A Single-arm Trial of Transcatheter Arterial Chemoembolization With Tandem Microspheres in the Treatment of Localized Hepatocellular Carcinoma
Phase: NA
Conditions: Localized Hepatocellular Carcinoma
Sponsor: Varian Medical Systems

Study Reference Number: S2382     
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A Single-arm Trial of Transcatheter Arterial Chemoembolization with Tandem 
Microspheres in the Treatment of Localized Hepatocellular Carcinoma 
 
A Study of Tandem Microspheres in Localized Hepatocellular Carcinoma 
STOPPER 
 
CLINICAL INVESTIGATION PLAN 
 
 
Study Reference Number：S2382 
 
 
Sponsor By 
 
BSC International Medical Trading (Shanghai) Co., Ltd, (“BSC China”) 
Part A, 2nd Floor, No.68, Rijing Road, 
WaiGaoQiao Free Trade Zone, 
Shanghai, China 200131 
 
 
 
 
This protocol contains confidential information for use by the Investigators and their 
designated representatives participating in this clinical investigation. It should be held 
confidential and maintained in a secure location. 
Do not copy or distribute without written permission from Boston Scientific Corporation. 
 
 
 
 
 
 
 

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Contact Information 
Role 
Contact  
Clinical Contact 
Hui Lin 
Associate Clinical Project Manager  
BSC China  
12th Floor, Building 2,The Word Profit Center, 
16 Tianze Road, Chaoyang District,  
Beijing 100125, P.R. China  
Mobile：+86 15810430945 
E-mail：Hui.lin@bsci.com 
 
Jade Shi 
Clinical Project Manager 
BSC China 
31 Floor, 763 Mengzi Road, Huangpu District, 
Shanghai  200023, P.R. China 
Mobile：+86186 21855739  
E-mail：JianJade.Shi@bsci.com 
 
Gang Chen 
Associate Director, Medical Affairs 
BSC China 
31 Floor, 763 Mengzi Road, Huangpu District, 
Shanghai  200023 
P.R. China 
Mobile：+8613621693047 
E-mail：gang.chen @bsci.com 
Coordinating Principal 
Investigator 
Gaojun Teng 
President, Professor, Chief 
Southeast University Affiliated Zhongda Hospital 
87 Ding Jia Qiao, Hunan Road, Gulou District, Nanjing City, 
Jiangsu 
Coordinating 
Co-Principal 
Investigator 
A list of other institutions involved in the trial is provided in the 
Manual of Operations. 
Vendors/Labs 
Vendors/Laboratory involved in the trial is provided in the Manual 
of Operations. 

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Original Release: January 16, 2017 
Current Version: March 23, 2018 
 
 
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2. Protocol Synopsis 
A Single-arm Trial of Transcatheter Arterial Chemoembolization with Tandem 
Microspheres in the Treatment of Localized Hepatocellular Carcinoma 
Study Objective 
The primary objective of this study is to evaluate the safety and 
efficacy of transcatheter arterial chemoembolization with 
Tandem Microspheres loaded with Epirubicin in the treatment 
of subjects with localized  hepatocellular carcinoma (HCC) 
Study Device 
Tandem Microspheres are spherical, tightly calibrated, 
biocompatible, non-resorbable, hydrogel microspheres coated 
with Polyzene®-F, an inorganic polymer.  
Planned Indication(s) 
for Use 
Tandem Microspheres are indicated for the embolization of 
arteriovenous malformations and hypervascular tumors 
Device Specifications 
Tandem Microspheres are stored in 2 ml and 3 ml sized syringes. 
They are available in a range of sizes (40, 75, and 100 μm). 
Microspheres used will be at the discretion of the treating 
physician(s) based on the tumor size and/or vascular structure. 
Microspheres Diameter
（µl） 
Size（ml） 
40 
2 
40 
3 
75 
2 
75 
3 
100 
2 
100 
3 
 
Study Design 
This is a prospective, single-arm, multicenter study to evaluate 
the safety and efficacy of transcatheter arterial 
chemoembolization with Tandem Microspheres loaded with 
Epirubicin in the treatment of subjects with localized  
hepatocellular carcinoma. All qualified subjects will be enrolled 
in the study and receive transcatheter arterial chemoembolization 
treatment with Tandem Microspheres loaded with Epirubicin 
Sample Size 
109 subjects (including 10% loss to follow-up) 
Number of Study 
Sites 
10 clinical centers will be participating in the study 
Primary Effectiveness 
Endpoint 
The primary effectiveness endpoint for this clinical trial is 6-
month objective tumor response rate (ORR).   

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Secondary Endpoints 
 ORR at 30-day and 3-month 
 Time to Progression (TTP)  
 Time to Extrahepatic Spread  
 Proportion Progression-Free (PPF) at one year 
 Overall survival at one year 
 The frequency of Tandem treatment associated adverse 
events 
Study Enrollment 
Subject will be qualified to be enrolled in the clinical trial once 
signed the IRB/EC approved informed consent, meet all 
inclusion criteria and does not meet any of the exclusion criteria. 
All enrolled subjects will receive the transcatheter arterial 
chemoembolization with Tandem Microspheres. Enrollment 
timepoint will be based on subject receiving transcatheter arterial 
chemoembolization treatment with Tandem Microspheres loaded 
with Epirubicin 
Follow-up Plan 
Follow-up will be conducted at 30 days and 3, 6, and 12 months 
post initial treatment. 
 
The tests during the follow-ups include: 
• 
Laboratory (include Complete Blood Count, blood 
biochemistry, blood coagulation function, renal and liver 
function, electrolyte , AFP) and imaging tests (include plain 
scan plus enhanced MRI, Chest plain scan CT) at 30 days 
and 3, 6 and 12 months post procedure 
• 
ECG at 3 months post procedure 
Study Duration 
The study will end when all subjects completed the 12-month 
follow-up post initial treatment, or withdraw (death, loss to 
follow-up or withdraw consent).  

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Inclusion Criteria 
Subjects may be included in the study only if they meet all of the 
following criteria: 
1. Subject is able to provide informed consent and must 
sign the Institutional Review Board/Ethics Committee 
(IRB/EC) approved Informed Consent Form.  
2. Male or female of age ≥18 and ≤75 years.  
3. Confirmed diagnosis of HCC according to the diagnostic 
criteria included in the management guideline issued by 
China’s Ministry of Health in 2017. 
4. HCC is diagnosed for the first time or recurrence of 
tumor after surgical or ablation treatment. 
5.  Single tumor less than 7cm in diameter or multiple 
tumors with maximum 3 lesions with >1cm in diameter, 
individual diameter <7cm and less than 10cm in total 
diameter. 
6. no previous chemotherapy, radiotherapy or transarterial 
embolization (with or without chemotherapy) for HCC 
7. Preserved liver function (Child-Pugh A or B7). 
8. ECOG Performance Status 0 or 1. 

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Exclusion Criteria 
 Subjects will be excluded for the following reasons: 
1. Presence of vascular invasion or extra-hepatic spread of 
disease, or  diffuse HCC, defined as >50% liver 
involvement , or arteriovenuous fistula 
2. Macrovascular invasion of main or primary branches of 
portal vein at entry into the study 
3. Any contraindication for TACE treatment 
4. Any contraindication for Epirubicin administration 
5. Advanced liver disease (bilirubin levels >2 mg/dl, AST 
or ALT >5 times upper limit of normal) 
6.  Renal failure or insufficient renal function (Creatinine 
levels >2 mg/dl) 
7. Subject unable to receive MRI examination 
8. Pregnant or breast feeding woman, or plan to become 
pregnant during treatment or within 12 months of 
treatment 
9. couldn’t commit reliable birth control measures during 
treatment or within 12 months of treatment 
10. Subject is participating other investigational drug or 
device clinical trial within 30 days of signing the 
informed consent 
11. Subject is not suitable to participate in the study as 
judged by investigator 
Statistical Methods 
Primary Study 
Hypotheses 
The primary hypothesis is that the 6-month ORR in the Tandem 
microspheres embolization and drug delivery arm is higher than 
the performance goal (PG).  
The null (H0) and alternative (H1) hypotheses for this primary 
endpoint are presented below. 
H0: Pe ≤ PG 
H1: Pe > PG 
where Pe is the expected 6-month ORR (%). 
Statistical Test 
A normal approximation test will be used to assess the one-sided 
hypotheses of the test device superior to the PG 

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Success Criteria for 
the PG 
The test device will be concluded to be superior to the PG in the 
primary analysis if the one-sided lower 97.5% confidence bound 
for the test device performance in 6-month ORR is greater than 
PG. 
Sample Size 
Parameters 
The overall sample size (N=109) is driven by the primary 
effectiveness endpoint. 
• Power ≥ 85% 
• One-sided significance level = 2.5% (alpha) 
• PG for 6-month ORR = 45%  
• Expected 6-month ORR = 60% 
• Total N=98 subjects are required for 6-month assessment 
• Attrition rate = 10% (loss to follow-up in 6 months) 
• Approximately N=109 subjects to enroll 
 
 
 

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3. Table of Contents 
1. 
Title Page  ............................................................................................................................ 1 
2. 
PROTOCOL SYNOPSIS ............................................................................................................ 6 
3. 
TABLE OF CONTENTS .......................................................................................................... 11 
4. 
INTRODUCTION ................................................................................................................... 16 
5. 
DEVICE DESCRIPTION ......................................................................................................... 17 
5.1. Device Description ................................................................................................... 17 
5.2. Device Labeling ....................................................................................................... 17 
6. 
STUDY OBJECTIVES ............................................................................................................ 18 
7. 
STUDY ENDPOINTS ........................................................................................................... 18 
8. 
STUDY DESIGN .................................................................................................................. 18 
8.1. Study Plan ................................................................................................................ 20 
8.2. Treatment Plan ......................................................................................................... 20 
8.3. Justification for the Study Design ............................................................................ 21 
9. 
SUBJECT SELECTION ........................................................................................................... 21 
9.1. Study Population and Eligibility .............................................................................. 21 
9.2. Inclusion Criteria ...................................................................................................... 21 
9.3. Exclusion Criteria..................................................................................................... 22 
10. SUBJECT ACCOUNTABILITY ................................................................................................ 23 
10.1.  Enrollment ............................................................................................................... 23 
10.2.  Withdrawal .............................................................................................................. 23 
10.3.  Enrollment Control ................................................................................................. 23 
11. STUDY METHODS ............................................................................................................... 23 
11.1.  Data Collection........................................................................................................ 23 
11.2.  Study Candidate Screening ..................................................................................... 25 
11.3.  Informed Consent .................................................................................................... 25 
11.4.  Screening/Baseline Survey...................................................................................... 25 

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11.5.  Initial Tandem Treatment ........................................................................................ 26 
11.6.  30-day Follow-up and Evaluation Post Initial Treatment and 2nd Treatment (if 
needed) ..................................................................................................................... 26 
11.7.  3-month Follow-up Post Initial Treatment and 30-day Evaluation after 3rd 
Treatment (if needed) ............................................................................................... 27 
11.8.  6-month Follow-up Post Initial Treatment and 30-day Evaluation after 4th  
Treatment (if needed) ............................................................................................... 27 
11.9.  12-month Clinical Follow-up Post Initial Treatment .............................................. 27 
11.10. Study Completion ................................................................................................... 28 
12. STATISTICAL CONSIDERATIONS .......................................................................................... 28 
12.1. Endpoints ................................................................................................................. 28 
12.1.1. Primary Endpoint ....................................................................................... 28 
12.1.1.1.  Hypotheses ............................................................................... 28 
12.1.1.2.  Sample Size .............................................................................. 29 
12.1.1.3.  Statistical Methods ................................................................... 29 
12.1.1.4.  Success Criteria ........................................................................ 29 
12.1.2. Secondary Endpoints ................................................................................. 29 
12.2.  General Statistical Considerations .......................................................................... 29 
12.2.1. Analysis Sets .............................................................................................. 29 
12.2.2. Control of Systematic Error/Bias ............................................................... 30 
12.2.3. Number of Subjects per Investigative Site ................................................ 30 
12.3.  Baseline Data Analyses ........................................................................................... 30 
12.3.1. Other Endpoints/Measurements ................................................................. 30 
12.3.2. Subgroup Analyses .................................................................................... 30 
12.3.3. Sensitivity Analysis for Missing Outcome Data ....................................... 30 
12.3.4. Multivariable Analyses .............................................................................. 30 
12.3.5. Analysis Software ...................................................................................... 31 
12.3.6. Changes to Planned Analyses .................................................................... 31 
13. DATA MANAGEMENT ......................................................................................................... 31 
13.1.  Data Collection, Processing, and Review ............................................................... 31 
13.2.  Data Retention ......................................................................................................... 32 
13.3.  Core Laboratories .................................................................................................... 32 
14. PROTOCOL AMENDMENTS .............................................................................................. 32 
15. PROTOCOL DEVIATIONS ................................................................................................. 32 

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16. DEVICE/EQUIPMENT ACCOUNTABILITY .............................................................................. 33 
17. COMPLIANCE ...................................................................................................................... 33 
17.1.  Statement of Compliance ........................................................................................ 33 
17.2.  Investigator Responsibilities ................................................................................... 34 
17.2.1. Delegation of Responsibility ..................................................................... 35 
17.3.  Institutional Review Board/ Ethics Committee ...................................................... 36 
17.4.  Sponsor Responsibilities ......................................................................................... 36 
17.5.  Insurance ................................................................................................................. 36 
18. MONITORING ...................................................................................................................... 37 
19. POTENTIAL RISKS AND BENEFITS ....................................................................................... 37 
19.1.  Anticipated Adverse Events .................................................................................... 37 
19.2.  Risk Minimization Actions ..................................................................................... 38 
19.3.  Anticipated Benefits  ............................................................................................... 39 
19.4.  Benefit-Risk Ratio  .................................................................................................. 39 
20. SAFETY REPORTING ............................................................................................................ 39 
20.1.  Events reported by the investigator to BSC ............................................................ 39 
20.2.  Definitions and classification .................................................................................. 40 
20.3.  Relationship to Study Device(s).............................................................................. 42 
20.4.  Investigator Reporting Requirements ..................................................................... 44 
20.5.  Boston Scientific Device Deficiencies .................................................................... 46 
20.6.  Reporting to Regulatory Authorities / IRBs / ECs / Investigators .......................... 46 
21. INFORMED CONSENT .......................................................................................................... 46 
22. COMMITTEES ...................................................................................................................... 48 
22.1.  Executive Committee .............................................................................................. 48 
22.2.  Safety Monitoring Process ...................................................................................... 48 
23. SUSPENSION OR TERMINATION ........................................................................................... 48 
23.1. Premature Termination of the Study ......................................................................... 48 
23.1.1. Criteria for Premature Termination of the Study ....................................... 48 
23.2. Termination of Study Participation by the Investigator or Withdrawal of IRB/ EC 
Approval ................................................................................................................... 49 

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23.3. Requirements for Documentation and Subject Follow-up ....................................... 49 
23.4. Criteria for Suspending/Terminating a Study Site.................................................... 49 
24. PUBLICATION POLICY ......................................................................................................... 50 
25. REIMBURSEMENT AND COMPENSATION FOR SUBJECTS ...................................................... 50 
25.1. Subject Reimbursement ............................................................................................ 50 
25.2. Compensation for Subject’s Health Injury ............................................................... 50 
26. LITERATURE ....................................................................................................................... 51 
27. ABBREVIATIONS AND DEFINITIONS .................................................................................... 52 
 
 
 

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3. Table of Tables 
Table 11.1: Baseline and Follow-up Evaluation Plan ............................................................. 24 
Table 19.1-1: Potential Complications and Incidence Rates .................................................. 37 
Table 20.2-1: Safety Reporting Definitions ............................................................................ 40 
Table 20.3-1: Criteria for Assessing Relationship of Study Device or Procedure to Adverse 
Event .................................................................................................................... 43 
Table 20.4-1: Investigator Reporting Requirements ............................................................... 44 
Table 27.1: Terms and Abbreviations ..................................................................................... 53 
Table 27.2: Definitions ........................................................................................................... 54 
 
 

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4. Introduction 
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. It is 
one of the most common cancer in the world, the third most common cause of cancer-related 
death1. A majority of HCC cases (60% to 80%) arise due to chronic hepatitis and cirrhosis. 
Major etiologies of liver cirrhosis include chronic hepatitis B and C, alcohol consumption, 
steatosis, diabetes, certain medications or exposures to toxic agents and genetic and 
metabolic diseases2. Obesity has also been identified as an independent risk factor for 
developing HCC3,4.  
 
HBV is the most frequently underlying cause of HCC in Asia. HBV carriers have a 5 to 15-
fold increased risk of HCC compared to the general population. Chronic HBV carriers in 
Asia develop HCC at an annual rate of 0.4-0.6%. In Western countries and Japan, the main 
risk factor is HCV infection and excessive alcohol intake, along with other causes of 
cirrhosis. The annual incidence rate of HCC in subjects with hepatitis C is 3.7-7.1%5. 
 
Various staging and classification systems have been proposed for HCC, which help to select 
treatment strategies, assess prognosis, and compare results from different clinical studies6. 
The Barcelona Clinic Liver Cancer (BCLC) staging system has been used for stratification of 
subjects with HCC in the practice guidelines established by the American Association of the 
Study of Liver Diseases (AASLD)7,8. In addition to estimating prognosis, the BCLC staging 
system also links staging to treatment recommendations. In this staging system, intermediate 
stage (BCLC-B) is formed by those subjects who are asymptomatic and harbor multifocal 
HCC without vascular invasion or extrahepatic spread and have preserved liver function 
(Child-Pugh Class A or B) and normal performance status (Eastern Cooperative Oncology 
Group Performance Status ECOG PS) of 0. Chemoembolization is recommended as the main 
treatment strategy for subjects in this intermediate stage. 
 
Transarterial chemoembolization (TACE) is a commonly used procedure to treat liver 
cancers using a catheter to deliver both chemotherapy medication and embolization materials 
into the blood vessels that lead to the tumor.  The American Cancer Society, Society of 
Interventional Radiology and the National Comprehensive Cancer Network have identified 
TACE procedures where doxorubicin (alone or mixed with other cytotoxic agents such as 
cisplatin and/or mitomycin C), is mixed with ethiodol and injected intra-arterially as an oily 
mixture into the vasculature of the tumor as the standard of care for subjects with 
unresectable hepatocellular carcinoma (HCC)7.1 Following the TACE procedure, embolic 
particles are injected to slow the blood flow to the tumor’s vasculature.  This procedure is 
also known as conventional TACE (cTACE). Although cTACE has shown survival benefit in 
properly selected HCC patients from two randomized studies and a meta-analysis,9-11 this 
often is associated with marked symptoms of postembolization syndrome and is not well 
tolerated by patients with advanced disease.12-14 
 
Unlike cTACE, chemoembolization with drug-eluting beads (DEB-TACE) using 
doxorubicin has been found to be well tolerated with minimal postembolization syndrome 

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symptoms. A recent randomized study comparing cTACE and DEB-TACE has shown better 
tolerability and fewer complications associated with DEB-TACE15-18.  
In order to 1) minimize the loss of doxorubicin into the bloodstream; 2) prolong the residence 
time of doxorubicin at the tumor site; and 3) standardize TACE procedures, microsphere 
technology has advanced to load doxorubicin using drug eluting beads (DEB) before 
injection.  The drug eluting bead procedure (DEB-TACE) is designed to embolize the HCC 
vasculature and release drug in a controlled manner.  Multiple clinical trials in Europe and in 
the US using DEB-TACE to treat HCC have demonstrated safety, and varying degrees of 
success of efficacy. 
 
5. Device Description 
5.1. Device Description 
Tandem Microspheres are 510(k) FDA cleared for embolization of arteriovenous 
malformations (AVM) and hypervascular tumors (HVT) including hepatoma. Tandem 
Microspheres are spherical, tightly calibrated, biocompatible, non-resorbable, hydrogel 
microspheres coated with an inorganic perfluorinated polymer (Polyzene®-F). They are 
available in a range of sizes suitable for embolic therapy.  Tandem Microspheres are opaque 
in color. 
 
Tandem Microspheres offer: 
 Deep penetration into the tumor vasculature due to very small sized 40, 75, and 100 
μm Microspheres. 
Microspheres Diameter
（µl） 
Size（ml） 
40 
2 
40 
3 
75 
2 
75 
3 
100 
2 
100 
3 
 
 High confidence when performing superselective and targeted embolization 
procedures as 95% of the microspheres are within the stated size variance. 
 Controlled embolization with precisely formulated and standardized microspheres. 
 Transcatheter arterial chemoembolization treatment with Tandem Microspheres 
loaded with epirubicin. 
 
5.2. Device Labeling 
STOPPER China Manuel of Operations includes Instruction for Use for Tandem 

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Microspheres. The labeling includes the following information: 
• 
Product Name 
• 
UPN 
• 
Lot Number 
• 
Specification (Diameters of microspheres in µm) and dosage (ml) 
• 
Expiration Date  
 
The labeling of products used for STOPPER China clinical trial should include the following 
statement: 
Used for clinical trial only 
The device labeling in Chinese weill be provided per China’s regulatory requirement. 
 
6. Study Objective 
The primary objective of the study is to evaluate the safety and efficacy of transcatheter 
arterial chemoembolization with Tandem Microspheres loaded with Epirubicin in the 
treatment of subjects with localized hepatocellular carcinoma (HCC). 
  
7. Study Endpoints 
The primary efficacy endpoint is overall ORR at 6 months. The secondary endpoints are:  
 ORR at 30 days and 3-month 
 Time to Progression (TTP)  
 Time to Extrahepatic Spread  
 Proportion Progression-Free (PPF) at one year 
 Overall survival at one year 
 The frequency of treatment associated adverse events 
 
 
8. Study Design 
This is a prospective, single-arm, multicenter study. The flow chart of the study is as follows: 
 
 
 
 
 
 
 
 
 

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Site initiation and 
training/Delivery of study device
Obtain informed consent from 
confirmed HCC subject 
Confirm inclusion/exclusion 
criteria 
TANDEM microspheres 
entering the subject’s body 
Subject signed informed consent？ 
Subject meet all criteria？ 
No 
enrollment 
No enrollment 
30 day follow-up/assessment 
post first treatment 
3-monthfollow-uppost first 
treatment 
6-month follow-up post first 
treatment 
12-month follow-up post first 
treatment 
3rd  DEB-TACE  (Treated 
within 14 days of assessment) 
2nd, 3rd or 4th  DEB-TACE  
(Treated within 14 days of 
assessment) 
2nd DEB-TACE  (Treated 
within 14 days of assessment) 
No 
No 
No 
If 
necessary 
If necessary 
30-dayassessment post 2nd treatment   
If necessary 

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8.1. Study Plan 
The study will enroll 109 subjects with confirmed diagnosis of localized HCC based on the 
2017 Guideline at 10 study sites. Each subject will be followed for 12 months after 
transcatheter arterial chemoembolization with Tandem Microspheres loaded with 
Epirubicin(subjects will be followed at 30-day, 3-month, 6-month and 12-month). ORR at 6 
months will be assessed as the primary endpoint. 
8.2. Treatment Plan 
The study will consecutively enroll 109 qualified HCC subjects according to the diagnostic 
criteria included in the management guideline issued by China’s Ministry of Health in 2017. 
All subjects will receive transcatheter arterial chemoembolization with Tandem 
Microspheres loaded with Epirubicin. Drug-loaded Tandem microspheres will be delivered 
into the tumor’s vasculature by superselective catheter positioning. The size and specification 
of microspheres used in the treatment will be decided by the physician based on the tumor 
size and/or vascular structure. The dose of epirubicin and the volume of Tandem will be at 
the discretion of the physician based on the subjects’s tumor situation. The treatment end 
point should be devascularization of tumor/lesion and delivering sufficient dose of epirubicin. 
If after delivering the desired drug/embolization dose, blood flow is still detectable in the 
tumor; then the procedure can either be stopped, or use bland Tandem microspheres to reach 
stasis based on the subject’s condition. Prior to the procedure, the treating physician must 
carefully read and be familiar with the appropriate product IFU/DFU including the Loading 
Guidance. 
 
DEB-TACE General Procedural Considerations 
 
 Prior to the procedure, angiography of the hepatic and mesenteric arteries is 
performed to map the liver vascular anatomy, identify the tumor-feeding arteries and 
check for arteriovenous shunts. 
 The goal is to deliver drug-loaded TANDEM embolic particles into the tumor’s 
vasculature as selectively as possible.  Subjects might be treated via segmental or 
lobar infusion if a selective or superselective approach is not feasible due to the 
subject’s anatomy and pathology.   
 Delivery of the microspheres will stop when either the total targeted microspheres 
have been delivered or a near stasis (slowed contrast flow for 2-5 heartbeats) endpoint 
has been reached. 
 The doxorubicin-loaded TANDEM microspheres should be injected slowly into the 
tumor feeding vessels.  SLOW INJECTION IS ESSENTIAL FOR BEST 
RESULTS. When flow starts to decrease, stop, wait several minutes, and then 
reevaluate.  Flow generally will increase again and additional volume of the 
microspheres can be delivered as microvasculature relaxes after initial blockage.  

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 The goal is to saturate as much of the tumor’s vascular bed as possible. The procedure 
is considered a technical success when the desired devascularization is achieved, or 
the desired dose is injected.  
 If small tumor feeder arteries are missed on the first treatment, they can be addressed 
during a subsequent treatment. 
 No embolization material other than Tandem microspheres should be used during the 
DEB-TACE procedure 
 
DEB-TACE treatment can be performed for a maximum of 4 times until complete tumor 
response is observed on imaging or one or more of the following events occurs: Imaging 
assessment not indicates partial response by mRECIST after two treatments within 6 months; 
Development of main portal vein thrombosis or extrahepatic spread of disease; Progression 
to ECOG performance status > 2 or evolution to sustained hepatic decompensation; 
Intolerable to treatment; Occurrence of any serious adverse event that would prompt the 
discontinuation of treatment. Other treatment can be initiated per investigator’s discretion if 
no partial response is reached after two consecutive treatments. The investigator may choose 
adequate treatment option if new hepatic lesion or extrahepatic metastasis appears. Any anti-
angiogenic drug, anti-cancer chemotherapy, immunotherapy, molecular therapy, and any 
investigational therapy are not allowed during the Tandem microspheres treatment. If 
necessary, appropriate anti-viral and/or liver protection treatments can be prescribed to 
chronic hepatitis patients.  
8.3. Justification for the Study Design 
Study has confirmed that early tumor response assessed by imaging evaluation can more 
accurately help to predict long-term survival in HCC patients treated with 
chemoembolization. Therefore, a 6-month objective tumor response rate (ORR) is used as the 
primary effectiveness endpoint. Since there is no report on 6-month ORR after cTACE in the 
Chinese population, this study selected 45% as the performance goal based on the 6-month 
ORR result in the cTACE controlled arm of a well-accepted international multicenter 
randomized controlled PRECISION V study. The PRECISION V study enrolled 212 subjects 
from 19 centers at France, Germany, Switzerland, Austria and Greece, The key inclusion 
criteria of this study is comparable with the PRECISION V study, including the BCLC 
staging (A/B), Child-Pugh score (A/B) and ECOG performance status (0/1).  
 
9. Subject Selection 
9.1. Study Population and Eligibility 
Prior to being eligible for the STOPPER study, a subject must meet all of the inclusion 
criteria (Section 9.2) and none of the exclusion criteria (Section 9.3). 
9.2. Inclusion Criteria 
Subjects may be enrolled in the study if they meet all of the following criteria: 

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1. Patient is able to provide informed consent and must sign the Institutional Review    
Board/Ethics Committee (IRB/EC) approved Informed Consent Form.  
2. Male or female of age ≥18 and ≤75 years.  
3. Confirmed diagnosis of HCC according to the diagnostic criteria included in the 
management guideline issued by China’s Ministry of Health in 2017. 
4. HCC is diagnosed for the first time or recurrence of tumor after surgical or ablation  
treatment 
5. Single tumor less than 7cm in diameter or multiple tumors with less than 3 lesions 
with >1cm in diameter, individual diameter <7cm and less than 10cm in total 
diameter. 
6. No previous chemotherapy, radiotherapy or transarterial embolization (with or   
without chemotherapy) for HCC 
7. Preserved liver function (Child-Pugh A or B7). 
8. ECOG Performance Status 0 or 1. 
9.3. Exclusion Criteria 
Subjects will be excluded for any of the following reasons: 
1. Presence of vascular invasion or extra-hepatic spread of disease, or  diffuse HCC, 
defined as >50% liver involvement , or arteriovenuous fistula 
2. Macrovascular invasion of main or primary branches of portal vein at entry into the 
study 
3. Any contraindication for TACE treatment 
4. Any contraindication for Epirubicin administration 
5. Advanced liver disease (bilirubin levels >2 mg/dl, AST or ALT >5 times upper limit 
of normal) 
6. Renal failure or insufficient renal function (Creatinine levels >2 mg/dl) 
7. Subject unable to receive MRI examination 
8. Pregnant or breast feeding woman, or plan to become pregnant during treatment or 
within 12 months of treatment 
9. Couldn’t commit reliable birth control measures during treatment or within 12 
months of treatment 
10. Subject is participating other investigational drug or device clinical trial within 30 dys 
of signing the informed consent 
11. Subject is not suitable to participate in the study as judged by investigator 
  

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10. Subject Accountability 
10.1. Enrollment 
Confirmed HCC patient, who has signed the IRB/IEC-approved study ICF, and has met all 
inclusion criteria and none of the exclusion criteria, will be considered eligible to be enrolled 
in the trial.  If the subject does not meet all of the inclusion criteria or meets any of the 
exclusion criteria, it will be regarded as screening failure, and the subject will not be enrolled 
in the study and receive investigational device, and will not be followed according to the 
study protocol. All qualified subjects will receive DEB-TACE treatment with Tandem. The 
enrollment timepoint will be based on subject receiving initial transcatheter arterial 
chemoembolization treatment with Tandem Microspheres loaded with Epirubicin  
10.2. Withdrawal 
All enrolled patients should be documented (including those withdraw from the study or lost 
to follow-up). The reason for withdrawal will be recorded in all cases of withdrawal. If such 
withdrawal is due to problems related to investigational device safety or performance, the 
investigator shall ask for the subject’s permission to continue to follow his/her 
status/condition. 
10.3. Enrollment Control 
A minimum of 98 enrolled subjects are needed to adequately assess the primary endpoint at 6 
months after initial treatment.  To account for attrition, minimum enrolment shall be 109 
subjects, assuming a maximum attrition of 10% for all reasons at 6 months.  The enrollment 
cap for each study site is 25% of total enrolled subjects, which is 27 subjects. The study 
recruitment will stop when 109 qualified subjects completed enrollment. 
 
11. Study Methods 
11.1. Data Collection 
The data collection plan is shown in Table 11.1. The follow-up window is 14 days. 
 
 

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Table 11.1   Baseline and Follow-up Evaluation Plan 
 
Screening/Baseline 
Treatment 
initiation 
30-day Follow-up 
post initial 
treatment 
30-day assessment 
post 2nd treatment 
(if necessary) 
3-month Follow-up 
post initial 
treatment 
6-month Follow-up 
post initial 
treatment 
12-month Follow-
up post initial 
treatment 
Within 14 days of 
treatment 
Day 0 
30±14 days 
 
91±14 days 
183±14 days 
365±14 days 
Informed Consent 
 
 
 
 
 
 
 
Inclusion/Exclusion 
 
 
 
 
 
 
 
Demographics (including date 
of birth, gender and ethnicity) 
 
 
 
 
 
 
 
Cancer and treatment history 
 
 
 
 
 
 
 
Physical examination 
 
 
 
 
 
 
 
Child-Pugh Score 
 
 
 
 
 
 
 
ECG 
 
 
 
 
 
 
 
Laboratory tests * 
 
 
 
 
 
 
 
Pregnancy Test  # 
(if applicable) 
 
 
 
 
 
 
 
Imaging and tumor 
measurement 
 
 
 
 
 
 
 
Chest plain CT 
 
 
 
 
 
 
 
ECOG performance status 
 
 
 
 
 
 
 
Concomitant Medication post 
treatment 
 
 
 
 
 
 
 
Adverse Events and device 
failure assessment 
 
 
 
 
 
 
 
Vital status  
 
 
 
 
 
 
 
 
* Baseline Laboratory Tests include：complete blood count (WBC, RBC, Hb, PLT), Blood biochemistry (TP, ALB, TBIL, IBIL), Liver function tests (ALT, AST, ALP)，Renal 
function tests (BUN, Cr), Anticoagulation (PT, APTT, INR), Electrolyte (K, Na, CI, Ca)，hepatitis B panel and anti-HCV, AFP 
# Serum and/or urine pregnant test 
All laboratory tests must be completed within 14 days of study treatment，childbearing woman should complete serum and/or urine pregnant test within 7 days of treatment 

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11.2. Study Candidate Screening 
Screening process will be performed to confirmed primary HCC subjects based on inclusion 
and exclusion criteria. Subjects who are suitable for DEB-TACE will be informed about the 
study and will be asked to sign the informed consent form (ICF) before participating in any 
screening procedure.  After signing the ICF, the subject will receive a screening number and 
will be documented in a screening log.  Each clinical investigator must keep a log of all 
screened subjects, including both eligible and non-eligible subjects (screening failures). The 
screening log will be kept by each study center. 
11.3. Informed Consent 
Before the initiation of the screening process, subjects who meet the clinical inclusion criteria 
will be asked to sign the IRB/IEC-approved study ICF.  Subjects must be given ample time 
to review ICF and have questions answered before signing ICF.  
Study personnel should explain to the subject that even if the subject agrees to participate in 
the trial and signs the ICF, the pre-treatment tests including pre-embolization radiography 
may demonstrate that the subject is not a suitable candidate for the clinical trial.  
11.4. Screening/Baseline Survey 
The procedures to be completed within 14 days prior to treatment are as follows. Among 
them hepatitis B markers, HBV-DNA (if necessary), anti-HCV and imaging test result within 
10 days of IC signature as well as other serum tests within 5 days of IC signature at the same 
research center can be accepted for screening and baseline survey data. 
 Obtain written subject informed consent.  
 Obtain detailed documentation of cancer history with treatments and outcomes.  
 Demographics. 
 Physical Examination (height, weight, pulse, blood pressure) 
 Child-Pugh Score 
 ECOG performance status 
 Plain and Enhanced MRI to assess intrahepatic tumor  
 Chest plain CT and other tests (if necessary) to exclude extrahepatic lesion 
 ECG.   
 Pregnancy Test:  If female is of child bearing potential, non-pregnancy to be 
confirmed with urine or serum test. 
 
Laboratory tests to be done at baseline: 
 Complete Blood Count (WBC, RBC, Hb, PLT) 
 Blood biochemistry (TP, ALB, TBIL, IBIL) 
 Liver function tests (ALT, AST, ALP)  
 Renal function tests (BUN, Cr) 

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 Anticoagulation (PT, APTT, INR) 
 Electrolyte (K, Na, CI, Ca) 
 Hepatitis B panel and anti-HCV (test HBV-DNA if HBsAg positive) 
 AFP 
 
MRI Imaging to be done at baseline and during the study treatment phase： 
MRI imaging system should be ensured during all assessments for each subject with the same 
technique being used throughout the treatment period for evaluating the lesions. Scanning 
sequence include coronal T2WI，transect T2WI、T1WI、DWI，enhanced scan using 3D 
T1WI. Tumor measurements will be assessed at Core laboratory. Sites should send the 
imaging for review. The target lesions must meet all of the following according to the 
mRECIST for HCC Guideline：The lesion can be measured in at least one dimension ≥ 1 
cm; The lesion appears to be suitable for accurate and repeat measurement; The lesion shows 
intratumoral arterial enhancement。 
 
Test to be done at baseline and during the study treatment phase to exclude extrahepatic 
metastasis 
Perform chest CT test to exclude lung metastasis. Other tests could also be done if necessary 
to exclude extrahepatic metastasis. 
11.5.  Initial Tandem Treatment 
 The end of initial treatment is defined as the completion of the first DEB-TACE with 
Tandem microspheres. Post-treatment evaluation will be conducted by site after each DEB-
TACE procedure to determine the need for next session, and complete the next embolization 
treatment within 14 days of assessment if necessary. A maximum of 4 treatment may be 
performed to the subject during the study. If a subject received 4 treatments, no 30-day post 
treatment assessment will be conducted, and the subject will continue to receive 6-month 
post treatment follow-up.See the flow chart for detailed post-treatment evaluation and 
follow-up plan on subjects receiving different times of DEB-TACE treatments. The 
following should be completed after each DEB-TACE procedure: 
 
Record the procedural date/time, microsphere lot #, microsphere size and volume, 
microcatheter used,epirubicin manufacturer, epirubicin lot #, epirubicin dose, contrast 
type and volume, infusion volume, lesion(s) treated and flow characteristic.   
 
AE and concomitant medicine used during DEB-TACE 
 
 
11.6. 30-day Clinical Follow-up Post Initial Treatment  
 Physical examination (weight, pulse, blood pressure) 

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 ECOG and Child-Pugh scores 
 Lab tests (Complete Blood Count, blood biochemistry, liver and renal functions, 
blood coagulation function, electrolyte, AFP,) 
 Enhanced MRI to assess the tumor response and Chest plain CT 
 Concomitant medications since last visit 
 Record of all adverse events that occurred from last subject contact 
Note: If the 30-day evaluation post initial treatment indicates complete response of the 
target lesion, the subject will received scheduled 3, 6 and 12-month follow; If the 2nd 
treatment is needed, it will be completed within 14 days of assessment, and a 30-day 
evaluation will be conducted after the 2nd treatment; If the 3rd treatment is needed, it will 
be completed within 14 days of assessment, and the subject will receive the post-
treatment evaluation and 3-month follow-up at the same time. 
 
11.7. 3-month (91±14 days) Clinical Follow-up Post Initial Treatment  
 Physical examination (weight, pulse, blood pressure) 
 ECOG and Child-Pugh scores 
 Lab tests (Complete Blood Count, blood biochemistry, liver and renal functions, 
blood coagulation function, electrolyte, AFP) 
 ECG 
 Enhanced MRI for tumor response and Chest plain CT  
 Concomitant medications since last visit 
 Record of all adverse events that occurred from last subject contact 
 
11.8. 6-month (183±14 days) Clinical Follow-up Post Initial Treatment  
 Physical examination (weight, pulse, blood pressure) 
 ECOG and Child-Pugh scores 
 Lab tests (Complete Blood Count, blood biochemistry, liver and renal functions, 
blood coagulation function, AFP) 
 Enhanced MRI for tumor response and Chest plain CT  
 Concomitant medications since last visit 
 Record of all adverse events that occurred from last subject contact 
 Vital status 
 
11.9. 12-month (365±14 天) Clinical Follow-up Post Initial Treatment 
 Physical examination 
 ECOG and Child-Pugh scores 

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 Lab tests (Complete Blood Count, blood coagulation function, AFP, liver and renal 
functions) 
 Enhanced MRI for tumor response and Chest plain CT  
 Concomitant medications since last visit 
 Record of all adverse events that occurred from last subject contact 
 Vital status 
 
11.10.  Study Completion 
All subjects who completed the 12 months follow-up, or withdrawn (due to death or loss to 
follow-up), or will be treated as study termination. Any adverse events occurred afterwards 
will be addressed by the physician per standard treatment. 
 
Subjects may withdraw their consent and discontinue participation in the clinical study at any 
time, for any reason, without prejudice to further treatment. If a subject no longer wants to 
receive study treatment, but is willing to come for follow-up appointments, the subject’s 
request should be honored, if possible.   
 
If for any reason a subject is withdrawn or terminated before completing the study, the 
reasons for withdrawal or termination must be documented.  
 
If a subject discontinues treatment due to an adverse event or clinical laboratory abnormality, 
the subject should be followed-up until the event resolves or the subject stabilized.  
 
12. Statistical Considerations 
12.1. Endpoints 
12.1.1.  Primary Endpoint 
The primary endpoint of the study is 6-month  ORR. Objective tumor response will be 
assessed by The European Association for the Study of the Liver (EASL) Response 
Evaluation Criteria in Solid Tumors and a modified Response Evaluation Criteria in Solid 
Tumors (mRECIST19). The mRECIST criteria can be more accurate to predict long-term 
survival in HCC subjects treated with chemoembolization20. The subject achieves complete 
response (CR) or partial response (PR) will be regarded as a responder. A subject without 
tumor assessment after the initiation of the treatment will be regarded as a missing data.   
12.1.1.1. 
Hypotheses 
The primary hypotheses is the 6-month ORR in subjects treated with transcatheter arterial 
chemoembolization with drug-loaded Tandem Microspheres exceeds the PG under a one-
sided significance level of 2.5%. The PG development is based on PRECISION V, an 
international multicenter study. The ORR will be assessed based on the EASL criteria. 
The null (H0) and the alternative (H1) hypotheses for the primary effectiveness endpoint are 
as follows: 

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H0: Pe  PG (not met) 
H1: Pe  > PG (met) 
where Pe is the expected 6-month ORR (%). 
12.1.1.2. 
Sample Size 
The overall sample size is driven by the primary effectiveness endpoint. Approximately 109 
subjects are planned to be enrolled in the study. The sample size justification is based on the 
following assumptions. 
• Power ≥ 85% 
• One-sided significance level = 2.5% (alpha) 
• PG for 6-month ORR = 45%  
• Expected 6-month ORR = 60% 
• A minimum of 98 evaluable subjects are required for 6-month assessment 
• Attrition rate = 10% (loss to follow-up in 6 months) 
• A sample size of 109 subjects will be enrolled in the study 
12.1.1.3. 
Statistical Methods 
A normal approximation test (e.g. Chi-Square Test) will be used to assess the superiority to 
the PG. 
12.1.1.4. 
Success Criteria 
The test device will be concluded to be superior to the PG if the one-sided 97.5% lower 
confidence bound for the observed performance in 6-month ORR is greater than PG. 
12.1.2. Secondary Endpoints 
The study is not powered for the secondary endpoints therefore there are no formal 
hypotheses. The secondary endpoints and analyses are shown below. 
Kaplan-Meier analyses will be used for time-to-event type of endpoints such as overall 
survival (OS), time to progression (TTP), and time to extrahepatic spread through 12 months. 
A binary proportion will be presented for ORR at 30-day and 3-month and progression-free 
(PPF) rate at 12 months. A frequency will be provided for treatment associated adverse 
events. 
12.2. 
General Statistical Considerations 
12.2.1.  Analysis Sets 
The primary and pre-specified secondary endpoints will be analyzed on a Per Protocol and as 
treated basis. Only enrolled subjects who receive the first treatment will be included in the 
analysis sample.  

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12.2.2. 
 Control of Systematic Errors/Bias 
Selection of subjects will be made from the Investigators’ general or professional referral 
population. All subjects meeting the inclusion/exclusion criteria and that have signed the 
protocol-specific ICF will be eligible for enrollment in the trial. Consecutively eligible 
subjects should be enrolled into the trial to minimize selection bias. the MRI core laboratory 
will independently analyze the images and the data obtained from the core laboratory will be 
utilized for analyses. 
12.2.3. 
 Number of Subjects per Investigative Site 
Each site will be allowed to enroll up to 25% of the total enrollment, with a maximum 
enrollment of 27 subjects. 
12.3. Baseline Data Analysis 
Baseline demographics, procedure and assessments will be summarized for the study. For 
continuous and/or ordinal variables, the descriptive statistics will include mean, standard 
deviation, number evaluated, minimum and maximum. Some specific variables may also 
include additional statistics such as median and confidence intervals. For binary or 
categorical variables, the descriptive statistics will include percentage, numerator, 
denominator, and number evaluated. Some variables may include confidence intervals as 
needed. 
12.3.1.  Other Endpoints/Measurements 
Other assessments including ad-hoc analyses will be observational only. 
12.3.2. Subgroup Analysis 
The primary endpoint and/or additional assessments may be summarized by the following 
categories as applicable: 
• Gender (male vs. female) 
• ECOG Score (0 vs. 1) 
• BCLC Stage (A vs. B7) 
12.3.3. Sensitivity Analysis for Missing Outcome Data 
Sensitivity analysis for the primary endpoint assessment will be conducted to assess the 
impact of missing data on the result’s robustness. In addition to the use of the worst-case 
analysis, the tipping point analysis will be performed for the ITT analysis set to consider all 
combinations of present/absent for all subjects with missing primary outcome. 
12.3.4. Multivariable Analyses 
Univariate and multivariable analyses may be performed as post-hoc analyses to assess the 
effect of potential predictors for the primary endpoint in a logistic regression model. 

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Clinically and/or statistical meaningful baseline covariates will be selected in the regression 
model if the analysis is performed. 
12.3.5. Analysis Software 
All statistical analyses will be performed using the Statistical Analysis Software (SAS), 
version 9.2 or later (Copyright © 2002-2010 by SAS Institute Inc., Cary, North Carolina 
27513, USA. All rights reserved) 
12.3.6. Changes to Planned Analyses  
Any changes to the planned statistical analyses made prior to performing the primary 
analyses will be documented in an amended Statistical Analysis Plan prior to performing the 
analyses. Changes from the planned statistical methods after performing the analyses will be 
documented in the clinical trial report along with a reason for the deviation. 
 
13. Data Management 
13.1. Data Collection, Processing, and Review 
Subject data will be recorded in a secure electronic data capture (EDC) system. Only 
personnel trained and authorized will have access to the system. 
 
The clinical database will reside on a production server provided by Medidata. All changes 
made to the clinical data can be tracked and available for review by BSC or its representative. 
The associated RAVE software and database have been designed to meet regulatory 
compliance for deployment as part of a validated system compliant with laws and regulations 
applicable to the conduct of clinical studies pertaining to the use of electronic records and 
signatures. Database backups are performed regularly. 
 
The Investigator provides his/her electronic signature on the appropriate eCRFs in 
compliance with local regulations. A written signature on printouts of the eCRFs must also 
be provided if required by local regulation. Changes to data previously submitted to the 
Sponsor require a new electronic signature by the Investigator acknowledging and approving 
the changes. 
 
Visual and/or electronic data review will be performed to identify possible data discrepancies. 
Manual and/or automatic queries will be created in the EDC system and will be issued to the 
center for appropriate response. Center staff will be responsible for resolving all queries in 
the database.  
 
Each study subject will be assured of signing the informed consent before participating in the 
study. Any missed follow-up, missed trial, missed test and correction of error and missing 
data will be clearly and faithfully recorded. 

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13.2. Data Retention 
The Principal Investigator or his/her designee will maintain, at the investigative site, all 
essential study documents and source documentation that support the data collected on the 
study subjects. Documents must be retained for 10 years after the formal discontinuation of 
the clinical investigation of the product. These documents will be retained by BSC until the 
product/device is no longer in use in compliance with local regulations.  
 
BSC will notify investigators and study sites the retention time of the documents. The 
investigators and study sites will take measures to ensure that these essential documents are 
not accidentally damaged or destroyed. If for any reason the investigators and study sites 
withdraw responsibility for maintaining these essential documents, custody must be 
transferred to an individual who will assume responsibility and BSC must receive written 
notification of this custodial change. 
13.3. Core Laboratory 
The STOPPER China clinical trial will use a Core Laboratory to conduct independent data 
analysis. See the Manuel of Operations for operating guide on data collection, analysis and 
interpretation. 
 
The independent Core Laboratory will assess the tumor response using EASL and mRECIST 
criteria (at baseline, 30-day, 3-month, 6-month and 12-month post initial treatment) based on 
the plain scan and enhanced MRI imaging performed for subjects enrolled at respective study 
sites. 
 
14.  Protocol Amendments 
If a protocol revision is necessary which affects the rights, safety or welfare of the subjects or 
scientific integrity of the data, an amendment is required. Appropriate approvals (e.g., 
IEC/CFDA) of the revised protocol must be obtained prior to implementation. 
 
15.  Protocol Deviations 
An Investigator must not make any changes or deviate from this protocol, except to protect 
the life and physical well-being of a subject in an emergency. An investigator shall notify the 
Sponsor and the reviewing IEC of any deviation from the investigational plan to protect the 
life or physical well-being of a subject in an emergency, and those deviations which affect 
the scientific integrity of the clinical investigation. Such notice shall be given as soon as 
possible, but no later than 5 working days after the emergency occurred, or per prevailing 
local requirements, if sooner than 5 working days.  
 
All deviations from the investigational plan, with the reason for the deviation and the date of 
occurrence, must be documented and reported to the Sponsor using the EDC CRF.  Centers 
may also be required to report deviations to the IEC, per local guidelines and government 
regulations. 

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All protocol deviations (PDs) are classified as “major” or “minor” as defined below:  
 A major PD is a protocol deviation that directly or potentially disrupts the study progress 
(i.e., the study design, study data and results can be compromised), OR a protocol 
deviation that compromises the safety and welfare of study participants. 
 A minor PD is a protocol deviation that does not disrupt study progress (i.e., the study 
design, study data and results will not be compromised), AND does not compromise the 
safety and welfare of study participants. 
 
The sponsor should ensure all investigators participating in the clinical trial will strictly 
follow the study protocol, and should notify and correct any non-compliance activity to 
relevant law and regulations, China Medical Device GCP and study protocol conducted by 
the study site and investigator. The sponsor should terminate the study if the violation is 
serious or continue, and report to provincial and city food and drug supervision and 
administration department and CFDA. 
 
16.  Device Accountability 
The investigational devices/equipment shall be securely maintained, controlled, and used 
only in this clinical study. The investigational medical device should be properly labeled as 
“Investigational use”. The sponsor shall keep records to document the physical location of all 
investigational Tandem microspheres from shipment of investigational devices from BSC or 
designated facility/equipment to the investigation sites until return or disposal. 
 
The principal investigator or an authorized designee shall keep records documenting the 
receipt, use, return and disposal of the investigational devices/equipment, which shall include 
the following 
 Date of receipt 
 Identification of each investigational device (batch number or unique code) 
 Expiry date 
 Date or dates of use 
 Subject identification 
 Date of return (and number) of unused, expired, or malfunctioning investigational 
devices/equipment, if applicable. Written documents are required per country regulation 
 
17.  Compliance 
17.1. Statement of Compliance 
This study will be conducted in accordance with ISO 14155:2011 (2nd Edition; 2011-02-01) 
Clinical Investigation of Medical Devices for Human Subjects- GCP, or the relevant parts of 
the ICH Guidelines for GCP, ethical principles that have their origins in the Declaration of 

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Helsinki, and pertinent China’s laws and regulations. The study shall not begin until the 
required approval/favorable opinion from the IRB/IEC and/or regulatory authority has been 
obtained, if appropriate. Any additional requirements imposed by the IRB/IEC or regulatory 
authority shall be followed, if appropriate. 
17.2. Investigator Responsibilities 
The Principal Investigator of an investigational site is responsible for ensuring that the study 
is conducted in accordance with the Clinical Study Agreement, the clinical investigation plan, 
ISO 14155 or ICH/GCP, ethical principles that have their origins in the Declaration of 
Helsinki, any conditions of approval imposed by the reviewing IEC, and prevailing local 
and/or country laws and/or regulations, whichever affords the greater protection to the 
subject. 
The Principal Investigator’s responsibilities include, but are not limited to, the following.  
 Prior to beginning the study, sign the Clinical Study Agreement and comply with the 
Investigator responsibilities as described in such Agreement. 
 Prior to beginning the study, sign the Investigator Brochure Signature Page and Protocol 
Signature page documenting his/her agreement to conduct the study in accordance with 
the protocol. 
 Provide his/her qualifications and experience to assume responsibility for the proper 
conduct of the study and that of key members of the site team through up-to-date 
curriculum vitae or other relevant documentation and disclose potential conflicts of 
interest, including financial, that may interfere with the conduct of the clinical study or 
interpretation of results. 
 Make no changes in or deviate from this protocol, except to protect the life and physical 
well-being of a subject in an emergency; document and explain any deviation from the 
approved protocol that occurred during the course of the clinical investigation. 
 Create and maintain source documents throughout the clinical study and ensure their 
availability with direct access during monitoring visits or audits; ensure that all clinical-
investigation-related records are retained per requirements. 
 Ensure the accuracy, completeness, legibility, and timeliness of the data reported to the 
Sponsor in the CRFs and in all required reports. 
 Record, report, and assess (seriousness and relationship to the device/procedure) every 
adverse event and observed device deficiency; and provide analysis report, which 
includes the causality assessed by both investigator and BSC and decision on study 
continuance, to IRB/EC per local and/or country requirements. 
 Report all SAEs and device deficiencies that could have led to a SAE and 
potential/USADE or UADE to BSC by written documents, per the protocol requirements.  
 Report to the IEC and regulatory authorities any SAEs and device deficiencies that could 
have led to a SADE and potential/USADE or UADE, if required by the national 
regulations or this protocol or by the IEC, and supply BSC with any additional requested 

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information related to the safety reporting of a particular event; provide all required 
source documents related to a death event to BSC and the IEC per local requirements. 
Maintain the device accountability records and control of the investigational device, 
ensuring that the investigational device is used only by authorized/designated users and in 
accordance with this protocol and instructions/directions for use. 
 Allow the Sponsor and Sponsor representatives to perform monitoring and auditing 
activities, and be accessible to the clinical research monitor or auditor and respond to 
questions during monitoring visits. 
 Allow and support regulatory authorities and the IEC when performing auditing activities. 
 Ensure that informed consent is obtained in accordance with this protocol and local IEC 
requirements. 
 Provide adequate medical care to a subject during and after a subject’s participation in a 
clinical study in the case of adverse events, as described in the ICF. 
 Inform the subject of the nature and possible cause of any adverse events experienced. 
 Inform the subject of any new significant findings occurring during the clinical 
investigation, including the need for additional medical care that may be required. 
 Provide the subject with well-defined procedures for possible emergency situations 
related to the clinical study, and make the necessary arrangements for emergency 
treatment as needed. 
 Ensure that clinical medical records are clearly marked to indicate that the subject is 
enrolled in this clinical study. 
 Ensure that, if appropriate, subjects enrolled in the clinical investigation are provided 
with some means of showing their participation in the clinical investigation, together with 
identification and compliance information for concomitant treatment measures (contact 
address and telephone numbers shall be provided). 
 Inform, with the subject’s approval or when required by national regulations, the 
subject’s personal physician about the subject’s participation in the clinical investigation. 
 Make all reasonable efforts to ascertain the reason(s) for a subject’s premature 
withdrawal from clinical investigation while fully respecting the subject’s rights. 
 Ensure that an adequate investigation center team and facilities exist and are maintained 
and documented during the clinical investigation. 
 Ensure that maintenance and calibration of the equipment relevant for the assessment of 
the clinical investigation is appropriately performed and documented, where applicable. 
17.2.1.  Delegation of Responsibility 
When specific tasks are delegated by an investigator (including but not limited to conducting 
the informed consent process), the Principal Investigator is responsible for providing 
appropriate training and adequate supervision of those to whom tasks are delegated. The 

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investigator is accountable for regulatory violations resulting from failure to adequately 
supervise the conduct of the clinical study. 
17.3. Institutional Review Board/ Ethics Committee 
A copy of the written IRB/EC and/or competent authority approval of the protocol (or 
permission to conduct the study) and Informed Consent Form, must be received by the 
sponsor before recruitment of subjects into the study and shipment of investigational 
product/equipment.  
 
Prior approval must also be obtained for other materials related to subject recruitment or 
which will be provided to the subject. 
 
Annual IRB/EC approval and renewals will be obtained throughout the duration of the study 
as required by local/country or IRB/EC requirements. Copies of the Investigator’s reports 
and the IRB/EC continuance of approval must be provided to the sponsor. 
17.4. Sponsor Responsibilities 
All information and data sent to BSC concerning subjects or their participation in this study 
will be considered confidential by BSC. Only authorized BSC personnel or a BSC 
representative including, but not limited to Contract Research Organization (CRO) will have 
access to these confidential records. Authorized regulatory personnel have the right to inspect 
and copy all records pertinent to this study. Study data collected during this study may be 
used by BSC for the purposes of this study, publication, and to support future research and/or 
other business purposes. All data used in the analysis and reporting of this study will be 
without identifiable reference to specific subject name. 
 
Boston Scientific will keep subjects’ identifiable health information confidential in 
accordance with all applicable laws and regulations.  Boston Scientific may use subjects’ 
health information to conduct this research, as well as for additional purposes, such as 
overseeing and improving the performance of its device, new medical research and proposals 
for developing new medical products or procedures, and other business purposes. 
Information received during the study will not be used to market to subjects; subject names 
will not be placed on any mailing lists or sold to anyone for marketing purposes. 
17.5. Insurance 
BSC will obtain insurance coverage for subjects in the study as per China’s regulatory 
requirement. In case the study related injury occurs, the study site will be responsible for the 
claim process in accordance with the relevant insurance process, and BSC will assume 
corresponding responsibilities according to the insurance clause, except that the injury is due 
to protocol violation or intended/serious negligence by study site. 
 

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18.  Monitoring 
Monitoring will be performed during the study according to the monitoring plan to assess 
continued compliance with the approved protocol/modifications and applicable regulations. 
In addition, the clinical research monitor will verify the informed consent of all enrolled 
participants at study sites, study records are adequately maintained, that data are reported in a 
satisfactory manner with respect to timeliness, adequacy, and accuracy, and that the Principal 
Investigator continues to have sufficient staff and facilities to conduct the study safely and 
effectively. The monitoring frequency will be increased and/or relevant corrective measures 
will be conducted if protocol violation and compliance exceeded the pre-specified setting. 
For this study, the source document includes at least, but not limited to: signed informed 
consent (ICF), subject’s original medical records, imaging results (if any), laboratory results, 
SAEs report and device inventory form. The device deficiencies recorded on the CRF, the 
relationship between AE and study device, and procedure and ADE prediction assessment 
related data can be regarded as the study’s source data 
 
The Principal Investigator/institution guarantees direct access to original digital or paper 
source documents (digital source document refers to the scanned document with physician’s 
signature conformation, paper source document refers to traditional handwriting medical 
record) by BSC personnel, their designees, and appropriate regulatory authorities. The copy 
of the source medical record must be verified if the original source medical record is 
unavailable due to subject’s visiting to the non-study site and non-study investigator. As 
described in Section 20, SAE related original record (from study site or non-study hospital if 
applicable) should be obtained and forwarded to BSC’s safety affairs office. 
 
The study may also be subject to a quality assurance audit by BSC or its designees, as well as 
inspection by appropriate regulatory authorities. It is important that the Principal Investigator 
and relevant study personnel are available during on-site monitoring visits or audits and that 
sufficient time is devoted to the process. 
 
19.  Potential Risks and Benefits 
19.1. Anticipated Adverse Events 
The following anticipated adverse events (AE) have been identified for this study： 
1. Vascular embolization is a high risk procedure. The procedure should be performed by 
specialized physicians trained in vascular embolization procedures. Complications can occur 
at any time during or after the procedure, and may include, but not limited to: 
Table 19.1-1：Potential complications and incidence rates 
Potential complication 
Incidence rates 
Post-embolization syndrome 
24.7% 
Liver abscess 
2.3-7.4% 
Liver failure 
1.2-4.6% 
Cholecystitis 
0.9-5.4% 

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Pancreatitis 
0.9-3.8% 
Renal complication 
1.3-2.8% 
Hypertension 
5% 
Myocardial infarction 
0.3-2.2% 
Vascular complication(include vessel injury and incision 
hematoma) 
2.4 -3% 
Non-target embolization 
1.8% 
Pulmonary embolism 
0.6-1.8% 
Pleural effussion 
4% 
Infection 
0.9-6% 
Death 
0-2.4% 
  * Definition of the post-embolization syndrome: symptoms of nausea, vomiting, local pain, 
fever, reflex intestinal distention or paralytic ileus and loss of appetite due to ischemic 
necrosis post tumor and organ embolization. 
 
2. Drug related adverse events observed in the clinical trials of epirubicin include (but not 
limited to): 
 Infection and infestation：infection 
 Benign and malignant tumor：acute lymphocytic leukemia，acute myeloid leukemia 
 Abnormal blood and lymphatic system：anemia、thrombopenia、febrile neutropenia、
neutropenia、leucopenia 
 Metabolic and nutritional abnormalities：anorexia 
 Eye abnormalities：conjunctivitis/keratitis 
 Abnormal cardiac function：congestive heart failure、ventricular tachycardia、
atrioventricular block、bundle branch block、bradycardia 
 Vascular anomaly：hot flashes、thrombus 
 Gastrointestinal tract abnormalities：nausea/vomiting、mucositis/stomatitis、diarrhea 
 Abnormal skin and subcutaneous tissue：alopecia、local toxicity、rash/itching、skin 
changes 
 Reproductive system and breast abnormalities：amenorrhoea 
 Abnormal systemic and drug delivery site：discomfort/fatigue、fever 
 Exam：asymptomatic left ventricular ejection fraction reduction，changes in the level 
of aminotransferase 
19.2. Risk Minimization Actions 
Additional risks may exist. Risks can be minimized through compliance with this protocol, 
performing procedures in the appropriate hospital environment, adherence to subject 
selection criteria, close monitoring of the subject's physiologic status during research 
procedures and/or follow-ups and by promptly supplying BSC with all pertinent information 
required by this protocol. 

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19.3. Anticipated Benefits 
Transcatheter Arterial  Chemoembolization (TACE) is expected to improve the survival in 
localized HCC patients. The patient’s health and medical status will be closely monitored, 
and may benefit from the tests that are performed as part of the study.  The data resulting 
from participation may be of a great value and help physicians and future patients. 
19.4. Benefit-Risk Ratio 
The Tandem microspheres will only be used for anticipated IFU. There are no unacceptable 
residual risks/intolerable risks and all applicable risks have been addressed through the 
provision of appropriate Directions for Use (DFU).  Evaluation of the risks and benefits that 
are expected to be associated with use of the Tandem microspheres demonstrate that when 
used under the conditions intended, the benefits associated with use of the Tandem 
microspheres should outweigh the risks. 
20.  Safety Reporting 
20.1. Events reported by investigator to sponsor 
It is the responsibility of the investigator to assess and report to BSC any event which occurs 
in any of following categories: 
 All Serious Adverse Events 
 All Investigational Device Deficiencies  
 Unanticipated Adverse Device Effects/Unanticipated Serious Adverse Device Effects 
 New findings/updates in relation to already reported events 
When possible, the medical diagnosis should be reported as the Event Term instead of 
individual symptoms. 
If it is unclear whether or not an event fits one of the above categories, or if the event cannot 
be isolated from the device or procedure, it should be submitted as an adverse event and/or 
device deficiency. 
Any AE event required by the protocol, experienced by the study subject after informed 
consent and once considered enrolled in the study (as defined in study subject classification 
section), whether during or subsequent to the procedure, must be recorded in the eCRF. 
Underlying diseases are not reported as AEs unless there is an increase in severity of 
frequency during the course of the investigation. For centers in Austria cancer must always 
be reported as a Serious Adverse Event. Death should not be recorded as an AE, but should 
only be reflected as an outcome of ONE (1) specific SAE (see Table 20.2-1 for AE 
definitions). 
Refer to Section 19 for the known risks associated with the study device(s). 
In-patient hospitalization is defined as the subjects being admitted to the hospital, with the 
following exceptions. 

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 A hospitalization that is uncomplicated and elective/planned (i.e., planned prior to 
enrollment) does not have to be reported as an SAE. 
• 
If complications or AEs occur during an elective/planned (i.e., planned prior to 
enrollment) hospitalization after enrollment, the complications and AEs must be reported 
as AEs or SAEs if they meet the protocol-specified definitions. However, the original 
elective/planned hospitalization(s) itself should not be reported as an SAE.  
20.2. Definitions and Classification 
Safety definitions are provided in Table 20.2-1 with reference from ISO 14155-2011 and 
MEDDEV 2.7/3 12/2010. 
 
Table 20.2-1: Safety Reporting Definitions 
Term 
Definition 
Adverse Event (AE) 
 
Ref: ISO 14155-2011 
 
 
 
Any untoward medical occurrence, unintended disease or 
injury, or any untoward clinical signs (including an abnormal 
laboratory finding) in subjects, users or other persons, whether 
or not related to the investigational medical device.  
NOTE 1: This includes events related to the investigational 
medical device or comparator. 
NOTE 2: This definition includes events related to the 
procedures involved (any procedure in the clinical investigation 
plan). 
NOTE 3: For users or other persons, this definition is restricted 
to events related to the investigational medical device.  
Adverse Device Effect 
(ADE) 
 
Ref: ISO 14155-2011 
 
 
Adverse event related to the use of an investigational medical 
device 
NOTE 1: This includes any adverse event resulting from 
insufficiencies or inadequacies in the instructions for use, the 
deployment, the implantation, the installation, the operation, or 
any malfunction of the investigational medical device. 
NOTE 2: This definition includes any event resulting from use 
error or intentional abnormal use of the investigational medical 
device. 
Serious Adverse Event 
(SAE) 
 
Ref: ISO 14155-2011 
 
 
Adverse event that: 
 Led to death, 
 Led to  serious deterioration in the health of the subject, that 
either resulted in: 
a life-threatening illness or injury, or 
a permanent impairment of a body structure or a body function, 

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Table 20.2-1: Safety Reporting Definitions 
Term 
Definition 
or 
in-patient hospitalization or prolongation of existing 
hospitalization of existing hospitalization, or 
medical or surgical intervention to prevent life-threatening 
illness or injury or permanent impairment to a body structure or 
a body function 
 Led to fetal distress, fetal death, or a congenital abnormality or 
birth defect. 
NOTE 1: Planned hospitalization for a pre-existing condition, 
or a procedure required by the clinical investigational plan, 
without serious deterioration in health, is not considered a 
serious adverse event.  
Serious Adverse Device 
Effect (SADE) 
 
Ref: ISO 14155-2011 
 
 
Adverse device effect that has resulted in any of the 
consequences characteristic of a serious adverse event. 
Unanticipated Adverse 
Device Effect (UADE) 
 
Ref: 21 CFR Part 812 
 
 
Any serious adverse effect on health or safety or any life-
threatening problem or death caused by, or associated with, a 
device, if that effect, problem, or death was not previously 
identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary 
plan or application), or any other unanticipated serious problem 
associated with a device that relates to the rights, safety, or 
welfare of subjects.   
Unanticipated Serious 
Adverse Device Effect 
(USADE) 
 
Ref: ISO 14155-2011 
 
 
 
Serious adverse device effect which by its nature, incidence, 
severity, or outcome has not been identified in the current 
version of the risk analysis report. 
NOTE 1: Anticipated serious adverse device effect (ASADE) is 
an effect which by its nature, incidence, severity or outcome 
has been identified in the risk analysis report. 
Device Deficiency 
 
Ref: ISO 14155-2011 
 
 
Inadequacy of a medical device related to its identity, quality, 
durability, reliability, safety or performance. This may include 
malfunctions, use error, or inadequacy in the information 
supplied by the manufacturer. 
NOTE 1:  All device deficiencies that could have led to a 
SADE if a) suitable action had not been taken or b) if 

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Table 20.2-1: Safety Reporting Definitions 
Term 
Definition 
intervention had not been made or c) if circumstances had been 
less fortunate shall be reported as required by the local IRB/EC, 
national regulations, or the protocol. 
 
20.3. Relationship to Study Device(s) 
The Investigator must assess the relationship of the AE to the study device, epirubicin or 
procedure. See criteria in Table 20.3-1 

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Table 20.3-1: Criteria for Assessing Relationship of Study Device or Procedure to 
Adverse Event 
Classification 
Description 
Not Related 
Relationship to the device or procedures can be excluded when: 
- the event is not a known side effect of the product category the device 
belongs to or of similar devices and procedures; 
- the event has no temporal relationship with the use of the 
investigational device or the procedures; 
- the serious event does not follow a known response pattern to the 
medical device (if the response pattern is previously known) and is 
biologically implausible; 
- the discontinuation of medical device application or the reduction of 
the level of activation/exposure - when clinically feasible – and 
reintroduction of its use (or increase of the level of 
activation/exposure), do not impact on the serious event; 
- the event involves a body-site or an organ not expected to be affected 
by the device or procedure; the serious event can be attributed to 
another cause (e.g. an underlying 
or concurrent illness/ clinical condition, an effect of another device, 
drug, treatment or other risk factors); 
- the event does not depend on a false result given by the 
investigational device used for diagnosis, when applicable; harms to the 
subject are not clearly due to use error; 
- In order to establish the non-relatedness, not all the criteria listed 
above might be met at the same time, depending on the type of 
device/procedures and the serious event. 
Unlikely Related 
The relationship with the use of the device seems not relevant and/or 
the event can be reasonably explained by another cause, but additional 
information may be obtained. 
Possibly Related 
The relationship with the use of the investigational device is weak but 
cannot be ruled out completely. Alternative causes are also possible 
(e.g. an underlying or concurrent illness/ clinical condition or/and an 
effect of another device, drug or treatment). Cases were relatedness 
cannot be assessed or no information has been obtained should also be 
classified as possible. 
Probably Related 
The relationship with the use of the investigational device seems 
relevant and/or the event cannot reasonably explained by another cause, 
but additional information may be obtained. 
Causal 
Relationship 
The serious event is associated with the investigational device or with 
procedures beyond reasonable doubt when: 
- the event is a known side effect of the product category the device 

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Classification 
Description 
belongs to or of similar devices and procedures; 
- the event has a temporal relationship with investigational device 
use/application or procedures; 
- the event involves a body-site or organ that 
o the investigational device or procedures are applied to; 
o the investigational device or procedures have an effect on; 
- the serious event follows a known response pattern to the medical 
device (if the response pattern is previously known); 
- the discontinuation of medical device application (or reduction of the 
level of activation/exposure) and reintroduction of its use (or increase 
of the level of activation/exposure), impact on the serious event (when 
clinically feasible); 
- other possible causes (e.g. an underlying or concurrent illness/ clinical 
condition or/and an effect of another device, drug or treatment) have 
been adequately ruled out; 
- harm to the subject is due to error in use; 
- the event depends on a false result given by the investigational device 
used for diagnosis, when applicable; 
- In order to establish the relatedness, not all the criteria listed above 
might be met at the same time, depending on the type of 
device/procedures and the serious event. 
20.4.  Investigator Reporting Requirements 
The communication requirements for reporting to BSC are as shown in Table 20.4-1. 
 
Table 20.4-1: Investigator Reporting Requirement 
Event 
Classification 
Communication Method  
Communication Timeline pre-
market studies* 
Unanticipated 
Adverse Device 
Effect  / 
Unanticipated Serious 
Adverse Device 
Effect  
Complete AE eCRF page 
with all available new and 
updated information.  
• 
Within 24 hours of first 
becoming aware of the event 
• 
Terminating at the end of the 
study 
Serious Adverse 
Event  
Complete AE eCRF page 
with all available new and 
updated information.  
• 
Within 24 hours of first 
becoming aware of the event 
• 
Reporting required through 
the end of the study 

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Event 
Classification 
Communication Method  
Communication Timeline pre-
market studies* 
Provide all relevant source 
documentation (unidentified) 
for reported event  
When source document is 
available. 
Serious Adverse 
Device Effects 
Complete AE eCRF page 
with all available new and 
updated information.  
• 
Within 24 hours of first 
becoming aware of the event 
• 
Reporting required through 
the end of the study 
Provide all relevant source 
documentation (unidentified) 
for reported event  
When source document is 
available. 
Device Deficiencies 
(including but not 
limited to failures, 
malfunctions, and 
product 
nonconformities) 
Note:  Any 
Investigational 
Device Deficiency 
that might have led to 
a serious adverse 
event if a) suitable 
action had not been 
taken or b) 
intervention had not 
been made or c) if 
circumstances had 
been less fortunate is 
considered a 
reportable event. 
Complete device malfunction 
page with all available new 
and updated information.  
 
Within 24 hours of first 
becoming aware of the event.  
 
Reporting required through 
the end of the study 
Adverse Event 
including Adverse 
Device Effects 
Complete AE eCRF page, 
which contains such 
information as date of AE, 
treatment of AE resolution, 
assessment of seriousness and 
relationship to the device.  
 
In a timely manner  but no 
later than 10 business days 
after becoming aware of the 
information 
 
 
 
Reporting required through 
the end of the study.  

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Abbreviations: AE=adverse event; CRF=case report form; IDE=Investigational Device Exemption; 
UADE=unanticipated adverse device effect 
20.5. Boston Scientific Device Deficiencies 
All device deficiencies (including but not limited to failures, malfunctions, use errors, 
product nonconformities, and inadequacy in the information supplied by the manufacturer) 
will be documented and reported to BSC. If possible, the device(s) should be returned to 
BSC for analysis. Instructions for returning the investigational device(s) will be provided in 
Device Management Plan. If it is not possible to return the device, the investigator should 
document why the device was not returned and the final disposition of the device. Device 
failures and malfunctions should also be documented in the subject’s medical record. 
 
Device deficiencies (including but not limited to failures, malfunctions, and product 
nonconformities) should not be reported as AEs. Instead, they should be reported on the 
appropriate eCRF. If an AE results from a device deficiency or other device issue, the AE 
must be reported on the appropriate eCRF. 
 
Device deficiencies that did not lead to an AE but could have led to a SAE if a) suitable 
action had not been taken, or b) intervention had not been made, or c) circumstances had 
been less fortunate must be reported as described in Table 20.4-1. 
20.6. Reporting to Regulatory Authorities/IRBs/ECs/ Investigators 
The Principal Investigator is responsible for informing the IRB/EC, and regulatory 
authorities of UADE and SAE as required by local/regional regulations. 
According to China local reporting requirements, Boston Scientific Corporation will report 
all SAEs  and device deficiencies that could lead to SAEs to the local regulatory authorities 
within 5 business days of BSC first becoming aware of the event, and notify all participating 
investigators/sites and IRBs/ECs in a timely manner.  
BSC shall notify all participating Chinese study centers if SAEs/SADEs occur which imply a 
possible increase in the anticipated risk of the procedure or use of the device or if the 
occurrence of certain SAEs/SADEs demands changes to the protocol or the conduct of the 
study in order to further minimize the unanticipated risks. 
 
21.  Informed Consent 
Subject participation in this clinical study is voluntary.  Informed Consent is required from 
each subject or his/her legally authorized representative. The Investigator is responsible for 
ensuring that Informed Consent is obtained prior to the use of any investigational devices, 
study-required procedures and/or testing, or data collection (except any screening tests 
waived in the protocol).  
 
The obtaining and documentation of Informed Consent must be in accordance with the 
principles of the Declaration of Helsinki; the relevant parts of ISO 14155: 2011 and the ICH 
guidelines for GCP; any applicable national regulations; and local Ethics Committee and/or 

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Regulatory authority body, as applicable. The ICF must be approved by the site’s IEC, if 
applicable. 
 
Boston Scientific Corporation will provide a study-specific template of the ICF to 
investigators participating in this study. The ICF template may be modified to meet the 
requirements of the investigative site’s IEC.  Any modification requires acceptance from 
BSC or authorized representative prior to use of the form. The ICF must be in a language 
understandable to the subject and if needed, BSC will assist the site in obtaining a written 
consent translation. Translated consent forms must also have IEC approval prior to their use. 
Privacy language shall be included in the body of the form or as a separate form as applicable.   
 
The process of obtaining Informed Consent shall: 
 be conducted by the Principal Investigator or designee authorized to conduct the process, 
 include a description of all aspects of the clinical study that are relevant to the subject’s 
decision to participate throughout the clinical study, 
 avoid any coercion of or undue influence of subjects to participate, 
 not waive or appear to waive subject’s legal rights, 
 use native language that is non-technical and understandable to the subject or his/her 
legal representative, 
 provide ample time for the subject to consider participation and ask questions if 
necessary, 
 ensure important new information is provided to new and existing subjects throughout 
the clinical study. 
 
The ICF shall always be signed and personally dated by the subject or legal representative 
and by the investigator or an authorized designee responsible for conducting the informed 
consent process. If a legal representative signs, the subject shall be asked to provide informed 
consent for continued participation as soon as his/her medical condition allows. The original 
signed ICF will be retained by the site and a copy of the signed and dated document and any 
other written information must be given to the person signing the form.  
Failure to obtain subject consent will be reported by BSC to the applicable regulatory body 
according to their requirements. Any violations of the informed consent process must be 
reported as deviations to the Sponsor and local regulatory authorities (e.g. IEC), as 
appropriate. 
 
If new information becomes available that can significantly affect a subject's future health 
and medical care, that information shall be provided to the affected subject(s) in written form 
via a revised ICF or, in some situations, enrolled subjects may be requested to sign and date 
an addendum to the ICF. In addition to new significant information during the course of a 
study, other situations may necessitate revision of the ICF, such as if there are amendments 
to the protocol, a change in Principal Investigator, administrative changes, or following 

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annual review by the IEC. The new version of the ICF must be approved by the IEC. 
Acceptance by Boston Scientific Corporation is required if changes to the revised ICF are 
requested by the site’s IEC. The IEC will determine the subject population to be re-consented. 
22. 
 Committee 
22.1. Executive Committee 
An Executive Committee composed of BSC Clinical Management, study Principal 
Investigator will be convened.  This committee will be responsible for the overall conduct of 
the study which will include protocol development, study progress, subject safety, overall 
data quality and integrity, and timely dissemination of study results through appropriate 
scientific sessions and publications.  As appropriate the Executive Committee may request 
participation of STOPPER CHINA Investigators on the Committee. 
22.2. Safety Monitoring Process 
To promote early detection of safety issues, the BSC Safety team and its delegated CRO 
Safety team will provide review, process, monitor and evaluation of the safety events defined 
in the study-specific safety plan. Success of this program requires dynamic collection of 
unmonitored data as soon as the event is reported. During regularly scheduled monitoring 
activities, clinical research monitors will support the dynamic reporting process through their 
review of source document and other data information. The BSC Medical Safety group 
includes physicians with the necessary therapeutic and subject matter expertise to evaluate 
and classify the events into the categories outlined above. 
 
23.  Suspension or Termination 
23.1. Premature Termination of the Study 
Boston Scientific Corporation reserves the right to terminate the study at any stage but 
intends to exercise this right only for valid scientific or administrative reasons and reasons 
related to protection of subjects.  Investigators, associated IRBs/ECs, and regulatory 
authorities, as applicable, will be notified in writing in the event of study termination. 
23.1.1. Criteria for Premature Termination of the Study 
Possible reasons for premature study termination include, but are not limited to, the 
following. 
 Important new information affecting continuation of the study (Such as safety and device 
performance) 
 The occurrence of unanticipated adverse device effects that present a significant or 
unreasonable risk to subjects enrolled in the study. 
 A decision on the regulatory authority to terminate this study early.  

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 A decision on the part of Boston Scientific to suspend or discontinue development of the 
device.  
 An enrollment rate far below expectation that prejudices the conclusion of the study. 
Note：According to protocol requirement listed in Section 20, the assessment and report of 
AE、SAE、SADE and device deficiencies in subjects receiving study devices need to be 
continued even if the study has been terminated.      
23.2. Termination of Study Participation by the Investigator or 
Withdrawal of IRB/ EC Approval 
Any investigator, or IRB/ EC in the STOPPER Study may discontinue participation in the 
study or withdrawal approval of the study, respectively, with suitable written notice to 
Boston Scientific. Investigators, associated IRBs/ECs, and regulatory authorities, as 
applicable, will be notified in writing in the event of these occurrences. 
23.3. Requirements for Documentation and Subject Follow-up 
In the event of premature study termination a written statement as to why the premature 
termination has occurred will be provided to all participating sites by Boston Scientific. The 
IRB/EC and regulatory authorities, as applicable, will be notified. Detailed information on 
how enrolled subjects will be managed thereafter will be provided.  
In the event an IRB or EC terminates participation in the study, participating investigators, 
associated IRBs/ECs, and regulatory authorities, as applicable, will be notified in writing. 
Detailed information on how enrolled subjects will be managed thereafter will be provided 
by Boston Scientific. 
In the event a Principal Investigator terminates participation in the study, study responsibility 
will be transferred to another investigator, if possible. In the event there are no opportunities 
to transfer Principal Investigator responsibility; detailed information on how enrolled 
subjects will be managed thereafter will be provided by Boston Scientific. 
The Principal Investigator or his/her designee must return all study-related documents and 
investigational product to Boston Scientific, unless this action would jeopardize the rights, 
safety, or welfare of the subjects. 
23.4. Criteria for Suspending/Terminating a Study Site  
Boston Scientific Corporation reserves the right to stop the inclusion of subjects at a study 
site at any time after the study initiation visit if no subjects have been enrolled  for a period 
beyond 3 months after site initiation, or if the site has multiple or severe protocol 
violations/noncompliance without justification and/or fails to follow remedial actions. 
In the event of termination of site participation, all study devices and testing equipment, as 
applicable, will be returned to BSC unless this action would jeopardize the rights, safety or 
well-being of the subjects. The IRB/EC and regulatory authorities, as applicable, will be 
notified. All subjects enrolled in the study at the site will continue to be followed for 12 

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months. The Principal Investigator at the site must make provision for these follow-up visits 
unless BSC notifies the investigational site otherwise. 
 
According to Section 20, all study participants who have received study device treatment will 
need continuous adverse events assessment and report. The principal investigators at study 
sites need to continue the follow-up unless being notified by Boston Scientific. 
 
24.  Publication Policy 
BSC requires disclosure of its involvement as a sponsor or financial supporter in any 
publication or presentation relating to a BSC study or its results. BSC will submit study 
results for publication (regardless of study outcome) following the conclusion or termination 
of the study. Boston Scientific Corporation adheres to the Contributorship Criteria set forth in 
the Uniform Requirements of the International Committee of Medical Journal Editors 
(ICMJE; http://www.icmje.org). In order to ensure the public disclosure of study results in a 
timely manner, while maintaining an unbiased presentation of study outcomes, BSC 
personnel may assist authors and investigators in publication preparation provided the 
following guidelines are followed. 
 
 All authorship and contributorship requirements as described above must be followed. 
 BSC involvement in the publication preparation and the BSC Publication Policy should 
be discussed with the Coordinating Principal Investigator(s) and/or Executive/Steering 
Committee at the onset of the project. 
 The First and Senior authors are the primary drivers of decisions regarding publication 
content, review, approval, and submission. 
 
25.  Reimbursement and Compensation for Subjects 
25.1. Subject Reimbursement 
Travel and other expenses incurred by subjects as a result of participation in the study will be 
reimbursed in accordance with pertinent country laws and regulations and per the study site’s 
regulations.   
25.2. Compensation for Subject’s Health Injury 
Boston Scientific Corporation will purchase an insurance policy to cover the cost of potential 
health injury for study subjects, and if required by applicable law. 
 
 

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26.  Literature 
1. 
Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin. 
Mar-Apr 2005;55(2):74-108. 
2. 
Verslype C, Rosmorduc O, Rougier P, et al. Hepatocellular carcinoma: ESMO-ESDO 
Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of 
oncology : official journal of the European Society for Medical Oncology / ESMO. 
Oct 2012;23 Suppl 7:vii41-48. 
3. 
Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular 
carcinoma. N Engl J Med. Jul 24 2008;359(4):378-390. 
4. 
Cheng AL, Kang YK, Chen Z, et al. Efficacy and safety of sorafenib in patients in the 
Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, 
double-blind, placebo-controlled trial. The lancet oncology. Jan 2009;10(1):25-34. 
5. 
Lencioni R. Loco-regional treatment of hepatocellular carcinoma. Hepatology. Aug 
2010;52(2):762-773. 
6. 
Llovet JM. Updated treatment approach to hepatocellular carcinoma. J Gastroenterol. 
Mar 2005;40(3):225-235. 
7.    Bruix J, Sherman M, American Association for the Study of Liver D. Management of 
hepatocellular carcinoma: an update. Hepatology. Mar 2011;53(3):1020-1022 
8. 
Bruix J, Sherman M, Practice Guidelines Committee AAftSoLD. Management of 
hepatocellular carcinoma. Hepatology. Nov 2005;42(5):1208-1236. 
9. 
Llovet JM, Real MI, Montana X, et al. Arterial embolisation or chemoembolisation 
versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: 
a randomised controlled trial. Lancet. May 18 2002;359(9319):1734-1739. 
10. 
Lo CM, Ngan H, Tso WK, et al. Randomized controlled trial of transarterial lipiodol 
chemoembolization for unresectable hepatocellular carcinoma. Hepatology. May 
2002;35(5):1164-1171. 
11. 
Camma C, Schepis F, Orlando A, et al. Transarterial chemoembolization for 
unresectable hepatocellular carcinoma: meta-analysis of randomized controlled trials. 
Radiology. Jul 2002;224(1):47-54. 
12. 
Sakamoto I, Aso N, Nagaoki K, et al. Complications associated with transcatheter 
arterial embolization for hepatic tumors. Radiographics : a review publication of the 
Radiological Society of North America, Inc. May-Jun 1998;18(3):605-619. 
13. 
Chung JW, Park JH, Han JK, et al. Hepatic tumors: predisposing factors for 
complications of transcatheter oily chemoembolization. Radiology. Jan 
1996;198(1):33-40. 
14. 
Solomon B, Soulen MC, Baum RA, Haskal ZJ, Shlansky-Goldberg RD, Cope C. 
Chemoembolization of hepatocellular carcinoma with cisplatin, doxorubicin, 
mitomycin-C, ethiodol, and polyvinyl alcohol: prospective evaluation of response and 
survival in a U.S. population. J Vasc Interv Radiol. Jun 1999;10(6):793-798. 
15. 
Malagari K, Pomoni M, Spyridopoulos TN, et al. Safety profile of sequential 
transcatheter chemoembolization with DC Bead: results of 237 hepatocellular 
carcinoma (HCC) patients. Cardiovascular and interventional radiology. Aug 
2011;34(4):774-785. 

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16. 
Malagari K, Alexopoulou E, Chatzimichail K, et al. Transcatheter chemoembolization 
in the treatment of HCC in patients not eligible for curative treatments: midterm 
results of doxorubicin-loaded DC bead. Abdominal imaging. Sep-Oct 
2008;33(5):512-519. 
17. 
Pomoni M, Malagari K, Moschouris H, et al. Post embolization syndrome in 
doxorubicin eluting chemoembolization with DC bead. Hepatogastroenterology. May 
2012;59(115):820-825. 
18. 
Vogl TJ, Lammer J, Lencioni R, et al. Liver, gastrointestinal, and cardiac toxicity in 
intermediate hepatocellular carcinoma treated with PRECISION TACE with drug-
eluting beads: results from the PRECISION V randomized trial. AJR Am J 
Roentgenol. Oct 2011;197(4):W562-570. 
19. 
Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular 
carcinoma. Seminars in liver disease. Feb 2010;30(1):52-60. 
20.    Shim JH, Lee HC, Kim SO, et al. Which response criteria best help predict survival of 
patients with hepatocellular carcinoma following chemoembolization? A validation 
study of old and new models. Radiology. 2012; 262: 708-718 
21. 
Lammer J, Malagari K, Vogl T, et al. Prospective randomized study of doxorubicin-
eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the 
PRECISION V study. Cardiovascular and interventional radiology. Feb 
2010;33(1):41-52. 
 
 
27.  Abbreviations and Definitions 
See Table 27.1 for Abbreviations.  

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Table 27.1   Terms and Abbreviations 
AE 
Adverse Event 
ALT 
Alanine aminotransferase, Serum glutamic pyruvic transaminase 
(SGPT) 
AST 
Asparagine aminotransferase, Serum glutamic oxaloacetic transaminase 
(SGOT) 
AVM 
Arteriovenous malformation 
BCLC 
Barcelona Clinical Liver Cancer staging 
CBC 
Complete Blood Count 
CR 
Complete Response 
CRO 
Contract Research Organization 
cTACE 
Conventional transarterial chemoembolization 
CRF 
Case Report Form 
DEB-TACE 
Drug eluting bead-transarterial chemoembolization 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
GCP 
Good Clinical Practices 
HBV 
Hepatitis B virus 
HCC 
Hepatocellular Carcinoma 
HCV 
Hepatitis C virus 
ICH-GCP 
International Conference on Harmonization-Good Clinical Practices 
IDE 
Investigational Device Exemption 
INR 
International normalized ratio 
IRB 
Institutional Review Board 
IRRP 
Independent Response Review Panel 
ISO 
International Standards 
ITT 
Intent-to-Treat 
mRECIST 
Modified RECIST 
MRI 
Magnetic Resonance Imaging 
PD 
Progressive Disease 
PR 
Partial Response 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
TACE 
Transarterial chemoembolization 
TTP 
Time to Disease Progression 
UADE 
Unanticipated Adverse Device Effect 

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See Tables 27.2 for Definitions 
Table 27.2: Definitions 
Term 
Definition 
BCLC Staging System 
The Barcelona Clinic Liver Cancer Staging System is a well-accepted system 
that uses tumor stage, liver function, physical status, and cancer related 
symptoms, to classify the stages with a treatment algorithm.4 
Child-Pugh Score 
The Child-Pugh score is a measure of liver function. 4  It is calculated from the 
sum of the points for each Child Pugh Classification (CPC) criteria. See 
Appendix B 
ECOG Performance Status 
An Eastern Cooperative Oncology Group (ECOG) assessment of performance 
status describes a patient’s level of functioning in terms of their ability to care 
for them self, daily activity, and physical ability (walking, working, etc.).  See 
Appendix A. 
Investigational Device 
Boston Scientific Corporation ONCOZENE™  or TANDEM™ Microspheres 
loaded with doxorubicin 
mRECIST Criteria 
A post-treatment assessment of tumor response by magnetic resonance imaging 
(MRI) scan. See Appendix C. 
Near-Stasis 
A degree of stasis where near complete loss of intra-tumoral vascularity is 
shown by a slowed contrast flow for 2-5 heartbeats. 
Source Data  
All information in original records of clinical findings, observations, or other 
activities in a clinical investigation, necessary for the reconstruction and 
evaluation of the clinical investigation. 
Target Tumor 
The lesion can be measured in at least one dimension ≥ 1 cm; The lesion 
appears to be suitable for accurate and repeat measurement; The lesion shows 
intratumoral arterial enhancement 
 

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Attachment A:  Diagnostic criteria included in the management guideline 
issued by China’s Ministry of Health in 2017 
1. Subject diagnosed as hepatitis B or C, or liver cirrhosis of any cause should receive 
ultrasound and AFP test at least every 6 months. The clinical diagnosis of HCC can be made 
if the intrahepatic nodule of ≤2cm in diameter is identified and at least two of the following 
four tests indicate the typical “fast in and fast out” HCC characteristics with significant 
enhancement of lesion in the arterial phase and reduced enhancement of portal vein or 
delayed phase: dynamic enhancement MRI, dynamic enhancement CT, contrast-enhanced 
ultrasonography and Primovist dynamic enhancement MRI. For intrahepatic nodule of >2cm 
in diameter, the clinical diagnosis of HCC can be made if one of the four tests indicate the 
typical HCC characteristics.  
2. Subject diagnosed as hepatitis B or C, or liver cirrhosis of any cause: HCC diagnosis can 
be confirmed with liver biopsy or close imaging follow-up if the intrahepatic nodule is ≤
2cm in diameter and only one of the above four imaging tests indicate typical HCC 
characteristics; For intrahepatic nodule >2cm in diameter and no typical HCC characteristics 
by any of the four tests, the diagnosis should be confirmed by liver biopsy.  
 

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Appendix B: ECOG Performance Status 
 
Performance Status Criteria: 
ECOG and Karnofsky Performance Scores 
 
 
Score 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature (e.g. light housework, office work). 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
5 
Dead 
 

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Appendix C: Child-Pugh Score  
 
 
1 point 
2 points 
3 points 
Serum 
Bilirubin  
mg/dL 
<2 
2-3 
>3 
µmol/L 
<34.2 
34.2-51.3 
>51.3 
Serum 
Albumin  
g/dL 
>3.5 
2.8-3.5 
<2.8 
g/L 
>35 
28-35 
<28 
INR 
<1.7 
1.7-2.30 
>2.30 
Ascites 
None 
Mild 
Severe 
Hepatic encephalopathy 
None 
Grade I-II 
Grade III-IV 
Class A: 5-6 points, Class B: 7-9 points, Class C: 10-15 points 
 
 

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Appendix D：mRECIST Response Assessment of Target Lesion for HCC 
 
Target Lesions 
Response Category 
mRECIST 
CR 
Disappearance of any intratumoral arterial enhancement in all target 
lesions 
PR 
At least a 30% decrease in the sum of the diameters of viable 
(enhancement in the arterial phase) target lesions, taking as reference 
the baseline sum of the diameters of target lesions. 
SD 
Any cases that do not qualify for either PR or PD 
PD 
An increase of at least 20% in the sum of the diameters of viable 
(enhancing) target lesions, taking as a reference the smallest sum of 
the diameters of viable (enhancing) target lesions recorded since 
treatment started. 
 
 
 
 
 

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Appendix E： EASL Response Assessment of target lesion for HCC 
Response Category 
EASL Criteria 
Complete Response (CR) 
Disappearance of all known disease and no new lesions 
determined by two observations not less than 4 weeks apart 
Partial Response (PR) 
At least 50% reduction in total tumor load of all measurable 
lesions determined by two observations not less than 4 
weeks apart 
Stable Disease (SD) 
Any cases that do not qualify for either PR or PD 
Disease Progression (PD) 
At least 25% increase in size of one or more measurable 
lesions or the appearance of new lesions