Accuracy of Magnetically Maneuvered Capsule Endoscopy for Detection of Esophagogastric Varices in Patients With Cirrhosis
Phase: NA
Conditions: Liver Cirrhosis, Portal Hypertension, Esophageal Varices, Gastric Varix
Sponsor: Changhai Hospital

 
1 
Accuracy of Magnetically Maneuvered Capsule 
Endoscopy for Detection of Esophagogastric 
Varices in Patients with Cirrhosis 
(CENTERS study) 
 
 
Principal Investigator: Prof. Zhuan Liao 
 
 
 
Protocol Version: V4.0 
Date: 2021-06-15 
Sponsored by: 
Changhai Hospital, Naval Medical University 
 
 
 
 
 
 
 
 
 
 
Statement of Confidentiality 
The information contained in this document is privileged and confidential. Any 
distribution, copying, or disclosure is strictly prohibited unless required by regulations. 
Any individual who has access to the document shall be aware that the document is 
proprietary or confidential and shall not disclose the document without authorization.  
 
 

 
2 
Investigator Protocol Signature Page 
I have read and understand the protocol and agree that it contains all the ethical, legal 
and scientific information necessary to conduct this study. I will conduct the study 
according to the protocol and complete the study within the specified period of time. I 
will provide copies of the protocol to all physicians, nurses and other professional 
personnel responsible to me who will participate in the study. I will discuss these 
materials with them to ensure that they fully understand how to conduct the trial. I am 
aware that this protocol must be approved by the Ethics Committee. I agree to adhere 
strictly to the attached protocol.  
 
 
Principal Investigator: 
 
Signed: _____________________             Date:_____________________ 
Institution:__________________________________________________________ 
         __________________________________________________________ 
 
 
 
 
 

 
3 
Abbreviations 
AE 
adverse events 
BBS 
black brown spots 
CE 
capsule endoscopy 
CECR 
capsule endoscopy completion rate       
CI 
confidential interval 
CRF 
case report form 
CRS 
cherry red spots 
DSMB 
data safety monitoring board 
ds-MCE 
detachable string magnetically maneuvered capsule endoscopy 
EC 
ethics committee 
ECE         esophageal capsule endoscopy 
eCRF 
electronic case report form 
EDC 
electronic data capture  
EGD   
esophagogastroduodenoscopy 
EGV 
esophagogastric varices 
ETT   
esophageal transit time   
EV          esophageal varices 
FPI 
first patient in 
GCP 
Good Clinical Practice 
GET  
gastric examination time 
GOV        gastroesophageal varices 
GTT    
gastric transit time     
GV          gastric varices 
HRV 
high-risk varices 
IEC 
independent ethics committee 
LC 
liver cirrhosis                         
LLT 
lower level term 
MCE        magnetically maneuvered capsule endoscopy 
mITT 
modified intent-to-treat 
MLP 
mosaic like pattern 
NPV         negative predictive value 
OC 
observed cases  
PHE         portal hypertensive enteropathy 
PHG         portal hypertensive gastropathy 
PHT    
portal hypertension                 
PI 
Principal Investigator 
PPS 
per protocol set 
PPV         positive predictive value                

 
4 
PT 
preferred term 
RPL  
red point lesions  
SAE 
serious adverse events 
SAP 
statistical analysis plan 
SAS 
safety analysis set 
SBTT   
small bowel transit time    
SCE  
string capsule endoscopy 
SOC 
primary system organ class 
TRT    
total recording time 
 
 
 

 
5 
Study Synopsis 
Title of study 
Accuracy of Magnetically Maneuvered Capsule Endoscopy for 
Detection of Esophagogastric Varices in Patients with Cirrhosis 
(CENTERS study) 
Condition 
Liver cirrhosis; esophagogastric varices 
Sponsor 
Changhai Hospital, Naval Medical University 
Principal Investigator 
Prof. Zhuan Liao  
Changhai Hospital, Naval Medical University, Shanghai, 
China 
 
Study Type 
Diagnostic accuracy study 
Objectives 
Using EGD as the reference standard, to estimate the diagnostic 
performance of the ds-MCE in identifying and grading 
esophagogastric varices in liver cirrhotic patients. 
Interventions 
Consenting patients with liver cirrhosis will be recruited to 
undergo ds-MCE first, followed by EGD within 48 hours. EGD 
is the reference standard against which ds-MCE is compared. 
Primary endpoint 
To estimate the diagnostic accuracy of ds-MCE in identifying 
EGV in patients with cirrhosis, using the detection by EGD as 
the reference. 
Secondary endpoints 
! 
To estimate the diagnostic accuracy of ds-MCE in 
identifying high-risk EV, using the detection by EGD as the 
reference. 
! 
To estimate the diagnostic accuracy of ds-MCE in 
identifying high-risk EGV, using the detection by EGD as 
the reference. 
! 
To estimate the diagnostic accuracy of ds-MCE in 
identifying EV, using the detection by EGD as the reference. 
! 
To estimate the diagnostic accuracy of ds-MCE in 
identifying large EV, using the detection by EGD as the 
reference. 
! 
To estimate the diagnostic accuracy of ds-MCE in 
identifying red signs of EV, using the detection by EGD as 
the reference. 
! 
To estimate the diagnostic accuracy of ds-MCE in 
identifying GV, using the detection by EGD as the reference. 
! 
To estimate the diagnostic accuracy of ds-MCE in 
identifying cardiofundal GV, using the detection by EGD as 
the reference. 
! 
To estimate the diagnostic accuracy of ds-MCE in 
identifying PHG, using the detection by EGD as the 
reference. 
! 
To assess the incidence of PHE in small bowel under ds-
MCE. 
! 
To evaluate the examination time of ds-MCE and EGD 
procedures. 
! 
To assess the patient satisfaction score of the ds-MCE and 

 
6 
EGD procedures. 
! 
Safety evaluation. 
Key 
inclusion 
and 
exclusion criteria 
Key inclusion criteria: Adult patients with clinically evident or 
biopsy-confirmed cirrhosis, aged 18 years or older. 
Key exclusion criteria: has dysphagia, known Zenker’s 
diverticulum, known or suspected gastrointestinal stenosis, 
pregnancy, active gastrointestinal bleeding, cardiac pacemaker 
or other implanted electromedical device, life-threatening 
conditions, plan to undergo magnetic resonance imaging 
examination before excretion of the MCE, current participation 
in another clinical study, refusal to give informed consent or any 
condition that precludes compliance with study. 
Number of subjects 
591 patients will be required. 
Trial duration 
First patient in to last patient out (months): January 2021 to 
January 2023 
Duration of the entire trial (months): 36 months 
Recruitment period (months): 24 months 
Subject participation duration: approximately two days 
Participating Centers 
14 centers in China 
ClinicalTrials.gov 
identifier 
NCT03748563 
 
 

 
7 
Table of content 
1 BACKGROUND INFORMATION AND RATIONALE .......................................................................... 9 
2 STUDY OBJECTIVES AND OUTCOME MEASURES ......................................................................... 11 
2.1 Primary objective ...................................................................................................................................... 11 
2.2 Secondary objectives ................................................................................................................................. 11 
3 SUMMARY OF STUDY DESIGN .......................................................................................................... 12 
4 STUDY RISKS AND BENEFITS ............................................................................................................. 14 
4.1 Known potential benefits .......................................................................................................................... 14 
4.2 Potential risks ............................................................................................................................................. 14 
4.3 Risk/benefit ratio ........................................................................................................................................ 14 
5 STUDY POPULATION ............................................................................................................................ 15 
5.1 Inclusion criteria ....................................................................................................................................... 15 
5.2 Exclusion criteria ...................................................................................................................................... 15 
5.3 Subject Identification and Enrollment ................................................................................................... 15 
5.4 Withdrawal .................................................................................................................................................. 16 
6 STUDY METHODOLOGY ...................................................................................................................... 17 
6.1 Baseline evaluation assessment .............................................................................................................. 17 
6.2 The ds-MCE and EGD examination procedures ................................................................................. 17 
6.3 Patient satisfaction assessment .............................................................................................................. 23 
6.4 Study follow-up .......................................................................................................................................... 23 
6.5 Outcome measures ..................................................................................................................................... 24 
7 SAFETY CONSIDERATION ................................................................................................................... 27 
7.1 Adverse Events (AE) .................................................................................................................................. 27 
7.2 Serious Adverse Events (SAE) ................................................................................................................ 27 
7.3 Follow-up of Adverse Events .................................................................................................................. 28 
7.4 Monitoring of safety risks ........................................................................................................................ 28 
8 DATA HANDLING AND RECORD KEEPING ..................................................................................... 28 
8.1 Data collection ........................................................................................................................................... 28 
8.2 Data management and quality ................................................................................................................ 29 
8.3 Confidentiality and Security .................................................................................................................... 29 
8.4 Record Retention and Archiving ............................................................................................................. 30 
9 STATISTICAL CONSIDERATIONS ....................................................................................................... 30 
9.1 Hypothesis ................................................................................................................................................... 30 
9.2 Sample size .................................................................................................................................................. 31 
9.3 Statistical Analysis Set .............................................................................................................................. 31 
9.4 Statistical Analyses .................................................................................................................................... 32 

 
8 
10 ETHICAL CONSIDERATIONS ............................................................................................................. 35 
10.1 Statement of compliance ........................................................................................................................ 35 
10.2 Subjects information and consent ........................................................................................................ 35 
10.3 Benefits and risks assessment ............................................................................................................... 36 
10.4 Compensation for injury ........................................................................................................................ 36 
11 MONITORING AND QUALITY ASSURANCE .................................................................................. 36 
12 PUBLIC DISCLOSURE AND PUBLICATION POLICY ...................................................................... 37 
13 STUDY ADMINISTRATION ................................................................................................................ 38 
13.1 Study committees ..................................................................................................................................... 38 
13.2 Funding source ........................................................................................................................................ 41 
13.3 Study timetable ......................................................................................................................................... 41 
14 REFERENCES ......................................................................................................................................... 42 
 
 
 
 

 
9 
1 Background information and rationale 
Portal hypertension (PHT) is the hemodynamic abnormality in patients with cirrhosis, 
which is associated with various pathological changes throughout the entire 
gastrointestinal tract, manifesting as esophagogastric varices (EGV), portal 
hypertensive gastropathy (PHG), and portal hypertensive enteropathy (PHE)1-6. EGV 
is the major cause of morbidity and mortality due to the risk of variceal hemorrhage7. 
It has been estimated that at least two thirds of cirrhotic patients develop esophageal 
varices (EV) during their lifetime8. Gastric varices (GV) are seen in 15%–20% of 
cirrhotic patients with a high mortality rate and a greater propensity to rebleed4. 
Moreover, the presence of large EV and “red sign” on varices relate to an increased risk 
of bleeding, which needs prophylactic treatment with appropriate medical or 
endoscopic treatment9-11. International practice guidelines recommended endoscopic 
screening and periodic surveillance for EGV and provide prophylactic treatment for 
high-risk varices (HRV) to prevent variceal bleeding1,12-15.  
Esophagogastroduodenoscopy (EGD) is recognized as the gold standard for detection 
of EGV in cirrhotic patients, allowing for direct mucosal visualization and therapeutic 
intervention. EGD is however an invasive procedure and there is potential for 
procedure-related complications, such as perforation and bleeding. Besides, conscious 
sedation is always required because the unpleasant procedure can’t be well tolerated by 
cirrhotic patients, leading to increased cost, risk, and inconvenience for the 
patients16.These factors lead to a decrease of patient compliance as well as the 
effectiveness of the screening program. In this context, noninvasive approaches have 
been proposed to determine the presence of varices so as to circumvent the need for 
screening endoscopies1,17. The combination of laboratory tests and radiological 
techniques showed encouraging results for excluding high-risk varices or varices 
needing treatment in approximately 20%-40% patients with compensated cirrhosis18-22. 
However, these techniques predict the presence, rather than confirming or grading, of 
varices. Besides, as recommended by guidelines, compensated patients with ongoing 
liver injury and decompensated patients still should undergo screening endoscopy and 
repeated surveillance endoscopies23.  
The capsule endoscopy (CE) system provides a noninvasive and relatively comfortable 
approach to visualize the GI tract, and the development of esophageal capsule 

 
10 
endoscopy (ECE) makes it possible to capture clear images of esophageal disease 
without the need for sedation24,25. Several studies have confirmed its safety and 
tolerability in diagnosis of EV26-33. But the accuracy of ECE is not currently sufficient 
to replace EGD for the detection and grading for the esophageal varices, which mainly 
restricted by the inability to distend the distal esophagus, wash bubbles, active control 
of ECE or real-time visualization of key areas during esophageal examination26-28,31. 
Furthermore, ECE has poor visualization of the stomach so that gastric varices and 
other clinically significant gastric lesions can’t be detected26-28. Ramirez et al34 
developed string capsule endoscopy (SCE) in 2005, allowing controllable movement 
of the capsule in esophagus. Studies showed that SCE had an acceptable accuracy for 
the diagnosis of clinically significant esophageal varices, but the ability of SCE for 
grading EV was far from precise35,36. The limitations still remained: (i) the string 
attachment procedure is complicated and time consuming; (ii) the lack of a validated 
grading system for differentiation between small and large gastroesophageal varices; 
(iii) observation of the stomach lesions including GV and PHG was not feasible. 
To overcome these limitations, a new technique, so-called detachable string 
magnetically maneuvered capsule endoscopy (ds-MCE) (Ankon Technologies Co., Ltd, 
Wuhan, China) was developed. The ds-MCE system consists of two parts: the 
magnetically maneuvered capsule endoscopy (MCE) system a1nd a transparent latex 
sleeve with a hollow string. The detachable latex hollow string is 120cm in length, with 
a thin latex sleeve at one end that can be attached to the CE and a thick latex sleeve at 
the other end that can be attached to the syringe. The capsule, which is partially 
enclosed within the sleeve, can be actively moved in the esophagus through the control 
of string. In this case, investigator can examine the entire esophageal mucosa several 
times under real time views. After completion of the esophageal examination, the 
capsule then could be detached from the string system through injecting air into the 
hollow string with the syringe. The magnetic capsule in the stomach can be accurately 
controlled through multidimensional rotation and adaptive matching of an external C-
arm robot. Previous studies have demonstrated that the diagnostic accuracy of MCE for 
detecting gastric focal lesions is comparable with that of conventional EGD37-40. Two 
previous studies of ds-MCE confirmed it was a feasible, safe and well-tolerated method 
for completely viewing esophagus and stomach, without the need for sedation41,42. 
Besides, the 8-10h battery life of the ds-MCE enables complete examination of the 
small bowel, which enables to provide a more comprehensive evaluation of 

 
11 
gastrointestinal changes43,44. 
This study intends to conduct a prospective, multicenter, diagnostic study to assess the 
diagnostic performance of ds-MCE in detecting and grading of EGV in patients with 
liver cirrhosis, using EGD as the reference.  
2 Study objectives and outcome measures 
2.1 Primary objective 
! 
To estimate the diagnostic accuracy of ds-MCE in identifying EGV in patients with 
liver cirrhosis, using detection by EGD as the reference. 
2.2 Secondary objectives 
2.2.1 Key secondary objective 
! 
To estimate the diagnostic accuracy of ds-MCE in identifying high-risk EV, using 
the detection by EGD as the reference. 
2.2.2 Other secondary objectives 
! 
To estimate the diagnostic accuracy of ds-MCE in identifying high-risk EGV, using 
the detection by EGD as the reference. 
! 
To estimate the diagnostic accuracy of ds-MCE in identifying EV, using the 
detection by EGD as the reference. 
! 
To estimate the diagnostic accuracy of ds-MCE in identifying large EV, using the 
detection by EGD as the reference. 
! 
To estimate the diagnostic accuracy of ds-MCE in identifying red signs of EV, 
using the detection by EGD as the reference. 
! 
To estimate the diagnostic accuracy of ds-MCE in identifying GV, using the 
detection by EGD as the reference. 
! 
To estimate the diagnostic accuracy of ds-MCE in identifying cardiofundal GV, 
using the detection by EGD as the reference. 
! 
To estimate the diagnostic accuracy of ds-MCE in identifying PHG, using the 
detection by EGD as the reference. 
! 
To assess the incidence of PHE in small bowel under ds-MCE. 
! 
To evaluate the examination time of ds-MCE and EGD procedures. 

 
12 
! 
To assess the patient satisfaction score of the ds-MCE and EGD procedures. 
! 
Safety evaluation: to record the adverse events occurring during the study.  
3 Summary of study design 
This is a multicenter, prospective diagnostic accuracy study. Five hundred and ninety-
one patients with liver cirrhosis will be recruited from 14 clinical centers. We will 
prospectively register appropriate candidates. After informed consent, eligible 
individuals will be enrolled, interviewed to obtain demographic and medical 
information, and asked to undergo ds-MCE and EGD examinations. EGD is the 
standard against which ds-MCE is compared, and it will be performed within 48 hours 
after ds-MCE examination. The duration of a participant’s involvement is 
approximately two days. The primary outcome is the sensitivity and specificity of ds-
MCE in identifying the presence of EGV in patients with cirrhosis, using detection by 
EGD as the reference. The diagnostic accuracy of ds-MCE in detection of high-risk EV, 
high-risk EGV, EV, large EV, red signs of EV, GV, cardiofundal GV and PHG 
compared with the EGD will also be assessed. The incidence of PHE in small bowel 
under ds-MCE, the examination time of ds-MCE and EGD procedures, patient 
satisfaction assessment and safety evaluation will also be determined. The study will 
run for approximately 3 years in recruiting centers.  
 
 

 
13 
Figure 1. Trial flow 
 
 
 
 

 
14 
4 Study risks and benefits 
4.1 Known potential benefits 
Knowledge gained from this study may benefit society by improving EGV and PHE 
screening and surveillance for cirrhotic patients in the future. Study participants may 
benefit directly from the study because they will be provided with a free ds-MCE 
examination and a free standard EGD examination that can fully evaluate the 
abnormalities in esophagus, stomach and small intestine. 
4.2 Potential risks 
! 
CE not being ejected outside the body within 2 weeks after initiation of the 
procedure indicates the stay of CE in the gastrointestinal tract. The incidence of 
this complication is reported to be around 1% in previous studies45. This risk will 
be informed to each participant prior to study enrollment.  
! 
As the CE be actively moved in the esophagus through the control of string, this 
may induce nausea in patients, and severe nausea probably lead to the variceal 
bleeding. 
! 
When patients undergo the EGD examination, there is potential for procedure-
related complications, such as perforation and bleeding. 
! 
These risks will be small since careful procedure will be provided during ds-MCE 
and EGD examinations. 
4.3 Risk/benefit ratio 
Given the minimal risks associated with this study and the potential benefits to society 
and individuals, the benefits outweigh the risks. As for any clinical study, there is a 
possibility of unknown and unforeseen risk; that possibility is small for this study. If 
unforeseen risks are recognized during the study, then the sponsor, ethics committees, 
and participants will be provided with relevant information. 
 
 

 
15 
5 Study population 
5.1 Inclusion criteria 
Subjects meeting all of the following criteria are eligible for enrollment as study 
participants: 
! 
Gender is not limited.  
! 
Patients aged 18 years or older.   
! 
Both inpatients and outpatients. 
! 
Clinically evident or biopsy-proven liver cirrhosis. 
! 
Able to provide informed consent. 
5.2 Exclusion criteria 
Subjects meeting any of the following criteria are not eligible for enrollment as study 
participants: 
! 
Patients aged less than 18 years.  
! 
Patients with dysphagia. 
! 
Patients with Zenker’s diverticulum. 
! 
Suspected or known intestinal stenosis or other known risk factors for capsule 
retention. 
! 
Pregnancy or suspected pregnancy. 
! 
Patients with active gastrointestinal bleeding. 
! 
Patients with cardiac pacemaker or other implanted electromedical devices which 
could interfere with magnetic resonance. 
! 
Patients with life-threatening conditions. 
! 
Patients plan to undergo magnetic resonance imaging examination before excretion 
of the MCE. 
! 
Patients who are participating in or have participated in other clinical trials. 
! 
Patients who refuse to give informed consent. 
! 
Patients with any condition that precludes compliance with the study.  
5.3 Subject identification and enrollment 
Subjects will be prospectively enrolled from the inpatient wards and outpatient clinics 
at participating centers. Subjects who are candidates for enrollment into the study will 

 
16 
be evaluated for eligibility by the investigator or their nominee, e.g. a member of the 
research team or the participant’s usual care team, to ensure that the inclusion and 
exclusion criteria have been satisfied and that the subject is eligible for participation in 
this clinical study. Once a subject is determined to be eligible by the clinical study site, 
the Investigator or designee will obtain informed consent from the subject, then assign 
a unique identification number, and enroll the subject in the electronic data capture 
(EDC) system. Once an identification number has been assigned, it cannot be reused. 
No subject may have any study procedures performed prior to study consent. 
5.4 Withdrawal 
Participants may withdraw voluntarily from study participation at any time. The 
investigator can decide to withdraw a subject from the study for any of the following 
reasons, but not limited to: non-adherence to the protocol requirements; subject no 
longer meets the protocol entrance criteria; urgent medical reasons; sponsor request 
(e.g., due to significant protocol deviations). The participants will be made aware that 
this will not affect their future care. At the time of withdrawal, all study procedures 
outlined for the End of Study visit should be completed. The primary reason for a 
subject’s withdrawal from the study is to be recorded in the case report form (CRF). All 
patients who cannot be analysed per protocol but have signed informed consent are 
called drop-outs. Patients who withdraw their participation or who are withdrawn by 
the principal investigator are also drop-outs and are labelled as withdrawals. 
 
 
 
 

 
17 
6 Study methodology 
6.1 Baseline evaluation assessment 
Subjects will be enrolled and consented by the investigator or their nominee. The 
baseline visit will occur prior to ds-MCE and EGD examinations. Demographic 
characteristics (age, sex, race, body weight, heigh and body mass index), etiology of 
liver diseases, patient’s medical history (e.g. history of ascites, splenectomy, bleeding 
esophagogastric varices, TIPS insertion, endoscopic variceal therapy), indicative 
physical findings (e.g. vascular spiders, palmar erythema, and leg edema), laboratory 
testing results (e.g. complete blood count, liver function tests, coagulation test, 
prothrombin time and renal parameters), radiographic features of the upper abdomen 
(e.g. irregular liver contour, portal vein thrombosis, ascites, collateral vein, 
splenomegaly, and hepatocellular carcinoma), liver biopsy findings, previous 
endoscopic findings, Child-Pugh score, liver cirrhosis compensation status and 
comorbidities (e.g. diabetes, hypertension, coronary artery disease, arrhythmia, and 
asthma) will be documented. 
6.2 The ds-MCE and EGD examination procedures 
6.2.1 The ds-MCE system and examination procedure 
6.2.1.1 The ds-MCE system 
The ds-MCE system (Ankon Technologies Co., Ltd, Wuhan, China) mainly consists of 
two parts: the NaviCam magnetically maneuvered capsule endoscopy (MCE) system 
and a detachable latex hollow string attachment. 
The MCE system consists of a guidance magnet robot, an endoscopic capsule, a capsule 
locator, a computer workstation with ESNavi software, and a data recorder (Fig. 2). The 
capsule has a size of 27×11.8 mm, weighs 4.8 g and has a permanent magnet inside its 
dome. Images are captured and recorded at 0.5-6 frames per second (fps) with a 
resolution of 480×480 pixels. The view angle of the capsule is 150°, and the view depth 
is 0 to 60 mm. The battery life of the capsule is more than 10 hours. The guidance 
magnet robot is a C-arm type robot, with two rotational and three translational degrees 
of freedom. The magnetic field generated by the magnetic robot can reach a maximum 
of 200mT and is adjustable. The computer workstation with ESNavi software is 

 
18 
designed for real-time viewing and controlling. The capsule locator is a device for 
activating the capsule and detecting whether it is inside the human body. The data 
recorder is used for receiving image data via wireless transmission from the capsule 
endoscope. There are two joysticks on the workstation desktop (Fig. 3). The left joystick 
controls capsule orientation in 2 rotational axes (horizontal and vertical directions), and 
the right one controls capsule location in 3 translational axes (forward/backward, 
up/down, left/right). The detachable latex hollow string is 120cm in length, with a thin 
latex sleeve at one end that can be attached to the capsule endoscopy and a thick latex 
sleeve at the other end that can be attached to the syringe (Fig. 4). The capsule, which 
is partially enclosed within the sleeve, can be actively moved in the esophagus through 
the control of string. After completion of the esophageal examination, the string can be 
separated from the capsule by injecting around 5mL of air using the syringe and 
removed from the mouth; the capsule then enters the stomach. 
Figure 2. The NaviCam magnetically maneuvered capsule endoscopy (MCE) system. 
It consists of (A) a guidance magnet robot and computer workstation; (B) a magnetic 
capsule endoscope; (C) a capsule locator; (D) ESNavi software; (E) a data recorder. 
 
 

 
19 
Figure 3. Two joysticks of the workstation. The left controls the capsule orientation in 
2 rotational axes (horizontal and vertical directions), and the right controls the capsule 
location in 3 translational axes (forward/backward, up/down, left/right). 
Figure 4. The procedure of ds-MCE. (A) the string system; (B) enclosing the capsule 
with the sleeve; (C) injecting air into the hollow string with the syringe; (D) the 
detachment of the capsule and the string system. 
6.2.1.2 The ds-MCE examination procedure 
The ds-MCE examination will be performed prior to EGD in all enrolled patients and 
be performed by a by a dedicated certified operator at each center with experience 
of >200 MCE operation cases and all operators had completed standardized training for 
ds-MCE examination before the enrollment.  
(1) Gastric and Small Bowel Preparation Regimen 
All enrolled patients will be instructed to maintain a clear liquid diet for the entire day 

 
20 
prior to the ds-MCE examination followed by a 12-h overnight fast. To improve the 
small bowel visualization, a purgative preparation (2L polyethylene glycol solution) or 
no purgative preparation will be used the night before the examination according to the 
patient’s condition. Forty minutes before the examination, patients are asked to ingest 
2.5g of dimethicone (Honghe Medicine, Zigong, China) as a defoaming agent and 
encouraged to walk freely to maximize contact with the gastric mucosa. Ten minutes 
before the examination, 100ml of water is ingested to initially flush the stomach cavity. 
Patients will then be encouraged to drink 500ml-1000ml water as tolerated just before 
swallowing the capsule to fill the stomach cavity for capsule navigation. Water 
ingestion will be repeated to optimize gastric distension during the examination. All the 
patients will be informed that clear fluids could be consumed 2 hours after capsule 
ingestion and solid food 4 hours after the capsule entering into the small bowel. 
(2) Esophagus examination of ds-MCE 
During esophageal examination, the capsule will be actively controlled by the latex 
hollow string. Before ingestion of the capsule, the CE is partially enclosed in the sleeve 
that could be detached from the string system through injecting air into the hollow string 
with the syringe (Fig. 4). Patient then swallows the capsule with water in a left lateral 
position, without sedation, and the capture rate of the capsule is set as 6 frames per 
second. Firstly, the CE will be allowed to travel down approximating the cardia, from 
where the string is slowly pulled up to inspect the esophagus under the guidance of real-
time viewing. The process will be repeated for at least three passages up and down, 
during which participants will be instructed to drink water to distend the distal 
esophagus and wash bubbles for better observation. Target areas of interest could be 
observed repeatedly as the capsule travels down with swallowed water and be pulled 
up by attached string. After completing the esophageal examination, the string will be 
separated from the capsule through injecting 5 ml of air with the syringe, took out of 
the mouth and discarded, and the capsule will enter the stomach with additional water 
ingestion. 
(3) Stomach examination of ds-MCE 
During the gastric examination, the capsule will be actively controlled by external 
magnetic field. When the capsule entering the stomach, the capsule will be lifted away 
from the posterior wall, rotated, and advanced to the fundus and cardiac regions, and 
then to the gastric body, angulus, antrum, and pylorus. Of note, target areas of interest 

 
21 
could be observed repeatedly. If distension is insufficient, water ingestion will be 
repeated. Stomach examination procedures will be performed twice in each participant 
according to standardized protocol46,47, and the mucosa of the gastric cardia, fundus, 
body, angulus and antrum will be fully recorded. Once the operator is satisfied that an 
adequate examination of stomach has been completed the capsule will be allowed to 
pass into the small bowel. 
(4) Small bowel examination of ds-MCE  
During the small bowel examination, the capsule moves passively under 
gastrointestinal peristalsis. After completion of the gastric examination, the operator 
then clicks the “small intestine mode” button under the “real-time view” interface. The 
capsule will be switched to “small intestine examination mode” with an adaptive 
capture rate of 0.5–6 fps. The capsule then moves passively under gastrointestinal 
peristalsis to further examine the small bowel. The patient will then be allowed to leave 
the hospital with the data recorder for further collection of images of the small intestine. 
Patients are allowed to drink clear water 2 hours after completing the gastric 
examination and a light meal 4 hours after completing the gastric examination. When 
the battery of capsule is exhausted or the capsule is discharged, the recording device 
and sensor array can be removed.  
“Procedural success of ds-MCE” is defined as complete evaluation of the esophagus 
and stomach, irrespective of the completeness of small bowel evaluation. For patients 
who fail to complete esophageal and gastric evaluation under ds-MCE, the reason will 
be documented in the case report form in time. 
(5) Collection of ds-MCE examination images 
The patients will be instructed to return the data recorder after the capsule battery 
expired or the capsule is discharged. Then all images captured by the CE will be 
downloaded to the computer workstation by operator.  
(6) Evaluation of ds-MCE examination 
The coded videos of ds-MCE examinations will be assessed by an independent imaging 
core-lab blinded to the patient identification information. Two different independent 
gastroenterologists, who are experienced in MCE reporting and are blinded to the 
results of EGD examinations, will analyse the recorded ds-MCE images and videos. A 
consensus reading will be performed by a senior gastroenterologist experienced in ds-

 
22 
MCE in case of discrepancies. They will be instructed to identify and grade the 
esophageal varices (EV) and gastric varices (GV) according to the ds-MCE grading 
system described in the “Study Outcomes Measurements” section, record the presence 
of portal hypertensive gastropathy (PHG) and portal hypertensive enteropathy (PHE). 
Besides, esophageal examination time (EET), gastric examination time (GET), gastric 
transit time (GTT), small bowel transit time (SBTT) and total recording time (TRT) of 
the ds-MCE will be recorded. Other focal lesions observed in the esophagus, stomach 
and small bowel will also be recorded. All the results will be documented on the 
designated CRF.  
6.2.2 The EGD examination procedure 
The EGD examinations will be performed by experienced endoscopists using peroral 
conventional standard forward-viewing upper gastrointestinal video endoscopes at each 
center, within 48 hours of ds-MCE procedure. The endoscopist will not be blinded to 
the patient’s prior medical history but will be blinded to the preceding ds-MCE results. 
All procedures are conducted either without sedation or with sedation, according to the 
standard procedure of the center and the preference of the patient. During the course of 
the endoscopy, a complete evaluation of the esophagus, stomach and duodenum will be 
carried out. Grading of esophageal varices (when present) will be performed by all 
endoscopists using a predefined protocol: after examination of the stomach, the gastric 
cavity is fully deflated; the EGD is then withdrawn into the esophagus, and the 
esophageal lumen will be fully inflated. At that point, esophageal varices and red color 
signs will then be evaluated. The esophageal varices will be graded as small (<5 mm) 
or large (≥5 mm) and, if in doubt, it will be measured against the open endoscopic 
biopsy forceps (5 mm). The video of entire EGD examination procedure and the 
captured pictures will be digitally recorded for each participant.  
“Procedural success of EGD” is defined as complete evaluation of the stomach and 
esophagus, irrespective of the completeness of duodenal evaluation. For patients who 
fail to complete esophageal and gastric evaluation under EGD, the reason will be 
documented in the case report form in time.  
The coded videos and captured pictures of EGD examinations will assessed by an 
independent imaging core-lab blinded to the patient identification information. Another 
two different independent gastroenterologists, who are experienced in EGD and are 

 
23 
blinded to the results of ds-MCE examinations, will analyse the recorded EGD images 
and videos. A consensus reading will be performed by a senior gastroenterologist 
experienced in ds-MCE in case of discrepancies. They will be instructed to identify and 
grade the esophageal varices (EV) and gastric varices (GV) according to the EGD 
grading system described in the “Study Outcomes Measurements” section, record the 
presence of portal hypertensive gastropathy (PHG). Besides, examination time of the 
whole EGD procedure will be recorded through the video and images. Other focal 
lesions observed in the esophagus, stomach and small bowel will also be recorded. All 
the results will be documented on the designated CRF. 
6.3 Patient satisfaction assessment 
After completing the ds-MCE procedure or EGD procedure, patients will undergo a 
face-to-face interview at which they are asked to respond to the questions on the three-
item questionnaire that addressed procedure satisfaction.  
(1) Did you experience discomfort during the ds-MCE/EGD procedure? 
4 = none; 3 = minor; 2 = mild; 1 = severe; 0 = intolerable 
(2) Did you experience discomfort after the ds-MCE/EGD procedure? 
4 = none; 3 = minor; 2 = mild; 1 = severe; 0 = intolerable 
(3) How would you rate the entire ds-MCE/EGD examination procedure? 
4 = very comfortable; 3 = comfortable; 2 = tolerable; 1 = uncomfortable; 0 = very 
uncomfortable 
6.4 Study follow-up 
Two weeks following the ds-MCE procedure, patients will be contacted to confirm 
excretion of the capsule and to verify that there are no changes in their wellbeing 
following participation in this study. If the patient has not observed capsule excretion 
within 2 weeks, an X-ray procedure will be performed to confirm the capsule exit if 
deemed necessary by the investigator. This study is designed to comply with the 
requirements of good clinical practices and the other regulatory requirements that 
govern clinical research in China. During the study, adverse event and serious adverse 
event surveillance and reporting will be conducted accordingly. 

 
24 
6.5 Outcome measures 
6.5.1 Primary outcome 
The primary outcome is the sensitivity and specificity of ds-MCE to identify EGV in 
patients with cirrhosis, using the detection by EGD as the reference.  
6.5.2 Secondary outcomes 
6.5.2.1 Key secondary outcome 
i. 
The sensitivity, specificity of ds-MCE in detection of high-risk EV, using the 
detection by EGD as the reference. 
The high-risk EV is identified by either large EV or small EV with presence of red 
signs according to the Baveno VI consensus1. 
6.5.2.2 Other secondary outcomes 
ii. 
The sensitivity, specificity, positive predictive value (PPV), negative predictive 
value (NPV) and overall diagnostic accuracy of ds-MCE in detection of high-risk 
EGV, using the detection by EGD as the reference.  
High-risk EGV are defined as high-risk EV or any GV19,48. 
iii. 
The sensitivity, specificity, PPV, NPV and overall diagnostic accuracy of ds-MCE 
in detection of EV, using the detection by EGD as the reference. 
iv. 
To investigate the optimal threshold of the proportion of ds-MCE esophageal 
luminal circumference occupied by the largest esophageal varix present in 
differentiating large EV from small or no EV, using the detection by EGD as the 
reference. 
a) EV identified during EGD are classified based on the standard Baveno III 
consensus to differentiate between large EV (varix diameter ≥5mm) and small 
EV (varix diameter <5mm)49.  
b) As grading EV by endoscopy requires fully distention of the esophagus with 
air insufflation, which is lacking in CE, there has been no consensus on the 
standard classification of large EV under ds-MCE. In this study, we grade the 
EV under ds-MCE according to the proportion of the esophageal luminal 
circumference occupied by the largest esophageal varix present26.  
c) The Youden Index, defined as [(sensitivity＋specificity)-1], will be calculated 

 
25 
to determine the optimal ds-MCE luminal circumference percentage threshold 
derived from the training cohort that resulted in the best combination of 
specificity and sensitivity for distinguishing large EV, using the results of EGD 
as the reference standard.  
v. 
The sensitivity, specificity, PPV, NPV and overall diagnostic accuracy of ds-MCE 
in detection of large EV, using the detection by EGD as the reference. 
a) EV under EGD are classified into three grades: no, small or large, with the 
latter signifying a diameter ≥5 mm.  
b) EV under ds-MCE are classified into three grades: no, small or large, with the 
latter signifying that the esophageal varix occupied more than the prespecified 
“optimal threshold” proportion of the capsule picture frame circumference. 
vi. 
The sensitivity, specificity, PPV, NPV and overall diagnostic accuracy of ds-MCE 
in detection of the red sign of EV, using the detection by EGD as the reference. 
vii. 
The sensitivity, specificity, PPV, NPV and overall diagnostic accuracy of ds-MCE 
in detection of gastric varices (GV), using the detection by EGD as the reference.  
GV are classified according to Sarin’s classification4. Gastric varices could be 
classified on the basis of its location in the stomach and its relationship with 
esophageal varices during ds-MCE procedure and EGD procedure. These are 
divided into two groups: gastroesophageal varices (GOV) and isolated gastric 
varices (IGV)4,46. GOV1 are the extension of esophageal varices which across the 
cardia onto the lesser curve, and GOV2 extend onto the fundus. Isolated gastric 
varices (IGV) are vascular protrusions without direct connection to the esophageal 
varices. IGV1 are located in the fundus, while IGV2 are located elsewhere in the 
stomach, typically in the distal body and antrum. 
viii. 
The sensitivity, specificity, PPV, NPV and overall diagnostic accuracy of ds-MCE 
in detection of cardiofundal GV, using the detection by EGD as the reference.  
Cardiofundal gastric varices including GOV2 and IGV1 are at high risk of bleeding 
due to the unique vascular anatomy as opposed to lesser-curvature gastric varices 
(GOV1)50. 
ix. 
The sensitivity, specificity, PPV, NPV and overall diagnostic accuracy of ds-MCE 
in detection of portal hypertensive gastropathy (PHG), using the detection by EGD 
as the reference.  
The PHG is classified as four elementary gastric endoscopic signs proposed by the 
NIEC group:1) mosaic like pattern (MLP); 2) red point lesions (RPL); 3) cherry 

 
26 
red spots (CRS); 4) black brown spots (BBS)3,51.  
x. 
The incidence of PHE in small bowel under ds-MCE. 
Endoscopic findings of PHE include mucosal inflammatory-like abnormalities, 
vascular lesions. In addition, mucosal inflammatory-like abnormalities and 
vascular lesions can lead to spontaneous bleeding52-54.  
xi. 
Examination time of ds-MCE and EGD procedures. 
Examination time of ds-MCE include esophageal transit time (ETT), gastric 
examination time (GET), gastric transit time (GTT), small bowel transit time 
(SBTT), and total running time (TRT). ETT is defined as the time between the first 
esophageal image and the first gastric image. GET is defined as the time for 
examination of gastric primary anatomic landmarks twice. GTT is defined as the 
time between the first gastric image and the first duodenal image. SBTT is defined 
as the time between the first duodenal image and the first cecal image. TRT is 
defined as the time of the last picture taken by the capsule. Capsule endoscopy 
completion rate (CECR) is also recorded which defined as the proportion of the 
capsule that has a complete visualization of the entire small bowel44. Examination 
time of EGD is defined as the duration from the endoscope entering to exiting from 
the esophagus. 
xii. 
Patient satisfaction score of ds-MCE and EGD procedures.  
The patient satisfaction score assessment is based on the questionnaire of Section 
6.3.  
xiii. 
Safety outcomes are based on adverse-event reporting. 
All adverse events occurring during the study will be recorded. 
 
 

 
27 
7 Safety consideration 
7.1 Adverse Events (AE) 
Adverse events are defined as any undesirable experience occurring to a subject during 
the study, whether or not considered related to trial procedure. As far as possible, each 
AE should be evaluated to determine the severity grade (mild, moderate, severe); its 
relationship to the study procedure; its duration (start and end dates or if continuing at 
final exam); action taken (no action taken; hospitalization); whether it constitutes a 
serious adverse event (SAE). All adverse events reported spontaneously by the subject 
or observed by the investigator or his staff will be recorded and documented on the 
designated CRF.  
7.2 Serious Adverse Events (SAE) 
A Serious Adverse Event is any unfavorable event within the study timeframe fulfilling 
at least one of the following criteria: 
! 
results in death; 
! 
life-threatening (at the time of the event);  
! 
inpatient hospitalization required or prolonged; 
! 
event that results in persistent or significant disability/incapacity; 
! 
medically important event or event that requires a medical or surgical intervention 
to prevent one of the above health implications.  
Any other important medical event that did not result in any of the outcomes listed 
above due to interventions but could have been based upon appropriate medical 
judgment. An elective hospital admission will not be considered as a serious adverse 
event.  
As far as possible, each SAE should be evaluated to determine the severity grade (mild, 
moderate, severe); its relationship to the study procedure; its duration (start and end 
dates or if continuing at final exam); action taken (no action taken; hospitalization).  
Serious adverse events will be immediately, after coming to notice of the investigator, 
reported to the trial coordinator, who is 24/7 available. The investigator will report the 
following SAEs occurring in the study period to the sponsor without undue delay of 
obtaining knowledge of the events: death from any cause; esophagogastric variceal 
hemorrhage during ds-MCE examination; acute esophagogastric variceal hemorrhage 

 
28 
during EGD examination; acute esophagogastric variceal hemorrhage during ds-MCE 
examination. The investigator should report to the sponsor and ethics committee within 
24 hours of SAEs. SAEs need to be documented additionally on a separate SAE form.  
7.3 Follow-up of Adverse Events 
All AEs will be followed until they have abated, or until a stable situation has been 
reached. Depending on the event, follow up may require additional tests or medical 
procedures as indicated, and/or referral to the general physician or a medical specialist. 
Assessment should be made at each visit (or more frequently, if necessary) of any 
changes in severity, the suspected relationship to the study, the interventions required 
to treat it and the outcome. For a follow-up report, the investigator may be required to 
collect further information for a detailed description and a final evaluation of the case, 
including copies of hospital reports and other relevant documents. 
SAEs need to be reported till the end of the study in China, as defined in the protocol. 
7.4 Monitoring of safety risks 
For the monitoring of safety risks and potential harms for the study participants caused 
by study procedure or study design, the sponsor and a Data Safety Monitoring Board 
(DSMB) will carefully review all (S)AEs. In case of any safety issue that might change 
the risk benefit balance unfavorable, the sponsor will take appropriate measures to 
guarantee the safety of the patients. 
8 Data handling and record keeping 
8.1 Data collection 
Source documents provide evidence of participant involvement, consent and permit 
collection of the data acquired. Data from source documents will be entered onto study 
CRFs. When the CRFs are complete, they will be reviewed and signed by the 
investigator and returned to the sponsor or designees. All data from the original CRF 
will be entered into a web-based electronic data capture (EDC) system by local research 
personnel. It allows the documentation of study data in electronic case report forms 
(eCRF). Subject records are coded by a unique study number. The local investigators 

 
29 
will keep a list showing codes and names. The EDC system includes password 
protection and internal quality checks to identify data that appear inconsistent, 
incomplete, or inaccurate. The technical support will be provided for the study centers 
during the study duration (administration of logins, roles and rights). The eCRF will be 
adapted due to changes in the study design, if necessary. 
8.2 Data management and quality  
The investigator is required to ensure that all CRFs are completed for every participant 
entered in the trial. When the data be entered in the EDC system, a comparison program 
will be run. Any out-of-range values and missing or inconsistent key variables will be 
reviewed, and any resulting queries will be resolved with the investigator and amended 
in the EDC system. All elements of data entry will be recorded in an electronic audit 
trail to allow all data changes in the database to be monitored and maintained in 
accordance with local regulations. At the end of the study, the entire database will be 
exported. The final data management process contains plausibility, consistency and 
range checks of the data. The missing data will be identified as well. If there are any 
queries, data clarification forms will be generated and will be sent to the respective 
study centers for clarification. The related data correction will be performed either 
direct in the eCRF by the study centers or with programmed scripts by the data 
management team. After all data management processes are completed, the cleaned 
data will be available for the statistical analysis. The final data can be delivered in a 
defined data format like SAS data file, including a data management report as well. 
8.3 Confidentiality and Security 
Subject confidentiality is strictly held in trust by the participating investigators, their 
staff, and the sponsor and their agents. This confidentiality includes documentation, 
investigation data, subjects’ clinical information, and all other information generated 
during participation in the study. No information concerning the study or the data 
generated from the study will be released to any unauthorized third party without prior 
written approval of the sponsor and the subject. The study monitor or other authorized 

 
30 
representatives of the sponsor or governmental regulatory agencies may inspect all 
documents and records required to be maintained by the investigators, including but not 
limited to medical records (office, clinic, or hospital) of the subjects in this study. The 
clinical study site will permit access to such records. 
Medical and research records should be maintained at each site in the strictest 
confidence. All study forms will be stored in locked secure locations and will not be 
available to personnel not associated with the study. Computerized data are accessible 
only by password. Electronic CRFs (eCRFs) will be identified by unique identification 
number only, to insure subject anonymity. No subject identifiers will be used in the 
presentation of data. The document linking the unique identification number to patients’ 
name and medical record numbers will be kept in a locked document, will not be 
accessible to personnel not associated with the study.   
8.4 Record Retention and Archiving 
In compliance with the Good Clinical Practice (GCP) guidelines and regulations, the 
site investigators will maintain all records and documents regarding the conduct of the 
study. These will be retained for at least 3 years, or for longer if required. If the 
responsible investigator is no longer able to maintain the study records, a second person 
will be nominated to take over this responsibility. Each site participating in this study 
will permit authorized representatives of the sponsor and regulatory agencies to 
examine (and when required by applicable law) clinical records for the purposes of 
clinical site monitoring, quality assurance reviews, audits, and evaluation of study 
safety and progress.  
9 Statistical considerations 
9.1 Hypothesis 
The primary objective of this study is to evaluate the diagnostic performance of ds-
MCE in detecting EGV by assessing its sensitivity and specificity, using EGD as the 
reference standard. The hypothesis is that both the sensitivity and specificity of ds-MCE 

 
31 
for detecting EGV will exceed 85% when compared to EGD. The target value of 85% 
is set based on literature review55 and expert consensus from the steering committee. 
H01: Sensitivity ≤85% 
H11: Sensitivity＞85% 
H02: Specificity ≤85% 
H12: Specificity＞85% 
 
9.2 Sample size 
As a single-arm confirmatory diagnostic accuracy study, we primarily aimed to test 
whether both the sensitivity and the specificity of ds-MCE for detecting EGV would 
be >85%. With estimated sensitivity of 90%, specificity of 94%, a two-sided alpha of 
5%, power of 80%, EGV prevalence of 62%, and a dropout rate of 3%, 591 patients 
would be needed. 
When considering the accuracy of ds-MCE for detecting high-risk EV (key secondary 
outcome), the validation cohort of approximately 200 patients would provide an 
estimation precision (CI width/2) of <7%, with estimated sensitivity of 90% and 
specificity of 94%, using CENTERS luminal circumference percentage threshold 
derived from the training cohort, and high-risk EV prevalence of 40%. 
9.3 Statistical Analysis Set 
The analyses will be performed on modified intent-to-treat (mITT), per protocol set 
(PPS) and safety analysis set (SAS). Each analysis set will summarize the number of 
subjects and its percentage from subjects. 
Efficacy set: The analysis of mITT is primary, and PPS is a sensitivity analysis of 
mITT. 
The effectiveness analyses will be based on mITT population who go through 
procedures of ds-MCE and EGD modalities and can be evaluated for the results of EV 
and GV.  
The effectiveness analyses will also be conducted on the PPS, which includes all 

 
32 
subjects in the mITT population who have no major protocol deviations (defined to be 
protocol violations that may have a significant impact on subject outcomes) and who 
do not meet any of the following criteria:  
! 
Subject withdraws  
! 
Capsule ingestion failure 
! 
Esophageal or gastric examination failure under ds-MCE  
! 
Esophageal or gastric examination failure under EGD 
! 
System technical failure of ds-MCE or EGD 
 
Safety Sets: The evaluation of safety parameters will be conducted on the SAS 
Safety Analysis Set (SAS): actual data that has been inspected at least once and has 
safety indicators recorded. Security missing values do not need to be carried forward. 
9.4 Statistical Analyses  
9.4.1 The general principle 
Descriptive statistics for continuous variables will include arithmetic mean (standard 
deviation) or median (interquartile ranges) as appropriate. Frequency and percentage 
will be calculated for categorical variables. Unless otherwise specified, for continuous 
variables, comparisons between groups will be assessed using the paired t test or 
Wilcoxon signed-rank test as appropriate. Categorical variables will be compared using 
the McNemar test as appropriate. 
All statistical analyses will be performed using SAS version 9.4 (SAS Institute Inc, 
Cary, NC) and R version 4.2.2 (R Foundation for Statistical Computing). Unless 
otherwise specified, all significance testing will be 2-tailed using α = 0.05. Tests will 
be declared statistically significant if the calculated p-value is ＜0.05. 
9.4.2 Interim Analyses 
No interim analysis is planned for this study.  
9.4.3 Missing data 
The primary analysis will be conducted on both mITT and PPS. For mITT analysis, the 

 
33 
observed cases (OC) for each visit will be used and the worst outcome carried forward 
(WOCF) method will be applied for the primary endpoint to impute missing data, unless 
otherwise specified. 
No imputation for missing data will be performed for the secondary and safety 
outcomes analysis. 
9.4.4 Multiple Comparisons 
Since the primary outcome hypothesis testing based on the two primary endpoints 
should be met simultaneously, no multiplicity adjustment will be performed. 
For the analysis of the secondary and safety outcomes, no adjustment for multiple 
comparisons will be made. 
9.4.5 Demographics and Baseline Characteristics 
All data recorded at baseline will be summarized using the methodology described in 
section 9.4.1. Summaries will be presented for the analysis set. 
Summary tables (descriptive statistics and/or frequency tables) will be provided for all 
variables at different endpoints. For continuous variables, means and standard 
deviations will be presented, unless the variable has a skewed distribution, in which 
case medians, 25th and 75th percentiles will be presented. For categorical variables, the 
number and percentage of participants within each category will be presented. For each 
variable (continuous or categorical), the number of missing values will be reported. 
9.4.6 Analysis for Primary Outcome 
The primary outcome is the diagnostic accuracy of ds-MCE for discrimination of 
patients with EGV using sensitivity and specificity, along with the corresponding 95% 
CIs estimated using the Wilson’s method. Sensitivity and specificity will be compared 
with 85% using one-sample exact test.  
The accuracy, and positive and negative predictive values (PPV and NPV) will be 
calculated as other measures simultaneously, along with the corresponding 95% CIs 
estimated using the Wilson’s method56. 

 
34 
9.4.7 Analyses for Secondary Outcomes 
The training cohort and validation cohort will be divided based on centers, in the order 
of the first patient in (FPI). Centers with earlier FPI date will be allocated to the training 
cohort (whose sample size should meet approximately 2/3 of the total sample size), and 
the remaining centers with later FPI date will be allocated to the validation cohort. 
The Youden Index57, defined as [(sensitivity＋specificity) - 1], will be calculated to 
determine the ds-MCE optimal luminal circumference percentage threshold derived 
from the training cohort that resulted in the best combination of specificity and 
sensitivity for distinguishing large EV, using the results of EGD as the reference 
standard. When the optimal threshold has decimals, its integer portion will be set as the 
modified optimal threshold for internal and external validation (for the ease of clinical 
application and ensuring sensitivity). Based on the training cohort, the modified optimal 
threshold is internally validated with bootstrap method, with 1000 replicates. The 
diagnostic accuracy of identifying large EV, high-risk EV and high-risk EGV will be 
assessed on the basis of the modified optimal threshold above in the validation cohort 
using sensitivity, specificity, PPV, NPV and accuracy, corresponding 95% CIs 
calculated using the Wilson’s method. 
The diagnostic accuracy of ds-MCE in detection of EV, red signs of EV, GV, PHG 
compared with the EGD will be assessed using sensitivity, specificity, PPV, NPV and 
accuracy, corresponding 95% CIs calculated using the Wilson’s method.  
Description and comparisons of other secondary outcomes of ds-MCE and EGD groups 
will be performed using the methodology described in section 9.4.1.  
9.4.8 Subgroup analysis  
To determine whether the accuracy is consistent across subgroups, the estimate of the 
between-group accuracy for EGV, high-risk EV based on the modified optimal 
threshold value, high-risk EGV based on the modified optimal threshold value will be 
estimated within each category of the following classification variables: 
! 
Cirrhosis stage (compensated phase, decompensated phase); 

 
35 
! 
Indication for endoscopy (screening, surveillance). 
9.4.9 Safety Analyses 
All adverse events and serious adverse events will be listed.  
10 Ethical considerations 
10.1 Statement of compliance 
The study will be conducted according to the principles of the Declaration of Helsinki. 
The study will be approved by the ethics committees of the participating hospitals. This 
study will be conducted in compliance with the protocol approved by the independent 
ethics committee (IEC) and according to GCP standards. No deviation from the 
protocol will be implemented without prior review and approval of the IEC except 
where it may be necessary to eliminate an immediate hazard to a research subject. In 
such case, the deviation will be reported to the IEC as soon as possible. All investigators 
undertaking this work have undertaking the necessary GCP training.  
10.2 Subjects information and consent 
All patients that are included have to give written informed consent. They will be 
provided a consent form describing the study and providing sufficient information for 
them to make an informed decision about the participation in this study. This consent 
form will be submitted with the protocol for review and approval by the IEC. The 
investigators should adequately explain the details of the clinical trial, including known, 
foreseeable risks and possible adverse event, etc., to the subject or to the guardians of 
subjects without capacity for civil conduct or with limited capacity for civil conduct. 
The rights and welfare of potential subjects will be protected by emphasizing that 
neither their access to medical care nor the quality of their care will be adversely 
affected if they decline to participate in this study. After full and detailed explanation, 
the subjects or their guardians sign the name and date in the informed consent form, 
and the investigators also need to sign the name and date in the informed consent form.  

 
36 
10.3 Benefits and risks assessment 
Knowledge gained from this study may benefit society by improving EGV and PHE 
screening and surveillance for cirrhotic patients in the future. Study participants may 
benefit directly from the study because they will be provided with a free ds-MCE 
procedure and a free standard EGD examination that can fully evaluate the upper 
gastrointestinal mucosa and small intestine mucosa. The main risk of ds-MCE is 
retention of the capsule behind a stricture, occurring in around 1% of patients with 
suspected small bowel disease45,47. When patients undergo the EGD examination, there 
is potential for procedure-related complications, such as bleeding. These risks will be 
small since careful procedure will be provided in the study.  
Given the minimal risks associated with this study and the potential benefits to society 
and individuals, the benefits outweigh the risks. As for any clinical study, there is a 
possibility of unknown and unforeseen risk; that possibility is small for this study. If 
unforeseen risks are recognized during the study, then the sponsor, ethics committees, 
and participants will be provided with relevant information. 
10.4 Compensation for injury 
Each participating center has purchased liability insurance. This insurance provides 
cover for damage to research subjects through injury or death caused by the study. The 
insurance applies to the damage that becomes apparent during the study or within 1 
year after the end of the study. 
11 Monitoring and quality assurance  
The principal investigator will ensure that all study personnel are appropriately trained, 
and applicable documentations are maintained on sites. The study investigators are 
responsible for conducting routine quality assurance and quality control activities to 
internal monitoring to ensure that, for this study: 
! 
human subjects’ rights and well-being are protected. 
! 
data are accurate, complete, and verifiable from source documents. 
! 
the study complies with the protocol/amendment(s), sponsor requirements, Good 
Clinical Practice (GCP) guidelines, and applicable regulatory requirements. 
In addition, monitoring visits by a sponsor-designated professional or monitor will 

 
37 
occur at scheduled intervals prior to, during, and at study completion. The extent, nature 
and frequency of on-site visits will be based on enrolment rate, the quality of the 
documents provided by the site, consistency of follow-up of the patients according to 
this protocol. Monitoring visits may include, but are not limited to, review of regulatory 
files, CRFs, informed consent forms, protocol compliance and the integrity and 
consistency of EDC data entry. Study monitors will check and assess the progress of 
the trial, review trial data collected, conduct source document verification and identify 
any issues and address their resolution. This will be done in order to verify that the data 
are authentic, accurate, and complete, that safety and rights of subjects are being 
protected and that the trial is conducted in accordance with the currently approved 
protocol (and any amendments), GCP, and all applicable regulatory requirements. 
Study monitors will meet with investigators to discuss any problems and actions to be 
taken and document visit findings and discussions. The investigational site will provide 
direct access to all trial-related sites, source data/documents, and reports for the purpose 
of internal monitoring and in the event of auditing by the sponsor and inspection by 
regulatory authorities. The review of medical records will be performed in a manner to 
ensure that patient confidentiality is maintained. Direct access to these documents must 
be guaranteed by the investigators, who must provide support at all times for these 
activities. 
12 Public disclosure and publication policy 
The results of this study will be presented at scientific meetings and/or published in a 
peer-reviewed scientific or medical journal. Participants will not be identified in any 
publications. The presentation or publication of any or all data collected by participating 
investigators on patients is under the direct control of the study’s steering committee. 
No individual participating investigator has the right to use this study’s data to perform 
analyses or interpretations, or to make public presentations or seek publication of any 
or all of the data without the specific approval of the study’s steering committee. Any 
presentation or publication related to this study should be circulated to participating 
investigators for review, comments and suggestions at least one weeks prior to 
submission of the manuscript to the presenting or publishing body. All publications 

 
38 
must give proper recognition to the funding source and should list all study participants 
(not necessarily as authors of the manuscript). The manuscript will be shared with the 
sponsor(s) one month before submission, but the sponsor(s) will have no influence on 
its contents.  
Anonymous data can be requested from the study steering committee with a detailed 
description containing the aims and methods of the study for which the data are 
intended to be used. Data will be made available for this purpose at least 18 months 
after publication of the main report. Under the approval of the study steering committee, 
data may also be shared with non-commercial parties for scientific purposes, and with 
commercial parties for regulatory purposes. 
These purposes should be specified in the informed consent form.  
13 Study administration 
13.1 Study committees 
Steering Committee: 
1. Chairman: Prof. Zhuan Liao, Department of Gastroenterology, Changhai Hospital, 
Naval Medical University, Shanghai, China; 
2. Prof. Zhao-Shen Li, Department of Gastroenterology, Changhai Hospital, Naval 
Medical University, Shanghai, China; 
3. Prof. Chang-Qing Yang, Department of Gastroenterology and Hepatology, Tongji 
Hospital, Tongji University School of Medicine, Shanghai, China; 
4. Prof. Xiu-Li Zuo, Department of Gastroenterology, Qilu Hospital, Cheeloo College 
of Medicine, Shandong University, Jinan, China; 
5. Prof. Shui-Xiang He, Department of Gastroenterology, the First Affiliated Hospital 
of Xi'an Jiaotong University. Xi’an, China. 
Coordinating Center: 
1. Dr. Xi Jiang, Department of Gastroenterology, Changhai Hospital, Naval Medical 
University, Shanghai, China; 
2. Dr. Jun Pan, Department of Gastroenterology, Changhai Hospital, Naval Medical 

 
39 
University, Shanghai, China. 
Statistical Center: 
1. Prof. Yan Hou, Department of Biostatistics, Peking University, Beijing, China. 
Safety events committee: 
1. Prof. Zhen Li, Department of Gastroenterology, Qilu Hospital, Cheeloo College of 
Medicine, Shandong University, Jinan, China; 
2. Dr. Xiao-Ou Qiu, Department of Gastroenterology, Changhai Hospital, Naval 
Medical University, Shanghai, China; 
3. Dr. Shan Wu, Department of Endoscopy, Shanghai Jiao Tong University affiliated 
Sixth People's Hospital, Shanghai, China. 
Core laboratory for EGD and ds-MCE imaging/video assessment 
1. Esophagogastroduodenoscopy (EGD):  
1) Prof. Wen-Bin Zou, Department of Gastroenterology, Changhai Hospital, Naval 
Medical University, Shanghai, China;  
2) Prof. Tian Xia, Department of Gastroenterology, Changhai Hospital, Naval 
Medical University, Shanghai, China;  
3) Prof. Xiao Liu, Department of Gastroenterology, Changhai Hospital, Naval 
Medical University, Shanghai, China; 
2. Detachable string magnetically maneuvered capsule endoscopy (ds-MCE):  
1) Prof. Yang-Yang Qian, Department of Gastroenterology, Changhai Hospital, Naval 
Medical University, Shanghai, China;  
2) Dr. Chen He, Department of Gastroenterology, Changhai Hospital, Naval Medical 
University, Shanghai, China; 
3) Dr. Ting Zhang, Department of Gastroenterology, Changhai Hospital, Naval 
Medical University, Shanghai, China. 
Enrolling Study Centers and Investigators: 
1. Department of Gastroenterology, Changhai Hospital, Naval Medical University, 
Shanghai, China: Zhuan Liao, M.D., Zhao-Shen Li, M.D., Xi Jiang, M.D., Jun Pan, 
M.D., Wei Zhou, M.D. 
2. Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University 

 
40 
School of Medicine, Shanghai, China: Duo-Wu Zou, M.D., Ye Chu, M.D., Chun-
Hua Zhou, M.D., Wei Wu, M.D. 
3. Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji 
University School of Medicine, Shanghai, China: Chang-Qing Yang, M.D., Qing 
Xu, M.D. 
4. Department of Endoscopy, Shanghai Jiao Tong University affiliated Sixth People's 
Hospital, Shanghai, China: Xin-Jian Wan, M.D., Shan Wu, M.D. 
5. Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, 
Tongji University School of Medicine, Shanghai, China: Mei-Dong Xu, M.D., 
Ben-Song Duan, M.D., Tao Chen, M.D., Mao Li, M.D. 
6. Department of Gastroenterology, Yangpu Hospital, Tongji University, Shanghai, 
China: Li Li, M.D., Jun-Zhi Cao, M.D. 
7. Department of Gastroenterology, Zhujiang Hospital, Southern Medical University, 
Guangzhou, China: Hua Mao, M.D., Shao-Qin Jin, M.D. 
8. Department of Gastroenterology, Qilu Hospital, Cheeloo College of Medicine, 
Shandong University, Jinan, China: Xiu-Li Zuo, M.D., Zhen Li, M.D., Cheng Peng, 
M.D. 
9. Department of Gastroenterology, The Third Xiangya Hospital, Central South 
University, Changsha, China: Xiao-Yan Wang, M.D., Ding-Hua Xiao, M.D., Shao-
Jun Liu, M.D., Zhen-Yu Yang, M.D., Fen Wang, M.D. 
10. Department of Gastroenterology, The First Affiliated Hospital of Xi'an Jiaotong 
University, Xi’an, China: Shui-Xiang He, M.D., Huan-Huan Sun, M.D. 
11. Department of Gastroenterology, Union Hospital, Tongji Medical College, 
Huazhong University of Science and Technology, Wuhan, China: Jun Liu, M.D., 
Xiao-Ping Xie, M.D., Yu-Hu Song, M.D. 
12. Department of Gastroenterology and Endoscopy, The fifth affiliated Zhuhai 
Hospital of Zunyi Medical University, Zhuhai, China: Chao-Hui He, M.D., Yang 
Yang, M.D., Yuan-Hong Xu, M.D. 
13. Department of Gastroenterology, The First Afilliated Hospital of Zhejiang Chinese 
Medical University, Hangzhou, China: Shuo Zhang, M.D., Hai-Biao Bao, M.D., 

 
41 
Lu Zhang, M.D., Jin-Feng Dai, M.D. 
14. Department of Gastroenterology, Shanghai Pudong New Area Gongli Hospital, 
Shanghai, China: Yi-Hai Shi, M.D., Li-Juan Hu, M.D. 
Data Safety Monitoring Board:  
1. Prof. Liang Zhong, Department of Gastroenterology and Endoscopy, Huashan 
Hospital, Fudan University, Shanghai, China. 
2. Prof. Feng Liu, Digestive Endoscopy Center, Shanghai Tenth People's Hospital, 
Tongji University School of Medicine, Shanghai, China. 
3. Prof. Cheng Wu, Department of Military Health Statistics, Naval Medical 
University, Shanghai, China. 
13.2 Funding source 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
13.3 Study timetable 
The CENTERS timeline includes a 6-month start up period, followed by approximately 
24 months of enrollment, approximately 6 months of close out and data analysis. 
 
The CENTERS trial is funded by Shanghai Municipal Hospital Emerging Frontier 
Technology Joint Project (to Z. Liao, No. SHDC12019105); "Ten Thousand Plan"-
National High Level Talents Special Support Plan (to Z. Liao).

 
42 
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