A Phase III Clinical Trial of Intra-arterial TheraSphere® in the Treatment of Patients With Unresectable Hepatocellular Carcinoma (HCC)
Phase: NA
Conditions: Unresectable Hepatocellular Carcinoma
Sponsor: Boston Scientific Corporation

Boston Scientific 
ClinicalTrials.gov NCT #: NCT01556490 
Study Title: Efficacy Evaluation of TheraSphere in Patients 
With Inoperable Liver Cancer (STOP-HCC)
Approved Document Date: 22 July 2019 
Redacted Document Date: 28 April 2023 

 
 
 
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Protocol Number: 
TS-103 
Protocol Short Title: 
STOP-HCC 
Protocol Name: 
A Phase III Clinical Trial of Intra-arterial TheraSphere® in the 
Treatment 
of 
Patients 
with 
Unresectable 
Hepatocellular 
Carcinoma (HCC)  
US Sponsor: 
 
BTG International Inc. 
 
 
                                              
  
Global Sponsor: 
Biocompatibles UK Ltd 
 
 
 
 
Global Principal 
Investigator 
 
  
 
 
 
 
  
US Medical Monitor 
 
Covance 
 
 
Protocol Medical Monitor 
 
Covance 
 
 
Device:   
TheraSphere®, Yttrium-90 Glass Microspheres 
FDA File #: 
IDE 100322 
CE Mark for EU sites only 
CE 0123 
Protocol Activation Date:  
2011/03/09 (YYYY/MM/DD)  
                                                                
TheraSphere® is a trademark of Theragenics Corporation used under license by BTG International Canada Inc. BTG and the BTG 
roundel logo are trademarks of BTG International Ltd, and are registered trademarks in the US, EU and certain other territories. All 
rights reserved. 
This document is the confidential property of the Sponsor. No part of it may be transmitted, reproduced, published, or used by other 
persons without prior written authorization. 
 

 
 
 
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Amendments: 
Version 2.0 2012/01/24 (YYYY/MM/DD) 
Version 3.0 2013/09/06 (YYYY/MM/DD) 
Version 4.0 2014/03/04 (YYYY/MM/DD) 
Version 4.1 2014/05/20 (YYYY/MM/DD) 
Version 5.0 2015/01/08  (YYYY/MM/DD) 
Version 6.0 2016/08/24  (YYYY/MM/DD) 
Version 6.1 2016/11/29  (YYYY/MM/DD) 
Version 7.0 2019/07/22 (YYYY/MM/DD) 
 
 
 

 
 
 
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INVESTIGATOR’S PROTOCOL REVIEW STATEMENT 
 
By my signature, I confirm that my staff and I have carefully read and understand the protocol, A 
Phase III Clinical Trial of Intra-arterial TheraSphere in the Treatment of Patients with Unresectable 
Hepatocellular Carcinoma (HCC), and agree to conduct the trial in accordance with the protocol, the 
appropriate regulations specified in the protocol, and the stipulations of the clinical study agreement 
 
 
__________________________________________ 
 
________________ 
Investigator  
 
 
 
 
 
Date 
__________________________________________ 
 
________________ 
Investigator Printed Name 
 
 

 
 
 
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Table of Contents 
PROTOCOL APPROVAL AND RELEASE SIGNATURE PAGE .......................................................................... 3 
1.0 
PROTOCOL SYNOPSIS .................................................................................................................. 10 
2.0 
TRIAL SCHEMA ............................................................................................................................ 20 
3.0 
SCHEDULE OF EVENTS ................................................................................................................. 21 
4.0 
LIST OF ABBREVIATIONS ............................................................................................................. 24 
5.0 
BACKGROUND AND RATIONALE ................................................................................................. 26 
5.1 
GENERAL DEVICE DESCRIPTION ............................................................................................................. 26 
5.2 
GLOBAL REGULATORY STATUS OF THERASPHERE ...................................................................................... 26 
5.3 
RATIONALE FOR THE TREATMENT OF HEPATOCELLULAR CARCINOMA ............................................................ 26 
5.4 
 
 ................................................................................. 29 
6.0 
STUDY OBJECTIVE ....................................................................................................................... 29 
7.0 
STUDY DESIGN ............................................................................................................................ 30 
8.0 
STUDY POPULATION AND ELIGIBILITY CRITERIA ......................................................................... 30 
8.1 
ELIGIBILITY CRITERIA ........................................................................................................................... 30 
9.0 
STUDY VISITS, EVALUATIONS AND PROCEDURES ........................................................................ 32 
9.1 
STUDY VISITS ..................................................................................................................................... 32 
9.1.1 
Screening/Randomization (Days -14 to Day 0) ...................................................................... 32 
9.1.2 
Patients randomized to the Control Group ............................................................................ 33 
9.1.3 
Patients randomized to the Treatment Group ....................................................................... 33 
9.1.4 
Patient Completion or Early Withdrawal ............................................................................... 34 
9.2 
STUDY EVALUATIONS AND PROCEDURES ................................................................................................. 35 
9.2.1 
Potentially Eligible Patients and Informed Consent ............................................................... 35 
9.2.2 
Demographics ........................................................................................................................ 35 
9.2.3 
Medical History ...................................................................................................................... 35 
9.2.4 
Physical Examination ............................................................................................................. 35 
9.2.5 
ECOG Performance Status ..................................................................................................... 35 
9.2.6 
Child-Pugh score status ......................................................................................................... 36 
9.2.7 
Medication and Prior Treatment History ............................................................................... 36 
9.2.8 
Liver Tumor Volume Determination ...................................................................................... 36 
9.2.9 
Clinical Labs ........................................................................................................................... 36 
9.2.10 
Pregnancy Test ...................................................................................................................... 37 
9.2.11 
Review Eligibility Criteria ....................................................................................................... 37 
9.2.12 
HCC Tumor Biomarker ........................................................................................................... 37 
9.2.13 
Quality of Life ........................................................................................................................ 37 
9.2.14 
Randomization (Study Day 0) ................................................................................................ 37 
9.2.15 
Study Treatments .................................................................................................................. 38 
9.2.16 
Efficacy Imaging – CT/MRI .................................................................................................... 45 
9.2.17 
 ............................................................................... 46 
9.2.18 
Study Treatment Medication Record ..................................................................................... 46 

 
 
 
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9.2.19 
Concurrent Medication Record .............................................................................................. 46 
9.2.20 
Study completion ................................................................................................................... 46 
10.0 
STATISTICS .................................................................................................................................. 47 
10.1 
SAMPLE SIZE ESTIMATE ....................................................................................................................... 47 
10.2 
STATISTICAL ANALYSIS PLAN ................................................................................................................. 48 
10.2.1 
Populations and Sub-Groups ................................................................................................. 48 
10.2.2 
Trial Endpoints ....................................................................................................................... 48 
10.2.3 
Efficacy Analysis..................................................................................................................... 50 
10.2.4 
Safety Analyses ...................................................................................................................... 52 
10.2.5 
Poolability and Other Analyses .............................................................................................. 53 
10.2.6 
Independent Data Monitoring Committee ............................................................................ 54 
10.2.7 
 ............................................................................................ 54 
11.0 
DATA COLLECTION AND MANAGEMENT ..................................................................................... 54 
11.1 
ELECTRONIC DATA COLLECTION (EDC) ................................................................................................... 54 
11.2 
DATA MANAGEMENT .......................................................................................................................... 55 
12.0 
ADVERSE EVENTS ........................................................................................................................ 55 
12.1 
ADVERSE EVENT DEFINITIONS ............................................................................................................... 55 
12.1.1 
Definitions of AE/SAE for Drugs ............................................................................................. 55 
12.1.2 
Definitions of ADE/SADE/UADE for devices ........................................................................... 56 
12.2 
RECORDING ADVERSE EVENTS ............................................................................................................... 56 
12.2.1 
Causality (Relationship to Medical Device) Assessment ........................................................ 57 
12.3 
SUBMITTING EXPEDITED SAFETY REPORTS ............................................................................................... 57 
12.4 
PERIODIC SAFETY REPORTING ............................................................................................................... 58 
12.5 
EXPECTED ADVERSE EVENTS ................................................................................................................. 58 
12.5.1 
TheraSphere Adverse Event Profile ........................................................................................ 58 
12.5.2 
Sorafenib Adverse Event Profile ............................................................................................. 58 
13.0 
INVESTIGATOR AND SITE QUALIFICATION AND OBLIGATIONS .................................................... 59 
13.1 
STUDY SITE AND INVESTIGATOR QUALIFICATION ....................................................................................... 59 
13.2 
INSTITUTIONAL APPROVAL AND DOCUMENTATION OF THE PROTOCOL .......................................................... 59 
13.3 
REGULATORY DOCUMENTS ................................................................................................................... 60 
13.4 
SOURCE RECORDS AND STUDY DOCUMENTATION ..................................................................................... 61 
13.5 
ETHICAL CONDUCT OF THE STUDY ........................................................................................................... 62 
13.6 
RESPONSIBLE CONDUCT OF RESEARCH .................................................................................................... 62 
13.7 
INFORMED CONSENT ........................................................................................................................... 63 
13.8 
PATIENT MEDICAL RECORDS ................................................................................................................. 63 
13.9 
PATIENT PRIVACY AND CONFIDENTIALITY................................................................................................. 63 
13.10 
ADDITIONAL INVESTIGATOR RESPONSIBILITIES ...................................................................................... 64 
14.0 
PROTOCOL DEVIATIONS .............................................................................................................. 64 
15.0 
MAJOR AND MINOR PROTOCOL DEVIATIONS ............................................................................. 64 
16.0 
STUDY MONITORING .................................................................................................................. 65 
17.0 
STUDY TERMINATION ................................................................................................................. 65 

 
 
 
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APPENDICES ........................................................................................................................................... 66 
REFERENCES ........................................................................................................................................... 67 
 

 
 
 
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1.0 PROTOCOL SYNOPSIS 
Protocol Number 
TS-103 
Protocol Short Title 
STOP-HCC 
Protocol Title 
A Phase III Clinical Trial of Intra-arterial TheraSphere in the Treatment of Patients 
with Unresectable Hepatocellular Carcinoma (HCC)  
 
Device 
TheraSphere, Yttrium-90 glass microspheres 
In the European Union, TheraSphere has been CE marked for the treatment of 
hepatic neoplasia. 
TheraSphere is currently approved in Canada for treatment of hepatic neoplasia in 
patients who have appropriately positioned arterial catheters. 
TheraSphere is currently approved for commercial distribution in the United States 
under a Humanitarian Device Exemption (HDE) for use in radiation treatment or as a 
neoadjuvant to surgery or transplantation in patients with unresectable 
hepatocellular carcinoma (HCC) who can have placement of appropriately positioned 
hepatic arterial catheters.  The device is also indicated for HCC patients with partial 
or branch portal vein thrombosis/occlusion, when clinical evaluation warrants the 
treatment. 
Standard-of-care 
Systemic therapy 
Sorafenib 
Type of Protocol 
Phase III  
Protocol Design 
This is an open-label, prospective, multi-center, randomized clinical trial. 
Study Objective 
To evaluate TheraSphere in the treatment of patients with unresectable 
hepatocellular carcinoma in whom treatment with standard-of-care sorafenib 
therapy is planned. 
Primary Endpoint 
 
Overall Survival (OS) from time of randomization 
Secondary Endpoints 
 
Time to progression (TTP) from time of randomization based on investigator 
assessment according  RECIST criteria v 1.1  
 
Time to untreatable progression (TTUP) from the time of randomization 
based one or more of the following: investigator assessment according to 
RECIST criteria v 1.1, contraindication to protocol treatments based on 
package insert or patient performance status.   
 
Time to symptomatic progression (TTSP) from the time of randomization  to 
ECOG performance status > 1 with or without tumor progression based on 
investigator assessment according to RECIST criteria v 1.1. Deterioration in 
performance status is to be confirmed at two subsequent evaluations at 8 
week intervals.    
 
Tumor response according to RECIST v 1.1 criteria based on investigator 
assessment.  Tumor response rate, according to the mRECIST criteria20 and 
based on a blinded centralized independent imaging assessment, will be an 
exploratory endpoint. 
 
Quality of life Assessments (including the Functional Assessment of Cancer 
Therapy – Hepatobiliary Questionnaire – FACT-Hep) 

 
 
 
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 
Adverse events (NCI-CTAE v 4.0) 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
  
 
 
 
 
 
 
  
 
  
 
 
 
  
 
  
 
 
 
Trial Population 
Patients diagnosed with unresectable HCC who are not eligible for any curative 
procedures and for whom standard-of-care therapy with sorafenib is planned. 
Number of patients 
The randomization of approximately 520 patients is planned, with up to a maximum 
of 700 patients being randomized based on a sample size re-estimation after the 
second interim analysis.  
Number of sites 
Up to  105 sites in North America, Europe and Asia 
Treatment Groups 
 
The Control group will receive planned standard-of-care therapy sorafenib in 
accordance with the approved product labeling. 
 
The Treatment group will receive TheraSphere prior to the initiation of 
standard-of-care sorafenib treatment.   All liver tumors observed at baseline 
that are amenable to treatment with TheraSphere should be treated with 
TheraSphere prior to the initiation of treatment with sorafenib.    
Study Duration 
Approximately 60 months of accrual and 18 months additional follow-up is planned; 
with approximately 66 months of accrual if required following sample size re-
estimation.   
 

 
 
 
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Eligibility  Criteria 
 
1. Must have signed informed consent prior to any study-related evaluation. 
2. Must be male or female patients over 18 years of age 
3. Must have unresectable HCC confirmed by histology or by non-invasive 
AASLD criteria  
4. Must have measurable disease defined as at least one uni-dimensional 
measurable lesion by CT or MRI (according to RECIST 1.1) 
5. Must have a Child Pugh score < 7 points 
6. Must have an ECOG Performance Status score of ≤ 1 
7. Must have a life expectancy of 12 weeks or more 
8. Must be eligible to receive standard-of-care sorafenib 
9. Must have a Platelet count > 50 x 109/L or > 50% prothrombin activity 
10. Must have a Hemoglobin ≥ 8.5 g/dL 
11. Must have Bilirubin ≤  2.5 mg/dL 
12. ALT and AST must be < 5X upper limit of normal 
13. Amylase or lipase  must be ≤ 2X upper limit of normal 
14. Serum creatinine must be ≤ 1.5X upper limit of normal 
15. INR must be < 2.0  
16. Must not have main portal vein thrombosis (PVT) (branch portal vein 
thrombosis is permissible). 
17. Must not be eligible for curative treatment (e.g ablation or transplantation) 
18. Must not have history of previous or concurrent cancer other than HCC 
unless treated curatively 5 or more years prior to entry 
19. Must not have confirmed presence of extra-hepatic disease except  lung 
nodules and mesenteric or portal lymph nodes ≤ 2.0 cm each 
20. Must not be at risk of hepatic or renal failure  
21. Must not have tumor replacement >70% of total liver volume based on 
visual estimation by the investigator OR  must not have tumor replacement 
>50% of total liver volume in the presence of albumin <3 g/dL 
22. Must not have any history of severe allergy or intolerance to contrast 
agents, narcotics sedatives or atropine that cannot be managed medically 
23. Must not have any contraindications to angiography and selective visceral 
catheterization 
24. Must not have history of organ allograft 
25. Must not have any known contraindications to sorafenib  including allergic 
reaction, pill-swallowing difficulty, evidence of severe or uncontrolled systemic 
diseases,  uncontrolled severe hypertension or cardiac arrhythmias, congestive 
heart failure >New York Heart Association (NYHA) class 2, myocardial infarct 
within 6 months, prolonged QT/QTc >450ms, evidence of torsades de pointe,  
or laboratory finding that in the view of the investigator makes it undesirable 
for the patient to participate in the trial , significant GI bleed within 30 days, 

 
 
 
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metastatic brain disease, renal failure requiring dialysis. 
26. Must not be taking any of the following:   Rifampicin, St. John’s Wort, 
phenytoin, carbamazepine, phenobarbital, and dexamethasone 
27. Must not be taking any other systemic anticancer agent (e.g. docetaxel, 
doxorubicin, irinotecan etc. ) 
28. Must not be taking any substrate agents for CYP2B6 (buproprion, 
cyclophosphamide, 
efavirenz, 
ifosfamide, 
methadone, 
pacilitaxel, 
amodiaquine, repaglinide) 
29. Must not be taking any UGT 1A1 and UGT 1A9 substrates (e.g., irinotecan) 
30. Must not be taking P-Gp substrates (e.g., Digoxin) 
31. Any prior liver resection must have taken place > 2 months prior to 
randomization  
32. Treatment with other locoregional therapies (other than study treatment) 
has not been planned for the duration of the clinical study period 
33. Has not received any prior external beam radiation treatment to the chest, 
liver or abdomen 
34. Has not received any prior yttrium-90 microsphere treatment to the liver 
35. Prior treatment with transarterial chemoembolization (TACE) or bland 
embolization must have occurred > 2 months prior to randomization and must 
have been applied to a treatment field and/or lobe that is not to be treated 
under this protocol. For patients with tumor progression in the treatment field 
and/or lobe previously treated with TA(C)E, vessels feeding the tumor(s) must 
be assessed for adequate blood flow using angiography (cone beam 
computerized tomography (CBCT) strongly recommended), and the TACE or 
bland embolization must have been applied >6 months prior to randomization.  
36. Has not received any anti-cancer therapy or any treatment with an 
investigational agent within 30 days prior to randomization 
37. Must not have any adverse effect due to prior therapy that is unresolved at 
randomization 
38. Has not received any prior systemic therapy for the treatment of HCC, 
including sorafenib given for more than 4 weeks during the 2 previous months 
prior to randomization; no prior sorafenib related toxicity  
39. No evidence of pulmonary insufficiency or  inadequately treated moderate 
grade or severe/very severe grade chronic obstructive pulmonary disease.    
40. Must not have undergone any intervention for, or compromise of, the 
Ampulla of Vater 
41. Must not have any clinically evident ascites (trace ascites on imaging is 
acceptable) 
42. Must not be pregnant or breast-feeding  
43. Women of childbearing potential must have a negative serum pregnancy 
test within 14 days prior to randomization  
44. Must not have any disease or condition that would preclude the safe use of 
TheraSphere, including concurrent dialysis treatment, or unresolved serious 

 
 
 
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infections. Patients infected with HIV can be considered, however, they must 
be well-managed and well controlled with an undetectable viral load 
45. Must not be participating in concurrent clinical trials evaluating treatment 
intervention(s).  
 

 
 
 
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Imaging Requirements 
 
Triple Phase CT – To determine liver volume measurement, identify hepatic 
vascular anatomy to determine TheraSphere dosimetry 
 
Spiral CT abdomen/pelvis –performed with cuts of 10 mm or less in slice 
thickness contiguously in the axial plane to assess hepatic and extra-hepatic 
lesions according to the RECIST criteria v1.1. 
 
Spiral CT Chest –performed with cuts of 10 mm or less in slice thickness 
contiguously in the axial plane to assess extra-hepatic lesions according to the 
RECIST criteria v 1.1  
 
MRI can replace CT scans; however, the same imaging modality should be used  
for all images in an individual patient throughout the study  
 
Images for efficacy assessments will require a duplicate set of images in DICOM 
format  
Hepatic angiography and 99mTc-MAA– selective celiac and superior mesenteric 
arteriograms are needed to evaluate the hepatic arterial anatomy for the whole 
liver, as well as evaluation of potential sources of extra-hepatic blood supply to 
tumors. Repeat 99mTc-MAA may be needed to estimate cumulative lung shunt or 
re-asses GI flow. 
Statistical Plan and 
Sample Size Calculation 
This study is an adaptive trial using a group sequential design with overall  survival 
(OS) as the primary efficacy endpoint. 
A modified Intention To Treat (mITT) Population will be used to analyze all efficacy 
endpoints.  This population is defined as randomized patients who met the study 
eligibility criteria at randomization. 
The study is designed to detect a 3.5 month increase in median OS time, from 10.7 
months in the sorafenib arm to 14.2 months in the TheraSphere arm (ie, hazard 
ratio = 0.754), using a log rank test.  Due to uncertainty in the expected treatment 
effect, a sample size re-estimation is planned, which would allow the sample size to 
increase in order to detect a 3.0 month increase in median OS time, from 10.7 
months in the sorafenib arm to 13.7 months in the TheraSphere arm (ie, hazard 
ratio = 0.781). 
A maximum of 417 deaths will yield 80% power to detect the target difference in 
median OS (ie, hazard ratio = 0.754) with a two-sided alpha of 0.05 using a group 
sequential design with 2 interim analyses.  It is estimated that a maximum of 520 
patients will need to be recruited over 60 months, with an 18 month additional 
follow-up period.  This includes an adjustment to take account of an assumed 5% of 
patients who will be lost to follow-up and for whom a date of death is not recorded, 
and an assumed additional 5% of patients who will be erroneously randomized 
because they did not meet the eligibility criteria at randomization.   
 
 
  
Analysis of primary endpoint 
OS will be compared between treatment arms using a log-rank test.  The hazard 
ratio and corresponding two-sided 95% confidence interval (CI) for the treatment 
effect will be computed.  Kaplan-Meier curves will also be produced. 
Interim analyses of primary endpoint: The first interim analysis is planned at 
approximately, but no less than, 188 deaths, with a two-sided p-value ≤0.0151 

 
 
 
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allowing the study to be stopped early for efficacy.  A second interim analysis is 
planned at approximately, but no less than, 250 deaths, with a two-sided p-value 
≤0.0151 allowing the study to be stopped early for efficacy.  
A conditional power of less than or equal to 15% at each of the interim analyses will 
result in the study stopping early for futility. 
Sample size modification will be considered at the second interim analysis following 
the approach described in Mehta & Pocock (2011)16 which employs an un-weighted 
test statistic at the final analysis as recommended by Burman & Sonneson (2006)17. 
Final Analysis of primary endpoint:  The final analysis, without a sample size 
modification, will be performed when approximately, but no less than, 417 deaths 
have occurred.  A two-sided p-value ≤0.0363 is required to declare a statistically 
significant improvement in median OS at the final analysis. 
If the sample size is increased after the second interim analysis, the final analysis 
will be performed when approximately, but no less than, 564 deaths have occurred, 
which will result in 80% power to detect an improvement in median OS from 10.7 
to 13.7 months using a log rank test with a final two-sided alpha of 0.0363. 
Analysis of secondary efficacy endpoints 
Comparison between treatment groups for all secondary endpoints will be 
conducted at the final analysis with a two-sided alpha of 0.05. 
Time to event endpoints (ie, TTP, TTUP, TTSP) will be compared between treatment 
arms using a log-rank test.  Tumor response rates will be compared between 
treatment arms using the continuity adjusted Newcombe-Wilson test.  The FACT-
Hep score will be compared between treatment arms using a mixed linear model 
with baseline score and the relative time from baseline as covariates. 
Safety Analysis: All patients who received study treatments at least once will 
be included in the safety analysis. All Adverse events (AEs) will be reported 
according to the National Cancer Institute Common Terminology Criteria for 
Adverse Events v 4.0 (CTCAE) grades and coded using the Medical Dictionary for 
Regulatory Activities (MedDRA). The incidence of treatment emergent adverse 
events (events which were not present at baseline or worsened in severity 
following the start of treatment) will be summarized according to MedDRA primary 
system-organ class (SOC) and preferred term (PT).  Laboratory values will be 
summarized by treatment group over time and overall. 
A feasibility safety assessment will be conducted after the first 20 patients in the 
treatment group have received both TS and sorafenib therapy.  
Poolability and Other Analysis: Multivariate Cox regression analysis of time-to-event 
efficacy endpoints will be conducted on stratification criteria and other factors such 
as age, gender, duration of disease prior to randomization. 
As a sensitivity analysis, to address the poolability of data across regions, study sites 
and gender, a Cox regression analysis of the primary efficacy endpoint, OS, will be 
conducted with factors of region, study site and gender, and to determine the 
impact of these factors on OS.  Note: region and study site will not be included 
simultaneously in the model due to collinearity. 
Should the impact of region, site or gender on OS be statistically and clinically 
relevant, the reasons for the observed differential treatment effect, such as patient 

 
 
 
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demographic or clinical characteristics, will be investigated and reported.  If the 
poolability of OS results are in direct question as a result of this sensitivity analysis, 
the primary endpoint (OS) will also be analyzed separately by region, site or gender.  
In addition, the primary endpoint (OS) will be analyzed separately by US and non-US 
region.    
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
Screening Period  
The following screening and enrollment evaluations should be performed within 14 
days prior to randomization: 
 
ICF (before any study required tests are performed),  
 
Physical examination,  
 
Medical history,  
 
Child-Pugh assessment of chronic liver disease 
 
Assessment of liver function, including presence/absence of portal 
hypertension and normal/abnormal bilirubin levels 
 
ECOG Performance Status assessment  
 
Triple-phase spiral CT/MRI to assess liver tumor presentation and estimate 
tumor burden in the liver. 
 
Chest CT/MRI to rule out extra-hepatic metastases 
 
FACT-Hep quality of life questionnaire 
 
Required laboratory blood work plus α-feto protein (AFP) 
The date of screening is the date all screening procedures are completed 
Randomization  
Upon meeting eligibility for study participation in accordance with the Eligibility 
criteria, patients will be randomized 1:1 between the Treatment and Control groups   

 
 
 
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In order to balance the treatment groups, patients will be stratified at randomization 
on the basis of Region (North America and Europe vs Asia), ECOG Performance Status 
(0 vs 1), presence or absence of branch portal vein thrombosis.  
Control Group 
(Sorafenib) 
All patients randomized to the Control group should start their planned standard-of-
care treatment with sorafenib as soon as possible after randomization.  
Patients will follow standard dosing for sorafenib according to the product label 
information as prescribed by the investigator. Medically appropriate dose 
adjustments and drug holidays due to adverse events and toxicity are allowable. 
Treatment Group  
(TheraSphere followed 
by Sorafenib) 
As soon as possible after randomization, hepatic angiography will be performed to 
assess hepatic vascular anatomy and tumor hypervascularity, followed by a 99mTc-
MAA scan to rule-out gastrointestinal flow or unacceptable lung shunting. 
Embolization may be performed, if necessary, to close off gastrointestinal flow so 
that the patient can qualify for treatment with TheraSphere. The lobe with the 
highest tumor burden should be scheduled for first treatment with TheraSphere.   
Patients will not be able to receive TheraSphere if the potential radiation dose to the 
lungs exceeds 30 Gy for a single treatment or cumulative 50 Gy or embolization 
cannot be performed to effectively block GI blood flow from the hepatic arterial 
system. If radiation exposure to the lungs exceeds 30 Gy (or 50 Gy cumulative), dose 
reduction of TheraSphere is permitted (minimum dose allowed is 90 Gy ± 10%).  
If after consideration of dose reduction, radiation exposure to the lung continues to 
be greater than 30 Gy (or 50 Gy cumulative), sorafenib treatment will be initiated as 
soon as possible and  99mTc-MAA will be repeated after 4 weeks of continuous 
treatment with sorafenib. If radiation exposure to the lung is less than 30Gy for a 
single treatment or 50Gy cumulative within a  target dose of 90-120 Gy +10%  , the 
patient may commence treatment with TheraSphere. In such instances, sorafenib 
should be discontinued at least 7 days prior to the administration of TheraSphere 
and resume sorafenib at least 2 weeks after the administration of TheraSphere. If 
radiation exposure to the lung is outside of the permitted range, treatment  with 
sorafenib should be continued.     
In the case where TheraSphere could not be delivered at at target dose of 120 Gy ± 
10% within 28 days of randomization, these  patients will be included in the 
Treatment Group Intent-to-Treat analysis, but not in the Treatment Group Per-
Protocol analysis. 
TheraSphere Treatment #1:  TheraSphere treatment should occur within 28 days of 
randomization, and prior to the initiation of sorafenib. The number of infusions 
required to achieve lobar treatment will be determined by the Investigator, based on 
the hepatic vascular anatomy.   
Patients will receive 120 Gy ± 10% of TheraSphere to the treated lobe of the liver and 
may be administered in multiple infusions to address vascular abnormalities.   
TheraSphere Treatment #2:  Patients who have bilobar disease at randomization 
should have TheraSphere administered to the untreated lobe.  If needed, a second 
angiogram and/or 99mTc-MAA scan should be performed.  Such treatments typically 
take place 28 days after the treatment to the first lobe.  
From 2 to 6 weeks following TheraSphere treatment of all treatable liver tumors 
observed at the time of randomization, patients should initiate standard-of-care 
sorafenib treatment in accordance with the sorafenib label directions.  
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treatable progression is detected during follow-up evaluations.  Any re-treatment 
should take place a minimum of 28 days from the last TheraSphere treatment 
administered to that lobe.  A maximum of 2 re-treatments are permitted in any 
patient.   
Study Visits and Follow-
up  
Screening evaluations should be completed within 14 days prior to randomization.    
For patients randomized to sorafenib, study visits will take place every 8 weeks for as 
long as the patient remains on the trial.  Additional visits may be scheduled as 
needed when initiating sorafenib treatment, and to manage any adverse events and 
adjustments to sorafenib dosing. 
For Patients randomized to TheraSphere, the pre-treatment evaluations and 
TheraSphere treatment to the first lobe should take place during the first 3 to 4 
weeks following randomization. For patients with bilobar disease, the evaluations 
and TheraSphere treatment to the 2nd lobe should take place during weeks 5 to 8 
weeks following randomization.  After TheraSphere treatment, subsequent study 
visits will take place every 8 weeks from randomization for as long as the patient 
remains on the trial. 
After start of sorafenib therapy, patients may have additional visits as needed to 
adjust sorafenib dosing.  Dosing of sorafenib should be consistent with the relevant  
label instructions, with allowance for appropriate adjustments based on the 
investigators medical judgment.   
In general, follow up visits take place approximately every 8 weeks from 
randomization until one of the study discontinuation criteria is met (see 9.2.19). The 
following assessments take place at the follow-up visit:  
o 
ECOG Performance Status assessment 
o 
Standard laboratory blood draw for CBC, differential, electrolytes, BUN, 
glucose, liver function test, coagulation panel, and α-fetoprotein biomarker 
o 
Triple phase spiral abdomen CT/MRI scan 
o 
Spiral CT/MRI scan of chest and pelvis 
o 
Child-Pugh Status 
o 
QOL questionnaire 
o 
Adverse event reporting 
 
Patients discontinuing sorafenib treatment in either arm of the study must be 
followed-up for survival until consent is explicitly withdrawn or any of the other 
study completion criteria is met (see Section 9.2.19).     
Independent Data 
Monitoring Committee 
This study will have oversight by an Independent Data Monitoring Committee who 
will meet as determined to review the enrollment, protocol deviations, and safety 
events. They will evaluate the data at interim analyses for consideration of stopping 
the study for overwhelming efficacy or futility and for sample size re-estimation at 
the second interim analysis.   The IDMC will evaluate the final study report. 
 
 
 
 
 
 
 
  
 
 
 

 
 
 
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2.0 TRIAL SCHEMA 
 
 

 
 
 
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4.0 LIST OF ABBREVIATIONS 
AE - Adverse event 
ADE – Adverse device effect 
AFP – Alphafeto protein 
ALT – Alanine Transaminase 
AST – Aspartate Transaminase 
BUN – Blood Urea Nitrogen 
CBC – Complete Blood Count 
CDR – Central Dosimetry Review 
CRC – Colorectal Cancer 
Cr - Chromium 
CT – Computed Tomography 
CTCAE – Common Toxicity Criteria for Adverse Events 
DSMB – Data Safety Monitoring Board 
ECOG – Eastern Cooperative Oncology Group 
eCRF – electronic Case Report Form 
FACT-Hep - Functional Assessment of Cancer Therapy – Hepatobiliary Questionnaire 
FHSI8 – Functional Assessment of Cancer Therapy – Hepatobiliary Symptom Index 8 
GBq - gigabecquerel 
GI – gastrointestinal 
Gy – Gray, a measure of irradiation dose 
HCC – Hepatocellular Carcinoma 
HDE – Humanitarian Device Exemption 
ICF – Informed Consent Form 
IDMC – Independent Data Monitoring Committee 
INR – International Normalized Ratio for prothrombin time 

 
 
 
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IRB – Institutional Review Board 
LFT – Liver function tests 
MIRD - Medical Internal Radiation Dose 
mITT – Modified Intention-To-Treat 
NCI – National Cancer Institute 
PE – Physical exam 
PFS – Progression Free Survival 
PT - Prothrombin Time 
PTT – Partial Thromboplastin Time 
RECIST – Response Evaluation Criteria in Solid Tumor 
SAE – Serious adverse event 
SADE – Serious adverse device effect 
SOC – Standard-of-care 
99mTc-MAA– Technetium-99m Magroaggregated albumin 
TS - TheraSphere 
TTP – Time-to-Progression 
TTUP – Time-to-Untreatable Progression 
UADE – Unanticipated Adverse Device Effect 
WBC – White Blood Cells 
Y-90 (Y-88, Y-91) – Ytrium-90 and isotopes 
 

 
 
 
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5.0 BACKGROUND AND RATIONALE 
5.1 
GENERAL DEVICE DESCRIPTION 
TheraSphere® (TS) consists of insoluble glass microspheres in which yttrium-90 (Y-90) is an integral 
component of the glass. The sphere diameter ranges from 20 to 30 µm with 22,000 to 73,000 
microspheres per milligram. TheraSphere is available in dose sizes ranging from 3 – 20 GBq (typically  
3 GBq, 5 GBq, 7 GBq, 10 GBq, 15 GBq and 20 GBq) each supplied in 0.6 mL of sterile, pyrogen-free water 
contained in a 1.0 mL vial secured within a clear acrylic vial shield. 
A pre-assembled single-use TheraSphere Administration Set is provided for each dose. Each user site is 
provided with a re-useable TheraSphere Administration Accessory Kit that provides both radiation 
protection for the user and physical support of the dose vial and Administration Set during administration 
of the product. 
Yttrium-90 is a pure beta emitter which decays to stable zirconium-90 with a physical half-life of 64.2 
hours. The average energy of the beta emissions from yttrium-90 is 0.9367 MeV with mean tissue 
penetration of approximately 2.5 mm.  
TheraSphere is administered through the hepatic artery which supplies blood to tumor tissue (the portal 
vein supplies blood to the normal hepatic tissue). The microspheres are trapped in the vasculature of the 
tumor due to arteriolar capillary blockage where they exert a local radiotherapeutic effect. In clinical use, 
the glass microspheres remain permanently trapped in the vasculature where the isotope decays to 
infinity leaving background radiation with no therapeutic value.  
5.2 
GLOBAL REGULATORY STATUS OF THERASPHERE 
TheraSphere received a Humanitarian Device Exemption (HDE) from the United States Food and Drug 
Administration (FDA) in 1999 (HDE H980006) and is currently approved for use in radiation treatment or as a 
neoadjuvant to surgery or transplantation in patients with unresectable hepatocellular carcinoma (HCC) 
who can have placement of appropriately positioned hepatic arterial catheters. The device is also indicated 
for HCC patients with partial or branch portal vein thrombosis/occlusion, when clinical evaluation warrants 
the treatment. The current US package insert is provided in Appendix 1a. 
TheraSphere is approved for use in Europe for the treatment of hepatic neoplasia. TheraSphere is approved 
in Canada for the treatment of hepatic neoplasia in patients who have appropriately positioned arterial 
catheters. In addition, TheraSphere is available commercially in Saudi Arabia, Hong Kong, Singapore, S. 
Korea, South Africa, Turkey, Kuwait, Brazil, Argentina and Mexico for the treatment of hepatic neoplasia. 
The current Canadian package insert and Instructions for Use in Europe are provided in Appendix 1b and 1c, 
respectively. 
5.3 
RATIONALE FOR THE TREATMENT OF HEPATOCELLULAR CARCINOMA 
According to the International Agency for Research on Cancer (IARC)1, primary liver cancer is a major 
health problem worldwide.  Globally, it is the sixth most commonly diagnosed cancer, with more than 
749,000 new cases in 2011. It is the third leading cause of cancer death in men and sixth among women. 

 
 
 
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In North America and Western or Northern Europe, areas with historically low rates, the incidence of liver 
cancer is increasing, possibly due to increased prevalence of hepatitis C.  
In 2007, the FDA2 approved sorafenib tosylate (Nexavar®), a small molecule Raf kinase and VEGF receptor 
kinase inhibitor, for the treatment of patients with unresectable hepatocellular carcinoma (HCC). 
The approval was based on the results of an international, multicenter, randomized, double-blind, 
placebo-controlled trial (SHARP3 trial) in patients with unresectable, biopsy-proven hepatocellular 
carcinoma.  Overall survival was the primary efficacy endpoint. A total of 602 patients were randomized; 
299 to sorafenib 400 mg twice daily and 303 to matching placebo. 
Demographics and baseline disease characteristics were similar between the sorafenib and placebo 
groups. Prior treatments included surgical resections (20 percent), locoregional therapies (including 
radiofrequency ablation, percutaneous ethanol injection and transarterial chemoembolization in 40 
percent), radiotherapy (5 percent), and systemic therapy (4 percent). 
The trial was stopped following a pre-specified second interim analysis for survival disclosing a statistically 
significant advantage for sorafenib [median 10.7 vs. 7.9 months; HR: 0.69 (95 percent CI: 0.55, 0.87), p= 
0.00058]. The final analysis of time-to-tumor progression (TTP) by independent radiological review was 
based on data from an earlier time point and demonstrated a statistically significant improvement in TTP 
in the sorafenib group [median 5.5 vs. 2.8 months; HR: 0.58 (95 percent CI: 0.45, 0.74), p=0.000007]. 
Sorafenib is now suggested as the standard-of-care (SOC) therapy4  for patients with advanced HCC, the 
patients classified as BCLC C according to the Barcelona Clinic Liver Cancer (BCLC) classification system.    
Sorafenib is included in the NCCN Clinical Practice Guidelines in Oncology5  (NCCN– Hepatobiliary cancers 
V.1.2010 – HCC5) as one of the possible treatments for patients with unresectable HCC and extensive liver 
disease who are not candidates for transplantation. 
Although sorafenib is a SOC in the treatment of patients with HCC, it is associated with only a modest 
improvement in median survival as compared to best supportive care.  Further, sorafenib treatment is 
associated with significant toxicity. The most common adverse reactions14 (≥20 percent) considered 
related to sorafenib were fatigue, weight loss, rash/ desquamation, hand-foot skin reaction, alopecia, 
diarrhea, anorexia, nausea and abdominal pain. Diarrhea was reported in 55 percent of sorafenib patients 
(grade 3 in 10 percent). Hand-foot syndrome (21 percent overall; grade 3 in 8 percent) and rash (19 
percent overall; grade 3 in 1 percent) were the most common dermatologic adverse reactions to 
sorafenib.  Sorafenib dose reductions and drug holidays are often required to manage these toxicities.   
Subsequent subset analysis of the SHARP trial data6 indicated that the efficacy of sorafenib is reduced in 
an important subset of patients with advanced HCC.  In patients with extrahepatic spread or macroscopic 
vascular invasion, the median survival was 8.9 months in patients treated with sorafenib as compared to 
6.7 months in patients treated with placebo.  
Salem et al7  recently published their long-term experience of TheraSphere in the treatment of patients 
with HCC. In this report, patients with HCC (n=291) were treated with TheraSphere as part of a single-
center, prospective, longitudinal cohort study. Toxicities were recorded using the Common Terminology 
Criteria version 3.0. Response rate and time to progression (TTP) were determined using World Health 
Organization (WHO) and European Association for the Study of the Liver (EASL) guidelines. Survival by 
stage was assessed. Univariate/multivariate analyses were performed. A total of 526 treatments were 

 
 
 
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administered (mean, 1.8; range, 1-5). Toxicities included fatigue (57%), pain (23%), and nausea/vomiting 
(20%); 19% exhibited grade 3/4 bilirubin toxicity. The 30-day mortality rate was 3%. Response rates were 
42% and 57% based on WHO and EASL criteria, respectively. The overall median TTP was 7.9 months (95% 
confidence interval, 6-10.3). Median survival times differed between patients with Child-Pugh A and B 
disease (A, 17.2 months; B, 7.7 months; P = .002). Patients with Child-Pugh B disease who had portal vein 
thrombosis (PVT) had a median survival of 5.6 months (95% confidence interval, 4.5-6.7). Baseline age; 
gender; performance status; presence of portal hypertension; tumor distribution; levels of bilirubin, 
albumin, and alpha-fetoprotein; and WHO/EASL response rate predicted survival. These investigators 
concluded that patients with Child-Pugh A disease, with or without PVT, benefited most from treatment. 
Patients with Child-Pugh B disease who had PVT had poor outcomes. TTP and overall survival varied by 
patient stage at baseline.  
Hilgard8 et al report treatment of 108 consecutive patients with advanced HCC using TheraSphere. 
Median overall survival from day of treatment was 16.4 months for all patients, with median time to 
progression of 10.0 months. Tumor response at 90 days evaluated by RECIST in 62 patients were complete 
or partial response 10 (16%), stable disease 46 (74%) and progressive disease 6 (10%). Toxicities were 
generally mild to moderate with the most common being transient fatigue during the week following 
administration (61%) and abdominal pain (56%). One case of radiation cholecystitis was treated with 
cholecystemtomy. There was no Grade 3 or 4 lung toxicities. Lymphopenia was observed without clinical 
sequellae. Because hepatic decompensation is a known risk of yttrium-90 microsphere therapy, all 
elevations in bilirubin values were considered to be treatment related hepatotoxicties. For patients with 
normal bilirubin at enrollment, 32% experienced Grade 1 or 2 elevations and three patients developed 
Grade 3 elevations. For patients with elevated bilirubin at enrollment, 17% experienced Grade 2 
elevations and 30% experienced Grade 3 or 4 elevations. In the majority of patients, bilirubin returned to 
baseline values within 4-6 weeks. The authors conclude the therapy is safe and effective, even in patients 
with compromised liver function.  
At the International Liver Cancer Association conference in September 2010, Metrakos9 et al reported 
preliminary results of a Phase II investigation of the safety, tolerability and efficacy of administering 
TheraSphere and Nexavar (sorafenib) treatment in patients with HCC. In this trial, all patients (N=26) 
began sorafenib 400 mg BID at least 7 weeks in advance of TheraSphere treatment which was 
administered in a sorafenib window. Most patients (65%) required sorafenib dosage adjustment. The 
most common toxicities were diarrhea, fatigue and hand foot syndrome with most being self-limiting and 
responsive to dose adjustment.  One single grade 4 toxicity of worsening cirrhosis was observed. Median 
survival is 15.5 months which exceeds that reported in the sorafenib or placebo arms of the SHARP study 
(10.7 and 7.9 months respectively). The reported toxicities are consistent with the toxicity profile of both 
TheraSphere and sorafenib with no apparent increase in severity or frequency.  
As illustrated by these published reports, there is now an extensive clinical experience demonstrating the 
safety of TheraSphere in the management of patients with unresectable HCC. 
The early reports of serious adverse events possibly associated with the use of TheraSphere included death, 
hepatorenal failure, liver abscess, hepatic encephalopathy, hepatic decompensation, radiation hepatitis, 
radiation pneumonitis, duodenal ulcer, gastrointestinal bleeding and cholecystitis. As clinical experience 
with TheraSphere increased, the pre-treatment high risk factors associated with these early serious events 
were identified, leading to improved patient selection criteria and thereby lowering the risk of these events 
occurring. These risk factors include infiltrative tumor type, bulk disease (tumor volume >70% or nodules 

 
 
 
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too numerous to count), AST or ALT > five times the upper limit of normal, bilirubin > 2 mg/dL, tumor 
volume >50% in the presence of an albumin < 3 g/dL and those in whom extra-hepatic shunting to the lungs 
or gastrointestinal tract cannot be managed through standard angiographic techniques. 
For those patients without the pre-treatment high risk factors noted above, TheraSphere is very well 
tolerated, with treatment in the US commonly administered in an outpatient setting.   Hospitalization for 
treatment effects associated with TheraSphere administration is rare. The most commonly reported adverse 
events associated with TheraSphere administration are fatigue, abdominal pain, nausea/vomiting and 
transient laboratory values including elevated bilirubin, AST, ALT, alkaline phosphatase, decreased platelets 
and lymphocyte depression with no clinical sequelae. 
In this trial, all patients with unresectable HCC eligible for treatment with SOC sorafenib may be 
considered for study participation.  Patients who meet the entry criteria will be randomized to either the 
patient’s planned SOC sorafenib therapy (Control group), or to TheraSphere administered prior to the 
patient’s SOC sorafenib therapy (Treatment group). The primary outcome measure for this trial is overall 
survival.   
Our outcome assumption in the Control group is based on the SHARP trial, with a median overall survival 
of 10.7 months for patients treated with sorafenib.  We assume a median overall survival of 14.2 months 
in the Treatment group, (hazard ratio = 0.754).  However, due to uncertainty in the expected treatment 
effect, a sample size re-estimation is planned, which would allow the sample size to increase in order to 
detect a smaller increase in median OS time, from 10.7 months in the sorafenib arm to 13.7 months in the 
TheraSphere arm (ie, hazard ratio = 0.781).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6.0 STUDY OBJECTIVE 
The objective of this clinical study is to evaluate TheraSphere in the treatment of patients with 
unresectable hepatocellular carcinoma.  

 
 
 
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7.0 STUDY DESIGN 
This is an open-label prospective, multi-center, randomized clinical trial. Patients with unresectable 
hepatocellular carcinoma in whom SOC sorafenib therapy is planned are eligible to participate.  The trial 
will evaluate the use of TheraSphere followed by the SOC sorafenib treatment. Up to 105 study centers 
will participate and recruit patients for the protocol. Participating study sites may be in the United States, 
Canada, Europe and Asia. All patients will be followed prospectively from randomization to death. 
8.0 STUDY POPULATION AND ELIGIBILITY CRITERIA 
Patients diagnosed with unresectable HCC who are not eligible for any curative procedures, and in whom 
treatment with SOC sorafenib is planned, may be screened for possible participation. 
8.1 
ELIGIBILITY CRITERIA 
Patients must meet all eligibility criteria: 
1. Must have signed informed consent prior to any study-related evaluation 
2. Must be male or female patients over 18 years of age 
3. Must have unresectable HCC confirmed by histology or by non-invasive AASLD10 criteria 
4. Must have measurable disease defined as at least one uni-dimensional measurable lesion by CT 
or MRI (according to RECIST 1.1) 
5. Must have a Child Pugh score ≤ 7 points 
6. Must have an ECOG Performance Status score of ≤ 1 
7. Must have a Life expectancy of 12 weeks or more 
8. Must have be eligible to receive SOC sorafenib 
9. Must have Platelet count > 50 x 109/L or > 50% prothrombin activity 
10. Must have Hemoglobin ≥ 8.5 g/dL 
11. Must have Bilirubin ≤  2.5 mg/dL 
12. ALT and AST must be < 5X upper limit of normal 
13. Amylase or lipase must be ≤ 2X upper limit of normal 
14. Serum creatinine must be ≤ 1.5X upper limit of normal 
15. INR must be ≤ 2.0 
16. Must not have main PVT (branch portal vein thrombosis is permissible) 
17. Must not be  eligible for curative treatment (e.g ablation or transplantation) 
18. Must not have a history of previous or concurrent cancer other than HCC unless treated 
curatively 5 or more years prior to entry 
19. Must not have confirmed presence of extra-hepatic disease with the exception of  lung nodules 
and mesenteric or portal lymph nodes ≤ 2.0 cm each 
20. Must not be at risk of hepatic or renal failure  

 
 
 
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21. Must not have tumor replacement >70% of total liver volume based on visual estimation by the 
investigator OR must not have tumor replacement >50% of total liver volume in the presence of 
albumin <3 g/dL 
22. Must not have any history of severe allergy or intolerance to contrast agents, narcotics sedatives 
or atropine that cannot be managed medically 
23. Must not have any contraindications to angiography and selective visceral catheterization 
24. Must not have history of organ allograft 
25. Must not have any known contraindications to sorafenib  including allergic reaction, pill-
swallowing difficulty, evidence of severe or uncontrolled systemic diseases, uncontrolled severe 
hypertension or cardiac arrhythmias, congestive cardiac failure >New York Heart Association 
(NYHA) class 2, myocardial infarct within 6 months, prolonged QT/QTc >450ms, evidence of 
torsades de pointe,  or laboratory finding that in the view of the investigator makes it 
undesirable for the patient to participate in the trial , significant GI bleed within 30 days, 
metastatic brain disease, renal failure requiring dialysis.  
26. Must not  be taking any of the following: Rifampicin, St. John’s Wort, phenytoin, carbamazepine, 
phenobarbital, and dexamethasone 
27. Must  not be taking any other systemic anticancer agent (e.g docetaxel, doxorubicin, irinotecan 
etc. ) 
28. Must not be taking substrate agents for CYP2B6 (buproprion, cyclophosphamide, efavirenz, 
ifosfamide, methadone, pacilitaxel, amodiaquine, repaglinide) 
29. Must not be taking UGT 1A1 and UGT 1A9 substrates (e.g., irinotecan) 
30. Must not be taking P-Gp substrates (e.g., Digoxin) 
31. Any prior liver resection must have taken place > 2 months prior to randomization 
32. Treatment with other locoregional therapies (other than study treatment) has not been planned 
for the duration of the clinical study period  
33. Has not received any prior external beam radiation treatment to the chest, liver or abdomen 
34. Has not received any prior yttrium-90 microsphere treatment to the liver 
35. Prior treatment with transarterial chemoembolization (TACE) or bland embolization must have 
occurred > 2 months prior to randomization and must have been applied to a treatment field 
and/or lobe that is not to be treated under this protocol. For patients with tumor progression in 
the treatment field and/or lobe previously treated with TA(C)E, vessels feeding the tumor(s) must 
be assessed for adequate blood flow using angiography (cone beam computerized tomography 
(CBCT) strongly recommended), and the TACE or bland embolization must have been applied >6 
months prior to randomization. 
36. Has not received any anti-cancer therapy or any treatment with an investigational agent within 
30 days prior to randomization 
37. Must not have any adverse effect due to prior therapy that is unresolved at randomization 
38. Has not received any prior systemic therapy for the treatment of HCC, including sorafenib given 
for more than 4 weeks during the 2 previous months prior to randomization; no prior sorafenib 
related toxicity  
39. No evidence of pulmonary insufficiency or inadequately treated moderate grade or severe/very 
severe grade  chronic obstructive pulmonary disease 
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41. Must not have any clinically evident ascites (trace ascites on imaging is acceptable) 
42. Must not be pregnant or breast-feeding  
43. Women of childbearing potential must have a negative serum pregnancy test within 14 days 
prior to randomization  
44. Must not have any disease or condition that would preclude the safe use of TheraSphere, 
including concurrent dialysis treatment, or unresolved serious infections. Patients infected with 
HIV can be considered, however, they must be well-managed and well controlled with an 
undetectable viral load   
45. Must not be participating in concurrent clinical trials evaluating treatment intervention(s).  
9.0 STUDY VISITS, EVALUATIONS AND PROCEDURES 
9.1 
STUDY VISITS 
Study treatment visits should occur at the time intervals outlined below and in the study visit schedule in 
Section 3.0.  All study visits that take place after the screening/randomization period should occur within 
+/- 14 days of the designated time interval for that study visit. 
9.1.1 SCREENING/RANDOMIZATION (DAYS -14 TO DAY 0) 
All screening and baseline evaluations must be completed within 14 days prior to randomization. CT/MRI 
scans obtained for clinical management within 28 days prior to randomization may be used for screening 
and baseline evaluations, as long as these scans conform to the protocol image specifications for efficacy 
and RECIST 1.1. Results from SOC tests and examinations taken within 14 days prior to randomization may 
be used. 
The following activities will be completed during the screening period within 14 days prior to 
randomization.   
1. Informed Consent must be signed (as described in Section 13.7. 
2. Patient demographic information will be collected as described in Section 9.2.2. 
3. Medical History information will be collected as described in Section 9.2.3. 
4. A physical examination as described in Section 9.2.4 will be done. 
5. ECOG Performance Status will be assessed as described in Section 9.2.5. 
6. Medication history & Prior treatment history will be obtained as described in Section 9.2.7.  
7. The liver tumor volume calculation will be completed as described in Section 9.2.8. 
8. Baseline clinical laboratory tests, blood chemistry, hematology and coagulation, as described in 
Section 0 will be done. 
9. Child-Pugh assessment of chronic liver disease 
10. A serum pregnancy test as described in Section 9.2.10 will be administered for all female patients 
of childbearing potential. 
11. The patient’s eligibility to participate will be assessed as described in Section 9.2.11. 
12. A baseline AFP level will be drawn. 
13. Baseline images for efficacy evaluation (Spiral CT of abdomen/pelvis and Spiral CT of chest) will 
be taken as described in Section 9.2.16. 
14. Baseline Quality of Life assessments will be made as described in Section 9.2.13. 
 
Following Screening, patients meeting the eligibility criteria will be randomized as described in Section 
9.2.14.  

 
 
 
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The date of screening is the date all screening procedures are completed 
9.1.2 PATIENTS RANDOMIZED TO THE CONTROL GROUP 
9.1.2.1  WEEKS 1-4 FOLLOWING RANDOMIZATION – CONTROL GROUP 
The following clinical patient management activities will be completed as appropriate and documented on 
the electronic case report forms.  Patients may need several visits during this period to adjust the dose of 
sorafenib. 
1. If treatment with sorafenib commences greater than 14 days after randomization, , complete 
appropriate clinical laboratory tests, including AFP, prior to treatment  as described in Section 0. 
2. Administer SOC sorafenib in Control Group as described in Section 9.2.15.2. 
3. Record details on the clinical assessments and administration of sorafenib. 
4. Record any treatment and concurrent medications and any adverse events as described in 
Sections 9.2.18, 9.2.19 and 12.2. 
 
9.1.2.2 Q 8 WEEKS FOLLOWING RANDOMIZATION – CONTROL GROUP 
In addition to the administration of sorafenib and the evaluations associated with that therapy, at every 8 
week visit following randomization, the following will be completed: 
 
1. Clinical laboratory tests as described in Section 0. 
2. CT/MR images will be taken as described in Section 9.2.16 for efficacy assessment. 
3. Quality of Life assessments will be obtained as described in Section 9.2.13. 
4. Record any treatment and concurrent medications and any adverse events as described in 
Sections 9.2.18, 9.2.19 and 12.2. 
 
For patients who discontinue sorafenib due to progressive disease and are unable to come in to the clinic 
for routine visits, sites should maintain telephone contact until death. 
 
9.1.3 PATIENTS RANDOMIZED TO THE TREATMENT GROUP 
9.1.3.1 WEEKS 1-4 FOLLOWING RANDOMIZATION – TREATMENT GROUP 
   The following clinical patient management activities will be completed and documented on the 
electronic case report forms (eCRF): 
1. If treatment commences greater than 14 days after randomization , complete appropriate clinical 
laboratory tests, including AFP, prior to treatment,  as described in Section 0. 
2. Conduct TheraSphere pre-treatment evaluations and administer TheraSphere in Treatment 
Group as described in Section 9.2.15.1. 
3. Record details on the clinical assessments and administration of TheraSphere 
4. Record any treatment and concurrent medications and any adverse events as described in 
Sections 9.2.18, 9.2.19 and 12.2. 
 
9.1.3.2 WEEKS 5-8 FOLLOWING RANDOMIZATION – TREATMENT GROUP 
The following clinical patient management activities will take place and will be documented on the eCRF: 
1. Complete appropriate clinical laboratory tests as described in Section 0. 

 
 
 
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2. Administer TheraSphere as described in Section 9.2.15.1.6 to the second lobe for patients in the 
Treatment Group with a bilobar treatment plan. 
3. Record details on the clinical assessments and administration of TheraSphere 
4. Record any treatments and concurrent medications and any adverse events as described in 
Sections 9.2.18, 9.2.19 and 12.2. 
9.1.3.3 >2 & <6 WEEKS AFTER COMPLETE THERASPHERE TREATMENT 
The following clinical patient management activities will take place and will be documented on the eCRF: 
1. Administer SOC sorafenib in Treatment Group as described in Section 9.2.15.2. 
2. Record details on the clinical assessments and administration of sorafenib. 
3. Record any concurrent medications and any adverse events as described in Sections 9.2.18, 
9.2.19 and 12.2. 
9.1.3.4 THERASPHERE RE-TREATMENT AFTER HEPATIC PROGRESSION – TREATMENT GROUP 
Additional TheraSphere treatments may be administered after hepatic progression if the lesions are 
amenable to treatment. The following activities will take place: 
1. Complete appropriate clinical laboratory tests, as described in Section 0. 
2. Conduct TheraSphere pre-treatment evaluations and administer TheraSphere in Treatment 
Group as described in Section 9.2.15.1. 
3. Record details on the clinical assessments and administration of TheraSphere 
4. Record any treatment and concurrent medications and any adverse events as described in 
Sections 9.2.18, 9.2.19 and 12.2. 
9.1.3.5 Q 8 WEEKS FOLLOWING RANDOMIZATION – TREATMENT GROUP 
In addition to the administration of SOC sorafenib and the evaluations associated with that therapy, at 
every 8 week visit following randomization, the following will be completed: 
1. Clinical laboratory tests as described in Section 0. 
2. CT/MR images will be taken (as described in Section 9.2.16) for efficacy assessment. 
3. Quality of Life assessments will be obtained as described in Section 9.2.13. 
4. Record any treatment and concurrent medications and any adverse events as described in 
Sections 9.2.18, 9.2.19 and 12.2. 
 
For patients who discontinue study treatment due to progressive disease and are unable to come in to 
the clinic for routine visits, sites should maintain telephone contact until death.  
 
9.1.4 PATIENT COMPLETION OR EARLY WITHDRAWAL 
If a patient completes the trial or withdraws early, the following activities will be completed as 
appropriate: 
1. Record the date and reason for study exit, as described in section 9.2.19  
2. Record the ECOG status as described in Section 9.2.5, as appropriate  
3. Complete, as appropriate, any clinical laboratory tests, including AFP, as described in Section 0 
4. Record any treatment and concurrent medications and any adverse events as described in 
Sections 9.2.18, 9.2.19 and 12.2 
5. Complete any CT/MR images, as appropriate, for efficacy assessment. 
6. Complete the Quality of Life assessments, as appropriate, as described in Section 9.2.13. 
 
 

 
 
 
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9.2 
STUDY EVALUATIONS AND PROCEDURES 
9.2.1 POTENTIALLY ELIGIBLE PATIENTS AND INFORMED CONSENT 
Any patient who appears to meet the eligibility criteria may be offered the opportunity to be evaluated 
for participation in this clinical trial. All such patients must sign an IRB approved informed consent form, 
and have the opportunity to ask the Investigator any questions regarding the trial, and their rights and 
obligations as a trial participant before any protocol related evaluations can be performed. The details 
regarding informed consent are described in Section 13.7. 
9.2.2 DEMOGRAPHICS  
Demographic data (age, gender, female childbearing potential, race, and ethnicity) will be obtained.  
9.2.3 MEDICAL HISTORY 
Medical history deemed clinically significant by the Investigator will be collected per body system 
(allergy/immunology, auditory/ear, blood/bone marrow, cardiac arrhythmia, cardiac general, 
dermatology/skin, endocrine metabolic, gastrointestinal, hemorrhage/bleeding, Hepatobiliary/pancreatic, 
infection, musculoskeletal/soft tissue, neurologic, ocular/vision, psychiatric, pulmonary/upper respiratory, 
renal/genitourinary, sexual reproductive function, vascular).  
The diagnoses and history of HCC will be recorded separately from other medical history and will include 
assessment of liver function, including Child-Pugh assessment of chronic liver disease, and presence of 
portal hypertension.  
All on-going medical conditions and adverse events arising from treatment of those conditions present for 
≥ 30 days are generally considered a part of the patient’s medical history and must be recorded at 
baseline.   
9.2.4 PHYSICAL EXAMINATION 
A physical examination will also be performed, which will cover the following: 
 
Vital signs:  heart rate (HR), respiratory rate (RR), blood pressure (BP) taken after sitting for 5 
minutes, and temperature (T) 
 
Height and weight 
 
Head, eyes, ears, nose, and throat 
 
Chest 
 
Heart 
 
Abdomen 
 
Extremities 
 
Brief neurological examination (level of consciousness, orientation, sensation, and motor 
function) 
 
Genitourinary, endocrine and allergy/immunology systems 
9.2.5 ECOG PERFORMANCE STATUS 
ECOG Performance Status11 will be assessed according to the following categories: 
Score 
Characteristics 
0 
Asymptomatic and fully active 

 
 
 
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1 
Symptomatic; fully ambulatory; restricted in physically strenuous activity 
2 
Symptomatic; ambulatory; capable of self-care; more than 50% of waking hours 
are spent out of bed. 
3 
Symptomatic; limited self-care; more than 50% of waking hours are spent in bed 
4 
Completely disabled; no self-care; bedridden. 
 
9.2.6 CHILD-PUGH SCORE STATUS 
Severity of liver disease will be assessed according to the Child-Pugh classification of Severity of Liver 
Disease (see Appendix 4) at screening and at every 8 weeks visit. 
9.2.7 MEDICATION AND PRIOR TREATMENT HISTORY 
The use of prior and concurrent medications (medications taken within 30 days of screening and during 
the conduct of the study respectively) will be obtained and documented on the relevant eCRF. Palliative 
medications and/or HCC treatments administered for patients discontinuing sorafenib must also be 
documented.   
Prior treatments for HCC will be recorded separately from treatment for other medical conditions. 
The start and stop dates for all such prior treatments for HCC or other cancer treatments as well as prior 
treatment of other medical conditions should be recorded. 
9.2.8 LIVER TUMOR VOLUME DETERMINATION 
Triple Phase CT is the fastest and most reproducible method of capturing liver volume measurement and 
mass calculations required prior to TheraSphere treatment.  Accurate imaging and volume calculation are 
essential for calculation of TheraSphere dosimetry.  
Using institutional standard equipment and techniques, lobar and tumor regions of interest will be drawn 
and the respective lobar and tumor volumes determined (a detailed discussion begins on page 1259 in 
Appendix 2).  
Tumor replacement, expressed as a per cent of total liver volume, will be recorded on the relevant eCRF.  
9.2.9 CLINICAL LABS  
The following clinical laboratory assessments will be completed at study visits during the trial and must be 
documented as described in Section 13.4. Laboratory assessments undertaken as part of SOC clinical 
assessment may be used. 
 
Hematology:  complete blood cell count (cBC) , differential white blood count (WBC), platelet 
count, hematocrit, hemoglobin,  
 
Coagulation: Prothrombin Time (PT), Partial Thromboplastin Time (PTT), International 
Normalized ratio for prothrombin time (INR) 
 
Chemistry panel: serum creatinine, blood urea nitrogen (BUN), glucose, aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), albumin, amylase, lipase, total bilirubin, 
and alkaline phosphatase. 

 
 
 
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 
Alpha-fetoprotein (AFP) 
9.2.10 PREGNANCY TEST 
A serum pregnancy test for females of child-bearing potential will be performed at the screening visit.  
Patients determined to be pregnant are not eligible to participate in this clinical trial. 
Female patients of childbearing potential must be advised that they should not become pregnant while 
participating in this clinical trial. Adequate methods of contraception must be used by these patients 
while they are enrolled in this clinical trial. Patients should not be breastfeeding while participating on this 
trial. 
9.2.11 REVIEW ELIGIBILITY CRITERIA 
Data detailing Demographic, Medical History, Physical Examination, ECOG Performance Status, 
Medication and Prior Oncologic Treatment, Tumor  volume and Clinical Labs will be reviewed against 
eligibility criteria to determine eligibility. The determination will be recorded on the relevant case report 
form (eCRF). 
9.2.12 HCC TUMOR BIOMARKER 
Blood will be collected prior to and at the 8 weeks study visits following randomization to determine the 
baseline and subsequent AFP values.   
9.2.13 QUALITY OF LIFE 
Functional Assessment of cancer Therapy – Hepatobiliary Questionnaire (FACT-HEP) quality of life 
instruments suitable for patients being treated for hepatocellular carcinoma will be administered at study 
visits every 8 weeks throughout the trial until death. The baseline QOL assessment will be obtained after 
the Informed Consent is signed and before the first treatment in either group is administered. 
9.2.14 RANDOMIZATION (STUDY DAY 0) 
Patients will be randomized 1:1 to study treatment, either the Control group or the Treatment group.   
If a patient is determined to be eligible to participate in the trial, the study site will contact the central 
randomization office where randomization will be determined using assignment by a computer-generated 
randomization scheme.  Upon randomization, each patient will be assigned a subject identity code 
consisting of the protocol number, the country code (e.g.01), the site number (e.g. 01) and a patient 
number (e.g. 001).   
In order to create a balance between study groups, patients will be stratified at randomization based on 
the following:  
 
Region (North America and Europe versus Asia) 
 
ECOG performance status (0 vs 1) 
 
Presence or absence of branch portal vein thrombosis 
Patients randomized to the Control group or the Treatment group who are unable to receive their 
planned study treatment will continue to be followed under their assigned study group for the purpose of 
the intent-to-treat analysis. 

 
 
 
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If a patient is found ineligible for the study, the patient will not be randomized and the reason for 
treatment ineligibility should be documented on the Screen Failure Log.  
9.2.15 STUDY TREATMENTS 
9.2.15.1 THERASPHERE  
TheraSphere will be administered to the diseased lobes present at randomization, before initiation of the 
SOC sorafenib treatment. Patients with unilobar disease will receive treatment of the diseased lobe. 
Patients with bilobar disease will have the second procedure visit such that the second administration 
occurs within Weeks 5-8 following randomization.  
SOC Sorafenib will be prescribed in accordance with the sorafenib package insert. To minimize the risk of 
additive or synergistic adverse events, sorafenib and TheraSphere should not be administered 
concurrently.  SOC sorafenib treatment will be initiated at least two (2) weeks after the administration of 
TheraSphere is completed.  Generally, patients should initiate SOC sorafenib between 2 and 6 weeks after 
TheraSphere has been administered to all disease present at randomization.  
Safety Risks will be minimized by treating all liver tumors present at randomization with TheraSphere 
followed by an interval of at least 2 weeks prior to initiating sorafenib therapy to allow decay of the 
radioactive microspheres and recovery from the expected transient adverse effects (fatigue, abdominal 
pain, nausea/vomiting) associated with TheraSphere administration. Ideally, SOC sorafenib should be 
started no later than 6 weeks following TheraSphere treatment. 
During follow-up, for patients in the Treatment group who have demonstrated hepatic progression with 
hepatic lesions amenable to TheraSphere, re-treatment with TheraSphere is allowed. Sorafenib will be 
discontinued seven (7) days prior to TheraSphere treatment (equivalent to approximately five to seven 
half-lives) through 2 weeks after TheraSphere treatment to permit radioactive decay and patient recovery 
from transient side effects.  

 
 
 
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9.2.15.1.1 
THERASPHERE PRE-TREATMENT EVALUATION 
Patients randomized to the Treatment group must undergo the following evaluations to determine 
eligibility to receive the TheraSphere. These are described in detail in Appendix 2, pages 1254-1255 and 
include: 
 
Hepatic Angiography: selective celiac and superior mesenteric arteriograms are needed to 
evaluate the hepatic arterial anatomy for the whole liver, as well as evaluation of potential 
sources of extra-hepatic blood supply to tumors.  The goal is to identify, within the hepatic 
vascular anatomy, a catheter placement location that allows a single TS infusion throughout the 
lobar tumor volume without administration of microspheres to extra-hepatic structures.   
 
A technetium-99m macroaggregated albumin (99mTc-MAA) scan is used to assess the potential for 
shunting microspheres to the lungs as well as the potential for the deposition of microspheres to 
the gastrointestinal (GI) tract. Repeat 99mTc-MAA may be needed for subsequent treatments to 
estimate cumulative lung shunt or re-asses GI flow.   Note that 3 technical factors, as discussed in 
Appendix 2 (time between administration of 99mTc-MAA and the scan, 99mTc-MAA particle size 
and the presence of free 99mTc-MAA) can lead to an over-estimation of shunting to the lungs and 
should be controlled. 
TheraSphere should not be administered to a patient randomized to the Treatment group if: 
 
Deposition of microspheres to the GI tract that cannot be corrected by placement of the catheter 
distal to collateral vessels or the application of standard angiographic techniques, such as coil 
embolization to prevent deposition of microspheres in the GI tract. 
 
 
Exposure of radiation to the lungs of 30 Gray (Gy) for a single infusion or a cumulative 50 Gy limit 
for all infusions of TheraSphere - estimated during TheraSphere dose calculation as described in 
Section 9.2.15.1.3 
 
In the event that the patient is determined not to be suitable and/or cannot be safely treated with 
TheraSphere, that patient may proceed to treatment with the planned SOC sorafenib regimen as 
described in Section 9.2.15.2.  
9.2.15.1.2 
THERASPHERE ADMINISTRATION STRATEGY 
For patients eligible to receive TheraSphere, the administration strategy (choice of artery position to 
infuse the target vascular bed; selection of placement of coil embolization or other techniques used to 
prevent microsphere deposition to the GI tract) should be determined as discussed in Appendix 2, pages 
1254 - 1257.  Dosimetry is based on the volume of the target vascular bed supplied by the artery selected 
for infusion.  Patients requiring coil embolization to prevent microsphere disposition to the GI tract should 
undergo this procedure during TheraSphere work-up.   
Since the treatment approach for TheraSphere is lobar, proper imaging and volume calculation is essential 
for dosimetry purposes.  The ability to understand hepatic anatomy relies on the sound understanding of 
the Couinaud hepatic segments12.  Anatomically, the middle hepatic vein separates the right and left 
lobes.  When drawing regions of interest and calculating lobar volumes, it is the middle hepatic vein that 
should be used as the anatomic delineator between the right and left lobes.  If the middle hepatic vein 
cannot be seen, then the gallbladder and its axis relative to the liver can be used.  This technique assumes 

 
 
 
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standard arterial anatomy with single right and left hepatic arteries.  If variants are observed 
angiographically, for example, an accessory right hepatic artery, then accurate angiographic correlations 
must be performed when drawing the regions of interest for lobar or segmental lobar volumes.  This will 
ensure that accurate volumes are obtained and three or more infusions are administered.  The volume 
that needs to be used for Y-90 dosimetry is that volume of liver that is perfused by the vessel that will be 
infused.  Target liver mass is determined by the positioning of the delivery catheter in the hepatic 
vasculature and the resulting liver area (segments) infused.  Since there is considerable individual 
variation in hepatic vascular anatomy, the determination of target liver mass will depend on the variant 
encountered.  The Table below presents the most commonly encountered variants with the 
corresponding segments associated to them.   
STANDARD AND VARIANT HEPATIC VASCULAR ANATOMY AND CORRESPONDING 
COUINAUD SEGMENTS 
Hepatic Vascular Anatomya: Angiographic 
Findings 
Target Segments 
– Infusion 1b 
Target Segments 
– Infusion 2 
Target Segments –
Additional 
Infusion  
Standard right and left hepatic arteries 
1, 5, 6, 7, 8 
2, 3, 4 
 
Replaced right hepatic with flow to medial 
segment left lobe 
1, 4, 5, 6, 7, 8 
2, 3 
 
Replaced right hepatic artery without flow to 
middle lobe, left hepatic artery with flow to medial 
and lateral segments left lobe 
1, 5, 6, 7, 8 
2, 3, 4 
 
Replaced left hepatic artery without flow to 
medial lobe 
1, 4, 5, 6, 7, 8 
2, 3 
 
Replaced left hepatic artery with flow to medial 
lobe 
1, 5, 6, 7, 8 
2, 3, 4 
 
Accessory right hepatic artery 
6, 7 
2, 3, 4 
1, 5, 8 
Right hepatic artery in the presence of an 
accessory right hepatic 
5, 8 
2, 3, 4 
1, 6, 7 
Middle hepatic artery (irrespective of origin) 
1, 5 ,6, 7, 8 
4 
2, 3 
Notes: 
a) vascular anatomy subject to variation 
b) assumes caudate lobe (segment 1) derives blood supply from right hepatic artery 
c) caudate lobe (segment 1), right anterior lobe (segments 5/8), right posterior lobe 
(segments 6/7), left medial lobe (4), left lateral lobe (2, 3) 
9.2.15.1.3 
THERASPHERE DOSE DETERMINATION  
The screening angiogram and 99mTc-MAA scan are used to determine lobar liver volume from CT or MR 
images, to identify vascular shunting to the gastrointestinal tract requiring use of angiographic occlusion 
techniques and to determine the lung shunt fraction. The target dose is 120 Gy ± 10%. If radiation 
exposure to the lungs exceeds 30 Gy (or 50 Gy cumulative), dose reduction of TheraSphere is permitted to 
a minimum dose of 90 Gy ± 10%.  
If after consideration of dose reduction, radiation exposure to the lung continues to be greater than 30 Gy 
(or 50 Gy cumulative), sorafenib treatment will be initiated as soon as possible and  99mTc-MAA will be 
repeated after 4 weeks of continuous treatment with sorafenib. If radiation exposure to the lung is less 
than 30Gy for a single treatment (or 50 Gy cumulative) within a  target dose of 90-120 Gy +10%  , the 
patient may commence treatment with TheraSphere. In such instances, sorafenib should be discontinued 

 
 
 
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at least 7 days prior to the administration of TheraSphere and resume sorafenib at least 2 weeks after the 
administration of TheraSphere. If radiation exposure to the lung is outside of the permitted range, 
treatment  with sorafenib should be continued. Calculation of Lung Shunt Factor:  Lung shunt factor is 
determined from the 99mTc-MAA scan using the following equation:  
Lung shunt Fraction (F) = total lung 
counts/(total lung+ liver counts) 
Calculation of Target Liver Mass (kg): Convert the target liver volume to mass assuming a conversion 
factor of 0.00103kg/cm3.   
 
Calculation of Activity required to deliver the desired dose of 120 Gy: 
The amount of radioactivity required to deliver the desired target dose (120 Gy) to the selected liver 
target, adjusted for the estimated fraction that will be shunted to the lung, is calculated using the 
following formula:  
Activity Required (GBq) = [Desired Dose (Gy)] [Mass of Selected Liver Target (kg)]  
50[1-F] 
Calculation of estimated lung radiation exposure (Gy): 
  
Lung Dose (Gy) per infusion = 50 * Calculated Activity in gigabecquerel (GBq) * F 
Cumulative exposure is the sum of estimated exposure per infusion for all planned infusions. 
 
9.2.15.1.4 
THERASPHERE DOSE VIAL SELECTION 
Selection of the dose vial size to supply the required activity (GBq) for delivery of the desired target dose 
to the selected target liver volume via the selected vascular route is dependent on the day and time of the 
scheduled patient treatment and must account for the time zone in which the hospital is located and the 
decay in radioactivity over time. The impact of time for available dose sizes is illustrated in the decay 
curve below. 
The TheraSphere Treatment Window Illustrator can be used to select the appropriate dose vial or 
combination of dose vial(s) required to deliver the calculated activity required. 

 
 
 
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9.2.15.1.5 
THERASPHERE ORDERING 
Orders must be placed using the order form provided by the sponsor. Standard dose vial sizes (3 GBq, 
5GBq, 7GBq, 10 GBq, 15GBq and 20GBq) are made to stock and can be ordered at anytime. Orders for 
custom size dose vials must be received at TheraSphere Customer Services by 12 noon Eastern Time    on 
the Tuesday before the desired Calibration Date (approximately Day 7-10 post-randomization). 
TheraSphere will be delivered to the institution’s designated radiopharmacy and handled according to 
institutional practices.  
Each vial of TheraSphere will be shipped with a packing slip, a copy of which must be transferred to the 
study coordinator for device accountability so that the vials used can be tracked to the specific infusion(s) 
for each patient.  Disposal of used or any unused vials will be handled in accordance with hospital 
standard practices for disposal of radioactive materials. 
9.2.15.1.6 
THERASPHERE ADMINISTRATION 
TheraSphere will be administered at a dose of 120 + 10% Gy to each lobe of the liver administered in one 
or more lobar administrations on separate days at least 28 days apart.   
Patients in the Treatment group who have hepatic progression with hepatic lesions that are still amenable 
to TheraSphere are eligible for re-treatment with TheraSphere.  In these cases, TheraSphere may be 
administered at the investigator’s discretion using lobar infusions on separate treatment days. If such a 
patient is being treated with sorafenib, sorafenib therapy should be discontinued at least seven (7) days 
prior through 2 weeks after hours after TheraSphere administration. 
TheraSphere should be administered by appropriately trained or designated personnel from the 
departments of Radiology, Nuclear Medicine, and/or Interventional Radiology. 
TheraSphere administration is generally considered to be an outpatient procedure in the United States. It 
is generally considered to be an inpatient procedure in Europe. The physical location for after-care and 

 
 
 
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recovery will be determined by individual institutional policies and facility configurations.  The location 
and sequencing of treatment procedure may vary depending on the physical location of the angiography 
and nuclear medicine suites, the availability of portable gamma cameras, and the clinical judgment of the 
physician responsible for the treatment plan. 
On the day of treatment, an arterial catheter will be placed percutaneously via the femoral or brachial 
artery under image guidance.  The interventional radiologist performs this procedure.  The patency of the 
catheter is maintained by an infusion of normal saline and a coagulation inhibitor (per institutional 
protocols) administered via a continuous infusion pump. Proper catheter positioning in the selected 
location in the hepatic artery will be verified on angiography before TheraSphere administration.  
Standard medication protocol for sedation, pain and infection prophylaxis should be implemented per 
established institutional protocols. Prophylaxis with a gastric inhibitor (H2 blocker) is recommended to 
minimize risk of post-treatment gastrointestinal side effects.  Although recommended for all patients 
undergoing treatment, this prophylaxis is especially important for patients undergoing TheraSphere 
treatment to the left lobe of the liver, due to the proximity of the gastrointestinal organs, and for patients 
with a prior history of peptic ulcer disease.  Therapy should begin on the day of TheraSphere treatment 
and continue for 14-21 days following each TheraSphere treatment. 
The TheraSphere labeling documents (Appendix 1) describes the specific procedure used to administer 
TheraSphere.   
9.2.15.1.7 
THERASPHERE ADMINISTRATION DOCUMENTATION 
Any technical problems or complications related to the delivery of TheraSphere treatment to the patient 
must be documented in the medical record.  The details of any event and its impact on the patient should 
be documented on an Adverse Event eCRF. Patients in the Treatment group must certify continued 
eligibility prior to administration of TheraSphere. A new blood draw for labs and pregnancy and an ECOG 
Performance Status test should be performed within 48 hours of administration. 
Using institutional practices, the activity of each vial of TheraSphere will be determined prior to 
administration. This activity will be used to calculate the actual dose delivered to the liver and lung which 
will be recorded on the appropriate eCRF. 
 
Calculation of the liver dose (Gy) delivered: 
Calculation of the delivered dose per infusion takes into account the activity lost to lung shunting plus 
activity associated with residual microspheres in the administration system and is provided by the 
following formula: 
 
Dose (Gy) =  
50[Injected Activity (GBq)][1-F][1-R] 
Mass of Selected Liver Target (kg) 
where  F = lung shunt fraction (determined in Section 9.2.14.1.3) 
R = residual fraction (1-fraction of microspheres delivered) 
Calculation of residual activity fraction for microspheres: 
The fraction of microspheres remaining in the device is calculated using the following formula: 
R = 
 (W-b’) 
(I-b) 
where R  = residual activity fraction 

 
 
 
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b = background dose rate prior to source vial measurement 
I = measured dose rate of source vial positioned greater than 30 cm from ionization chamber (or 
other measuring device) 
b’ = background dose rate prior to waste measurement and W = average dose rate of shielded 
waste container (containing discarded vial, microcatheter, tubing) positioned with center in same 
location as I 
 
Calculation of Actual Lung Radiation Exposure: 
Calculation of the lung dose (Gy) delivered in each infusion is provided by the following formula: 
Lung dose (Gy) = 50* activity delivered (GBq)*F 
9.2.15.1.8 
THERASPHERE POST-TREATMENT PATIENT MANAGEMENT 
Immediately following treatment, the patient should remain under observation consistent with 
institutional SOC guidelines for aftercare in procedures involving femoral or brachial artery 
catheterization.  These aftercare guidelines are unique and subject to the policies and procedures dictated 
by the respective radiology and radiation safety departments at each institution.  Prophylactic treatment 
using gastric inhibitor (H2 blocker) should continue for 14 – 21 days post treatment. In addition, steroids 
(e.g., Medrol Dose Pack) may be taken (with food) over the first six days post-treatment. 
Prior to discharge, patients should be instructed regarding after-care and provided with a 24-hour 
telephone number that they may use to contact the Site Investigator if they develop a problem or have 
questions about their treatment.  
Any concurrent medication or therapy deemed necessary, including gastric prophylaxis, to provide 
adequate supportive care to the patient in the post-treatment period may be administered according to 
institutional standard of clinical care and should be documented on the Concurrent Medications eCRF. 
9.2.15.1.9 
RADIATION SAFETY IN THE IMMEDIATE POST-TREATMENT PERIOD 
Special radiation isolation procedures for Treatment group patients are not necessary following 
TheraSphere Treatment. The existence of a small amount of long-lived radioactive byproducts in 
TheraSphere is a function of the production method13: The predominant by-products are Y-91, Y-88 and 
Cr-51 with respective half-lives of 59, 107 and 28 days. The 3 year accumulated dose to the patient’s liver 
is estimated to be 1/1000 of the planned treatment dose. 
Should a patient die or require surgery in the period immediately following-TheraSphere treatment the 
hospital radiation safety officer should be consulted. At 60 days after the TheraSphere calibration date, a 
surgeon explanting a treated liver in a procedure lasting one hour would be exposed to an estimated dose 
to the hands of <0.6 mrem. This is similar to estimated background doses from natural radiation sources 
which range from 0.5 to 0.8 mrem/day.  Institutional radiation safety guidelines for handling of the body 
and/or body tissues should be followed.   
9.2.15.2 SOC SORAFENIB TREATMENT 
All patients will receive SOC treatment with sorafenib in accordance with the package insert.  Special 
attention should be paid to patients with hypertension or prolonged QT or at risk of developing QT 
prolongation (patients with a congenital long QT syndrome, patients treated with a high cumulative dose 
of anthracycline therapy, patients taking certain anti-arrhythmic medicines or other medicinal products 

 
 
 
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that lead to QT prolongation, and those with electrolyte disturbances such as hypokalemia, hypocalcemia, 
or hypomagnesemia). Blood pressure monitoring plus electrocardiogram with magnesium and calcium 
laboratory tests done at screening and first post-therapy visit then every 6-8 weeks are recommended.  
Abnormal results or adverse events related to these conditions observed in study subjects should be 
recorded as adverse events. Therapies used to manage such adverse events should be recorded in the 
Concomitant Medication eCRF 
 Dosage adjustments and drug holidays will be determined to be in the patient’s best interest at the 
discretion of the physician. Consider discontinuing sorafenib if QT/QTc increases over 500ms or increases 
to 60ms above the baseline reading. All dosage adjustments must be logged on the Treatment Medication 
eCRF. 
Caution is recommended when considering concomitant administration of the following medications; 
please consult the sorafenib summary of product characteristics/prescribing information for details: 
 
Warfarin, phemprocoumon or CYP2B6, CYP2C8 and CYP2C9 substrates (monitor regularly for 
changes in prothrombin time, INR or episodes of clinical bleeding) 
 
Inducers of metabolic enzymes such as rifampicin, St. John’s wort, phenytoin, carbamezepione, 
phenobarbital, dexamethasone may increase  sorafenib metabolism and decrease sorafenib 
concentrations 
 
UGT1A1 or UGT1A9 pathways metabolized compounds due to glucuronidation inhibition 
 
Control group patients will start SOC sorafenib therapy as soon as possible after randomization. 
Treatment group patients should initiate the SOC sorafenib regimen at least 2 weeks after the completion 
of TheraSphere administration, and generally from 2 to 6 weeks following completion of TheraSphere 
administration. 
For Patients in the Treatment group who have initiated SOC sorafenib treatment and have progression 
with hepatic lesions amenable to further TheraSphere treatment, sorafenib should be discontinued seven 
(7) days prior to the administration of each subsequent TheraSphere treatment. If considered medically 
appropriate, SOC sorafenib therapy may be resumed after TheraSphere administration, but should only 
be resumed at least 2 weeks after TheraSphere has been administered.  
Sorafenib should be discontinued from seven (7) days prior through 48 hours after each angiographic 
procedure to reduce the risks of bleeding. 
9.2.16 EFFICACY IMAGING – CT/MRI 
Baseline efficacy imaging scans will be obtained during screening. Efficacy assessment scans will be taken 
in accordance with SOC clinical management guidelines every 8 weeks post randomization until death. 
Most patients will be evaluated by CT images. MRI images are also permitted. The imaging modality used 
at baseline must continue to be used for all efficacy images throughout the study. Duplicate DICOM 
images will be submitted to the sponsor or designee to permit future Central Imaging Review in 
accordance with image submission instructions.   
Triple Phase Spiral CT abdomen – must be performed with cuts of 10 mm or less in slice thickness 
contiguously in the axial plane.  From these images, hepatic and extra-hepatic lesions will be read 
according to the RECIST criteria v1.1 (Appendix 3).  

 
 
 
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Spiral CT chest and pelvis – must be performed with cuts of 10 mm or less in slice thickness contiguously 
in the axial plane.  From these images, extra-hepatic lesions will be read according to the RECIST criteria v 
1.1 (Appendix 3). 
For Secondary Study Endpoints based on radiographic assessment, the investigator will identify, read and 
measure hepatic lesions for size at Baseline using RECIST v 1.1 criteria.  At all subsequent follow-up visits, 
the images (using the same modality) will be read and measured and compared back to the Baseline 
images and then categorized as Complete Response, Partial Response, Stable, or Progressing at each time 
point using RECIST v 1.1 (Appendix 3).   These data will be captured on the eCRF and may be summarized 
showing tumor response over time.   
The tumor response, according to the mRECIST criteria and based on a blinded centralized independent 
imaging assessment, will be recorded as an exploratory endpoint. Investigators will not be required to 
perform mRECIST assessments.     
 
 
 
 
 
 
 
 
 
9.2.18 STUDY TREATMENT MEDICATION RECORD 
The administration of treatment during the trial will be recorded throughout the trial on the appropriate 
eCRF.  Start/stop dates, dates of change of dosage, and any drug holidays will be recorded. 
9.2.19 CONCURRENT MEDICATION RECORD 
At every study visit new medications or changes in concurrent medications will be documented on the 
appropriate concurrent medication eCRF.  Documentation will include dosage, start/stop dates, date of 
change of dosage and any drug holidays. 
9.2.20  STUDY COMPLETION 
Patients complete the trial upon reaching the primary efficacy endpoint of death.  A patient may also 
decide he/she no longer wishes to participate in the trial. In accordance with the Declaration of Helsinki, 
and applicable state and federal regulations, a trial subject has the right to withdraw from the study at 
any time and for any reason. Every effort should be made to have patients complete the study within the 
provisions of informed consent. However, the participation of the patient may be discontinued at any 
time during the study when, in the judgment of the investigator, sponsor or subject, it is appropriate.  
The reasons for study completion include: 
 
Death of the patient 
 
Patient’s desire for any reason to withdraw consent 
 
Administrative reasons 
 
It is considered necessary by the investigator or sponsor, for any reason 

 
 
 
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Lost to follow-up is not an adequate reason for withdrawal. Patients should be encouraged to attend 
study visits until completion of the study or until a decision is taken to withdraw for one of the above-
noted reasons. 
If intolerance to the study treatment, the patient  should be under medical supervision as long as deemed 
appropriate by the treating physician. Similarly, if study treatment is discontinued due to an AE, the event 
will be followed until it resolves to the Investigator’s satisfaction or is considered stable. The details and 
reasons for discontinuation must be carefully and completely documented. In either situation, the patient 
must be followed-up for survival until one of the reasons for study completion is met.    
10.0 STATISTICS 
10.1 SAMPLE SIZE ESTIMATE 
This study is a randomized open label multi-center Phase III adaptive trial using a group sequential design 
with a primary endpoint of overall  survival (OS).  
The study is designed to detect a 3.5 month increase in median OS from 10.7 months in the control arm to 
14.2 months in the TheraSphere arm (i.e., hazard ratio  = 0.754), using a log rank test.  
A maximum of 417 deaths will yield 80% power to detect the target difference in median OS (ie, 
HR=0.754) with a two-sided alpha of 0.05 using a group sequential design with 2 interim analyses and 
stopping boundary defined by the rho family error spending function with rho=1.5 (Jennison and Turnbull, 
2000)18.  It is estimated that a maximum of 520 patients will need to be recruited over 60 months, with an 
18 month additional follow-up period.  This includes an adjustment to take account of an assumed 5% of 
patients who will be lost to follow-up and for whom a date of death is not recorded, and an assumed 
additional 5% of patients who will be erroneously randomized because they did not meet the eligibility 
criteria at randomization. 
Sample size modification will be considered at the second interim analysis using the approach described 
in Mehta and Pocock (2011)16 which employs an un-weighted test statistic at the final analysis as 
recommended by Burman and Sonneson (2006)17.  If the sample size is increased after the second interim 
analysis, the final analysis is planned when approximately, but no less than, 564 deaths have occurred, 
which will result in 80% power to detect an improvement in median OS from 10.7 to 13.7 months (ie, 
hazard ratio=0.781) using a log rank test with a final two-sided alpha of 0.0363.  It is estimated that 
approximately 700 patients will need to be recruited over 66 months, with an 18 month additional follow-
up period, in order to observe 564 deaths.  This includes an adjustment to take account of an assumed 5% 
of patients who will be lost to follow-up and for whom a date of death is not recorded, and an assumed 
additional 5% of patients who will be erroneously randomized because they did not meet the eligibility 
criteria at randomization. 
Sample size calculations were performed and verified with PROC SEQDESIGN, SAS 9.3. 
 
 
  

 
 
 
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10.2 STATISTICAL ANALYSIS PLAN 
The statistical analysis plan will be written based on the final protocol and will be updated, as required, in 
association with any protocol amendments. The plan will include tables, listings and graphs and describe 
statistical programming considerations. 
10.2.1 POPULATIONS AND SUB-GROUPS 
 
Modified Intent To Treat population (mITT) 
A modified Intention To Treat (mITT) Population will be used to analyze all efficacy endpoints.  This 
population is defined as randomized patients who met the study eligibility criteria at randomization. 
The analyses using this population will be performed according to the treatment group to which 
patients were randomized. 
 
Per Protocol Population (PP) 
The PP population comprises patients in the mITT Population without major protocol deviations 
which may affect the efficacy evaluation.  The analyses using this population will be performed 
according to the treatment actually received.  
 
Safety Analysis Population (SA) 
All randomized patients who received study treatments at least once will be included in the safety 
analysis, and will be analyzed according to the treatment actually received. 
 
 
 
 
 
 
10.2.2 TRIAL ENDPOINTS 
10.2.2.1 PRIMARY EFFICACY ENDPOINT 
The primary study endpoint is OS which will be calculated as the interval between the randomization date 
and the date of death for any cause, with censoring at the date of last contact for patients alive at last 
contact.    
10.2.2.2 SECONDARY STUDY ENDPOINTS 
Time-to-progression will be compared between the Treatment and Control groups from time of 
randomization to radiological progression (including new liver lesions and extra-hepatic lesions) according 
to RECIST v 1.1 criteria by investigator determination.   
Time-to-untreatable-progression will be compared between the Treatment and Control groups from 
randomization to radiological progression (including new liver lesions and extra-hepatic lesions) according 
to RECIST v 1.1 criteria by investigator determination.  For patients randomized to the Treatment group, 
any liver lesion still amenable to TheraSphere treatment is not considered to be an untreatable 
progression. Untreatable progression will be defined as one of the following: 
o 
Intolerance to sorafenib 

 
 
 
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o 
Occurrence of specific contraindications to sorafenib 
o 
Assessment of progression in the target lesions or occurrence of new lesions after 
treatment and, for patients randomized to the treatment group, a maximum of 2 re-
treatments with  TheraSphere  
o 
Occurrence of specific contraindications to TheraSphere and or appearance of 
lung/intestinal shunts or anatomical constraints not correctable by radiological 
procedures for the Treatment group. 
o 
Confirmed extra-hepatic metastases  
o 
Deterioration of liver function (Child Pugh score >B7) 
o 
Clinical progression to ECOG performance status >1. Such deterioration in PS should be 
observed at two subsequent evaluations at 8 week intervals. 
 
Time to symptomatic progression (TTSP): from the time of randomization to ECOG performance status >1 
with or without tumor progression based on RECIST v1.1. Deterioration in performance status is to be 
confirmed at two subsequent evaluations at 8 week intervals.   
Tumor Response according to RECIST v 1.1 criteria based on investigator assessment.  At Baseline, target 
tumors are identified, read and measured for size.  At all subsequent follow-up visits, the images (using 
the same modality) for the same target lesions will be read and measured and compared back to the 
Baseline images and then categorized according to the following table: 
 
RECIST v 1.1 
BEST RESPONSE 
Change in the sum of diameter of target lesions 
CR 
Disappearance of all target lesions 
PR 
≥30% decrease in the sum of diameters of target lesions 
SD 
Neither CR nor PR nor PD 
PD 
≥20% increase in the sum of the longest diameter of target lesions from 
the smallest value on study.  
The sum of diameters must also demonstrate an absolute increase of at 
least 5mm e.g. Two lesions increasing from 2mm to 3mm does not qualify.   
 
Quality of Life Assessments:  Functional Assessment of Cancer Therapy – Hepatobiliary Questionnaire – 
FACT-Hep. Patients will be asked to complete the questionnaire at Baseline and each of the 8 week study 
visits. 
Safety will be assessed at all visits for enrolled patients using v 4.0 of the National Cancer Institute’s 
Common Terminology for Adverse Events (NCI: CTAE). All adverse events, serious adverse events, and 
unanticipated adverse device effects as defined by the study protocol will be collected throughout the 
duration of the study.  These events will be documented and recorded on the Adverse Event eCRF using 
the NCI Common Toxicity Criteria for Adverse Events; CTCAE v. 4.0 standards, and will be coded using the 
Medical Dictionary for Regulatory Activities (MedDRA). 
 
 
 
 
 
 
 
 
 
  

 
 
 
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o 
  
 
 
 
  
 
  
 
 
 
 
 
 
  
 
  
 
 
 
  
 
  
 
 
 
10.2.3 EFFICACY ANALYSIS 
The efficacy analyses will be performed on the mITT and PP populations. 
10.2.3.1 
PRIMARY ENDPOINT STATISTICAL ANALYSIS PLAN 
Overall survival (OS) time will be calculated as the interval between the randomization date and the date 
of death for any cause, with censoring at the date of last contact for patients alive. The Kaplan-Meier 
method will be used to estimate the OS curves in the two treatment groups; comparison between the 
curves will be performed using the log-rank test.  
Interim Analyses: Two interim analyses of OS are planned to be performed by the Independent Data 
Monitoring Committee (IDMC) based on group sequential stopping rules using an alpha boundary defined 
by the rho family error spending function with rho=1.5. The first interim analysis is planned at 
approximately, but no less than, 188 deaths, with a two-sided p-value ≤0.0151 allowing the study to be 
stopped early for efficacy.  A second interim analysis is planned at approximately, but no less than, 250 
deaths, with a two-sided p-value ≤0.0151 allowing the study to be stopped early for efficacy.   
A conditional power of less than or equal to 15% at each of the interim analyses will result in the study 
stopping early for futility, using the method described in Proschan et al (2006)19. 
Sample size modification will be considered at the second interim analysis using the approach described 
in Mehta and Pocock (2011)16. 
Final Analysis: The final analysis, without a sample size modification, is planned when approximately, but 
no less than, 417 deaths have occurred.  A two-sided p-value ≤0.0363 is required to declare a statistically 
significant improvement in median OS at the final analysis. 
If the sample size is increased after the second interim analysis, the final analysis is planned when 
approximately, but no less than, 564 deaths have occurred, which will result in 80% power to detect an 
improvement in median OS from 10.7 to 13.7 months using a log rank test with a final two-sided alpha of 
0.0363. 

 
 
 
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 
Time to untreatable progression (TTUP) will be calculated as the interval between the 
randomization date and the first occurrence of one of the events listed in Section 0. The Kaplan-
Meier method will be used to estimate the TTUP curves in the two treatment arms; comparison 
between the curves will be performed using the log-rank test.  
 
Time to symptomatic progression (TTSP) will be calculated as the time from randomization to 
ECOG performance status >1 with or without tumor progression (as defined in Section 0). The 
Kaplan-Meier method will be used to estimate the TTSP curves in the two treatment arms; 
comparison between the curves will be performed using the log-rank test. 
 
Tumor response rate. The response probability will be estimated in each of the two treatment 
groups as proportion of CR+PR (as defined in Section 0, tumor response according to RECIST v 
1.1) over the total number of  mITT or PP patients The disease control rate (ie, CR+PR+SD) will 
also be compared between the treatment arms.  Tumor response will be compared using the 
continuity adjusted Newcombe-Wilson test.  The corresponding 95% confidence limits will be 
calculated.  
 
Quality of Life.  The total score of FACT-Hep will be calculated, the scores of each domain and 
each question at each time-point and their differences from baseline will be summarized for each 
treatment group. The two treatment groups will be compared applying a mixed model repeated 
measures analysis with the treatment, visit and the interaction between treatment as factors, 
the baseline score as a covariate and further adjusted for the interaction between baseline and 
visit. A deterioration in QOL is defined as a 7-point decline in the total score or death whichever 
occurs first.  The time to deterioration in QoL (TTDQoL) will be calculated as the interval between 
the randomization date and deterioration in QoL.  The Kaplan-Meier method will be used to 
estimate the TTDQoL curves in the two treatment arms; comparison between the curves will be 
performed using the log-rank test   
 
A detailed description of data censoring handling for patients will be defined in the Statistical Analysis 
Plan.  
 
10.2.4 SAFETY ANALYSES 
The safety analyses will be performed on the SA population. 
All treatment emergent adverse events (TEAEs), defined as events which were not present at baseline or 
worsened in severity following the start of treatment, will be reported according to NCI Criteria.  The 
incidence of TEAEs will be summarized according to MedDRA coded primary system-organ class (SOC) and 
preferred term (PT).   The summaries will be presented overall (severity grades 1-5) and for grade 3 
events and by treatment discontinuation. These summaries will present the number and percentage of 
patients reporting an adverse event for each classification level as well as the number of events reported.  
 
Serious adverse events (SAEs) will be tabulated by treatment group.  
Laboratory values will be summarized by treatment group over time and overall.  
10.2.4.1 FEASIBILITY SAFETY ANALYSIS 
After the first 20 patients in the Treatment group have received both TheraSphere and sorafenib 
treatment and completed at least 2 weeks of sorafenib therapy, a feasibility safety assessment will be 
conducted.  The IDMC will review the safety results of both the Control and Treatment groups in an 
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The IDMC will take into consideration the established safety profiles of TheraSphere and sorafenib in this 
patient population as described in the product labelling, as well as the expected high rates of adverse 
events and death that are associated with disease progression in patients with intermediate to advanced 
HCC. The impact of disease progression in these patients may be understood by considering the placebo 
control data from the SHARP3 trial, as summarized in the SHARP trial publication and an EMEA14 overview 
of sorafenib including a safety review of the SHARP trial data.  
A consideration for stopping further enrollment to trial may be made if there is  
 
An unanticipated patient death definitely or probably related to the sequential administration of 
TS followed by sorafenib, or  
 
there is a pattern of serious toxicity clearly related to the sequential administration of TS 
followed by sorafenib  
as assessed by the IDMC experts based on the severity of disease of the enrolled population. Such a 
toxicity pattern must be clearly different from, or more severe than, what might be expected from 
independent administration of the products. The potential adverse impact of any such pattern of toxicity 
on the survival or well being of the patient should be considered in the context of the safety and outcome 
expectations of patients with advanced HCC.  
10.2.5 POOLABILITY AND OTHER ANALYSES 
The number of randomized patients, the number of patients treated, the number of patients in each 
analysis population will be summarized.  The number of patients discontinuing from active treatments 
and reasons for discontinuation will be summarized. In the same manner the number of patients 
discontinuing follow up and reasons for discontinuations will be reported.  
Listings of reasons for discontinuation from active treatments, from follow up, and reasons efficacy data 
cannot be evaluated in the PP population will be also provided.  
Duration of follow up will be described by descriptive statistics such as median and interquartile range.  
Demographic, patient and disease characteristics will be listed and summarized using appropriate 
descriptive statistics.  
Multivariate Cox regression analysis of time-to-event efficacy endpoints will be conducted on 
stratification criteria and other factors such as age, gender, duration of disease prior to randomization to 
determine the impact of these factors on study endpoints. 
As a sensitivity analysis, to address the poolability of data across regions, study sites and gender, a Cox 
regression analysis of the primary efficacy endpoint, OS, will be conducted with factors of region, study 
site and gender, and to determine the impact of these factors on OS.  Note: region and study site will not 
be included simultaneously in the model due to collinearity. 
Should the impact of region, site or gender on OS be statistically and clinically relevant, the reasons for 
the observed differential treatment effect, such as patient demographic or clinical characteristics, will be 
investigated and reported.  If the poolability of OS results are in direct question as a result of this 
sensitivity analysis, the primary endpoint (OS) will also be analyzed separately by region, site or gender.  
In addition, the primary endpoint (OS) will be analyzed separately by US and non-US region. The specific 

 
 
 
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mechanism of merging low enrolling study sites into virtual sites for purposes of analysis will be detailed 
in the Statistical Analysis Plan.   
An exploratory analysis will be performed to compare the tumor response rate, based on mRECIST 
criteria20 and on a blinded centralized independent imaging assessment, between treatment arms using 
the continuity adjusted Newcombe-Wilson test.  
 
10.2.6 INDEPENDENT DATA MONITORING COMMITTEE 
An Independent Data Monitoring Committee (IDMC) will be established to oversee the conduct of the 
study, will follow the FDA’s Guidance on IDMCs/DSMBs and comply with ISO 14155.  The IDMC will meet 
periodically during the study to review enrollment, protocol deviations, and safety events for the study.  
In addition, the IDMC will conduct and review the feasibility safety analysis (per Section 10.2.4.1) and will 
evaluate the data at interim analyses for consideration of stopping the study for overwhelming efficacy or 
futility and for sample size re-estimation at the second interim analysis.  The IDMC will make formal 
recommendations to the study Sponsor at the time of the feasibility safety analysis, at the time of the 
interim analyses, and during the conduct of the study based on detailed decision rules specified in the 
IDMC charter. An IDMC member or designate may act as the study independent medical monitor. The 
IDMC will evaluate the final study report. 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
11.0 DATA COLLECTION AND MANAGEMENT 
11.1 ELECTRONIC DATA COLLECTION (EDC) 
Data from this trial will be captured on electronic case reporting forms (eCRFs), and will be entered into a 
validated clinical database.  An audit trail will be maintained to document all data changes in the 
database.  Procedures will be followed to ensure the validity and accuracy of the clinical database.  

 
 
 
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The investigator will sign and date all indicated places on the eCRFs.  This signature will indicate that 
thorough inspection of the data has been made and will certify that the Site Investigator has reviewed and 
approved the data contained on the forms. 
11.2 DATA MANAGEMENT 
The investigator will ensure that trial data quality is maintained to current standards of Good Clinical 
Practice and that data are submitted in a timely manner as outlined in the protocol and supporting 
documentation, including responses to data queries, until the trial is terminated. The investigator must 
sign an affirmation statement verifying the content of all subjects' eCRFs. 
Errors must be corrected in accordance with EDC data entry guidelines. 
12.0 ADVERSE EVENTS 
Adverse experience will be considered synonymous with the term adverse event and vice versa. 
12.1 ADVERSE EVENT DEFINITIONS 
Adverse experience will be considered synonymous with the term adverse event and vice versa.  
12.1.1 DEFINITIONS OF AE/SAE FOR DRUGS 
Adverse Event (AE) 
An AE is any untoward medical occurrence or undesirable event(s) experienced in a subject or clinical 
investigation subject that begins or worsens following administration of the study drug, whether or not 
considered related to the treatment by the investigator.  
An undesirable event(s) can be, but is not limited to, symptoms experienced by a subject or objective 
findings, such as significant clinical laboratory abnormalities. 
Serious Adverse Event (SAE)  
Any untoward medical occurrence that at any dose: 
 
results in death; 
 
is life-threatening (“life-threatening” refers to an event in which the subject was at risk of death 
at the time of the event; it does not refer to an event which hypothetically might have caused 
death if it were more severe); 
 
requires inpatient hospitalization or prolongation of existing hospitalization; 
 
results in a persistent or significant disability/incapacity; or 
 
is a congenital anomaly/birth defect. 
 
Medical and scientific judgment should be exercised in deciding whether medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may 
require intervention to prevent one of the other outcomes listed in the definition above, should also be 
considered serious. 
 

 
 
 
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12.1.2 DEFINITIONS OF ADE/SADE/UADE FOR DEVICES 
Adverse Device Effect (ADE) 
An adverse device effect is an adverse event (AE – previously defined) related to a medical device and 
includes any event resulting from insufficiencies or inadequacies in the instructions for use or the 
deployment, implantation, installation or malfunction of the device; any event that is the result of user 
error; or any potential adverse device effect which might have occurred is suitable action had not been 
taken or intervention had not been made or if circumstances had been less fortunate. 
Serious Adverse Device Effect (SADE) 
A Serious Adverse Device Effect is an adverse device effect that has resulted in any of the consequences 
characteristic of a serious adverse event (SAE – previously defined) or might have led to any of these 
consequences if suitable action had not been taken; intervention had not been made or circumstances 
had been less fortunate. 
Unanticipated Adverse Device Event (UADE) 
An unanticipated adverse device effect is any serious adverse effect which by its nature, incidence, 
severity and outcome has not been identified in the risk assessment, the informed consent form as well as 
the protocol. 
12.2 RECORDING ADVERSE EVENTS 
All adverse events and adverse device effects will be documented from the date of randomization until 
study exit. For patients who permanently discontinue sorafenib in either arm of the study, AEs will be 
documented for 30 days from the date of discontinuation. After this period, only AEs considered to be 
related to TheraSphere will be collected.    
In this study, patients should be encouraged to report adverse events spontaneously or in response to 
general, non-directed questions.  At any time during the study, the patient may volunteer information 
that resembles an adverse event. Once it is determined that an adverse event has occurred, the 
Investigator should obtain all the information required to complete the adverse event form.  Any medical 
management of an event and the date of resolution of the event must be recorded in the source 
document and on the appropriate case reports form(s) using medical terminology according to sponsor 
instructions. 
For each AE, the following information will be recorded:  
 
Adverse event 
 
Serious/non-Serious 
 
Severity (Toxicity Grade) 
 
Action taken 
 
Relationship to study treatment 
 
Expected/Unexpected 
 
Date and time of onset 
 
Date and time of resolution 
 
An expected adverse event is any AE, the nature or severity of which is identified in the relevant Package 
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Any AE experienced by a subject will be followed until the AE has resolved to the investigator's or 
physician sub-investigator's satisfaction.  If a problem still exists, then the investigator or physician sub-
investigator at his/her discretion will ask the subject to come back to the clinic for further evaluation.  Any 
serious adverse events should be managed as discussed in Section 12.3. 
Once the subject has been discharged from the study, the investigator has no obligation to seek further 
follow-up with the subject in order to identify new AEs. However, if the investigator becomes aware of an 
SAE that has occurred following the subject's discharge from the study and the investigator considers the 
SAE possibly, probably, or definitely related to a study drug or device, then the investigator should report 
the SAE as described in the protocol. 
12.2.1 CAUSALITY (RELATIONSHIP TO MEDICAL DEVICE) ASSESSMENT 
The investigator or physician sub-investigator must indicate whether he/she believes the AE is not related, 
unlikely related, possibly related (reasonable possibility that the medical device caused the AE), probably 
related, or definitely related to the medical device.  
The Investigator should pay careful attention to the attribution of relation for all adverse events.  Because 
there are many similar events between the TheraSphere and the sorafenib safety profile, judgment of 
relation by time of administration and patient assignment to treatment or control group should be 
considered. 
An adverse event becomes an adverse device effect when the adverse event is considered associated with 
the use of the test device if the attribution is Possibly, Probably or Definitely Related.  Relation to 
TheraSphere (screening, procedure, embolization or radiation) is not appropriate for the Control Group.  
Only those events with a possible, probable or definitely related attribution to TheraSphere will subject to 
expedited reporting. All other events documented in the trial will be addressed through periodic clinical 
trial reporting. 
 
12.3 SUBMITTING EXPEDITED SAFETY REPORTS 
Any SADE or UADE (defined previously) must be reported by telephone or fax to the sponsoror designate 
as specified in the study procedures within 24 hours of learning of the event.  In the event of an 
emergency, the Investigator will contact the CRO using the coordinates specified in the study procedures. 
The SAE form provided by the sponsor should be completed and signed by the investigator or physician 
sub-investigator. The entire SAE form needs to be completed, if possible, to keep requests for additional 
information to a minimum. Patients experiencing SAE, SADE or UADE should be followed clinically and 
with laboratory studies, if appropriate, until medical treatment and/or medical monitoring of the event 
is no longer required because the event resolves or stabilizes, returns to baseline if a baseline value is 
available, can be attributed to agents other than the study treatments or a referral for appropriate 
follow-up care has been made. 
The Investigator must promptly inform the IRB of all unexpected SAE or UADE. These events will be 
reported by the sponsor or it’s designate as appropriate to the regulatory authorities according to 
relevant jurisdictional medical device regulations. The Investigator will receive notification of these events 
across all study centers from the sponsor.  

 
 
 
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Each AE reported on an SAE form must also be reported in the adverse event section of the eCRF. 
12.4 PERIODIC SAFETY REPORTING 
Adverse events will be recorded on the AE form and coded using NCI CTCAE v 4.0.  The investigator or 
physician sub-investigator will judge the severity of each AE and whether or not it is treatment-related.   
All AEs that occur after randomization, including events likely to be related to the underlying disease or 
likely to represent concurrent illness, will be reported, including events present at Baseline which 
worsened during the trial.   
Periodic safety reports prepared by the sponsor will be distributed across all study centers. The 
Investigator will be responsible for informing the IRB. 
12.5 EXPECTED ADVERSE EVENTS  
12.5.1 THERASPHERE ADVERSE EVENT PROFILE 
TheraSphere has been approved for the treatment of HCC since 1999. Adverse events known to be 
related to the device or the procedure listed in the current package insert (Appendix 1). Those adverse 
events identified in clinical trials investigating treatment with TheraSphere of liver lesions metastatic to 
non-HCC primary cancers are listed below in decreasing order of frequency. 
Frequency 
Description of Adverse Event (per NCI-CTCAE v 3.0) 
Common - >10% 
Fatigue, pain, nausea, vomiting, anorexia and laboratory value abnormalities 
including increased alkaline phosphatase, AST, ALT, bilirubin and decrease albumin 
Infrequent - <10% 
Lymphopenia with no clinical sequelae; constipation, heartburn, weight loss, fever, 
ascites, muscle weakness, variations in hemoglobin, neutrophils and leukocytes, GI 
ulcer, dyspnea, arrhythmia, diarrhea, liver dysfunction, hypotension, insomnia, 
rigors/chills, sweating, distension, GI obstruction, hematoma, GI hemorrhage, 
pleural effusion 
Rare – < 1% 
Alopecia, bruising, pruritis, rash, hot flashes, dehydration, taste alteration, 
hemorrhage, infection, dizziness, mood alteration, sensory neuropathy, somnolence, 
cough, urine color change, intraoperative injury, flu-like symptoms, tumor lysis 
syndrome, 
thrombosis, 
metabolic/laboratory 
abnormalities 
– 
creatinine, 
hypercalcemia, hyperglycemia, hyperkalemia, hypermagnesemia, lipase 
In addition, the following events, which may or may not be related to the use of TheraSphere or the 
administration procedure, have been reported in clinical trials of treatment of primary or secondary liver 
cancer: 
Abdominal pain, dyspnoea, abdominal distention, anxiety, blurred vision, chills, hot flashes, bladder 
infection, lower extremity edema, gastrointestinal stoma complication including mild pain, hepatic 
encephalopathy, hepatorenal failure, edema, malaise, hepatic decompensation, hepatitis, duodenal ulcer, 
hypertension, hypertension, aspiration pneumonia, fall, gastrointestinal bleeding, elevated AFP, elevated 
LDH, elevated prothrombin time, elevated BUN, bacterial sepsis, hypoglycemia, abnormal platelets and 
electrolyte disturbances including hypercalcemia, hyperkalemia, hypomagnesemia, hyponatremia, low 
serum bicarbonate and low serum chloride. 
12.5.2 SORAFENIB ADVERSE EVENT PROFILE 

 
 
 
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Sorafenib has been approved for treatment of HCC since 2007 and adverse events known to be related to 
this therapy are listed in the current package insert. Safety updates to the commercial package insert by 
the manufacturer automatically apply to this trial. 
13.0 INVESTIGATOR AND SITE QUALIFICATION AND OBLIGATIONS 
13.1 STUDY SITE AND INVESTIGATOR QUALIFICATION 
This study will be performed by qualified investigators at multiple research centers in the United States, 
Canada, Europe, and Asia.  
All participating study sites will be reviewed by the study Sponsor or designee in order to verify that they 
are able to conduct the trial.  Each participating institution must have an established IRB and clinical 
protocol review process in compliance with the appropriate regulations (21 CFR 56 or ISO 14155)  so the 
clinical protocol can be adequately evaluated and approved at the institutional level.     
The institution must have appropriately qualified investigators, and clinical and administrative support 
staff in place to adequately conduct the trials according to GCP in general, and must have adequate 
expertise and staff in the treatment of patients with hepatocellular carcinoma and the ability to 
adequately conduct clinical research under Good Clinical Practice Standards (GCP) consistent with the 
regulations of 21 CFR 812, Investigational Device Exemptions, and ISO 14155. 
In addition, all participating study sites must be appropriately experienced in the use of Y-90 microspheres 
for the treatment of liver tumors, and must have completed adequate training in order to use the 
TheraSphere Y-90 microsphere product.  The required training will be specified by the sponsor.  Generally, 
an adequate level of experience consists of a minimum of five (5) TheraSphere administrations for sites 
without radioembolization experience and   at least three (3) administrations of TheraSphere for sites 
experienced in radioembolization with different radioactive microsphere product. 
13.2 INSTITUTIONAL APPROVAL AND DOCUMENTATION OF THE PROTOCOL 
Prior to initiating the clinical study, each participating institution must have documentation that the 
Institution Review Board (IRB) has reviewed and approved the protocol and the Informed Consent Form 
(ICF).  
The final IRB approved protocol, consent form, documentation of IRB approval of the consent and 
protocol, Study  Contract, Statement of Investigator, CVs of all investigators and study coordinators, 
records of protocol training, and all  other study-related required regulatory documentation as described 
in the Sections below must also be maintained in the clinical study files for this trial. 
The Site Principal Investigator is ultimately responsible for ensuring that required study documentation 
has been obtained, that all study procedures are properly followed, and that all enrolled patients meet 
the eligibility criteria prior to enrollment under this protocol. 
The Investigator is responsible for submission of the protocol, informed consent form, any patient 
education materials, and any recruitment or advertising materials and the institution’s IRB.  

 
 
 
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 
Written approval of the protocol and Informed Consent Form must be obtained prior to 
recruitment of patients into the trial at each site and prior to administration of protocol 
treatment to any randomized patient.   
 
Written approval of the recruitment and advertising materials must have IRB approval before 
use.   
 
The Investigator is responsible for obtaining and maintaining IRB approval at his facility and 
providing copies of all IRB correspondence to the Sponsor or designee.   
This protocol is a multi-center protocol and as such must remain consistent with all other sites. 
13.3 REGULATORY DOCUMENTS  
The following documentation must be obtained before study enrollment can begin (with the exception of 
Final Report). 
 
Institutional Review Board Approval 
A copy of the protocol and any amendments, the proposed informed consent form (ICF), other written 
subject information and any proposed advertising material must be submitted by the Investigator to the 
IRB for written approval.  A copy of the written approval of the protocol and ICF must be received by the 
sponsor or designee before recruitment of subjects into the study and administration of protocol 
treatment. 
The investigator must submit and, where necessary, obtain approval from the IRB for all subsequent 
protocol amendments and changes to the ICF.  The investigator should notify the IRB of deviations from 
the protocol and SAEs as required by local procedures. 
The investigator will be responsible for updating the IRB about the status of the trial at least annually and 
obtaining any required approvals renewal throughout the duration of the study.  Copies of any 
correspondence and other documentation between the investigator and the IRB must be retained as part 
of the site documentation of the study. Copies of all such documents must be sent to the sponsor or 
designee. 
 
Institutional Review Board Membership Roster 
The investigator must submit a complete and current roster of the IRB to the sponsor or designee.  Some 
institutions, on grounds of confidentiality, may not release the IRB roster.  In such instances, the 
institution’s General Assurance Number, assigned by the Department of Health and Human Services, is an 
acceptable substitute. 
 
Statement of Investigator 
The investigator will be required to sign and date a Statement of investigator form provided to them by 
the sponsor.  A copy of this form will be given to the investigator for their files.  The original form will be 
maintained by the sponsor. 
 
Curriculum Vitae 

 
 
 
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The investigator will provide the sponsor or designee with his/her up-to-date curriculum vitae (to within 
two years throughout the duration of the trial) and those of any sub-investigators or staff personnel with 
significant trial responsibilities. 
 
Laboratory Certification and Normal Values 
The Investigator will provide the sponsor with the name and location of the clinical laboratory to be 
utilized for determination of laboratory assays, copy of certification and a list of the normal range of 
values of all laboratory tests.  Any changes in laboratory, certification or normal ranges will be 
communicated promptly to the sponsor or designee. 
 
Financial Disclosure 
Financial disclosure statements will be completed for the investigator and all sub-investigators to disclose 
potential conflicts of interest (per 21 CFR 54 and ISO 14155).  The investigator is responsible for ensuring 
completed and signed financial disclosure forms, which are provided by the sponsor or designee.  A copy 
of the form(s) will be given to the investigator for their files.  The original form(s) will be maintained by 
the sponsor Financial disclosure information will be collected by the sponsor before the start of the study 
and maintained for one year after study completion. 
 
Final Report 
Upon completion of the clinical trial, a final study report will be provided by the sponsor; The Investigator 
will prepare and submit to the IRB a final report, including final study report.   
13.4 SOURCE RECORDS AND STUDY DOCUMENTATION 
Investigators are required to prepare and maintain adequate source documentation.  Source 
documentation includes: 
 
documents relative to the patient’s medical history that verify the eligibility criteria  
 
records covering the patient’ participation in the study which include but are not limited to basic 
identification information, results of physical examinations and diagnostic tests, therapy, device 
administration, concurrent medication information and visit/consult notes. 
The Investigator will initial and date all laboratory reports or initial and date statements at each study visit 
that all clinical laboratory data was reviewed. 
Federal regulations concerning the period during which study records must be maintained by the 
Investigator vary from country to country. Investigators are required to comply with their local regulatory 
authority for storage of study documentation. For the purpose of this study the minimum retention for 
Study Documentation is a period of two (2) years after the later of the following:  (a) date on which the 
Study is terminated or completed; or (b) date records are no longer required to support a premarket 
approval application, notice of completion of a product development protocol, or other application for 
research or marketing permit.  
 

 
 
 
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Completed eCRFs that are dated and signed by the investigator must be made available for review and 
retrieval by the sponsor or designee at the time the subject completes the study.  The sponsor or 
designee will provide the investigator with a copy of completed eCRFs for their files. 
In order to ensure the accuracy of data collected in the eCRFs, it is mandatory that representatives of the 
sponsor, as well as representatives of a regulatory agency (eg, the Food and Drug Administration) or the 
institutional review board (IRB), have access to source documents (ie, subject records, subject charts, and 
laboratory reports).  During the review of these documents, the anonymity of the subject will be 
maintained with strict adherence to professional standards of confidentiality.  The sponsor reserves the 
right to terminate the study for refusal of the investigator to supply source documentation of work 
performed in this clinical trial. 
13.5 ETHICAL CONDUCT OF THE STUDY  
This study will be conducted in compliance with standard operating procedures of the sponsor or 
designee, which are designed to ensure adherence to good clinical practice (GCP) guidelines as required 
by the following:  
1. World Medical Association (WMA), Declaration of Helsinki, Ethical Principles for Medical 
Research Involving Human Subjects, Adopted by the 18th WMA General Assembly, Helsinki, 
Finland, June 1964, and as amended at subsequent WMA General Assembly meetings. 
 
2. E6 Good Clinical Practice: Consolidated Guidance (International Conference on Harmonization of 
Pharmaceuticals for Human Use [ICH], April 1996 governing drugs and ISO 14155 governing 
devices. 
 
3. Title 21 of the Code of Federal Regulations (21 CFR) Parts 50, 54, and 56. 
 
13.6 RESPONSIBLE CONDUCT OF RESEARCH 
The Sponsor will ensure that this trial is conducted in full conformity with the current revision of the 
‘Declaration of Helsinki’, ISO 14155, the U.S. Code of Federal Regulations 21 CFR 812, and applicable state 
and federal regulations, whichever affords the greatest protection to the patient.  The Sponsor is 
responsible for providing monitoring oversight for the study to ensure the involvement of the Investigator 
in the trial, to ensure the rights, safety and well-being of the patients, compliance to the protocol and to 
all applicable laws, and to oversee the completeness, accuracy and consistency of the data collected in 
support of a premarket approval application.  
The procedures defined in the protocol and the eCRFs will be carefully reviewed by the Sponsor with the 
Investigator and staff prior to time of trial initiation to ensure appropriate interpretation and 
implementation.  No deviations from the protocol may be made without advance approval from the 
sponsor and the IRB as required by the policies of the IRB. 
Monitors from the Sponsor, or their designees, will periodically visit the site to review case report forms, 
the Regulatory Binder, patient medical records including electronic records, imaging files, laboratory 
reports, device accountability, site training and authorization of delegation and any other records related 
to the study conduct.  Investigator will maintain and release the records for review, provide access to the 
records and copies as needed, and will meet with the monitor as needed to discuss study progress and 

 
 
 
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needs.  The Investigator should maintain the files suitable for inspection at any time by a trial monitor 
from the sponsor, or the appropriate regulatory authority, or designate representing these organizations. 
13.7 INFORMED CONSENT 
An IRB approved signed informed consent form (ICF) must be obtained from a patient before that patient 
can enter the trial, and before any study related evaluations can be performed on that patient. 
The investigator is responsible for the creation of the ICF and must ensure that the informed consent 
adheres to the U.S Code of Federal Regulations, 21 CFR 50, ISO 14155or equivalent, as appropriate to 
his/her country.  The Investigator will ensure that the local IRB has approved the protocol and the 
informed consent prior to the initiation of the trial.  The signed informed consent from each patient must 
be kept in the patient’s study file.   
The investigator or designee will review the treatment plan with the patient and the patient will have an 
opportunity to ask questions regarding study procedures, the required visit schedule, risks/benefits of the 
use of the approved device (TheraSphere), and alternative treatment options prior to signing the ICF.  The 
patient will receive a copy of the signed informed consent to keep for their records.  Periodically during 
the study, revisions to the informed consent form may be needed.  Patients will be informed of such 
revisions and any revisions must be signed and kept in the patient’s study file.   
The acquisition of informed consent should be documented in the subject’s medical record and the ICF 
should be signed and personally dated by the subject and by the person who conducted the informed 
consent discussion (not necessarily by the investigator).   
Patients for whom English is not their first language may need a written translation of the document 
and/or a patient advocate, according to the policies of the IRB.  The Investigator will provide the sponsor a 
copy of the IRB approved translation, if any. 
13.8 PATIENT MEDICAL RECORDS 
The Investigator must maintain adequate medical records regarding their care of the patient, including 
case histories, to support the clinical data in the case report forms.  These records must be maintained 
and made available for monitoring and auditing by the Sponsor, or their designee, and the appropriate 
regulatory agency.  All CT/MRIs will be maintained or archived along with the medical chart for review for 
at least 2 years after premarket approval of the device. 
13.9 PATIENT PRIVACY AND CONFIDENTIALITY 
All collected patient data will be treated confidentially. Patients will be identified anonymously and in 
accordance with national laws and regulations.   Medical records relating to this trial, including those that 
are electronically maintained and those that may contain information that would identify an individual 
patient will remain confidential, but may be reviewed by, released, and/or transmitted to representatives 
of the hospital, the appropriate regulatory agency, the Sponsor or its agents, and the Independent Data 
Monitoring Committee when reasonable and appropriate for the conduct of the trial. 
As part of the required content of the informed consent, the patient must be informed that his/her 
records will be reviewed by the sponsor and/or a representative of the appropriate regulatory agency and 
the Independent Data Monitoring Committee. The informed consent or related document will also state 

 
 
 
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that patient privacy will be maintained pursuant to the Health Insurance Portability and Accountability Act 
(HIPAA), 21 CFR 21  or equivalent for countries other than the United States.  Should access to the medical 
record require a separate HIPAA waiver or authorization per institutional confidentially policies, it is the 
Investigator’s responsibility to obtain such permission from the patient in writing before the patient is 
entered into the trial. 
13.10 ADDITIONAL INVESTIGATOR RESPONSIBILITIES 
Additional Investigator responsibilities are noted in ISO 14155and in Section 11 of the US 21 CFR 812.100, 
812.110 and in country-specific guidelines and laws and responsibilities for reporting of unanticipated 
adverse device events and deviations from the investigational plan per 812.150 as well as the following: 
 
Ensure compliance with institutional and appropriate relevant jurisdictional Radiation Safety 
policies and procedures 
 
Assemble and coordinate a team that includes a designated co-investigator in all of the medical 
disciplines necessary for the efficient conduct of the protocol (oncology, interventional radiology, 
nuclear medicine, diagnostic radiology, etc). 
 
Provide a trial coordinator who will be responsible for assisting the Investigator in meeting data 
collection and reporting requirement and for scheduling, management and follow-up of trial 
patients. 
 
Provide adequate access to study materials for the sponsor to monitor the trial at appropriate 
and convenient intervals and provide an adequate, secure area, within the study site facility for 
the sponsor representative to conduct these monitoring activities. 
14.0 PROTOCOL DEVIATIONS 
It is vital to the success of the study that the investigator adheres to the details of the protocol. A protocol 
deviation is any change, divergence or departure from the study protocol regardless of the consequences 
to the patient or study outcomes.    
 
15.0 MAJOR AND MINOR PROTOCOL DEVIATIONS  
A major protocol deviation is defined as a divergence from the protocol that materially (a) reduces the 
quality or completeness of the data, (b) makes the Informed Consent Form inaccurate, or (c) impacts a 
subject's safety, rights, or welfare, example:  
 
 
Enrollment Violations   
 
Eligibility criteria deviations 
 
Inadequate informed consent Intentional repeated deviations from the protocol   
 
TheraSphere Administration Violations: TheraSphere treatment dose outside the range of 90- 
120 Gy ± 10%  
 
Post-Treatment Violations: Administration of any liver-directed local regional therapy, except as 
specified by the protocol, following intra-hepatic progression.  
 

 
 
 
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A  minor protocol deviation is defined as a divergence from the protocol that is without significant 
consequences to the patient and the study data. An example is  missing a visit window because a patient 
is traveling. 
16.0 STUDY MONITORING 
The study will be monitored by qualified personnel from the sponsor or a contract research organization 
(CRO) contracted to provide such monitoring by the sponsor.  Data management and statistical analyses 
will be the responsibility of the sponsor who will contract with one or more organizations to manage 
these functions.  
Before initiation of the trial, representatives from the sponsor will, together with the investigator, review 
the protocol and the facilities.  At trial initiation, the sponsor's representative will thoroughly review the 
protocol and go over the eCRFs and electronic data entry procedures with the investigator(s) and other 
authorized staff.   
During the course of the trial, a study monitor or other authorized representatives of the sponsor will visit 
the investigator at suitable intervals.  The purpose of these visits will be to verify compliance with 
applicable government regulations and adherence to the protocol, ensure correct completion of the 
eCRFs. 
In order to perform his/her role effectively, the study monitor(s) must be given access to source 
documentation (eg, clinic charts, original laboratory records), which support data on the eCRF, and 
informed consent forms.  The monitor must be able to verify data appearing in the eCRFs against data in 
the subject's clinic chart (eg, chart notes) or in printout forms (eg, laboratory results). 
17.0 STUDY TERMINATION 
The sponsor reserves the right to discontinue this study for administrative reasons at any time.  The end 
of the study is defined as the reaching of the required number of deaths and all TheraSphere treated 
patients have been followed-up for a minimum of 30 days from the last TheraSphere treatment, and all 
sorafenib treated patients in the control arm have been followed-up for a minimum of 30 days after the 
last dose of sorafenib.   
 

 
 
 
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APPENDICES 
1. TheraSphere Product Labeling 
a. US Package Insert 
b. CA Package Insert 
c. 
EU Instructions for Use 
 
2. Salem R, Thurston KG. Radioembolization with 90Yttrium microspheres: a state-of-the-art 
brachytherapy treatment for primary and secondary liver malignancies. Part 1: Technical and 
methodologic considerations. J Vasc Interv Radiol. 2006 Aug; 17(8):1251-78. Review. Erratum in: J 
Vasc Interv Radiol. 2006 Oct; 17(10):1594.  
3. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, 
Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R,Lacombe D, Verweij J. New response evaluation 
criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47 
4. Child Pugh Classification 
Assess severity of liver disease by assigning points for each of the five parameters in the table below 
and adding the points to obtain a total score. Record the resulting Child Pugh Grade: A (well 
compensated disease) 5-6 points; B (functional compromise, worsening disease) 7-9 points and C 
(decompensated disease) 10-15 points. 
Parameter 
1 point 
2 points 
3 points 
Bilirubin 
<34 µmol/L 
34–50 µmol/L 
>50 µmol/L 
Albumin 
>35 g/L 
28-35 g/L 
<28 g/L 
Prothrombin Time 
<1.8 (INR) or <4 secs 
(Seconds over control) 
1.8-2.2 (INR) or 4-6 
secs 
>2.2 (INR) or >6 
secs 
Ascites 
absent 
Slight 
(medically 
controlled) 
Moderate 
(poorly 
controlled) 
Encephalopathy* 
None 
Grade 1-2 
Grade 3-4 
 
*Grades of Encephalopathy 
Grade 1 – Inverted sleep pattern; forgetfulness, agitation, irritability, apraxia 
Grade 2 – Lethargy; Disorientation for time or place, Subtle personality change; 
Asterixis, ataxia 
Grade 3 – Somnolence but rousability; Disorientation as regards place; Asterixis, 
hyperactive reflexes, Babinski signs, muscle rigidity 
Grade 4 – Coma (unresponsive to verbal or noxious stimuli) 
 

 
 
 
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REFERENCES 
                                                                
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7 Salem R, Lewandowski RJ, Mulcahy MF, Riaz A, Ryu RK, Ibrahim S, Atassi B, Baker T, Gates V, Miller FH, 
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Sorafenib and Yttrium-90 radio-embolization in the treatment of advanced HCC: preliminary survival data 
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12 Fischer L, et al.  The segments of the hepatic veins – is there a spatial correlation to the Couinaud liver 
segments?  Eur J Radiol 53(2):245-255, 2005. 
 
13 Data on File, BTG 

 
 
 
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14Full Prescribing information for Nexavar. Revised 11/2013. NDA 21923 Nexavar FDA Approved 22 Nov 
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16Mehta, C. R. and Pocock, S. J. (2011), Adaptive increase in sample size when interim results are 
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Semin Liver Dis. 2010 Feb;30(1):52-60 
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of Patients with COPD, 2004  
 

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Signed: 30-Jul-2019 | 12:09
Electronic Record and Signature Disclosure: 
      Not Offered via DocuSign
Sent: 30-Jul-2019 | 11:09
Viewed: 01-Aug-2019 | 18:00 
Signed: 01-Aug-2019 | 18:01
Electronic Record and Signature Disclosure: 
      Not Offered via DocuSign

Intermediary Delivery Events
Status
Timestamp
Certified Delivery Events
Status
Timestamp
Carbon Copy Events
Status
Timestamp
Sent: 01-Aug-2019 | 19:02
Viewed: 01-Aug-2019 | 19:17 
Electronic Record and Signature Disclosure: 
      Not Offered via DocuSign
Witness Events
Signature
Timestamp
Notary Events
Signature
Timestamp
Envelope Summary Events
Status
Timestamps
Envelope Sent
Hashed/Encrypted
01-Aug-2019 | 19:02
Certified Delivered
Security Checked
01-Aug-2019 | 19:02
Signing Complete
Security Checked
01-Aug-2019 | 19:02
Completed
Security Checked
01-Aug-2019 | 19:02
Payment Events
Status
Timestamps
Electronic Record and Signature Disclosure

By Signing this disclosure, I agree that my electronic signature is the legally binding equivalent 
to my handwritten signature. Whenever I execute an electronic signature using DocuSign for 
BTG documents, it has the same validity and meaning as my handwritten signature. I will not, at 
any time repudiate the meaning of my electronic signature or claim that my electronic signature 
is not legally binding. 
Electronic Record and Signature Disclosure created on: 26-Jan-2018 | 11:38
Parties agreed to: 

By Signing this disclosure, I agree that my electronic signature is the legally binding equivalent
to my handwritten signature. Whenever I execute an electronic signature using DocuSign for
BTG documents, it has the same validity and meaning as my handwritten signature. I will not, at
any time repudiate the meaning of my electronic signature or claim that my electronic signature
is not legally binding.
Electronic Record and Signature Disclosure created on: 15-Jan-2018 | 13:21
Parties agreed to: