________ 
Signature: _______________ 
Date: ____ / ____ / ______ (YYYY/MM/DD) 
 
C. Co-Investigator / Associate Investigator: 
Name (Print): _______________ 
Signature: _______________ 
Date: ____ / ____ / ______ (YYYY/MM/DD) 
 

 
 
D. Principal Investigator: 
Name (Print): _______________ 
Signature: _______________ 
Date: ____ / ____ / ______ (YYYY/MM/DD) 
(Required if the participant meets the condition described in Section I of the Consent 
Signing Instructions) 
 
E. Legal Representative / Authorized Consenter / Guardian / Conservator: 
Name (Print): _______________ 
Signature: _______________ 
Date: ____ / ____ / ______ (YYYY/MM/DD) 
Relationship to the Participant: _______________ 
(Required if the participant meets the condition described in Section II of the Consent 
Signing Instructions) 
 
F. Witness: 
Name (Print): _______________ 
Signature: _______________ 
Date: ____ / ____ / ______ (YYYY/MM/DD) 

 
 
 
 
 
[Chang Gung Medical Foundation / Chang Gung University / Chang Gung 
University of Science and Technology – Information for Research 
Participants] 
Dear Participant, Family Member, or Member of the Public, 
If you meet the eligibility criteria for a clinical trial or research study, you may 
be invited to participate in a study conducted by Chang Gung Memorial 
Hospital, Chang Gung University, or Chang Gung University of Science and 
Technology. The following information is provided to protect your safety and 
rights as a research participant. It explains the role and responsibilities of the 
Institutional Review Board (IRB) at Chang Gung Medical Foundation, how 
research is reviewed, and what your rights are as a participant. 
 
What is Research? 
Research is different from treatment. 
Treatment involves procedures and medications that have already been 
studied and are known to have predictable outcomes and side effects. 
Research, on the other hand, aims to discover new knowledge and often 
involves uncertainty about outcomes. Participation in research is completely 
voluntary, and choosing not to participate will not affect your right to receive 
medical care or result in any form of unfair treatment. 
 
What is the Institutional Review Board (IRB)? 
The Institutional Review Board (IRB) is a committee established to ensure 
that research involving human participants is scientifically and ethically 
appropriate. 
It is composed of medical professionals, legal experts, community 
representatives, and members of non-medical backgrounds who help 
researchers understand the concerns of participants to ensure their safety and 
rights are protected. 
If you have any questions about your rights, you may contact the IRB of Chang 
Gung Medical Foundation. 
 
How Does the IRB Review Clinical Trials or Research Studies? 
1. All research conducted at Chang Gung Memorial Hospital, Chang Gung 
University, or Chang Gung University of Science and Technology must be 
reviewed and approved by the IRB before it can begin. 
2. Research protocols submitted to the IRB are independently and 
professionally reviewed by committee members and experts. 
The review focuses on whether participants are fully informed about the 
study — including: 
o The purpose of the study 
o The procedures involved 
o Possible alternative treatments 

 
 
o Potential risks, side effects, and benefits 
o How to withdraw from the study 
o How privacy and confidentiality will be protected 
3. During review, the IRB evaluates potential risks to participants, which may 
include: 
o Physical discomfort or harm 
o Psychological stress 
o Social or financial impact 
The IRB ensures that all risks are minimized and justified by the potential 
benefits — either to the participant, or to future patients through scientific 
knowledge. 
Studies that pose high risk with no reasonable benefit will not be approved. 
4. After a study is approved, the IRB and the research institution will continue 
monitoring the research to ensure that it is carried out exactly as 
approved and that participants’ rights and safety remain protected. 
 
What Are Your Rights as a Research Participant? 
 
Right to Be Informed 
You have the right to clear and complete information about: 
1. Purpose of the study 
The researcher must explain the aim of the study in simple and 
understandable language. 
2. What will happen during the study 
You should know what procedures will be involved, how often visits occur, 
whether blood samples will be taken, and any inconvenience to your daily 
life. 
3. Alternative treatment options 
You have the right to know about other treatments available if you choose 
not to participate. 
4. Risks and side effects 
All research involves risk. You must be informed of potential risks and side 
effects, and what to do in case of an emergency — including who to 
contact and who will provide follow-up medical care and cover related 
costs. 
5. Potential benefits and expected outcomes 
Researchers must explain any direct benefits to you, or how the study may 
help others in the future through new discoveries. 
6. How to withdraw from the study 
You must be informed about how to withdraw at any time, what happens 
to your data after withdrawal, and whether follow-up care is available. 
7. Freedom to ask questions 
You may ask the research team questions at any time. 
 
 
Right to Voluntary Participation 
You will only officially become a participant after the researcher explains the 
study purpose, procedures, risks, benefits, and your rights, and after you sign 
the informed consent form of your own free will. 
You may also withdraw at any time without giving a reason. 
Your decision to withdraw will not affect your future medical care or cause 
you to be treated unfairly. 
 
 
Right to Protection 
1. Privacy and confidentiality 
Any personal information collected during the study will be kept 
confidential. 

 
 
If study results are published, or reviewed by the IRB or regulatory 
agencies (e.g., the Ministry of Health and Welfare), your identity will not 
be revealed. 
2. Retention of your legal rights 
Participation in a clinical study does not mean you give up any legal rights 
you currently have