Comparison of Vonoprazan Fumarate-based Triple Therapy Versus Proton Pump Inhibitor and Bismuth Based Quadruple Therapy in the Eradication of Helicobacter Pylori: a Single-center Prospective Open-label Controlled Study
Phase: NA
Conditions: Helicobacter Pylori Infection
Sponsor: wang xiaoyan

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Comparison of Vonoprazan fumarate-based Triple Therapy Versus 
Proton Pump Inhibitor and Bismuth Based Quadruple Therapy in the 
Eradication of Helicobacter Pylori: A Single-center Prospective Open-
label Controlled Study   
Version: 1.3 Date: 23, May 2021 
Main researcher: Tang Yanliu
 
Research Organization: Third Xiangya Hospital, Central South University 
Contract Research Organization: None 
 
Declaration of secret 
The confidential information about the trial involved in this program belongs to 
Third Xiangya Hospital, Central South University and is reviewed only by the 
researchers of this clinical trial, the ethics committee and the supervision and 
administration department of medical institutions. Without written permission from 
Third Xiangya Hospital, Central South University, it is strictly prohibited to disclose to 
unrelated organization. 
 
 

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Proposal Signing Page 
The principal investigator agrees: 
I confirm that I have read and understood this program and any other 
supporting information. I agree to conduct this study in accordance with the 
requirements of this program, while respecting the rights, safety, privacy, and health 
of the subjects of the study, and in accordance with: 
• Ethical principles in the Helsinki Declaration. 
• The International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use /E6. 
• All applicable laws and regulations in China, including but not limited to laws 
and regulations regarding privacy protection and disclosure of clinical trials. 
• Regulatory requirements for reporting serious adverse events. 
 
 
 
Third Xiangya Hospital, Central South University 
 
Main Researcher Signatures:
 
 
   Date:  23, May 2021  
 
 

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Program abstract 
The name of 
the scenario 
Comparison of Vonoprazan fumarate-based Triple Therapy Versus 
Proton Pump Inhibitor and Bismuth Based Quadruple Therapy in 
the Eradication of Helicobacter Pylori: A Single-center Prospective 
Open-label Controlled Study 
Version 
number 
1.3 
date 
2021-05-16 
The bidder 
Department of Gastroenterology, Third Xiangya Hospital, Central 
South University 
Indications 
Diagnosed with Hp infection 
The purpose 
of 
the 
experiment 
Compare the four treatments [(1) Vonoprazan fumarate + 
amoxicillin + doxycycline, (2) Vonoprazan fumarate + furazolidone 
+ doxycycline, (3) esomeprazole + colloidal bismuth tartrate + 
amoxicillin + doxycycline, and (4) esomeprazole + colloidal 
bismuth tartrate + furazolidone + doxycycline] for Helicobacter 
pylori (hereafter referred to as Hp), and assess the effectiveness, 
safety, drug compliance, and socioeconomic evaluation.  
experimental 
design 
 
A single-center, prospective, open-label, parallel control 
design was conducted to enroll 596 patients with confirmed 
Helicobacter pylori infection. Patients were randomly divided into 
four groups, respectively accept four treatment regimens 
including (1) Vonoprazan fumarate + amoxicillin + doxycycline, (2) 
Vonoprazan fumarate + furazolidone + doxycycline, (3) 
esomeprazole + colloidal bismuth tartrate + amoxicillin + 
doxycycline, and (4) esomeprazole + colloidal bismuth tartrate + 
furazolidone + doxycycline. The effectiveness, safety and 
compliance of the four regimens were compared, and the cost-
benefit analysis of the different regimens was conducted. The 
purpose of this study was to explore the most appropriate 
treatment plan for radical treatment of Helicobacter pylori. 
Total number 
of cases 
596 cases are planned for the group 
Number 
of 
research 
Single center 

4 
 
centres 
The duration 
of the study 
2021-06-17～2022-06-17 
Case selection 
criteria 
and 
exit criteria 
 
 
 
 
Case selection 
criteria 
and 
exit criteria 
 
 
 
 
 
 
 
 
Group criteria:  
1. The age ≥ 18 and ≤ 80 
2. The Urea Breath Test (UBT) tested positive for Hp infection 
3. Anti-Hp therapy without any treatment 
4. Have a gastroscopy within 1 month 
5. Clearly understand, volunteer to participate in the study 
and sign an informed consent form by himself 
Exclusion criteria: 
Subjects who meet any of the following criteria cannot be 
selected for this test: 
First, the patient's physical condition cannot accept Hp 
eradication treatment 
1. 
Allergic to the drugs used in this clinical study 
2. 
Use of PPI, histamine H2 receptor antagonists, 
antibiotics, palladium, probiotics, or antibacterial 
drugs before 4 weeks of treatment  
3. 
Use adrenal corticosteroids, nonsteroidal anti-
inflammatory drugs and anticoagulants 
4. 
Diseases or clinical conditions that may interfere with 
research and treatment assessment, such as liver 
disease, cardiovascular disease, lung disease, kidney 
disease, metabolic disease, mental illness, or 
malignant tumors 
5. 
Pregnant or lactating women 
6. 
Participate in other clinical studies before 3 months 
Second, do not agree to participate in this study 
Third, there are other problems that do not meet the 
requirements of this study or affect the results of the study: 
1. Suspected history of antibiotic abuse 
2. Brain injury, mental illness or epilepsy, etc. can not 
communicate with patients or other diseases that may affect 
follow-up 
Termination criteria: 
If the subject meets any of the following criteria, the 
researcher will discontinue the study early: 
1. An allergic reaction to the drug or other component 
used in this clinical trial 
2. Existence of a adverse event, the researchers 

5 
 
determined that the study needed to be terminated early because 
continued participation in the study may pose an unacceptable 
risk to the subject's health, or because the subject was reluctant 
to continue the study because of the adverse event 
Exit criteria: 
    If the subject meets any of the following criteria, the patient 
will withdraw from the study: 
1. The subject withdrew his informed consent 
2. The subjects were not interviewed. 
During the study period, when the subjects meet the above 
suspension/exit criteria, the researcher can terminate the 
participation and should follow up in medical procedures. The 
reason and date of the subject's withdrawal must be recorded in 
the case report form and the original information. 
Research 
steps 
Research steps: 
1. 
Informed consent and patient screening: Inform the 
patients in the proposed group of the specific content of 
this study and possible risks. All patients in the group or 
the authorized trustees of the patients need to sign the 
informed consent form, and then in accordance with the 
selection criteria and exclusion criteria, a single center 
selected confirmed infection of Hp patients (about 596 
cases). 
2. 
Collect patient information: including initials, gender, age, 
outpatient number, hospitalization number, date of entry, 
education, occupation, smoking, alcohol consumption 
and gastroscopy results (ulcers, atrophic gastritis, tumors, 
etc).  
3. 
Random Grouping: A table of random numbers pre-
generated with SPSS20.0 and divided it into four groups 
of 1:1:1:1. The treatment plan is determined by the 
random number of randoms drawn by the patient, and 
the random process is done by the specified study 
designer. 
4. 
Eradication treatment: four groups of patients received 
Vonoprazan fumarate + amoxicillin + doxycycline, 
Vonoprazan fumarate + furazolidone + doxycycline, 
esomeprazole + colloidal bismuth tartrate + amoxicillin + 
doxycycline, and esomeprazole + colloidal bismuth 
tartrate + furazolidone + doxycycline 
5. 
Follow-up: Each patient receives two follow-ups. The first 
follow-up is conducted on the first day after the patient 
has concluded eradication treatment, and the follow-up 
is to evaluate the patient's drug compliance and whether 

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adverse reactions occurre. Basing on the patient's actual 
situation, determine whether the patient needs other 
treatment. The second follow-up is 4-8 weeks after the 
patient had discontinued proton pump inhibitors, 
vonoprazan fumarate, and antibiotics.  At this point, the 
researchers reminded the patient to undergo a urea 
exhalation test and determine whether the patient had 
succeeded in eradicating HP.  
6. 
Remedy: If the patient finds failure on the second follow-
up, he will receive treatment different from the previous 
treatment and be followed up again at 14th days after 
taking the drug and one month after discontinuation. If 
the second treatment fails, the drug will be discontinued 
for half a year, and after six months, the patient will be 
treated in a different way.  Remedy after adverse 
reactions: immediately discontinue medication and go to 
the hospital in time if symptoms are severe. According to 
the corresponding symptoms ，give support treatment  
including but not limited to rehydration, anti-inflammatory 
anti-allergy, anti-shock treatment.   
7. 
Collect information on treatment effectiveness and cost 
of treatment: Record study participants reviewing UBT 
trial results, adverse reactions in medication, drug 
compliance, and total drug costs.  
Observe 
the 
indicator 
Key evaluation indicator eradication rate 
Minor evaluation indicators: 
1. 
Drug compliance 
2. 
Rate of all types of adverse events 
3. 
Cost-benefit analysis 
Security 
metrics 
Incidence of adverse events/severe adverse events/suspected 
unanimity serious adverse events.  
Statistical 
analysis 
 
 
Statistical 
1. 
Sample size calculation: Refer to previous studies, the 
Hp eradication rate of triple therapy containing Vonoprazan 
fumarate was 91.4%, and the hp eradication rate of quadrol 
therapy containing proton pump inhibitors and colloidal tartaric 
acid was 81.3%. Assuming a 90% certainty, the α is 0. 05 (two-
sided), a total of 476 patients are required, assuming a follow-up 
loss of 20% and a planned sample size of 596 patients (149 
patientsper group) [1-6].   
2. 
General principles: 
The adoption rate (%) and mean ± standard deviations 

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analysis 
to the classification variables and continuous variables for 
standard descriptive statistics. The classification variable 
comparison is based on the square test, and the continuous 
variable comparison uses the two-sample t-test. 
3. 
Demographics and baseline characteristics: 
Summarize all demographic variables and baseline 
characteristics. Continuity variables are used for descriptive 
statistics, and classification variables are calculated in 
frequency and percentage ratios.  
4. 
Evaluation and security indicators: 
Analysis of demographic data, baseline characteristics, 
Hp eradication, and drug compliance. 
Statistics the incidence of adverse events/severe adverse 
events/suspected unanimity serious adverse events. 
Using the Markov model, the cost-effectiveness of 
treating HP in different treatment options is analyzed and the 
best cost-effective solution is selected. 
This study does not conduct interim analysis. 
 
 
 
 

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Directory 
1. BACKGROUND OF THE STUDY ....................................................................................................... 8 
2. RESEARCH PURPOSES ................................................................................................................. 12 
3. SUBJECTS .................................................................................................................................... 12 
4. RESEARCH AND DESIGN .............................................................................................................. 13 
5. TEST STEPS: ................................................................................................................................. 15 
6. RESULTS EVALUATION INDEX ....................................................................................................... 19 
7. SECURITY METRICS: .................................................................................................................... 20 
8. STATISTICAL METHODS ............................................................................................................... 21 
9. THE RESEARCH PROCESS ............................................................................................................. 23 
1 0. MANAGEMENT AND QUALITY CONTROL OF CLINICAL TRIALS ................................................... 25 
11. PAPERS PUBLISHED ................................................................................................................... 27 
12． DATA PRESERVATION ............................................................................................................. 27 
13． REFERENCES .......................................................................................................................... 29 
 
1. Background of the study 
1.1 The current situation of research at home and abroad 
Helicobacter pylori (Hp)infection is one of the most common chronic infections in 
humans. Epidemiological surveys show that more than half of the world's natural population 
has Hp infection, more than almost all chronic infectious diseases, and infection rates are 
generally higher in developing countries than in developed countries. China is one of the 
countries with a high incidence of Hp infection, and epidemiological surveys show that the 
prevalence of Hp infection in China is 42% to 64%. Given our large population base, China is 
probably the most infected country in the world, so Hp infection and related diseases are 
serious health problems [7, 8].  
Hp infection is generally difficult to remove spontaneously leading to lifelong infection, 
unless eradication treatment, or stomach mucosa in severe intestinal metaplasia. Hp 
infections are closely related to the occurrence of chronic active gastritis, peptic ulcers, gastric 
mucosa-related lymphoma (MALT) lymphoma and stomach cancer and were defined as Class 
I carcinogens by the World Health Organization / International Agency for Research on Cancer 

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in1994[1]. In 2018, the range of indications that detect the presence of Hp infections will be 
significantly expanded. In 2020, the Taipei Global Consensus emphasizes the role of 
eradicating Hp in achieving the goal of reducing or eliminating stomach cancer[11].  
Eradication of Hp can prevent the recurrence of peptic ulcers and reduce the risk of 
gastric cancer. Although many studies and consensus conferences have provided treatment 
recommendations that are considered the latest [12, 13], compared with other infectious 
diseases, the overall treatment success of H. pylori is still very low [14]. There are many 
different therapies for the treatment of Hp, including triple therapy consisting of proton 
pump inhibitors, amoxicillin and clarithromycin, metronidazole, fluoroquinolone or rifabutin; 
bismuth quadruple therapy; proton pump inhibition Drug and amoxicillin dual therapy and a 
group of 4 drug treatments consisting of proton pump inhibitors, amoxicillin, clarithromycin, 
and metronidazole. Despite 30 years of treatment experience in the world, the ideal H. 
pylori eradication program is still unclear, and H. pylori treatment cannot avoid the increase 
in global antimicrobial resistance. The efficacy of triple therapy combining proton pump 
inhibitors and two antibiotics (amoxicillin and clarithromycin) is gradually decreasing, from 
95% to 80% globally and from 89% to 78 % in China % [15, 16] . Since then, quadruple 
therapy has gradually replaced triple therapy as the first-line treatment for Hp infection [17]. 
In China, bismuth-containing quadruple therapy is highly recommended as the first-line 
treatment for Hp infection. Although the eradication rate has increased, the therapy still has 
limitations, including bismuth-related side effects, poor patient compliance with 
medications, high resistance to clarithromycin and metronidazole, and high drug costs. In 
addition, PPI often exhibits problems such as slow onset of action and large inter-individual 
variability [18]. Therefore, there is an urgent need to study a new alternative therapy.  
 1.2 Basis for project establishment 
In recent years, a new antisecretory drugs - potassium ion competitive acid blockers are 
introduced, these drugs and K + competition H +, K + - ATP enzyme (proton pump) binding 
sites on cells thus inhibiting the secretion of stomach acid Compared with PPI drugs, H+ and 
K+-ATPase can be inhibited without acid activation, and the acid suppression effect is not 
affected by CYP2C19 gene polymorphism. Its novel mechanism of action and unique 

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pharmacokinetic characteristics make it show better characteristics than PPI, such as fast 
onset, stable structure, long-lasting acid suppression effect, small individual differences, and 
fewer adverse reactions [19]. 
As its representative drug, vonoprazan fumarate green tablets were launched in Japan 
in 2015 and are mainly used to treat acid-related diseases, including reflux esophagitis, 
gastric ulcer, and duodenal ulcer. In 2019, vonoprazan fumarate green tablets were 
approved by the U.S. Food and Drug Administration (FDA ) as triple combination with 
amoxicillin and clarithromycin, or double combination with amoxicillin for the treatment of 
Hp infection. Several clinical studies have shown that vonoprazan fumarate raw tablets are 
safe, effective, and well tolerated in the treatment of reflux esophagitis and eradication of 
Hp [20]. A network meta-analysis of published randomized controlled trials found that in the 
first-line empirical treatment of Hp infection, the triple therapy of vonoprazan fumarate 
tablets achieved a high eradication rate of more than 90%, while the standard triple therapy 
was the most ineffective therapy [21]. However, unfortunately, although the analysis 
showed that the triple therapy of vonoprazan fumarate green tablets performed well, 
Japan's clarithromycin resistance is very high, resulting in a decline in the effectiveness of 
the therapy, with a reported cure rate of <90% [ 22]. According to reports, in the presence of 
clarithromycin resistance, the cure rate is about 80%, so most patients (estimated at 88%) 
receive clarithromycin unnecessarily, which leads to global antibiotic resistance [23]. In areas 
with high clarithromycin resistance, a recent study in Japan found that [3] Wonoprazan - 
Amoxicillin dual therapy achieved a Hp eradication rate like Wonuo's triple therapy. 
However, although this program has the smallest type, the smallest dose, and the shortest 
course of treatment, the adverse reactions caused by the excessive dose of amoxicillin limit 
the use of this program. Therefore, this program is generally used for salvage treatment. We 
are trying to find other therapies based on vonoprazan fumarate green tablets that can be 
used as a first-line solution for Hp eradication. 
As a developing country with a high incidence of Hp infection and relatively insufficient 
medical resources in some regions, the Hp infection eradication treatment program 

11 
 
applicable in China needs to consider both effectiveness and efficiency. 2017 Nian Fifth 
National Consensus on treatment of Helicobacter pylori infection [7] concerning the 
eradication of Hp treatment, the recommended PPI + bismuth + 2 antibiotics scheme fifth 
national consensus report Helicobacter pylori infection treatment, antibiotic amoxicillin is 
recommended, Clarithromycin, metronidazole, levofloxacin, tetracycline and furazolidone. 
In recent years, studies have found that the resistance rate of Hp to clarithromycin, 
metronidazole, and levofloxacin (fluoroquinolones) is on the rise, with double, triple or more 
resistance. Contrary to the high resistance rate of the above three antibiotics, the resistance 
rate of Hp to amoxicillin (0%~5%), tetracycline (0%~5%) and furazolidone (0%~1%) is still 
very low in China. [7, 24, 25]. World Gastroenterology Organization developing countries 
issued Hp global guidelines state that in Hp infection high, relatively resource-poor 
developing countries, furazolidone price of the most affordable in all alternative antibiotics, 
the resistant rate is also very low, at Hp It has an important position in the eradication 
treatment of infection [26]. Tetracycline has many adverse reactions due to liver and kidney 
function damage, and it is difficult to be widely promoted in clinical practice. As a semi-
synthetic tetracycline, doxycycline has the same antibacterial mechanism as tetracycline, 
and its antibacterial effect is 2 to 4 times stronger than tetracycline. Doxycycline can be 
completely absorbed by oral administration and is not affected by food. Its half-life is if 16 
hours in the body. Doxycycline is metabolized in the liver and is mainly excreted through the 
kidneys. However, when renal function is impaired, gastrointestinal excretion becomes the 
main excretion pathway. It can be used for patients with renal insufficiency and is the least 
toxic kind of tetracycline antibiotics. 
Therefore, this study chose four treatment options: triple therapy based on Vonoprazan 
fumarate + amoxicillin + doxycycline, Vonoprazan fumarate + furazolidone + doxycycline, and 
PPI and bismuth-based quadruple therapy - esomeprazole + colloidal bismuth tartrate + 
amoxicillin + doxycycline, esomeprazole + colloidal bismuth tartrate + furazolidone + 
doxycycline. Considering the main result, the objectivity of the detection of Hp eradication 
rate, the open-label design is unlikely to bias the results. We carry out a single-center, 
prospective, open-label clinical controlled study for the eradication of Hp infection to evaluate 

12 
 
the effectiveness of the four treatment options, the incidence of adverse events, patient 
compliance and economic benefits. Trying to determine whether triple therapy based on 
vonoprazan fumarate tablets can be used as a first-line treatment to eradicate Hp in Chinese 
patients, thereby improving clinical outcomes, improving patient compliance, avoiding 
unnecessary side effects, and reducing the incidence of Hp infection the cost of.  
2. Research purposes 
Comparison of four treatment options for radical treatment of Hp (F (1) Vonoprazan 
fumarate + amoxicillin + doxycycline, (2) Vonoprazan fumarate + furazolidone + doxycycline, 
(3) esomeprazole + colloidal bismuth tartrate + amoxicillin + doxycycline, and (4) esomeprazole 
+ colloidal bismuth tartrate + furazolidone + doxycycline), to evaluate the effectiveness, safety, 
and patient compliance of the four regimens, And socioeconomic evaluation. 
3. Subjects 
Inclusion criteria: 
1. Age≥ 18 years old, ≤ 80 years old 
2. Urea breath test (UBT) test is positive for Hp infection. 
3. Anti-Hp therapy without any treatment 
4. Gastroscopy within 1 months 
5. Clearly understand, volunteer to participate in the study and sign an informed consent 
form by himself 
Exclusion criteria: 
Subjects who meet any of the following criteria may not be selected for this test: 
First, the patient's physical condition cannot accept Helicobacter pylori root treatment: 
1. Allergic to the drugs used in this clinical study. 
2. Use PPI, histamine H2 receptor antagonist, antibiotics, bismuth, probiotics, or drugs 
with antibacterial effect within 4 weeks before study treatment. 
3. Use adrenal corticosteroids, non-steroidal anti-inflammatory drugs, and anticoagulants. 
4. There are diseases or clinical conditions that may interfere with the evaluation of 
research and treatment, such as liver disease, cardiovascular disease, lung disease, kidney 

13 
 
disease, metabolic disease, mental disease, or malignant tumor. 
5. Pregnant or lactating women. 
6. Participate in other clinical studies within 3 months before the registration of this 
clinical study.  
Second, do not agree to participate in this study 
Third, there are other problems that do not meet the requirements of this study or affect 
the results of the study: 
1. Suspected history of antibiotic abuse 
2. Patients with craniocerebral injury, mental illness, or epilepsy, etc. unable to 
communicate with patients or other diseases that may affect follow-up 
Termination criteria: 
If the subject meets any of the following criteria, the researcher will suspend the study early: 
1. Allergic reactions to the drugs or other components used in this clinical trial 
2. In the event of an adverse event, the investigator judges that the study needs to be 
terminated early, because continuing to participate in the study may bring unacceptable risks 
to the health of the subject, or the subject is unwilling to continue participating in the study 
due to adverse events 
Exit criteria: 
If the subject meets any of the following criteria, the patient will withdraw from the study: 
1. 
Subject withdrew informed consent 
2. 
Subject was lost to follow-up. 
During the research period, when the subject meets the above suspension / 
withdrawal criteria, the researcher can terminate the subject’s participation, and should try 
to follow medical routines for subsequent treatment and follow-up. The reason and date of 
the subject’s withdrawal must be recorded in the case report form and original data. 
 4. Research and design 
4.1 Design principle 
This trial adopts a single-center, prospective, open-label parallel control design. It is 
planned to enroll 596 patients with confirmed Hp infection; the patients were randomly 

14 
 
divided into four groups and received Vonoprazan fumarate + furazolidone + doxycycline. 
Plan, vonoprazan fumarate + Amoxicillin + Doxycycline Plan, Esomeprazole + Colloidal 
Bismuth Tartrate + Furazolidone + Doxycycline Plan, and Esomeprazole + Colloidal Tartaric 
Acid Bismuth + amoxicillin + doxycycline regimen. Compare the effectiveness, safety, and 
patient compliance of the four programs, and conduct cost-benefit analysis of different 
programs at the same time. The purpose of this trial is to find the most suitable treatment 
plan for the radical cure of Hp.  
4.2. Open label design and random grouping 
Due to the obvious differences between the different groups of drugs, clinicians and 
patients will inevitably know the status of patients taking drugs, so this trial adopts an 
open-label design. To this end, we have set up a non-blind team and a blind team. The 
non-blind team includes all researchers who need access to randomization information 
and do not participate in the evaluation, including researchers who randomize patients, 
who are responsible for diagnosis and Physician who prescribes medicine. The blinded 
research team is a researcher who participates in subject follow-up, safety evaluation, 
data collection and analysis. During the entire trial process, unblinded researchers are not 
allowed to disclose any information and documents related to drug grouping to any 
blinded personnel, subjects, and sponsors. Any relevant documents related to drug 
grouping should be kept separately by authorized non-blind researchers, and irrelevant 
personnel should not be contacted at will to avoid breaking blindness. 
With the help of SPSS20.0 software, a random number table is generated in advance, 
and it is divided into four groups 1:1:1:1, corresponding to four radical cure programs. 
According to the random number assigned to the patient, the radical treatment plan is 
determined.  
 

15 
 
5. Test steps: 
5.1 Informed consent with patient screening 
Firstly, inform the patients who are to be enrolled about the study, including the source, 
purpose, significance, and possible benefits and risks of participating in the study. After the 
patients have a complete understanding of the study, they can decide by themselves whether 
to participate. If the patient voluntarily participates, they sign the informed consent form and 
the investigator also signs. According to the inclusion and exclusion criteria, the single center 
selected 596 eligible patients.  
5.2 Collect patient-related information 
Collect patient-related information, including initials, gender, age, outpatient number, 
hospitalization number, enrollment date, education, occupation, smoking status, drinking 
status; height, weight, other comorbid diseases, whether close contacts have Hp infection, 
Results of gastroscopy and laboratory tests. The result of gastroscopy is whether ulcers, 
atrophic gastritis, etc. are found. 
5.3 Random grouping 
Use the random number table generated in advance by SPSS20.0 software and divide it 
into four groups 1:1:1:1. According to the random number drawn by the patients, the radical 
treatment plan is determined. The random process is completed by the study designer. 
5.4 Eradication treatment 
The patients were randomly divided into four groups (Group1, Group2, Group3, Group4) 
according to 1:1:1:1 and were treated with Hp eradication for 14 days according to the course 
of treatment. All study patients received instructions and were required to take the medication 
strictly and regularly. Record the time of first treatment and the time of termination of 
treatment.  
Table 1: Four treatment options included in the study 
 
Group1 
Group2 Group3 Group4 
Esomeprazole (5mg, 2 times /d, orally half an hour 
before meals) 
√ 
√ 
 
 
Colloidal bismuth tartrate (220mg, 2 times /d, √ 
√ 
 
 

16 
 
orally half an hour before meals) 
Amoxicillin (1000mg, 2 times /d, orally after meals)  √ 
 
√ 
 
Furazolidone (100mg, 2 times /d, orally after 
meals)  
 
√ 
 
√ 
Doxycycline (100mg, 2 times /d, orally after meals)  √ 
√ 
√ 
√ 
vonoprazan fumarate (20 mg, 2 times /d). 
 
 
√ 
√ 
 
5.5 Follow-up 
Each patient will be followed up twice. The first follow-up is on the first day after the 
patient ends the eradication treatment. The content of the follow-up is to evaluate the 
patient's drug compliance and whether adverse reactions have occurred. According to the 
actual situation of the patient, determine whether the patient needs to continue to receive 
other treatments. The second follow-up was 6-8 weeks after the patient stopped using proton 
pump inhibitors, fumarate, and antibiotics. The researcher reminded the patient to accept a 
UBT test at this time and judge whether the patient successfully eradicated Hp.  
5.6 Remedial measures 
5.6.1 Remedy for failure to eradicate 
If the patient finds that no radical cure is successful at the second follow-up visit, he will 
receive a treatment that is different from the previous radical cure plan and follow up again 
after taking the drug for 14 days and one month after stopping the drug. If the second radical 
cure fails, the drug will be discontinued for half a year, and after half a year, the patient will 
receive a different treatment from the previous two radical cures.  
5.6.2 Remedies after adverse reactions: Certain adverse reactions may occur during the 
use of study drugs. We will inform patients in detail of the adverse reactions and precautions 
in medication (Table 2). When an adverse reaction occurs, our remedy measures are as follows 
and inform the patient: stop the drug immediately and go to the hospital for treatment if the 
symptoms are severe. Symptomatic and supportive treatment based on corresponding 
symptoms, including but not limited to fluid replacement, anti-inflammatory and anti-allergic, 
anti-shock, and other treatments. 
Table 2 Adverse reactions and precautions of study drugs 

17 
 
 
adverse reactions 
Precautions 
Essomelazole 
Whole body: abdominal swelling, allergic reactions, fatigue, 
back pain, chest pain, pain under the breastbone, facial 
edema, peripheral edema, hot flashes, fatigue, fever, flu-
like symptoms, generalized edema, leg edema, discomfort, 
pain, chills: 
Cardiovascular: flushing, hypertension, tachycardia. 
Endocrine: Goiter. 
Gastrointestinal tract: abnormal bowel function, 
constipation, dyspepsia, dysphagia, gastrointestinal 
dysplasia, upper abdominal pain, belching, esophageal 
disease, frequent stools, gastroenteritis, gastrointestinal 
bleeding, gastrointestinal symptoms (non-specific ), 
hiccups, melena, oral disease, pharyngopathy, rectal 
disease, increased serum gastrin, tongue disease, tongue 
edema, ulcerative stomatitis, vomiting, gastrointestinal 
candidiasis, clostridium difficile Diarrhea, pancreatitis, 
bilirubinemia, abnormal liver function; 
Hearing: earache, tinnitus. 
Immune system: immediate allergic reaction/shock. 
blood system: anemia, hemoglobin reduction anemia, 
cervical lymphadenopathy, snoring, leukocytosis, 
leukopenia, thrombocytopenia. 
Metabolism/Nutrition: Diabetes, hyperuricemia, 
hyponatremia, elevated alkaline phosphatase, thirst, 
vitamin B12 deficiency, weight change. 
Musculoskeletal system: joint pain, worsening arthritis, 
arthropathy, cramps, anal pruritus, skin rash, erythema, 
maculopapular rash, skin inflammation, increased 
sweating, urticaria. 
Feelings: otitis media, perverted sense of smell, loss of 
taste, perverted sense of taste, blurred vision, 
Urogenital system: abnormal urine, albuminuria, cystitis, 
dysuria, fungal infection, hematuria, frequent urination, 
candidiasis, genital candidiasis, polyuria.  
Prohibited for drug allergies 
The lowest dose and shortest course of 
treatment suitable for the treatment 
situation. 
It may increase the risk of fractures of 
the hip, wrist or spine caused by 
osteoporosis. 
It is expected that PPI therapy needs to 
be extended or combined with drugs 
such as digoxin or drugs that can cause 
magnesemia (eg, diuretics). Medical 
professionals may consider monitoring 
the blood magnesium concentration 
before starting PPI therapy and 
regularly. 
Accompanied by rare genetic diseases, 
patients with glucose intolerance, 
glucose-galactose malabsorption, or 
sucrase-isomaltase deficiency should 
not take this product 
Patients who have been treated with 
the drug for a long time (especially 
those treated for more than 1 year) 
should be monitored regularly. 
There may be a decrease in the 
absorption of vitamin B12 due to 
decreased penicillin or skin deficiency. 
Therefore, in long-term treatment, for 
patients with reduced body expansion 
or risk factors for reduced vitamin B12 
absorption, this risk needs to be 
considered. 
Colloidal 
tartare 
The mouth may smell of ammonia, the tongue coating and 
stool are gray-black, nausea, and constipation 
Drug allergies are forbidden; cannot be 
taken with milk and antacids at the same 
time 
Amoxicillin 
Diarrhea, indigestion, nausea, vomiting, urticaria and 
erythema 
Drug allergies are forbidden; those with 
liver and kidney dysfunction/creatinine 
clearance less than 30 ml/min should 
be used with caution; those with 
anticoagulants should be used with 
caution. 

18 
 
Furazolidone 
Nausea, vomiting, diarrhea, headache, dizziness, drug-heat 
rash, anal itching, asthma, orthostatic hypotension, 
hypoglycemia, lung infiltration, hemolytic anemia, jaundice, 
polyneuritis 
Disabled for drug allergies; disabled for 
glucose-6-phosphate 
dehydrogenase 
deficiency; forbidden to drink alcohol; 
not suitable for patients with ulcer 
disease or bronchial asthma 
Doxycycline 
Nausea, vomiting, abdominal pain, diarrhea, liver toxicity, 
pancreatitis, allergic reactions (macro papules and 
erythema, urticaria, angioedema, allergic purpura, 
pericarditis and systemic lupus erythematosus skin lesions, 
exfoliative dermatitis, Anaphylactic shock and asthma) 
blood system (hemolytic anemia, thrombocytopenia, 
neutropenia and eosinophilia); central nervous system 
(headache, vomiting, optic nerve head edema) double 
infection; reduction of normal flora in the body , Vitamin 
deficiency, fungal reproduction (dry mouth, pharyngitis, 
angular cheilitis and glossitis) 
The drug is disabled for allergies 
Vonoprazan 
fumarate 
Diarrhea, constipation, nausea, and bloating. Headache, 
rash, edema, eosinophilia, liver toxicity, jaundice, skin, and 
subcutaneous diseases such as erythema multiforme 
Drug allergies are prohibited; patients 
who are receiving atazanavir or rilpivirin 
are contraindicated  
 
5.7 Cost indicator collection: 
Collect the relevant expenses of the radical treatment plan, excluding outpatient 
expenses and depreciation expenses of testing, excluding indirect costs such as wage losses, 
transportation expenses, and hidden costs (physical and mental pain and loss caused by 
patients and family members). 
5.8 Combined medication 
The subjects' use of any drug other than the study drug is a combination drug, and all 
drug treatments used by the subject within 7 days before randomization and throughout the 
study must be recorded in the case report form (CRF). The study drug may interact with other 
drugs or things (Table 3), so other drugs that interact with the study drug are prohibited as 
much as possible during the study period. 
 
Table 3: Study the combined drug interactions of drugs 
 
Drug/food interactions 
Esomeprazole 
Omeprazole (esomeprazole is its enantiomer) can interact with some reversal antiviral drugs (atazanavir, 
nelfinavir), so combined therapy is not recommended. 

19 
 
It can inhibit gastric acid secretion. Therefore, for drugs whose bioavailability is greatly affected by gastric 
pH (such as ketoconazole, itraconazole, atazanavir, iron salts and digoxin), esomeprazole Can affect its 
absorption. 
Be cautious or prohibit other drugs related to the metabolism of CYP2C19 and CYP3A4 (such as diazepam, 
citalopram, imipramine, clomipramine, phenytoin, voriconazole, cilostazol, rifampin, Hypericum 
perforatum, etc.). 
Co-administration with tacrolimus can lead to an increase in the blood concentration of tacrolimus. 
The decrease in gastric acid caused by the drug can lead to the proliferation of intestinal chromaffin-like 
cells and the increase of chromogranin A levels, thus interfering with the examination of neuroendocrine 
tumors. 
Combined use with methotrexate may increase the serum concentration of methotrexate and/or its 
metabolites. 
 
Colloidal 
bismuth 
tartrate  
Milk and antacids can interfere with the effect of this product and should not be taken at the same time. 
Taking tetracycline together will affect the absorption of the latter. 
If it is used at the same time with other drugs, drug interactions may occur. For details, please consult 
your physician or pharmacist. 
Amoxicillin 
This product may reduce the effect of oral contraceptives; it is not recommended to use probenecid or 
allopurinol in combination. 
Furazolidone 
 
Combination with tricyclic antidepressants can cause acute toxic psychosis and should be avoided. 
Can enhance the effect of levodopa. 
Sympathomimetic amines, foods rich in tyramine, appetite suppressants, monoamine oxidase inhibitors, 
etc. can enhance the effect of this product. 
Doxycycline 
This product can inhibit the activity of plasma prothrombin, so patients receiving anticoagulant therapy 
need to adjust the dose of anticoagulant. 
When barbiturates, phenytoin or carbamazepine are used together with this product, the above-
mentioned drugs can reduce the blood concentration of doxycycline due to the induction of microsomal 
enzyme activity, so the dose of doxycycline must be adjusted. 
Vonoprazan 
fumarate 
Should not be taken with atazanavir or rilpivirin, be cautious with nelfinavir, itraconazole, tyrosine kinase 
inhibitors (gefitinib, nilotinib, erlotinib), Take caution with digoxin and methyldigoxin, and take caution with 
CYP3A4 inhibitor clarithromycin 
 
6. Results Evaluation index 
6.1 Main evaluation indicators: Hp eradication rate 
6-8 weeks after the end of the eradication treatment, a UBT test is performed to 
determine whether Hp is eradicated. During this period, no antibacterial drugs, bismuth, or 
PPI are taken. Use ITT analysis and PP analysis.  
6.2 Secondary results 
1. Medication compliance  Use the MMAS scale to judge medication compliance. The 
full scale of the scale is 8 points, a score of < 6 is considered poor compliance, a score of 6-8 is 

20 
 
considered moderate compliance, and a score of 8 is considered good compliance. 
2. The incidence of adverse events  Adverse events include but are not limited to allergic 
reactions and shock, constipation, nausea, dizziness, diarrhea, and other adverse symptoms. 
3. Drug costs  The drug costs of the two treatment plans are calculated according to the 
2021 Drug Pricing Catalogue of Changsha City. The price is expressed in U.S. dollars, and the 
renminbi is converted into U.S. dollars at the exchange rate reported in 2021: US $ 1.00 = 
6.4962 CNY. According to the HP eradication rate, the Markov model is used to conduct a cost-
benefit analysis of the two methods to determine which method is more cost-effective from 
an economic point of view  
7. Security metrics: 
The incidence of adverse events/serious adverse events/suspected unexpected serious 
adverse events.  
1. Adverse events (AE) refer to adverse medical events that occur after subjects sign 
informed consent in clinical trials, but they may not be causally related to study drugs or 
research procedures. Therefore, adverse events can be any adverse or undesirable symptoms, 
signs, or diseases, including adverse drug events, important laboratory abnormalities, new 
diseases that appear during the study, and so on. For possible adverse events in this trial, refer 
to the "Test Procedures-Remedial Measures, Adverse Events" section. 
  2. A serious adverse event (SAE) refers to an adverse event that occurs during the 
research process after the subject has signed the informed consent form, and it meets one or 
more of the following criteria: 
• lethal 
• Life-threatening 
• Lead to hospitalization or prolonged hospital stay 
• Cause significant or permanent disability/loss of function 
• Cause congenital abnormalities or birth defects 
• Serious medical incident  
 3. Suspected unanticipated serious adverse events (SUSAR) are defined as: all 
unanticipated and serious adverse events that occur during the clinical trial that are related to 

21 
 
or suspicious of the trial operation process. 
  4. The causal relationship between the research procedure and the event can be 
divided into positively related, possibly related, possibly related, positively related, and 
impossible to judge. 
• Relevant: the time of the reaction conforms to the time sequence of the test, and the 
reaction conforms to the known reaction type of the test. After the test is stopped, it will be 
improved, and if the test is continued, it will appear again. 
• Possibly related: the time of occurrence of the reaction conforms to the chronological 
order of the test, the reaction conforms to the known reaction type of the test, and the 
patient's clinical state or other treatment methods may also produce the reaction. 
• Possibly irrelevant: The response time does not match the chronological order of the 
test, the response does not match the known response type in the test, and the patient's 
clinical state or other treatment methods may also produce the response. The possibility 
cannot be ruled out and tested. 
• Irrelevant: the time of the reaction does not match the chronological order of the test, 
and the reaction has a response type that is not known from the test. The patient's clinical 
state or other treatment methods may also produce the response, the disease state improves 
or the response is eliminated by stopping other treatments, Repeated use of other treatment 
methods appears, which is closely related to other risk factors. 
• Unable to determine: the time of the reaction has no clear relationship with the time 
sequence of the test. The reaction is like the known reaction type in the test. Other drugs used 
at the same time may also cause the same reaction. There is no sufficient basis for judgment. 
8. Statistical methods 
8.1 sample size calculation: 
With reference to previous studies, the Hp eradication rate of triple therapy containing 
vonoprazan fumarate was 91.4%, and that of quadruple therapy containing proton pump 
inhibitor + colloidal bismuth tartrate was 81.3%. Assuming 90% power, α is 0.05 (bilateral), a 
total of 476 patients are required, assuming a follow-up loss of 20%, and the planned sample 
size is 596 patients (149 patients in each group) [1-6].  

22 
 
8.2 General Principles: 
The eradication rate (%) and mean ± standard deviation was used to perform standard 
descriptive statistics on categorical and continuous variables. The comparison of categorical 
variables uses the chi-square test, and the comparison of continuous variables uses the two-
sample t test. According to the eradication rate and treatment cost, a Markov model was 
constructed, and the cost-benefit analysis of different treatments was carried out.  
8.3 Demographics and baseline characteristics: 
S Summarize all demographic variables and baseline characteristics (such as gender, age, 
education, occupation, smoking, drinking, and other comorbidities of the patient, etc.). 
Descriptive statistics (number of subjects, average, standard deviation, minimum, median, and 
maximum) were used for continuous variables, and categorical variables were used to 
calculate frequency and percentage rate.  
8.4 Evaluation indicator: 
The Hp radical cure rate and medication compliance were compared among the four 
groups of patients. 
Statistic the incidence of adverse events/serious adverse events/suspected unexpected 
serious adverse events. 
Analyze the relationship between demographic data and Hp eradication. 
The Markov model is used to analyze the cost-effectiveness of different treatment options 
for the treatment of Hp and choose the best cost-effective option.  
8.5 Subject Distribution: 
Summarize and describe the screening of the subjects, the enrollment, the completion of 
the study, the reason for the screening failure, and the reason for early withdrawal. Summarize 
and describe the case distribution of each data set, the removal of each analysis set, and the 
reasons for the removal, etc. Summarize and describe the violation of at least one important 
plan. 
8.6 Security Analysis: 
SS set is used to analyze the security. According to the SOC/PT summary of the cases of 
adverse events during the trial, the number and incidence of adverse events and other 
occurrences were summarized. If there are multiple adverse events in the same subject, it is 

23 
 
counted as 1 case when calculating the incidence; when the subject has the same AE multiple 
times, it is counted as 1 case in the calculation of the incidence of the AE. Severity of AE: If 
multiple AEs occur in the same subject, the most severe AE will participate in the analysis; 
when the subject has multiple AEs, the most severe one will participate in the analysis of the 
severity of the AE. Provide a list of cases in which adverse events have occurred. 
9. The research process 
Table 4 Clinical Research Process Table 
 
 
Project 
The 
screening 
period 
Treatment period 
Follow-up period 
 
Day -6 to 0 
Week 1 
Week 2 
Day 1 after 
treatment 
6-8 
weeks 
after 
treatment 
Basic information 
Informed 
consent 
 
 
 
 
 
Inclusion 
/ 
Excluded 
Criteria 
 
 
 
 
 
Demographic 
information 
 
 
 
 
 
Vital signs 
 
 
 
 
 
Physical 
examination 
 
 
 
 
 
Other 
comorbidities 
 
 
 
 
 
Auxiliary check 
Blood routine 
 
 
 
 
 
UBT Test 
 
 
 
 
 
Gastroscopy 
 
 
 
 
 
Classify adverse events 
Diarrhea 
 
 
 
 
 
Stomachache 
 
 
 
 
 
Nausea 
 
 
 
 
 
Vomit 
 
 
 
 
 
Drug allergies 
 
 
 
 
 
Black stool 
 
 
 
 
 
Yellow urine 
 
 
 
 
 
Loss of appetite 
 
 
 
 
 

24 
 
other 
Combined 
medication 
 
 
 
 
 
Random 
grouping 
 
 
 
 
 
Amount spent 
 
 
 
 
 
 
Note: Various inspections and test procedures are carried out according to the time of the 
research flow sheet, and occasional changes during the inspection item window period due 
to festivals, holidays or other management reasons are allowed; laboratory inspections are 
accepted within 1 week before randomization of the laboratory inspection results of our 
center.  
[1] Physical examination: examination of the main body system (general condition, skin 
mucosa and lymph nodes, head, neck, chest, abdomen, genitalia, musculoskeletal, nervous 
system, other).  
[2] Blood Routine: Red Blood Cells (RBC), White Blood Cells (WBC), Neutrophils (NEUT), 
Hemoglobin (HB), Platelets (PLT). 
[3] Classify the incidence of adverse events: the respective incidence of each adverse event 
in operation, such as the incidence of sedative low blood pressure.  
 
 
 
 
 
 

25 
 
1 0. Management and quality control of clinical trials 
10.1 Declaration 
This clinical trial will be conducted in accordance with the standard operating 
specifications of the Third Xiangya Hospital for clinical trials and will comply with the 
"Declaration of Helsinki", China's GCP and clinical trial regulations. When the investigator 
signs the plan, he will agree to follow the instructions and procedures set out in the plan 
and follow the principles of clinical trial quality management practices that this plan 
complies with, as well as all the principles of managing local regulations and medical 
research. 
10.2 Ethics Section 
This study was designed and prepared on the basis of the Declaration of Helsinki of the 
World Medical Association, taking into account the rights and welfare of patients. The main 
investigator or investigator of the clinical trial explains to the patient the purpose of the trial 
and all potential possibilities. The patient voluntarily agrees to participate in the clinical trial 
and signs the informed consent form to become a subject. Clinical trial investigators and 
researchers participating in the trial should correctly analyze and be familiar with the 
research plan, and be able to prepare measures in advance, such as response measures in 
the event of unexpected adverse events, required reports, and adequate training. Clinical 
investigators must comply with the "Clinical Trial Quality Management Standards" when 
conducting clinical trial research. The main investigator and the personnel participating in 
the research should abide by the content specified in the test plan, and scientifically 
maintain the currently recognized technical level to conduct the test. According to national 
policies and regulations, researchers provide relevant test documents to the ethics 
committee. Before a clinical trial starts, the approval of the ethics committee must be 
obtained. The modification of the research protocol needs to be submitted to the ethics 
committee for approval. In the process of clinical research, if any serious adverse event or 
unexpected adverse event related to the safety of clinical research occurs, which may affect 
the safety of the patient and the implementation of the trial, the investigator must inform 
the ethics committee. The investigator is responsible for explaining to each subject the 

26 
 
purpose, methods, benefits and potential risks of this clinical trial, alternative treatment 
methods, and the rights and obligations of subjects in accordance with the Declaration of 
Helsinki; Subjects should be informed that they have the right to withdraw from the trial at 
any time, and their personal interests will not be harmed. Before any operational 
procedures related to clinical trials, an informed consent form signed by the subject must 
be obtained. Oral explanations must be made when giving written informed consent to 
subjects. The informed consent must be dated and signed by each subject or their legal 
guardian or agent. The signed informed consent form and information page shall be kept by 
the subject, and another signed informed consent form shall be kept and kept as a research 
file. Before any research-related process starts, the consent form must be approved and 
signed by the subject. Before any research-related process begins, the consent form must 
be approved and signed by the subject. Before obtaining informed consent, the investigator 
or its designated personnel shall provide the subject with sufficient time and opportunity to 
inquire about the details of the trial and decide whether to participate in the trial. The 
informed consent process needs to be recorded in the disease course record on the day of 
the screening visit. The investigator is responsible for the informed consent process. If any 
information related to the subject's willingness to continue participating in the trial is 
obtained during the trial, the written informed consent must be updated, and the subject 
must be given to confirm whether the subject is willing to continue participating. The 
revised informed consent form needs to be ethically approved before being provided to the 
subjects. By signing the informed consent form, the subject/patient will agree to allow the 
hospital and the health administrative department to verify the original data about the 
clinical research that has been obtained, and the reviewer must abide by the confidentiality 
statement. 
10.3 Quality assurance and audit 
All drugs and materials used in clinical research must be based on quality control. The 
hospital's clinical trial research center, scientific research department and other management 
departments and related medical management institutions have the right to review clinical 
research, the purpose of which is to ensure the authenticity of clinical research record data 
and comply with the provisions of the clinical research plan. When necessary, the researcher 

27 
 
will invite people outside the project team to conduct third-party audits, allowing the auditors 
to directly access the original data/documents, including all medical records, research-related 
documents and letters, and the informed consent documents for the clinical trial Wait. 
Subjects of clinical research will be informed of the review process of clinical research, but the 
subject's privacy and data will be strictly protected. 
10.4 Medical Records Report Form 
In clinical research, the CRF should be completed in time after each visit to record the 
condition of the subject. The medical history records and other records related to the subject’s 
disease progression during the study are kept by the investigator. These records should include 
the following as much as possible: original or photocopy of laboratory data and other medical 
test results, which must be kept in the center together with the subjects’ medical records. 
10.5 Intellectual Property 
All information obtained from the experiment belongs to the intellectual property rights of 
the Third Xiangya Hospital and the researcher team. Therefore, clinical trial investigators and 
all other relevant personnel must strictly keep confidential, and shall not disclose to third 
parties without the prior consent of the main investigator of the trial. 
10.6 Subject Privacy 
Researchers must ensure that the privacy of clinical trial subjects is maintained. In all 
public documents outside the hospital, only the screening number and initials of the clinical 
trial can be used to determine the identity of the clinical trial subject, but the subject’s name 
cannot be indicated. Researchers must properly keep the names and addresses of relevant 
clinical trial subjects and the enrollment form corresponding to the clinical trial number. These 
entry forms are kept strictly confidential by the investigator and cannot be submitted to a third 
party. 
11. Papers published 
The Third Xiangya Hospital, as the sponsor, has exclusive rights to this research. Regarding 
the manuscript and publication, the Third Xiangya Hospital and the main researchers have the 
final decision. 
12． Data preservation 

28 
 
The investigator is responsible for keeping the following data for at least 5 years after the 
end of the trial, and can be extended if necessary: the data obtained in the trial; the trial 
protocol; the original research data; the case report form; the original or photocopy of the 
informed consent form; the ethics committee approval, etc. 
 
 

29 
 
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Hong, H. Lu, Y . Yamaoka, F. Megraud, F. Chan, J. Sung, J. Lin, D. Graham, M. Wu, and E. El-Omar,  
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V. Lamy, A. Tonkic, K. Przytulski, C. Beglinger, M. Venerito, P. Bytzer, L. Capelle, T. Milosavljević, 
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31 
 
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Hunt Rh Fau - Xiao, S.D., F. Xiao Sd Fau - Megraud, R. Megraud F Fau - Leon-Barua, F. Leon-
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M. Vaz Coelho L g Fau - Fock, S. Fock M Fau - Fedail, H. Fedail S Fau - Cohen, P. Cohen H Fau - 
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32 
 
 
Informed consent 
Project name 
Comparison of Vonoprazan fumarate-based Triple Therapy Versus 
Proton Pump Inhibitor and Bismuth Based Quadruple Therapy in 
the Eradication of Helicobacter Pylori: A Single-center Prospective 
Open-label Controlled Study 
Clinical research unit 
Third Xiangya Hospital, Central South University 
Main researcher 
Anliu Tang 
Sponsor 
Department of Gastroenterology, Third Xiangya Hospital, Central 
South University 
Funding source 
No 
Informed 
Consent 
Version 
1.1 
Informed 
Consent 
Version Date 
2021-5-22 
 
 
 

33 
 
We sincerely invite you to participate in a clinical study comparing Helicobacter 
pylori eradication programs. Your participation in this study is completely voluntary 
and you can choose not to participate. If you decide not to participate, this will not 
affect the relationship between you and the doctor. In order for you to decide 
whether or not to participate in this study, it is important to understand the content 
of the study in detail. Please read the following information carefully, and you can 
also discuss it with your family, friends, and doctor. If you don't understand anything 
or want to learn more about this study, please feel free to ask your doctor. 
1.Test drug 
The triple therapy and quadruple therapy in this project are composed of two 
types of drugs, basic experimental drugs and antibiotics, and a total of 4 treatment 
options. The treatment plan of triple therapy is: vonoprazan fumarate + amoxicillin + 
doxycycline, vonoprazan fumarate + furazolidone + doxycycline. The treatment plan 
of quadruple therapy is esomeprazole + colloidal bismuth tartrate + amoxicillin + 
doxycycline, and esomeprazole + colloidal bismuth tartrate + furazolidone + 
doxycycline.  
The basic test drug for triple therapy is vonoprazan fumarate, a drug produced 
by Tianjin Takeda Company, which is a powerful drug that inhibits gastric acid 
secretion, mainly by blocking the K + channel of H + , K + -ATPase , Competitively 
blocking the binding of K + with the enzyme, can stay in the parietal cells for a long 
time, thereby quickly inhibiting the secretion of gastric acid. Although the current 
indication for the vonoprazan fumarate produced by Tianjin Takeda is to treat reflux 
esophagitis, the drug has been approved by the U.S. Food and Drug Administration 
(FDA ) and believes that it can cure Helicobacter pylori together with antibiotics. , 
China’s Fifth National Consensus Report on the Treatment of Helicobacter Pylori 
Infection" mentioned that the use of this drug can increase the cure rate of 
Helicobacter pylori. In addition, the treatment plan of the drug combined with 
antibiotics has been confirmed in several studies in Japan due to the traditional 
quadruple therapy. 

34 
 
The basic test drugs for quadruple therapy are esomeprazole and colloidal 
bismuth tartrate capsules, produced by AstraZeneca Co., Ltd., and Shanxi 
Xinbaoyuan Company, respectively; among them, esomeprazole is a proton pump 
inhibitor. It can inhibit the secretion of gastric acid and is a commonly used acid 
suppressing drug in clinical practice; colloidal bismuth tartrate capsule is a commonly 
used gastric mucosal protective drug. After oral administration, a colloidal sol with 
excellent colloidal properties is formed in the gastric juice to form a protective film 
to isolate gastric acid. 
There are two combinations of antibiotics for triple therapy and quadruple 
therapy: amoxicillin + doxycycline and furazolidone + doxycycline. Amoxicillin is 
produced by Hainan General Sanyo Pharmaceutical Co., Ltd., and is one of the most 
used semi-synthetic penicillin broad-spectrum β-lactam antibiotics. Furazolidone is 
produced by Tianjin Lisheng Company and is a nitrofuran antibiotic. Doxycycline is 
produced by Jiangsu Yongxin Company and is clinically classified as a tetracycline 
antibiotic. It is mentioned in the "Fifth National Consensus Report on the Treatment 
of Helicobacter Pylori Infection in China" that the resistance rate of Helicobacter 
pylori in China to these three antibiotics is very low. 
Currently, there are other treatment options for Helicobacter pylori, including 
sequential therapy. If you do not want to participate in this study, you can use this 
program to eradicate Helicobacter pylori.  
2. Research purpose and basic research content 
Helicobacter pylori ( Hp ) infection is one of the most common chronic infections 
in humans. China is one of the countries with a high incidence of Hp infection. 
Epidemiological surveys show that the current Hp infection rate in China is 42% -64% . 
Hp infection is closely related to the occurrence of chronic active gastritis, peptic ulcer, 
gastric mucosa-associated lymphoid tissue (MALT) lymphoma and gastric cancer. 
There are many different therapies for the treatment of Hp . In China, bismuth-
containing quadruple therapy is highly recommended as the first-line treatment for 
Hp infection. Although the eradication rate has increased, the therapy still has 

35 
 
limitations, including bismuth-related side effects, poor patient compliance with 
medications, high resistance rates to clarithromycin and metronidazole, and high drug 
costs. In recent years, a new acid-suppressing drug-potassium ion competitive acid 
blocker has been introduced. Its novel mechanism of action and unique 
pharmacokinetic characteristics make it show better characteristics than PPI, such as 
fast onset, The structure is stable, the acid suppression effect is long-lasting, the 
individual differences are small, and the adverse reactions are few. As its 
representative medicine, vonoprazan fumarate green tablets are mainly used to treat 
acid-related diseases, including reflux esophagitis, gastric ulcer, and duodenal ulcer. A 
number of clinical studies have shown that vonoprazan fumarate raw tablets are safe, 
effective and well tolerated in the treatment of reflux esophagitis and eradication of 
Hp. Considering the high drug resistance rate of clarithromycin and the huge side 
effects caused by the large dose of amoxicillin in dual therapy, we are trying to find a 
better alternative therapy based on vonoprazan fumarate green tablets, which can as 
a first-line solution for Hp eradication. 
Four treatment options were selected in this study: triple therapy based on 
vonoprazan fumarate + amoxicillin + doxycycline, vonoprazan fumarate + furazolidone 
+ doxycycline, and quadruple therapy based on PPI and colloidal bismuth tartrate 
capsules-esomeprazole + colloidal bismuth tartrate capsules + amoxicillin + 
doxycycline, esomelar Azole + colloidal bismuth tartrate capsules + furazolidone + 
doxycycline. Considering the main result, the objectivity of the detection of Hp 
eradication rate, the open-label design is unlikely to bias the results. We carry out a 
single-center, prospective, open-label clinical controlled study for the eradication of 
Hp infection to evaluate the effectiveness of the four treatment options, the incidence 
of adverse events, patient compliance and economic benefits. Trying to determine 
whether triple therapy based on vonoprazan fumarate can be used as a first-line 
treatment to eradicate Hp in Chinese patients , thereby improving clinical outcomes, 
improving patient compliance, avoiding unnecessary side effects, and reducing the 
incidence of Hp infection the cost of. 

36 
 
Entry criteria： 
6. 年龄≥18 岁，≤80 岁 
7. Age ≥18 years old, ≤80  years old； 
8. Urea breath test (UBT) is positive for Hp infection 
9. Receive gastroscopy within 1 month 
10. Clearly understand, participate in the research voluntarily, and sign the informed 
consent form 
11. Anti-Hp treatment without any treatmentform 
Includsion criteria： 
Subjects who meet any of the following criteria cannot be selected for this trial: 
： 
Firstly, the patient's physical condition is unable to receive Helicobacter pylori radical 
treatment ： 
7. Allergic to the drugs used in this clinical study； 
8. Use PPI, histamine H2 receptor antagonist, antibiotics, bismuth, probiotics or 
drugs with antibacterial effect within 4 weeks before study treatment； 
9. Use adrenal corticosteroids, non-steroidal anti-inflammatory drugs and 
anticoagulants; 
10. 
There are diseases or clinical conditions that may interfere with the evaluation 
of research and treatment, such as liver disease, cardiovascular disease, lung disease, 
kidney disease, metabolic disease, mental disease or malignant tumor; 
11. 
Pregnant or breastfeeding women; 
12. 
Participate in other clinical studies within 3 months before the registration of 
this clinical study;； 
Secondly, Disagree to participate in this research. 
Thirdly, There are other problems that do not meet the requirements of this research 
or that affect the results of the research： 
1. Suspected history of antibiotic abuse 
2. Patients with craniocerebral injury, mental illness or epilepsy, etc. unable to 
communicate with patients or other diseases that may affect follow-up： 

37 
 
If the subject meets any of the following criteria, the researcher will suspend the study 
early: 
1. Allergic reactions to the drugs or other components used in this clinical trial 
2. In the event of an adverse event, the investigator judges that the study needs to 
be terminated early, because continuing to participate in the study may bring 
unacceptable risks to the health of the subject, or the subject is unwilling to 
continue participating in the study due to adverse events 
Exit criteria： 
    If the subject meets any of the following criteria, the patient will withdraw from 
the study： 
1. Subject withdrew informed consent 
2. Subject was lost to follow-up. 
The project has been approved by the ethics committee of Third Xiangya Hospital 
of Central South University. This study was conducted at the Third Xiangya Hospital 
of Central South University. A total of about 596 patients infected with Helicobacter 
pylori participated in this study. The study time limit is 2021.06.15-2022.06.15, and 
all participating patients have a one-quarter chance of being randomly assigned to 
the four schemes (Table 1). 
Table 1 The specific medications of the four groups of patients 
 
Group1 
Group2 
Group3 
Group4 
Esomeprazole (5mg, 2 times /d, orally half an hour 
before meals) 
√ 
√ 
 
 
Colloidal bismuth tartrate (220mg, 2 times /d, orally 
half an hour before meals) 
√ 
√ 
 
 
Amoxicillin (1000mg, 2 times /d, orally after meals)  
√ 
 
√ 
 
Furazolidone (100mg, 2 times /d, orally after meals)   
√ 
 
√ 
Doxycycline (100mg, 2 times /d, orally after meals)  
√ 
√ 
√ 
√ 
vonoprazan fumarate (20 mg, 2 times /d). 
 
 
√ 
√ 
If you choose not to participate in this study, it will not affect your current and 

38 
 
future treatment at all. You can use other radical treatment options, such as 
sequential therapy. 
3. Research process and methods 
This research is roughly divided into the following steps: 
a) Informed Consent and Patient Screening 
b) Collect patient-related information 
c) Random grouping 
d) Eradication therapy 
e) Patient follow-up 
f) Remedial measures for failure to eradicate and adverse reactions 
g) Result evaluation index collection, including eradication, drug compliance, 
incidence of adverse events, drug costs 
h) Statistical Analysis 
The duration of this study is roughly: the screening period is 7 days, the treatment 
period is 14 days, and the follow-up period is 4-8 weeks. During the entire study 
period, you need to visit the hospital 3 times during the screening period and the 
follow-up period. During the study period, you will have multiple or one of the blood 
routine, UBT examination, gastroscopy, and questionnaire survey. The specific 
frequency of each examination will be determined by the doctor according to the 
development of your condition. The total expected cost is not much different from 
the normal Hp eradication program. 
4-6 weeks after the end of the eradication treatment, a UBT test was performed to 
determine whether Hp was eradicated. During this period, no antibacterial drugs, 
bismuth, or PPI were taken. Use ITT analysis and PP analysis. 
The first visit is the screening period. Your eligibility will be screened. If you 
meet all the selection criteria, you will participate in this study. The contents of the 
examination are as follows: medical history collection and physical examination: 
examination of the main body systems (general conditions, skin, mucous membranes 
and lymph nodes, head, neck, chest, abdomen, anogenitals, musculoskeletal, 
nervous system, etc.); blood; UBT Check: to determine whether you have Hp 

39 
 
infection; gastroscopy. 
 
The second visit is the first day after the end of treatment, and it lasts for one 
day. You will have the following examinations or inquiries: physical examination, 
MMAS questionnaire, occurrence of adverse events, and drug costs. 
The third visit is 4-8 weeks after the end of treatment, and lasts for 1 day. You 
will have the following examinations: physical examination, UBT test. 
4. Possible risks and inconveniences 
All drugs usually have side effects, and no matter which treatment you take, 
there will be other risks. We list the possible adverse reactions and precautions of 
each drug in accordance with the latest version of the drug instructions (Table 2). In 
addition, we have listed all other drugs that may interact with the study drug (Table 
3). During the treatment period, we hope that you should disable or use other drugs 
with caution. If you have any discomfort, please tell your doctor in time. 
Table 2 Possible adverse reactions and precautions of study medication 
 
adverse reactions 
Precautions 
Essomelazole 
Whole body: abdominal swelling, allergic reactions, 
fatigue, back pain, chest pain, pain under the breastbone, 
facial edema, peripheral edema, hot flashes, fatigue, fever, 
flu-like symptoms, generalized edema, leg edema, 
discomfort, pain, chills: 
Cardiovascular: flushing, hypertension, tachycardia. 
Endocrine: Goiter. 
Gastrointestinal tract: abnormal bowel function, 
constipation, dyspepsia, dysphagia, gastrointestinal 
dysplasia, upper abdominal pain, belching, esophageal 
disease, frequent stools, gastroenteritis, gastrointestinal 
bleeding, gastrointestinal symptoms (non-specific ), 
hiccups, melena, oral disease, pharyngopathy, rectal 
disease, increased serum gastrin, tongue disease, tongue 
edema, ulcerative stomatitis, vomiting, gastrointestinal 
candidiasis, clostridium difficile Diarrhea, pancreatitis, 
bilirubinemia, abnormal liver function; 
Hearing: earache, tinnitus. 
Prohibited for drug allergies 
The lowest dose and shortest course of 
treatment suitable for the treatment 
situation. 
It may increase the risk of fractures of 
the hip, wrist or spine caused by 
osteoporosis. 
It is expected that PPI therapy needs to 
be extended or combined with drugs 
such as digoxin or drugs that can cause 
magnesemia (eg, diuretics). Medical 
professionals may consider monitoring 
the blood magnesium concentration 
before starting PPI therapy and 
regularly. 
Accompanied by rare genetic diseases, 
patients with glucose intolerance, 
glucose-galactose malabsorption, or 

40 
 
Immune system: immediate allergic reaction/shock. 
blood system: anemia, hemoglobin reduction anemia, 
cervical lymphadenopathy, snoring, leukocytosis, 
leukopenia, thrombocytopenia. 
Metabolism/Nutrition: Diabetes, hyperuricemia, 
hyponatremia, elevated alkaline phosphatase, thirst, 
vitamin B12 deficiency, weight change. 
Musculoskeletal system: joint pain, worsening arthritis, 
arthropathy, cramps, anal pruritus, skin rash, erythema, 
maculopapular rash, skin inflammation, increased 
sweating, urticaria. 
Feelings: otitis media, perverted sense of smell, loss of 
taste, perverted sense of taste, blurred vision, 
Urogenital system: abnormal urine, albuminuria, cystitis, 
dysuria, fungal infection, hematuria, frequent urination, 
candidiasis, genital candidiasis, polyuria.  
sucrase-isomaltase deficiency should 
not take this product 
Patients who have been treated with 
the drug for a long time (especially 
those treated for more than 1 year) 
should be monitored regularly. 
There may be a decrease in the 
absorption of vitamin B12 due to 
decreased penicillin or skin deficiency. 
Therefore, in long-term treatment, for 
patients with reduced body expansion 
or risk factors for reduced vitamin B12 
absorption, this risk needs to be 
considered. 
Colloidal 
tartare 
The mouth may smell of ammonia, the tongue coating and 
stool are gray-black, nausea, and constipation 
Drug allergies are forbidden; cannot be 
taken with milk and antacids at the same 
time 
Amoxicillin 
Diarrhea, indigestion, nausea, vomiting, urticaria and 
erythema 
Drug allergies are forbidden; those with 
liver and kidney dysfunction/creatinine 
clearance less than 30 ml/min should 
be used with caution; those with 
anticoagulants should be used with 
caution. 
Furazolidone 
Nausea, vomiting, diarrhea, headache, dizziness, drug-heat 
rash, anal itching, asthma, orthostatic hypotension, 
hypoglycemia, lung infiltration, hemolytic anemia, jaundice, 
polyneuritis 
Disabled for drug allergies; disabled for 
glucose-6-phosphate 
dehydrogenase 
deficiency; forbidden to drink alcohol; 
not suitable for patients with ulcer 
disease or bronchial asthma 
Doxycycline 
Nausea, vomiting, abdominal pain, diarrhea, liver toxicity, 
pancreatitis, allergic reactions (macro papules and 
erythema, urticaria, angioedema, allergic purpura, 
pericarditis and systemic lupus erythematosus skin lesions, 
exfoliative dermatitis, Anaphylactic shock and asthma) 
blood system (hemolytic anemia, thrombocytopenia, 
neutropenia and eosinophilia); central nervous system 
(headache, vomiting, optic nerve head edema) double 
infection; reduction of normal flora in the body , Vitamin 
deficiency, fungal reproduction (dry mouth, pharyngitis, 
angular cheilitis and glossitis) 
The drug is disabled for allergies 
Vonoprazan 
fumarate 
Diarrhea, constipation, nausea, and bloating. Headache, 
rash, edema, eosinophilia, liver toxicity, jaundice, skin, and 
subcutaneous diseases such as erythema multiforme 
Drug allergies are prohibited; patients 
who are receiving atazanavir or rilpivirin 
are contraindicated  

41 
 
 
Table 3: Study the combined drug interactions of drugs 
 
Drug/food interactions 
Esomeprazole 
Omeprazole (esomeprazole is its enantiomer) can interact with some reversal antiviral drugs (atazanavir, 
nelfinavir), so combined therapy is not recommended. 
It can inhibit gastric acid secretion. Therefore, for drugs whose bioavailability is greatly affected by gastric 
pH (such as ketoconazole, itraconazole, atazanavir, iron salts and digoxin), esomeprazole Can affect its 
absorption. 
Be cautious or prohibit other drugs related to the metabolism of CYP2C19 and CYP3A4 (such as diazepam, 
citalopram, imipramine, clomipramine, phenytoin, voriconazole, cilostazol, rifampin, Hypericum 
perforatum, etc.). 
Co-administration with tacrolimus can lead to an increase in the blood concentration of tacrolimus. 
The decrease in gastric acid caused by the drug can lead to the proliferation of intestinal chromaffin-like 
cells and the increase of chromogranin A levels, thus interfering with the examination of neuroendocrine 
tumors. 
Combined use with methotrexate may increase the serum concentration of methotrexate and/or its 
metabolites. 
 
Colloidal 
bismuth 
tartrate  
Milk and antacids can interfere with the effect of this product and should not be taken at the same time. 
Taking tetracycline together will affect the absorption of the latter. 
If it is used at the same time with other drugs, drug interactions may occur. For details, please consult 
your physician or pharmacist. 
Amoxicillin 
This product may reduce the effect of oral contraceptives; it is not recommended to use probenecid or 
allopurinol in combination. 
Furazolidone 
 
Combination with tricyclic antidepressants can cause acute toxic psychosis and should be avoided. 
Can enhance the effect of levodopa. 
Sympathomimetic amines, foods rich in tyramine, appetite suppressants, monoamine oxidase inhibitors, 
etc. can enhance the effect of this product. 
Doxycycline 
This product can inhibit the activity of plasma prothrombin, so patients receiving anticoagulant therapy 
need to adjust the dose of anticoagulant. 
When barbiturates, phenytoin or carbamazepine are used together with this product, the above-
mentioned drugs can reduce the blood concentration of doxycycline due to the induction of microsomal 
enzyme activity, so the dose of doxycycline must be adjusted. 
Vonoprazan 
fumarate 
Should not be taken with atazanavir or rilpivirin, be cautious with nelfinavir, itraconazole, tyrosine kinase 
inhibitors (gefitinib, nilotinib, erlotinib), Take caution with digoxin and methyldigoxin, and take caution with 
CYP3A4 inhibitor clarithromycin 
 
The adverse reactions and risks that you may have during the study period 
include but are not limited to the above. Any study drug may have other unforeseen 
or even serious adverse reactions. If new adverse reaction information is discovered 
during the period, the research doctor will also inform you in time. At the same time, 
the study doctor will closely observe your condition and determine whether you 

42 
 
have had an adverse reaction, and if necessary, other drugs will be used to treat you 
to reduce the adverse reaction or discomfort. 
If you are breastfeeding or pregnant, you will not be able to participate in this 
project. 
5. Expected benefits 
Using the new drugs in this study and strict follow-up, you may get a safer 
treatment process and better medication experience; in addition, you will receive 
follow-up follow-up 1 day, 4-8 weeks after treatment, and the eradication Patients 
who fail and have adverse reactions actively undergo relevant evaluation and 
treatment, which helps to ensure the safety of your treatment. In general, you will 
receive stricter clinical monitoring during the study period and will be able to discuss 
your treatment with the study doctor. 
Due to individual differences, we cannot predict whether different medication 
regimens will have side effects on you, and the size of the side effects, so you may 
not benefit from this clinical trial. If you do not want to participate in the project, use 
our hospital's conventional Hp eradication treatment plan. This program is relatively 
widely used and has good safety, but there are still a series of side effects. 
The free check you need to complete during the trial is as follows: MMAS score. 
6. Compensation and treatment 
When you have a serious adverse reaction during treatment, the trial will be 
terminated immediately, and we will take all necessary measures to rescue you. If 
you find that the radical cure is not successful at the second follow-up visit, you will 
receive a treatment that is different from the previous radical cure plan and follow 
up again after taking the medicine for 14 days and one month after stopping the 
medicine. If the second radical cure fails, the drug will be discontinued for half a 
year, and after half a year, the patient will receive a different treatment from the 
previous two radical cures. 
This study will not increase your treatment risks, inspection costs, and 
treatment costs. In addition, you need to undergo follow-up and evaluation within 1-
3 days and 4-8 weeks after treatment, each time it may take 10-20 minutes. If you 

43 
 
experience any discomfort, new changes in your condition, or any unexpected 
situation during this study, regardless of whether it is related to the operation, 
please inform your study doctor in time, and they will make serious judgments and 
rigorous medical treatment. deal with. 
When the test-related damage occurs to the subject, the sponsor shall bear all 
the costs of the treatment and the corresponding economic compensation or 
compensation. The specific amount of compensation will be determined by the 
results of the appraisal of the relevant department and the negotiation between the 
two parties (the subject and the hospital). 
7. Privacy and confidentiality 
Your medical information will be kept confidential at all times. In addition to 
your research doctor, the sponsors, monitors, auditors, ethics committees, and 
health supervision departments of this research may consult your original medical 
data related to the research to ensure that the research is standardized and the data 
is true and reliable . However, all information will be kept confidential, and the 
results of this study may be published in medical journals, but your identity will not 
be revealed. 
8. Precautions for subjects before, after and during the research 
process 
Before participating in this research, please read carefully the selection criteria 
and exclusion criteria of the study, and make sure that you meet the selection criteria 
and there are no problems mentioned in the exclusion criteria; during the research 
process, if you have any physical discomfort, please Inform your doctor, and the 
doctor will deal with your situation accordingly; when you need to follow-up, please 
cooperate with the follow-up doctor as much as possible to make a more accurate and 
timely diagnosis, which is beneficial to your treatment; finally, you are studying During 
the process, if you have any questions about this study, you can contact your research 
doctor, who will answer you in detail. 
There are a variety of solutions to cure H. pylori. If you encounter the following 
situations and need to terminate the clinical trial, you will continue to receive the 

44 
 
hospital's conventional treatment plan or other alternatives under the supervision of 
the clinician. 
The following are the circumstances and reasons that the project may be 
terminated: 
When the subject has more serious adverse reactions, such as anaphylactic shock, 
severe liver and kidney damage, the test will be terminated immediately and all 
necessary measures will be taken for rescue. 
9. Your rights 
If you are unwilling to participate in the project, use our hospital's conventional 
Hp eradication treatment plan, including but not limited to sequential plan, or other 
bismuth-containing quadruple radical treatment plan. This will not affect your Hp 
eradication process. 
If there is any important new information about the study drug during the study 
period that may affect your willingness to continue participating in the study, we will 
notify you and discuss with you whether you should continue the study. 
You can request to withdraw from this study at any time for any reason. To 
ensure your safety, please complete the last visit so that the doctor can complete all 
the inspection items required by the last inspection and discover possible adverse 
reactions. Whether you participate or refuse to participate in this study, or withdraw 
from the study halfway, you will not be discriminated against or retaliated, and your 
medical treatment and rights will not be affected. 
If the informed consent form is updated during the research process, you will 
need to sign the new version of the informed consent form again. After the study is 
over, if you need specific information about medication, you can consult your study 
doctor. 
During the research process, we will provide you with a comprehensive 
evaluation of relevant indicators (screening period), drug use monitoring (treatment 
period), and evaluate whether Hp is eradicated (follow-up period); after the study, if 
you still have Medical questions related to this project need to be consulted. After 
contacting your research doctor, we will try our best to answer you. 
10. Special protection for vulnerable subjects 

45 
 
Vulnerable subjects refer to subjects who are insufficient or have lost the ability 
to maintain their own wishes and rights, whose willingness to participate in clinical 
trials voluntarily, may be expected to benefit from the trial, or who refuse to 
participate may be improperly affected by retaliation. Including: the researcher’s 
students and subordinates, the sponsor’s staff, military personnel, prisoners, 
patients with incurable diseases, patients in critical situations, people staying in 
orphanages, homeless persons, persons with no capacity for civil conduct, or 
restricted civil conduct Ability people and so on. 
Special protective measures: The above-mentioned patients will be excluded 
from the subjects. 
11. Collection, preservation, utilization and external provision of 
biological specimens (if involved) 
The blood samples collected during the research process will be collected in the 
fifth examination and sent by the research doctor to the laboratory of our hospital 
for processing. There is no need to leave the country, and no genetic information is 
involved. 
12. Contact information 
If you have any concerns or questions about the study, or in any emergency, 
please contact your doctor in time. Please keep this information. 
Doctor's name：____________________ 
Contact number：____________________ 
If you have any questions about your rights, you can contact: 
Ethics Committee of the Third Xiangya Hospital of Central South University 
Contact number: 0731-88618938

46 
 
Consent statement 
I have read the above content and understand the nature and purpose of the 
study, and the possible adverse effects of the drug, and I could discuss and ask 
questions about this study with the doctor. All the questions I raised have been 
answered satisfactorily. 
I agree to visit the doctor on time during the study, and accept the 
corresponding examinations related to this study. I will abide by the instructions and 
requirements of the subjects, and fully cooperate with the researchers, truthfully 
and objectively provide the researchers with the health status and related 
information before participating in the study, during the study and during each 
follow-up period. 
I understand that participation in the study is voluntary. I confirm that I have 
sufficient time to consider this, and I understand that I can withdraw from the study 
at any time, and my subsequent treatment will not be adversely affected by this. I 
understand that the doctor has the right to be at any time based on my situation. 
Discontinue the study. 
I hereby express my consent to participate in this clinical study, and I will obtain 
a signed and dated copy of the informed consent form.  
 
Subject's name : Tel: ______________________                                                         
Subjects Signature: Date: _________ Year ______ month _____ day                                         
 
(If involved) Guardian (relationship): Tel: _____________________                                          
Check Name: Date: _________ Year ______ month _____ day                                              
 

47 
 
(If involved) Name of fair witness: Tel: _____________________                                  
Check Name: Date: _________ Year ______ month _____ day                                              
 
I have explained the relevant details of the study to the above-mentioned subjects who 
participated in the study, and provided the subjects with a signed informed consent form. 
 
Researcher's 
name
：                  
Tel：______________________ 
Researchers 
Signature
：                  
Date：__________________